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

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

PubMed

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

2018-03-01

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

Specific Binding, Uptake, and Transport of ICAM-1-Targeted Nanocarriers Across Endothelial and Subendothelial Cell Components of the Blood-Brain Barrier

PubMed Central

Hsu, Janet; Rappaport, Jeff; Muro, Silvia

2014-01-01

Purpose The blood-brain barrier (BBB) represents a target for therapeutic intervention and an obstacle for brain drug delivery. Targeting endocytic receptors on brain endothelial cells (ECs) helps transporting drugs and carriers into and across this barrier. While most receptors tested are associated with clathrin-mediated pathways, clathrin-independent routes are rather unexplored. We have examined the potential for one of these pathways, cell adhesion molecule (CAM)-mediated endocytosis induced by targeting intercellular adhesion molecule 1 (ICAM-1), to transport drug carriers into and across BBB models. Methods Model polymer nanocarriers (NCs) coated with control IgG or antibodies against ICAM-1 (IgG NCs vs. anti-ICAM NCs; ~250-nm) were incubated with human brain ECs, astrocytes (ACs), or pericytes (PCs) grown as monocultures or bilayered (endothelial+subendothelial) co-cultures. Results ICAM-1 was present and overexpressed in disease-like conditions on ECs and, at a lesser extent, on ACs and PCs which are BBB subendothelial components. Specific targeting and CAM-mediated uptake of anti-ICAM NCs occurred in these cells, although this was greater for ECs. Anti-ICAM NCs were transported across endothelial monolayers and endothelial+subendothelial co-cultures modeling the BBB. Conclusions CAM-mediated transport induced by ICAM-1 targeting operates in endothelial and subendothelial cellular components of the BBB, which may provide an avenue to overcome this barrier. PMID:24558007

Specific binding, uptake, and transport of ICAM-1-targeted nanocarriers across endothelial and subendothelial cell components of the blood-brain barrier.

PubMed

Hsu, Janet; Rappaport, Jeff; Muro, Silvia

2014-07-01

The blood-brain barrier (BBB) represents a target for therapeutic intervention and an obstacle for brain drug delivery. Targeting endocytic receptors on brain endothelial cells (ECs) helps transport drugs and carriers into and across this barrier. While most receptors tested are associated with clathrin-mediated pathways, clathrin-independent routes are rather unexplored. We have examined the potential for one of these pathways, cell adhesion molecule (CAM)-mediated endocytosis induced by targeting intercellular adhesion molecule -1 (ICAM-1), to transport drug carriers into and across BBB models. Model polymer nanocarriers (NCs) coated with control IgG or antibodies against ICAM-1 (IgG NCs vs. anti-ICAM NCs; ~250-nm) were incubated with human brain ECs, astrocytes (ACs), or pericytes (PCs) grown as monocultures or bilayered (endothelial+subendothelial) co-cultures. ICAM-1 was present and overexpressed in disease-like conditions on ECs and, at a lesser extent, on ACs and PCs which are BBB subendothelial components. Specific targeting and CAM-mediated uptake of anti-ICAM NCs occurred in these cells, although this was greater for ECs. Anti-ICAM NCs were transported across endothelial monolayers and endothelial+subendothelial co-cultures modeling the BBB. CAM-mediated transport induced by ICAM-1 targeting operates in endothelial and subendothelial cellular components of the BBB, which may provide an avenue to overcome this barrier.

Bioactive Food Components, Inflammatory Targets, and Cancer Prevention

PubMed Central

Kim, Young S.; Young, Matthew R.; Bobe, Gerd; Colburn, Nancy H.; Milner, John A.

2012-01-01

Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-κB–mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-β. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor β. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous. PMID:19258539

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

PubMed Central

2015-01-01

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

Intelligibility for Binaural Speech with Discarded Low-SNR Speech Components.

PubMed

Schoenmaker, Esther; van de Par, Steven

2016-01-01

Speech intelligibility in multitalker settings improves when the target speaker is spatially separated from the interfering speakers. A factor that may contribute to this improvement is the improved detectability of target-speech components due to binaural interaction in analogy to the Binaural Masking Level Difference (BMLD). This would allow listeners to hear target speech components within specific time-frequency intervals that have a negative SNR, similar to the improvement in the detectability of a tone in noise when these contain disparate interaural difference cues. To investigate whether these negative-SNR target-speech components indeed contribute to speech intelligibility, a stimulus manipulation was performed where all target components were removed when local SNRs were smaller than a certain criterion value. It can be expected that for sufficiently high criterion values target speech components will be removed that do contribute to speech intelligibility. For spatially separated speakers, assuming that a BMLD-like detection advantage contributes to intelligibility, degradation in intelligibility is expected already at criterion values below 0 dB SNR. However, for collocated speakers it is expected that higher criterion values can be applied without impairing speech intelligibility. Results show that degradation of intelligibility for separated speakers is only seen for criterion values of 0 dB and above, indicating a negligible contribution of a BMLD-like detection advantage in multitalker settings. These results show that the spatial benefit is related to a spatial separation of speech components at positive local SNRs rather than to a BMLD-like detection improvement for speech components at negative local SNRs.

An Integrated Approach to Change the Outcome Part II: Targeted Neuromuscular Training Techniques to Reduce Identified ACL Injury Risk Factors

PubMed Central

Myer, Gregory D.; Ford, Kevin R.; Brent, Jensen L.; Hewett, Timothy E.

2014-01-01

Prior reports indicate that female athletes who demonstrate high knee abduction moments (KAMs) during landing are more responsive to neuromuscular training designed to reduce KAM. Identification of female athletes who demonstrate high KAM, which accurately identifies those at risk for noncontact anterior cruciate ligament (ACL) injury, may be ideal for targeted neuromuscular training. Specific neuromuscular training targeted to the underlying biomechanical components that increase KAM may provide the most efficient and effective training strategy to reduce noncontact ACL injury risk. The purpose of the current commentary is to provide an integrative approach to identify and target mechanistic underpinnings to increased ACL injury in female athletes. Specific neuromuscular training techniques will be presented that address individual algorithm components related to high knee load landing patterns. If these integrated techniques are employed on a widespread basis, prevention strategies for noncontact ACL injury among young female athletes may prove both more effective and efficient. PMID:22580980

Discriminating crop and other canopies by overlapping binary image layers

NASA Astrophysics Data System (ADS)

Doi, Ryoichi

2013-02-01

For optimal management of agricultural fields by remote sensing, discrimination of the crop canopy from weeds and other objects is essential. In a digital photograph, a rice canopy was discriminated from a variety of weed and tree canopies and other objects by overlapping binary image layers of red-green-blue and other color components indicating the pixels with target canopy-specific (intensity) values based on the ranges of means ±(3×) standard deviations. By overlapping and merging the binary image layers, the target canopy specificity improved to 0.0015 from 0.027 for the yellow 1× standard deviation binary image layer, which was the best among all combinations of color components and means ±(3×) standard deviations. The most target rice canopy-likely pixels were further identified by limiting the pixels at different luminosity values. The discriminatory power was also visually demonstrated in this manner.

Bridging evidence-practice gaps: improving use of medicines in elderly Australian veterans.

PubMed

Roughead, Elizabeth E; Kalisch Ellett, Lisa M; Ramsay, Emmae N; Pratt, Nicole L; Barratt, John D; LeBlanc, Vanessa T; Ryan, Philip; Peck, Robert; Killer, Graeme; Gilbert, Andrew L

2013-12-12

The Australian Government Department of Veterans' Affairs (DVA) funds an ongoing health promotion based program to improve use of medicines and related health services, which implements interventions that include audit and feedback in the form of patient-specific feedback generated from administrative claims records. We aimed to determine changes in medicine use as a result of the program. The program provides targeted patient-specific feedback to medical practitioners. The feedback is supported with educational material developed by a clinical panel, subject to peer review and overseen by a national editorial committee. Veterans who meet target criteria also receive educational brochures. The program is supported by a national call centre and ongoing national consultation. Segmented regression analyses (interrupted time series) were undertaken to assess changes in medication use in targeted veterans pre and post each intervention. 12 interventions were included; three to increase medicine use, seven which aimed to reduce use, and two which had combination of messages to change use. All programs that aimed to increase medicine use were effective, with relative effect sizes at the time of the intervention ranging from 1% to 8%. Mixed results were seen with programs aiming to reduce inappropriate medicine use. Highly specific programs were effective, with relative effect sizes at the time of the intervention of 10% decline in use of NSAIDs in high risk groups and 14% decline in use of antipsychotics in dementia. Interventions targeting combinations of medicines, including medicine interactions and potentially inappropriate medicines in the elderly did not change practice significantly. Interventions with combinations of messages targeting multiple components of practice had an impact on one component, but not all components targeted. The Veterans' MATES program showed positive practice change over time, with interventions increasing use of appropriate medicines where under-use was evident and reduced use of inappropriate medicines when single medicines were targeted. Combinations of messages were less effective, suggesting specific messages focusing on single medicines are required to maximise effect. The program provides a model that could be replicated in other settings.

Domain specificity versus expertise: factors influencing distinct processing of faces.

PubMed

Carmel, David; Bentin, Shlomo

2002-02-01

To explore face specificity in visual processing, we compared the role of task-associated strategies and expertise on the N170 event-related potential (ERP) component elicited by human faces with the ERPs elicited by cars, birds, items of furniture, and ape faces. In Experiment 1, participants performed a car monitoring task and an animacy decision task. In Experiment 2, participants monitored human faces while faces of apes were the distracters. Faces elicited an equally conspicuous N170, significantly larger than the ERPs elicited by non-face categories regardless of whether they were ignored or had an equal status with other categories (Experiment 1), or were the targets (in Experiment 2). In contrast, the negative component elicited by cars during the same time range was larger if they were targets than if they were not. Furthermore, unlike the posterior-temporal distribution of the N170, the negative component elicited by cars and its modulation by task were more conspicuous at occipital sites. Faces of apes elicited an N170 that was similar in amplitude to that elicited by the human face targets, albeit peaking 10 ms later. As our participants were not ape experts, this pattern indicates that the N170 is face-specific, but not specie-specific, i.e. it is elicited by particular face features regardless of expertise. Overall, these results demonstrate the domain specificity of the visual mechanism implicated in processing faces, a mechanism which is not influenced by either task or expertise. The processing of other objects is probably accomplished by a more general visual processor, which is sensitive to strategic manipulations and attention.

Improved composite targets for small scale 64Cu production comparing Au- and Pt-foils as 64Ni backing

NASA Astrophysics Data System (ADS)

Walther, M.; Preusche, S.; Fuechtner, F.; Pietzsch, H. J.; Steinbach, J.

2012-12-01

Advantages of a stacked assembly of target support components for 64Cu production via 64Ni(p,n)64Cu reaction were reported recently. The present work shows the applicability of these composite targets for beam currents up to 22 μA. Gold and platinum foils were evaluated as 64Ni backing. The effective specific activity (ESA) and specific activity (SA) were determined by TETA titration at room temperature and at 80 °C and compared with additional copper quantification results via ICP-MS and stripping voltammetric trace analysis (VA).

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

Biomarkers for diet and cancer prevention research: potentials and challenges.

PubMed

Davis, Cindy D; Milner, John A

2007-09-01

As cancer incidence is projected to increase for decades there is a need for effective preventive strategies. Fortunately, evidence continues to mount that altering dietary habits is an effective and cost-efficient approach for reducing cancer risk and for modifying the biological behavior of tumors. Predictive, validated and sensitive biomarkers, including those that reliably evaluate "intake" or exposure to a specific food or bioactive component, that assess one or more specific biological "effects" that are linked to cancer, and that effectively predict individual "susceptibility" as a function of nutrient-nutrient interactions and genetics, are fundamental to evaluating who will benefit most from dietary interventions. These biomarkers must be readily accessible, easily and reliably assayed, and predictive of a key process(es) involved in cancer. The response to a food is determined not only by the effective concentration of the bioactive food component(s) reaching the target tissue, but also by the amount of the target requiring modification. Thus, this threshold response to foods and their components will vary from individual to individual. The key to understanding a personalized response is a greater knowledge of nutrigenomics, proteomics and metabolomics.

Important cellular targets for antimicrobial photodynamic therapy.

PubMed

Awad, Mariam M; Tovmasyan, Artak; Craik, James D; Batinic-Haberle, Ines; Benov, Ludmil T

2016-09-01

The persistent problem of antibiotic resistance has created a strong demand for new methods for therapy and disinfection. Photodynamic inactivation (PDI) of microbes has demonstrated promising results for eradication of antibiotic-resistant strains. PDI is based on the use of a photosensitive compound (photosensitizer, PS), which upon illumination with visible light generates reactive species capable of damaging and killing microorganisms. Since photogenerated reactive species are short lived, damage is limited to close proximity of the PS. It is reasonable to expect that the larger the number of damaged targets is and the greater their variety is, the higher the efficiency of PDI is and the lower the chances for development of resistance are. Exact molecular mechanisms and specific targets whose damage is essential for microbial inactivation have not been unequivocally established. Two main cellular components, DNA and plasma membrane, are regarded as the most important PDI targets. Using Zn porphyrin-based PSs and Escherichia coli as a model Gram-negative microorganism, we demonstrate that efficient photoinactivation of bacteria can be achieved without detectable DNA modification. Among the cellular components which are modified early during illumination and constitute key PDI targets are cytosolic enzymes, membrane-bound protein complexes, and the plasma membrane. As a result, membrane barrier function is lost, and energy and reducing equivalent production is disrupted, which in turn compromises cell defense mechanisms, thus augmenting the photoinduced oxidative injury. In conclusion, high PDI antimicrobial effectiveness does not necessarily require impairment of a specific critical cellular component and can be achieved by inducing damage to multiple cellular targets.

Spatial Light Rebroadcaster Architecture Study

DTIC Science & Technology

1992-12-01

specifications on the lenslet arrays described in [ Borelli ] and summarized 3 here: Lenslet diameter: 70,m < D < 1000/Am Lenslet spacing: 151m < Delta Focal...which leads to k2 < 1/3. We will use as our baseline, a lenslet array with D, = 300 um and3 A1 = 45 14m which is within the specifications of [ Borelli ...Target Recognizer Working Group), "Automatic Target Recognizer Component Definitions," ATRWG Report No. 87-002, April 1987. Borelli , N., et al

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

PubMed Central

Mann, J. John; Ogden, R. Todd

2017-01-01

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

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.

Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma

PubMed Central

Kakarla, Sunitha; Chow, Kevin KH; Mata, Melinda; Shaffer, Donald R; Song, Xiao-Tong; Wu, Meng-Fen; Liu, Hao; Wang, Lisa L; Rowley, David R; Pfizenmaier, Klaus; Gottschalk, Stephen

2013-01-01

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors. PMID:23732988

Simultaneous targeting of prostate stem cell antigen and prostate-specific membrane antigen improves the killing of prostate cancer cells using a novel modular T cell-retargeting system.

PubMed

Arndt, Claudia; Feldmann, Anja; Koristka, Stefanie; Cartellieri, Marc; Dimmel, Maria; Ehninger, Armin; Ehninger, Gerhard; Bachmann, Michael

2014-09-01

Recently, we described a novel modular platform technology in which T cell-recruitment and tumor-targeting domains of conventional bispecific antibodies are split to independent components, a universal effector module (EM) and replaceable monospecific/monovalent target modules (TMs) that form highly efficient T cell-retargeting complexes. Theoretically, our unique strategy should allow us to simultaneously retarget T cells to different tumor antigens by combining the EM with two or more different monovalent/monospecific TMs or even with bivalent/bispecific TMs, thereby overcoming limitations of a monospecific treatment such as the selection of target-negative tumor escape variants. In order to advance our recently introduced prostate stem cell antigen (PSCA)-specific modular system for a dual-targeting of prostate cancer cells, two additional TMs were constructed: a monovalent/monospecific TM directed against the prostate-specific membrane antigen (PSMA) and a bivalent/bispecific TM (bsTM) with specificity for PSMA and PSCA. The functionality of the novel dual-targeting strategies was analyzed by performing T cell activation and chromium release assays. Similar to the PSCA-specific modular system, the novel PSMA-specific modular system mediates an efficient target-dependent and -specific tumor cell lysis at low E:T ratios and picomolar Ab concentrations. Moreover, by combination of the EM with either the bispecific TM directed to PSMA and PSCA or both monospecifc TMs directed to either PSCA or PSMA, dual-specific targeting complexes were formed which allowed us to kill potential escape variants expressing only one or the other target antigen. Overall, the novel modular system represents a promising tool for multiple tumor targeting. © 2014 Wiley Periodicals, Inc.

Novel targets for ATM-deficient malignancies

PubMed Central

Winkler, Johannes; Hofmann, Kay; Chen, Shuhua

2014-01-01

Conventional chemo- and radiotherapies for the treatment of cancer target rapidly dividing cells in both tumor and non-tumor tissues and can exhibit severe cytotoxicity in normal tissue and impair the patient's immune system. Novel targeted strategies aim for higher efficacy and tumor specificity. The role of ATM protein in the DNA damage response is well known and ATM deficiency frequently plays a role in tumorigenesis and development of malignancy. In addition to contributing to disease development, ATM deficiency also renders malignant cells heavily dependent on other pathways that cooperate with the ATM-mediated DNA damage response to ensure tumor cell survival. Disturbing those cooperative pathways by inhibiting critical protein components allows specific targeting of tumors while sparing healthy cells with normal ATM status. We review druggable candidate targets for the treatment of ATM-deficient malignancies and the mechanisms underlying such targeted therapies. PMID:27308314

Auditory memory for timbre.

PubMed

McKeown, Denis; Wellsted, David

2009-06-01

Psychophysical studies are reported examining how the context of recent auditory stimulation may modulate the processing of new sounds. The question posed is how recent tone stimulation may affect ongoing performance in a discrimination task. In the task, two complex sounds occurred in successive intervals. A single target component of one complex was decreased (Experiments 1 and 2) or increased (Experiments 3, 4, and 5) in intensity on half of trials: The task was simply to identify those trials. Prior to each trial, a pure tone inducer was introduced either at the same frequency as the target component or at the frequency of a different component of the complex. Consistent with a frequency-specific form of disruption, discrimination performance was impaired when the inducing tone matched the frequency of the following decrement or increment. A timbre memory model (TMM) is proposed incorporating channel-specific interference allied to inhibition of attending in the coding of sounds in the context of memory traces of recent sounds. (c) 2009 APA, all rights reserved.

A new methodology based on functional principal component analysis to study postural stability post-stroke.

PubMed

Sánchez-Sánchez, M Luz; Belda-Lois, Juan-Manuel; Mena-Del Horno, Silvia; Viosca-Herrero, Enrique; Igual-Camacho, Celedonia; Gisbert-Morant, Beatriz

2018-05-05

A major goal in stroke rehabilitation is the establishment of more effective physical therapy techniques to recover postural stability. Functional Principal Component Analysis provides greater insight into recovery trends. However, when missing values exist, obtaining functional data presents some difficulties. The purpose of this study was to reveal an alternative technique for obtaining the Functional Principal Components without requiring the conversion to functional data beforehand and to investigate this methodology to determine the effect of specific physical therapy techniques in balance recovery trends in elderly subjects with hemiplegia post-stroke. A randomized controlled pilot trial was developed. Thirty inpatients post-stroke were included. Control and target groups were treated with the same conventional physical therapy protocol based on functional criteria, but specific techniques were added to the target group depending on the subjects' functional level. Postural stability during standing was quantified by posturography. The assessments were performed once a month from the moment the participants were able to stand up to six months post-stroke. The target group showed a significant improvement in postural control recovery trend six months after stroke that was not present in the control group. Some of the assessed parameters revealed significant differences between treatment groups (P < 0.05). The proposed methodology allows Functional Principal Component Analysis to be performed when data is scarce. Moreover, it allowed the dynamics of recovery of two different treatment groups to be determined, showing that the techniques added in the target group increased postural stability compared to the base protocol. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

PubMed

Jenkins, Michael; Grubert, Anna; Eimer, Martin

2018-05-01

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

Genre-Pragmatic Strategies in English Letter-of-Application Writing of Jordanian Arabic--English Bilinguals

ERIC Educational Resources Information Center

Al-Ali, Mohammed N.

2006-01-01

This study reports an investigation of the genre components and pragmatic strategies of letters of applications written by Jordanian Arabic--English bilinguals. Specifically it is set up to trace how far novice non-native speakers of English are able to utilise the generic components and politeness strategies of the target language that strongly…

The role of the cell wall in fungal pathogenesis

PubMed Central

Arana, David M.; Prieto, Daniel; Román, Elvira; Nombela, César; Alonso‐Monge, Rebeca; Pla, Jesús

2009-01-01

Summary Fungal infections are a serious health problem. In recent years, basic research is focusing on the identification of fungal virulence factors as promising targets for the development of novel antifungals. The wall, as the most external cellular component, plays a crucial role in the interaction with host cells mediating processes such as adhesion or phagocytosis that are essential during infection. Specific components of the cell wall (called PAMPs) interact with specific receptors in the immune cell (called PRRs), triggering responses whose molecular mechanisms are being elucidated. We review here the main structural carbohydrate components of the fungal wall (glucan, mannan and chitin), how their biogenesis takes place in fungi and the specific receptors that they interact with. Different model fungal pathogens are chosen to illustrate the functional consequences of this interaction. Finally, the identification of the key components will have important consequences in the future and will allow better approaches to treat fungal infections. PMID:21261926

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

PubMed

Fuggetta, Giorgio; Duke, Philip A

2017-05-01

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

Solar thermal technology evaluation, fiscal year 1982. Volume 2: Technical

NASA Technical Reports Server (NTRS)

1983-01-01

The technology base of solar thermal energy is investigated. The materials, components, subsystems, and processes capable of meeting specific energy cost targets are emphasized, as are system efficiency and reliability.

Modeling health gains and cost savings for ten dietary salt reduction targets.

PubMed

Wilson, Nick; Nghiem, Nhung; Eyles, Helen; Mhurchu, Cliona Ni; Shields, Emma; Cobiac, Linda J; Cleghorn, Christine L; Blakely, Tony

2016-04-26

Dietary salt reduction is included in the top five priority actions for non-communicable disease control internationally. We therefore aimed to identify health gain and cost impacts of achieving a national target for sodium reduction, along with component targets in different food groups. We used an established dietary sodium intervention model to study 10 interventions to achieve sodium reduction targets. The 2011 New Zealand (NZ) adult population (2.3 million aged 35+ years) was simulated over the remainder of their lifetime in a Markov model with a 3 % discount rate. Achieving an overall 35 % reduction in dietary salt intake via implementation of mandatory maximum levels of sodium in packaged foods along with reduced sodium from fast foods/restaurant food and discretionary intake (the "full target"), was estimated to gain 235,000 QALYs over the lifetime of the cohort (95 % uncertainty interval [UI]: 176,000 to 298,000). For specific target components the range was from 122,000 QALYs gained (for the packaged foods target) down to the snack foods target (6100 QALYs; and representing a 34-48 % sodium reduction in such products). All ten target interventions studied were cost-saving, with the greatest costs saved for the mandatory "full target" at NZ$1260 million (US$820 million). There were relatively greater health gains per adult for men and for Māori (indigenous population). This work provides modeling-level evidence that achieving dietary sodium reduction targets (including specific food category targets) could generate large health gains and cost savings for a national health sector. Demographic groups with the highest cardiovascular disease rates stand to gain most, assisting in reducing health inequalities between sex and ethnic groups.

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.

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.

Both IIC and IID Components of Mannose Phosphotransferase System Are Involved in the Specific Recognition between Immunity Protein PedB and Bacteriocin-Receptor Complex.

PubMed

Zhou, Wanli; Wang, Guohong; Wang, Chunmei; Ren, Fazheng; Hao, Yanling

2016-01-01

Upon exposure to exogenous pediocin-like bacteriocins, immunity proteins specifically bind to the target receptor of the mannose phosphotransferase system components (man-PTS IIC and IID), therefore preventing bacterial cell death. However, the specific recognition of immunity proteins and its associated target receptors remains poorly understood. In this study, we constructed hybrid receptors to identify the domains of IIC and/or IID recognized by the immunity protein PedB, which confers immunity to pediocin PA-1. Using Lactobacillus plantarum man-PTS EII mutant W903, the IICD components of four pediocin PA-1-sensitive strains (L. plantarum WQ0815, Leuconostoc mesenteroides 05-43, Lactobacillus salivarius REN and Lactobacillus acidophilus 05-172) were respectively co-expressed with the immunity protein PedB. Well-diffusions assays showed that only the complex formed by LpIICD from L. plantarum WQ0815 with pediocin PA-1 could be recognized by PedB. In addition, a two-step PCR approach was used to construct hybrid receptors by combining LpIIC or LpIID recognized by PedB with the other three heterologous IID or IIC compounds unrecognized by PedB, respectively. The results showed that all six hybrid receptors were recognized by pediocin PA-1. However, when IIC or IID of L. plantarum WQ0815 was replaced with any corresponding IIC or IID component from L. mesenteroides 05-43, L. salivarius REN and L. acidophilus 05-172, all the hybrid receptors could not be recognized by PedB. Taken altogether, we concluded that both IIC and IID components of the mannose phosphotransferase system play an important role in the specific recognition between the bacteriocin-receptor complex and the immunity protein PedB.

Exploring the Therapeutic Mechanism of Desmodium styracifolium on Oxalate Crystal-Induced Kidney Injuries Using Comprehensive Approaches Based on Proteomics and Network Pharmacology.

PubMed

Hou, Jiebin; Chen, Wei; Lu, Hongtao; Zhao, Hongxia; Gao, Songyan; Liu, Wenrui; Dong, Xin; Guo, Zhiyong

2018-01-01

Purpose: As a Chinese medicinal herb, Desmodium styracifolium (Osb.) Merr (DS) has been applied clinically to alleviate crystal-induced kidney injuries, but its effective components and their specific mechanisms still need further exploration. This research first combined the methods of network pharmacology and proteomics to explore the therapeutic protein targets of DS on oxalate crystal-induced kidney injuries to provide a reference for relevant clinical use. Methods: Oxalate-induced kidney injury mouse, rat, and HK-2 cell models were established. Proteins differentially expressed between the oxalate and control groups were respectively screened using iTRAQ combined with MALDI-TOF-MS. The common differential proteins of the three models were further analyzed by molecular docking with DS compounds to acquire differential targets. The inverse docking targets of DS were predicted through the platform of PharmMapper. The protein-protein interaction (PPI) relationship between the inverse docking targets and the differential proteins was established by STRING. Potential targets were further validated by western blot based on a mouse model with DS treatment. The effects of constituent compounds, including luteolin, apigenin, and genistein, were investigated based on an oxalate-stimulated HK-2 cell model. Results: Thirty-six common differentially expressed proteins were identified by proteomic analysis. According to previous research, the 3D structures of 15 major constituents of DS were acquired. Nineteen differential targets, including cathepsin D (CTSD), were found using molecular docking, and the component-differential target network was established. Inverse-docking targets including p38 MAPK and CDK-2 were found, and the network of component-reverse docking target was established. Through PPI analysis, 17 inverse-docking targets were linked to differential proteins. The combined network of component-inverse docking target-differential proteins was then constructed. The expressions of CTSD, p-p38 MAPK, and p-CDK-2 were shown to be increased in the oxalate group and decreased in kidney tissue by the DS treatment. Luteolin, apigenin, and genistein could protect oxalate-stimulated tubular cells as active components of DS. Conclusion: The potential targets including the CTSD, p38 MAPK, and CDK2 of DS in oxalate-induced kidney injuries and the active components (luteolin, apigenin, and genistein) of DS were successfully identified in this study by combining proteomics analysis, network pharmacology prediction, and experimental validation.

CD10-/ALDH- cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy.

PubMed

Ffrench, Brendan; Gasch, Claudia; Hokamp, Karsten; Spillane, Cathy; Blackshields, Gordon; Mahgoub, Thamir Mahmoud; Bates, Mark; Kehoe, Louise; Mooney, Aoibhinn; Doyle, Ronan; Doyle, Brendan; O'Donnell, Dearbhaile; Gleeson, Noreen; Hennessy, Bryan T; Stordal, Britta; O'Riain, Ciaran; Lambkin, Helen; O'Toole, Sharon; O'Leary, John J; Gallagher, Michael F

2017-10-19

It is long established that tumour-initiating cancer stem cells (CSCs) possess chemoresistant properties. However, little is known of the mechanisms involved, particularly with respect to the organisation of CSCs as stem-progenitor-differentiated cell hierarchies. Here we aimed to elucidate the relationship between CSC hierarchies and chemoresistance in an ovarian cancer model. Using a single cell-based approach to CSC discovery and validation, we report a novel, four-component CSC hierarchy based around the markers cluster of differentiation 10 (CD10) and aldehyde dehydrogenase (ALDH). In a change to our understanding of CSC biology, resistance to chemotherapy drug cisplatin was found to be the sole property of CD10 - /ALDH - CSCs, while all four CSC types were sensitive to chemotherapy drug paclitaxel. Cisplatin treatment quickly altered the hierarchy, resulting in a three-component hierarchy dominated by the cisplatin-resistant CD10 - /ALDH - CSC. This organisation was found to be hard-wired in a long-term cisplatin-adapted model, where again CD10 - /ALDH - CSCs were the sole cisplatin-resistant component, and all CSC types remained paclitaxel-sensitive. Molecular analysis indicated that cisplatin resistance is associated with inherent- and adaptive-specific drug efflux and DNA-damage repair mechanisms. Clinically, low CD10 expression was consistent with a specific set of ovarian cancer patient samples. Collectively, these data advance our understanding of the relationship between CSC hierarchies and chemoresistance, which was shown to be CSC- and drug-type specific, and facilitated by specific and synergistic inherent and adaptive mechanisms. Furthermore, our data indicate that primary stage targeting of CD10 - /ALDH - CSCs in specific ovarian cancer patients in future may facilitate targeting of recurrent disease, before it ever develops.

The use of the sexual function questionnaire as a screening tool for women with sexual dysfunction.

PubMed

Quirk, Frances; Haughie, Scott; Symonds, Tara

2005-07-01

To determine if the validated Sexual Function Questionnaire (SFQ), developed to assess efficacy in female sexual dysfunction (FSD) clinical trials, may also have utility in identifying target populations for such studies. Data from five clinical trials and two general population surveys were used to analyze the utility of the SFQ as a tool to discriminate between the presence of specific components of FSD (i.e., hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder, and dyspareunia). Sensitivity/specificity analysis and logistic regression analysis, using data from all five clinical studies and the general population surveys, confirmed that the SFQ domains have utility in detecting the presence of specific components of FSD and provide scores indicative of the presence of a specific sexual disorder. The SFQ is a valuable new tool for detecting the presence of FSD and identifying the specific components of sexual functions affected (desire, arousal, orgasm, or dyspareunia).

Equine IgE responses to non-viral vaccine components.

PubMed

Gershwin, Laurel J; Netherwood, Kristina A; Norris, Meredith Somerville; Behrens, Nicole E; Shao, Matt X

2012-12-14

Vaccination of horses is performed annually or semi-annually with multiple viral antigens, either in a combination vaccine or as separate injections. While this practice undoubtedly prevents infection from such diseases as rabies, equine influenza, West Nile virus, and equine herpes virus, the procedure is not without repercussions. Hypersensitivity reactions, including fatal anaphylactic shock, after vaccination, although uncommon, have increased in incidence in recent years. Studies reported herein document the development of IgE antibodies against non-target antigen components of equine viral vaccines. We hypothesize that viral vaccines can induce an IgE response to non-target antigens, which could elicit an adverse response after vaccination with another viral vaccine containing the same component. In one study IgE responses to components of West Nile virus vaccine were evaluated by ELISA before and after vaccination in 30 horses. In a second five-year study 77 horses were similarly tested for IgE antibodies against bovine serum albumin (BSA), a component of most viral vaccines. Mast cell sensitization was evaluated in horses with high, moderate, and negative serum BSA specific IgE using an intradermal skin test with BSA. Over the five-year period high IgE responder horses showed gradually increasing BSA specific serum IgE levels and positive skin test reactivity, yet none had an adverse event. Sera from horses that had developed adverse vaccine reactions were also tested for IgE antibodies. Several of these horses had extremely high levels of BSA-specific IgE. These data suggest that non-essential protein components of vaccines may sensitize horses for future adverse responses to vaccination. Copyright © 2012 Elsevier Ltd. All rights reserved.

Sequential Processing and the Matching-Stimulus Interval Effect in ERP Components: An Exploration of the Mechanism Using Multiple Regression

PubMed Central

Steiner, Genevieve Z.; Barry, Robert J.; Gonsalvez, Craig J.

2016-01-01

In oddball tasks, increasing the time between stimuli within a particular condition (target-to-target interval, TTI; nontarget-to-nontarget interval, NNI) systematically enhances N1, P2, and P300 event-related potential (ERP) component amplitudes. This study examined the mechanism underpinning these effects in ERP components recorded from 28 adults who completed a conventional three-tone oddball task. Bivariate correlations, partial correlations and multiple regression explored component changes due to preceding ERP component amplitudes and intervals found within the stimulus series, rather than constraining the task with experimentally constructed intervals, which has been adequately explored in prior studies. Multiple regression showed that for targets, N1 and TTI predicted N2, TTI predicted P3a and P3b, and Processing Negativity (PN), P3b, and TTI predicted reaction time. For rare nontargets, P1 predicted N1, NNI predicted N2, and N1 predicted Slow Wave (SW). Findings show that the mechanism is operating on separate stages of stimulus-processing, suggestive of either increased activation within a number of stimulus-specific pathways, or very long component generator recovery cycles. These results demonstrate the extent to which matching-stimulus intervals influence ERP component amplitudes and behavior in a three-tone oddball task, and should be taken into account when designing similar studies. PMID:27445774

Sequential Processing and the Matching-Stimulus Interval Effect in ERP Components: An Exploration of the Mechanism Using Multiple Regression.

PubMed

Steiner, Genevieve Z; Barry, Robert J; Gonsalvez, Craig J

2016-01-01

In oddball tasks, increasing the time between stimuli within a particular condition (target-to-target interval, TTI; nontarget-to-nontarget interval, NNI) systematically enhances N1, P2, and P300 event-related potential (ERP) component amplitudes. This study examined the mechanism underpinning these effects in ERP components recorded from 28 adults who completed a conventional three-tone oddball task. Bivariate correlations, partial correlations and multiple regression explored component changes due to preceding ERP component amplitudes and intervals found within the stimulus series, rather than constraining the task with experimentally constructed intervals, which has been adequately explored in prior studies. Multiple regression showed that for targets, N1 and TTI predicted N2, TTI predicted P3a and P3b, and Processing Negativity (PN), P3b, and TTI predicted reaction time. For rare nontargets, P1 predicted N1, NNI predicted N2, and N1 predicted Slow Wave (SW). Findings show that the mechanism is operating on separate stages of stimulus-processing, suggestive of either increased activation within a number of stimulus-specific pathways, or very long component generator recovery cycles. These results demonstrate the extent to which matching-stimulus intervals influence ERP component amplitudes and behavior in a three-tone oddball task, and should be taken into account when designing similar studies.

Rapid top-down control over template-guided attention shifts to multiple objects.

PubMed

Grubert, Anna; Fahrenfort, Johannes; Olivers, Christian N L; Eimer, Martin

2017-02-01

Previous research has shown that when observers search for targets defined by a particular colour, attention can be directed rapidly and independently to two target objects that appear in close temporal proximity. We investigated how such rapid attention shifts are modulated by task instructions to selectively attend versus ignore one of these objects. Two search displays that both contained a colour-defined target and a distractor in a different colour were presented in rapid succession, with a stimulus onset asynchrony (SOA) of 100ms. In different blocks, participants were instructed to attend and respond to target-colour objects in the first display and to ignore these objects in the second display, or vice versa. N2pc components were measured to track the allocation of spatial attention to target-colour objects in these two displays. When participants responded to the second display, irrelevant target-colour objects in the first display still triggered N2pc components, demonstrating task-set contingent attentional capture while a feature-specific target template is active. Critically, when participants responded to the first display instead, no N2pc was elicited by target-colour items in the second display, indicating that they no longer rapidly captured attention. However, these items still elicited a longer-latency contralateral negativity (SPCN component), suggesting that attention was oriented towards template-matching objects in working memory. This dissociation between N2pc and SPCN components shows that rapid attentional capture and subsequent attentional selection processes within working memory can be independent. We suggest that early attentional orienting mechanisms can be inhibited when task-set matching objects are no longer task-relevant, and that this type of inhibitory control is a rapid but transient process. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification of lanthanum-specific peptides for future recycling of rare earth elements from compact fluorescent lamps.

PubMed

Lederer, Franziska L; Curtis, Susan B; Bachmann, Stefanie; Dunbar, W Scott; MacGillivray, Ross T A

2017-05-01

As components of electronic scrap, rare earth minerals are an interesting but little used source of raw materials that are highly important for the recycling industry. Currently, there exists no cost-efficient technology to separate rare earth minerals from an electronic scrap mixture. In this study, phage surface display has been used as a key method to develop peptides with high specificity for particular inorganic targets in electronic scrap. Lanthanum phosphate doped with cerium and terbium as part of the fluorescent phosphors of spent compact fluorescent lamps (CFL) was used as a target material of economic interest to test the suitability of the phage display method to the separation of rare earth minerals. One random pVIII phage library was screened for peptide sequences that bind specifically to the fluorescent phosphor LaPO 4 :Ce 3+ ,Tb 3+ (LAP). The library contained at least 100 binding pVIII peptides per phage particle with a diversity of 1 × 10 9 different phage per library. After three rounds of enrichment, a phage clone containing the surface peptide loop RCQYPLCS was found to bind specifically to LAP. Specificity and affinity of the identified phage bound peptide was confirmed by using binding and competition assays, immunofluorescence assays, and zeta potential measurements. Binding and immunofluorescence assays identified the peptide's affinity for the fluorescent phosphor components CAT (CeMgAl 11 O 19 :Tb 3+ ) and BAM (BaMgAl 10 O 17 :Eu 2+ ). No affinity was found for other fluorescent phosphor components such as YOX (Y 2 O 3 :Eu 3+ ). The binding specificity of the RCQYPLCS peptide loop was improved 3-51-fold by using alanine scanning mutagenesis. The identification of peptides with high specificity and affinity for special components in the fluorescent phosphor in CFLs provides a potentially new strategic approach to rare earth recycling. Biotechnol. Bioeng. 2017;114: 1016-1024. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Specific Visualization of Tumor Cells Using Upconversion Nanophosphors

PubMed Central

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

2014-01-01

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

Statistics of Shared Components in Complex Component Systems

NASA Astrophysics Data System (ADS)

Mazzolini, Andrea; Gherardi, Marco; Caselle, Michele; Cosentino Lagomarsino, Marco; Osella, Matteo

2018-04-01

Many complex systems are modular. Such systems can be represented as "component systems," i.e., sets of elementary components, such as LEGO bricks in LEGO sets. The bricks found in a LEGO set reflect a target architecture, which can be built following a set-specific list of instructions. In other component systems, instead, the underlying functional design and constraints are not obvious a priori, and their detection is often a challenge of both scientific and practical importance, requiring a clear understanding of component statistics. Importantly, some quantitative invariants appear to be common to many component systems, most notably a common broad distribution of component abundances, which often resembles the well-known Zipf's law. Such "laws" affect in a general and nontrivial way the component statistics, potentially hindering the identification of system-specific functional constraints or generative processes. Here, we specifically focus on the statistics of shared components, i.e., the distribution of the number of components shared by different system realizations, such as the common bricks found in different LEGO sets. To account for the effects of component heterogeneity, we consider a simple null model, which builds system realizations by random draws from a universe of possible components. Under general assumptions on abundance heterogeneity, we provide analytical estimates of component occurrence, which quantify exhaustively the statistics of shared components. Surprisingly, this simple null model can positively explain important features of empirical component-occurrence distributions obtained from large-scale data on bacterial genomes, LEGO sets, and book chapters. Specific architectural features and functional constraints can be detected from occurrence patterns as deviations from these null predictions, as we show for the illustrative case of the "core" genome in bacteria.

Component analysis and target cell-based neuroactivity screening of Panax ginseng by ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

PubMed

Yuan, Jinbin; Chen, Yang; Liang, Jian; Wang, Chong-Zhi; Liu, Xiaofei; Yan, Zhihong; Tang, Yi; Li, Jiankang; Yuan, Chun-Su

2016-12-01

Ginseng is one of the most widely used natural medicines in the world. Recent studies have suggested Panax ginseng has a wide range of beneficial effects on aging, central nervous system disorders, and neurodegenerative diseases. However, knowledge about the specific bioactive components of ginseng is still limited. This work aimed to screen for the bioactive components in Panax ginseng that act against neurodegenerative diseases, using the target cell-based bioactivity screening method. Firstly, component analysis of Panax ginseng extracts was performed by UPLC-QTOF-MS, and a total of 54 compounds in white ginseng were characterized and identified according to the retention behaviors, accurate MW, MS characteristics, parent nucleus, aglycones, side chains, and literature data. Then target cell-based bioactivity screening method was developed to predict the candidate compounds in ginseng with SH-SY5Y cells. Four ginsenosides, Rg 2 , Rh 1 , Ro, and Rd, were observed to be active. The target cell-based bioactivity screening method coupled with UPLC-QTOF-MS technique has suitable sensitivity and it can be used as a screening tool for low content bioactive constituents in natural products. Copyright © 2016 Elsevier B.V. All rights reserved.

Activateable Imaging Probes Light Up Inside Cancer Cells | Center for Cancer Research

Cancer.gov

Imaging can be used to help diagnose cancer as well as monitor tumor progression and response to treatment. The field of molecular imaging focuses on techniques capable of detecting specific molecular targets associated with cancer; the agents used for molecular imaging—often called probes—are multifunctional, with components that allow them to both interact with their molecular target and emit a detectable signal.

An MCNP-based model of a medical linear accelerator x-ray photon beam.

PubMed

Ajaj, F A; Ghassal, N M

2003-09-01

The major components in the x-ray photon beam path of the treatment head of the VARIAN Clinac 2300 EX medical linear accelerator were modeled and simulated using the Monte Carlo N-Particle radiation transport computer code (MCNP). Simulated components include x-ray target, primary conical collimator, x-ray beam flattening filter and secondary collimators. X-ray photon energy spectra and angular distributions were calculated using the model. The x-ray beam emerging from the secondary collimators were scored by considering the total x-ray spectra from the target as the source of x-rays at the target position. The depth dose distribution and dose profiles at different depths and field sizes have been calculated at a nominal operating potential of 6 MV and found to be within acceptable limits. It is concluded that accurate specification of the component dimensions, composition and nominal accelerating potential gives a good assessment of the x-ray energy spectra.

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

PubMed

Jiang, Yunpeng; Wu, Xia; Gao, Xiaorong

2017-10-17

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

Task difficulty modulates brain activation in the emotional oddball task.

PubMed

Siciliano, Rachel E; Madden, David J; Tallman, Catherine W; Boylan, Maria A; Kirste, Imke; Monge, Zachary A; Packard, Lauren E; Potter, Guy G; Wang, Lihong

2017-06-01

Previous functional magnetic resonance imaging (fMRI) studies have reported that task-irrelevant, emotionally salient events can disrupt target discrimination, particularly when attentional demands are low, while others demonstrate alterations in the distracting effects of emotion in behavior and neural activation in the context of attention-demanding tasks. We used fMRI, in conjunction with an emotional oddball task, at different levels of target discrimination difficulty, to investigate the effects of emotional distractors on the detection of subsequent targets. In addition, we distinguished different behavioral components of target detection representing decisional, nondecisional, and response criterion processes. Results indicated that increasing target discrimination difficulty led to increased time required for both the decisional and nondecisional components of the detection response, as well as to increased target-related neural activation in frontoparietal regions. The emotional distractors were associated with activation in ventral occipital and frontal regions and dorsal frontal regions, but this activation was attenuated with increased difficulty. Emotional distraction did not alter the behavioral measures of target detection, but did lead to increased target-related frontoparietal activation for targets following emotional images as compared to those following neutral images. This latter effect varied with target discrimination difficulty, with an increased influence of the emotional distractors on subsequent target-related frontoparietal activation in the more difficult discrimination condition. This influence of emotional distraction was in addition associated specifically with the decisional component of target detection. These findings indicate that emotion-cognition interactions, in the emotional oddball task, vary depending on the difficulty of the target discrimination and the associated limitations on processing resources. Copyright © 2017 Elsevier B.V. All rights reserved.

Moly99 Production Facility: Report on Beamline Components, Requirements, Costs

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

Bishofberger, Kip A.

2015-12-23

In FY14 we completed the design of the beam line for the linear accelerator production design concept. This design included a set of three bending magnets, quadrupole focusing magnets, and octopoles to flatten the beam on target. This design was generic and applicable to multiple different accelerators if necessary. In FY15 we built on that work to create specifications for the individual beam optic elements, including power supply requirements. This report captures the specification of beam line components with initial cost estimates for the NorthStar production facility.This report is organized as follows: The motivation of the beamline design is introducedmore » briefly, along with renderings of the design. After that, a specific list is provided, which accounts for each beamline component, including part numbers and costs, to construct the beamline. After that, this report details the important sections of the beamline and individual components. A final summary and list of follow-on activities completes this report.« less

All set, indeed! N2pc components reveal simultaneous attentional control settings for multiple target colors.

PubMed

Grubert, Anna; Eimer, Martin

2016-08-01

To study whether top-down attentional control processes can be set simultaneously for different visual features, we employed a spatial cueing procedure to measure behavioral and electrophysiological markers of task-set contingent attentional capture during search for targets defined by 1 or 2 possible colors (one-color and two-color tasks). Search arrays were preceded by spatially nonpredictive color singleton cues. Behavioral spatial cueing effects indicative of attentional capture were elicited only by target-matching but not by distractor-color cues. However, when search displays contained 1 target-color and 1 distractor-color object among gray nontargets, N2pc components were triggered not only by target-color but also by distractor-color cues both in the one-color and two-color task, demonstrating that task-set nonmatching items attracted attention. When search displays contained 6 items in 6 different colors, so that participants had to adopt a fully feature-specific task set, the N2pc to distractor-color cues was eliminated in both tasks, indicating that nonmatching items were now successfully excluded from attentional processing. These results demonstrate that when observers adopt a feature-specific search mode, attentional task sets can be configured flexibly for multiple features within the same dimension, resulting in the rapid allocation of attention to task-set matching objects only. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Simultaneously measuring multiple protein interactions and their correlations in a cell by Protein-interactome Footprinting

PubMed Central

Luo, Si-Wei; Liang, Zhi; Wu, Jia-Rui

2017-01-01

Quantitatively detecting correlations of multiple protein-protein interactions (PPIs) in vivo is a big challenge. Here we introduce a novel method, termed Protein-interactome Footprinting (PiF), to simultaneously measure multiple PPIs in one cell. The principle of PiF is that each target physical PPI in the interactome is simultaneously transcoded into a specific DNA sequence based on dimerization of the target proteins fused with DNA-binding domains. The interaction intensity of each target protein is quantified as the copy number of the specific DNA sequences bound by each fusion protein dimers. Using PiF, we quantitatively reveal dynamic patterns of PPIs and their correlation network in E. coli two-component systems. PMID:28338015

Targeted delivery of TLR ligands to human and mouse dendritic cells strongly enhances adjuvanticity.

PubMed

Tacken, Paul J; Zeelenberg, Ingrid S; Cruz, Luis J; van Hout-Kuijer, Maaike A; van de Glind, Gerline; Fokkink, Remco G; Lambeck, Annechien J A; Figdor, Carl G

2011-12-22

Effective vaccines consist of 2 components: immunodominant antigens and effective adjuvants. Whereas it has been demonstrated that targeted delivery of antigens to dendritic cells (DCs) improves vaccine efficacy, we report here that co-targeting of TLR ligands (TLRLs) to DCs strongly enhances adjuvanticity and immunity. We encapsulated ligands for intracellular TLRs within biodegradable nanoparticles coated with Abs recognizing DC-specific receptors. Targeted delivery of TLRLs to human DCs enhanced the maturation and production of immune stimulatory cytokines and the Ag-specific activation of naive CD8(+) T cells. In vivo studies demonstrated that nanoparticles carrying Ag induced cytotoxic T-lymphocyte responses at 100-fold lower adjuvant dose when TLRLs were co-encapsulated instead of administered in soluble form. Moreover, the efficacy of these targeted TLRLs reduced the serum cytokine storm and related toxicity that is associated with administration of soluble TLRLs. We conclude that the targeted delivery of adjuvants may improve the efficacy and safety of DC-based vaccines.

PLANT HOMOLOGOUS TO PARAFIBROMIN is a component of the PAF1 complex and assists in regulating expression of genes within H3K27ME3-enriched chromatin.

PubMed

Park, Sunchung; Oh, Sookyung; Ek-Ramos, Julissa; van Nocker, Steven

2010-06-01

The human Paf1 complex (Paf1C) subunit Parafibromin assists in mediating output from the Wingless/Int signaling pathway, and dysfunction of the encoding gene HRPT2 conditions specific cancer-related disease phenotypes. Here, we characterize the organismal and molecular roles of PLANT HOMOLOGOUS TO PARAFIBROMIN (PHP), the Arabidopsis (Arabidopsis thaliana) homolog of Parafibromin. PHP resides in an approximately 670-kD protein complex in nuclear extracts, and physically interacts with other known Paf1C-related proteins in vivo. In striking contrast to the developmental pleiotropy conferred by mutation in other plant Paf1C component genes in Arabidopsis, loss of PHP specifically conditioned accelerated phase transition from vegetative growth to flowering and resulted in misregulation of a very limited subset of genes that included the flowering repressor FLOWERING LOCUS C. Those genes targeted by PHP were distinguished from the bulk of Arabidopsis genes and other plant Paf1C targets by strong enrichment for trimethylation of lysine-27 on histone H3 (H3K27me3) within chromatin. These findings suggest that PHP is a component of a plant Paf1C protein in Arabidopsis, but has a more specialized role in modulating expression of a subset of Paf1C targets.

Immune Response to Recombinant Adenovirus in Humans: Capsid Components from Viral Input Are Targets for Vector-Specific Cytotoxic T Lymphocytes

PubMed Central

Molinier-Frenkel, Valérie; Gahery-Segard, Hanne; Mehtali, Majid; Le Boulaire, Christophe; Ribault, Sébastien; Boulanger, Pierre; Tursz, Thomas; Guillet, Jean-Gérard; Farace, Françoise

2000-01-01

We previously demonstrated that a single injection of 109 PFU of recombinant adenovirus into patients induces strong vector-specific immune responses (H. Gahéry-Ségard, V. Molinier-Frenkel, C. Le Boulaire, P. Saulnier, P. Opolon, R. Lengagne, E. Gautier, A. Le Cesne, L. Zitvogel, A. Venet, C. Schatz, M. Courtney, T. Le Chevalier, T. Tursz, J.-G. Guillet, and F. Farace, J. Clin. Investig. 100:2218–2226, 1997). In the present study we analyzed the mechanism of vector recognition by cytotoxic T lymphocytes (CTL). CD8+ CTL lines were derived from two patients and maintained in long-term cultures. Target cell infections with E1-deleted and E1-plus E2-deleted adenoviruses, as well as transcription-blocking experiments with actinomycin D, revealed that host T-cell recognition did not require viral gene transcription. Target cells treated with brefeldin A were not lysed, indicating that viral input protein-derived peptides are associated with HLA class I molecules. Using recombinant capsid component-loaded targets, we observed that the three major proteins could be recognized. These results raise the question of the use of multideleted adenoviruses for gene therapy in the quest to diminish antivector CTL responses. PMID:10906225

Evaluation and control of miRNA-like off-target repression for RNA interference.

PubMed

Seok, Heeyoung; Lee, Haejeong; Jang, Eun-Sook; Chi, Sung Wook

2018-03-01

RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago-miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity.

Dimension reduction: additional benefit of an optimal filter for independent component analysis to extract event-related potentials.

PubMed

Cong, Fengyu; Leppänen, Paavo H T; Astikainen, Piia; Hämäläinen, Jarmo; Hietanen, Jari K; Ristaniemi, Tapani

2011-09-30

The present study addresses benefits of a linear optimal filter (OF) for independent component analysis (ICA) in extracting brain event-related potentials (ERPs). A filter such as the digital filter is usually considered as a denoising tool. Actually, in filtering ERP recordings by an OF, the ERP' topography should not be changed by the filter, and the output should also be able to be modeled by the linear transformation. Moreover, an OF designed for a specific ERP source or component may remove noise, as well as reduce the overlap of sources and even reject some non-targeted sources in the ERP recordings. The OF can thus accomplish both the denoising and dimension reduction (reducing the number of sources) simultaneously. We demonstrated these effects using two datasets, one containing visual and the other auditory ERPs. The results showed that the method including OF and ICA extracted much more reliable components than the sole ICA without OF did, and that OF removed some non-targeted sources and made the underdetermined model of EEG recordings approach to the determined one. Thus, we suggest designing an OF based on the properties of an ERP to filter recordings before using ICA decomposition to extract the targeted ERP component. Copyright © 2011 Elsevier B.V. All rights reserved.

Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting.

PubMed

Dung, Vuu My; Suong, Dang Ngoc Anh; Okamaoto, Yuji; Hiramatsu, Yu; Thao, Dang Thi Phuong; Yoshida, Hideki; Takashima, Hiroshi; Yamaguchi, Masamitsu

2018-05-15

Pyruvate dehydrogenase complex deficiency (PDCD) is a common primary cause of defects in mitochondrial function and also can lead to peripheral neuropathy. Pyruvate dehydrogenase E1 component subunit beta (PDHB) is a subunit of pyruvate dehydrogenase E1, which is a well-known component of PDC. In Drosophila melanogaster, the CG11876 (dPDHB) gene is a homolog of human PDHB. In this study, we established a Drosophila model with neuron-specific knockdown of dPDHB to investigate its role in neuropathy pathogenesis. Knockdown of dPDHB in pan-neurons induced locomotor defects in both larval and adult stages, which were consistent with abnormal morphology of the motor neuron terminals at neuromuscular junctions and mitochondrial fragmentation in brains. Moreover, neuron-specific knockdown of dPDHB also shortened the lifespan of adult flies. In addition, flies with knockdown of dPDHB manifested a rough eye phenotype and aberrant photoreceptor axon targeting. These results with the Drosophila model suggest the involvement of PDHB in peripheral neuropathy. Copyright © 2018 Elsevier Inc. All rights reserved.

Evidence for an attentional component of inhibition of return in visual search.

PubMed

Pierce, Allison M; Crouse, Monique D; Green, Jessica J

2017-11-01

Inhibition of return (IOR) is typically described as an inhibitory bias against returning attention to a recently attended location as a means of promoting efficient visual search. Most studies examining IOR, however, either do not use visual search paradigms or do not effectively isolate attentional processes, making it difficult to conclusively link IOR to a bias in attention. Here, we recorded ERPs during a simple visual search task designed to isolate the attentional component of IOR to examine whether an inhibitory bias of attention is observed and, if so, how it influences visual search behavior. Across successive visual search displays, we found evidence of both a broad, hemisphere-wide inhibitory bias of attention along with a focal, target location-specific facilitation. When the target appeared in the same visual hemifield in successive searches, responses were slower and the N2pc component was reduced, reflecting a bias of attention away from the previously attended side of space. When the target occurred at the same location in successive searches, responses were facilitated and the P1 component was enhanced, likely reflecting spatial priming of the target. These two effects are combined in the response times, leading to a reduction in the IOR effect for repeated target locations. Using ERPs, however, these two opposing effects can be isolated in time, demonstrating that the inhibitory biasing of attention still occurs even when response-time slowing is ameliorated by spatial priming. © 2017 Society for Psychophysiological Research.

Communication of ALS Patients by Detecting Event-Related Potential

NASA Astrophysics Data System (ADS)

Kanou, Naoyuki; Sakuma, Kenji; Nakashima, Kenji

Amyotrophic Lateral Sclerosis(ALS) patients are unable to successfully communicate their desires, although their mental capacity is the same as non-affected persons. Therefore, the authors put emphasis on Event-Related Potential(ERP) which elicits the highest outcome for the target visual and hearing stimuli. P300 is one component of ERP. It is positive potential that is elicited when the subject focuses attention on stimuli that appears infrequently. In this paper, the authors focused on P200 and N200 components, in addition to P300, for their great improvement in the rate of correct judgment in the target word-specific experiment. Hence the authors propose the algorithm that specifies target words by detecting these three components. Ten healthy subjects and ALS patient underwent the experiment in which a target word out of five words, was specified by this algorithm. The rates of correct judgment in nine of ten healthy subjects were more than 90.0%. The highest rate was 99.7%. The highest rate of ALS patient was 100.0%. Through these results, the authors found the possibility that ALS patients could communicate with surrounding persons by detecting ERP(P200, N200 and P300) as their desire.

Simultaneous Binding of Hybrid Molecules Constructed with Dual DNA-Binding Components to a G-Quadruplex and Its Proximal Duplex.

PubMed

Asamitsu, Sefan; Obata, Shunsuke; Phan, Anh Tuân; Hashiya, Kaori; Bando, Toshikazu; Sugiyama, Hiroshi

2018-03-20

A G-quadruplex (quadruplex) is a nucleic acid secondary structure adopted by guanine-rich sequences and is considered to be relevant to various pharmacological and biological contexts. Although a number of researchers have endeavored to discover and develop quadruplex-interactive molecules, poor ligand designability originating from topological similarity of the skeleton of diverse quadruplexes has remained a bottleneck for gaining specificity for individual quadruplexes. This work reports on hybrid molecules that were constructed with dual DNA-binding components, a cyclic imidazole/lysine polyamide (cIKP), and a hairpin pyrrole/imidazole polyamide (hPIP), with the aim toward specific quadruplex targeting by reading out the local duplex DNA sequence adjacent to designated quadruplexes in the genome. By means of circular dichroism (CD), fluorescence resonance energy transfer (FRET), surface plasmon resonance (SPR), and NMR techniques, we showed the dual and simultaneous recognition of the respective segment via hybrid molecules, and the synergistic and mutual effect of each binding component that was appropriately linked on higher binding affinity and modest sequence specificity. Monitoring quadruplex and duplex imino protons of the quadruplex/duplex motif titrated with hybrid molecules clearly revealed distinct features of the binding of hybrid molecules to the respective segments upon their simultaneous recognition. A series of the systematic and detailed binding assays described here showed that the concept of simultaneous recognition of quadruplex and its proximal duplex by hybrid molecules constructed with the dual DNA-binding components may provide a new strategy for ligand design, enabling targeting of a large variety of designated quadruplexes at specific genome locations. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

General Aspects of Two-Component Regulatory Circuits in Bacteria: Domains, Signals and Roles.

PubMed

Padilla-Vaca, Felipe; Mondragón-Jaimes, Verónica; Franco, Bernardo

2017-01-01

All living organisms are subject to changing environments, which must be sensed in order to respond swiftly and efficiently. Two-component systems (TCS) are signal transduction regulatory circuits based typically on a membrane bound sensor kinase and a cytoplasmic response regulator, that is activated through a histidine to aspartate phosphorelay reactions. Activated response regulator acts usually as a transcription factor. The best known examples were identified in bacteria, but they are also found in fungi, algae and plants. Thus far, they are not found in mammals. Regulatory circuits coupled to two-component systems exhibit a myriad of responses to environmental stimuli such as: redox potential, pH, specific metabolites, pressure, light and more recently to specific antimicrobial peptides that activate a sensor kinase responsible for expressing virulence factors through the active response regulator. In this review we explore general aspects on two-component systems that ultimately can play a role on virulence regulation, also the intriguing domain properties of the sensor kinases that can be a potential target for antimicrobial compounds. Only a handful of sensor kinases are extensively characterized, the vast majority belong to what we call 'the dark matter of bacterial signal transduction' since no known signal, structure and biochemical properties are available. Regulatory circuits from vertebrate pathogenic organisms can explain virulence in terms of either response to environmental factors or specific niche occupancy. Hopefully, knowledge on these signal transduction systems can lead to identify novel molecules that target two-component systems, since the increase of drug resistant microorganisms is worrisome. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Targeting the extracellular matrix of ovarian cancer using functionalized, drug loaded lyophilisomes.

PubMed

van der Steen, Sophieke C H A; Raavé, René; Langerak, Sjoerd; van Houdt, Laurens; van Duijnhoven, Sander M J; van Lith, Sanne A M; Massuger, Leon F A G; Daamen, Willeke F; Leenders, William P; van Kuppevelt, Toin H

2017-04-01

Epithelial ovarian cancer is characterized by a high mortality rate and is in need for novel therapeutic avenues to improve patient outcome. The tumor's extracellular matrix ("stroma") offers new possibilities for targeted drug-delivery. Recently we identified highly sulfated chondroitin sulfate (CS-E) as a component abundantly present in the ovarian cancer extracellular matrix, and as a novel target for anti-cancer therapy. Here, we report on the functionalization of drug-loaded lyophilisomes (albumin-based biocapsules) to specifically target the stroma of ovarian carcinomas with the potential to eliminate cancer cells. To achieve specific targeting, we conjugated single chain antibodies reactive with CS-E to lyophilisomes using a two-step approach comprising sortase-mediated ligation and bioorthogonal click chemistry. Antibody-functionalized lyophilisomes specifically targeted the ovarian cancer stroma through CS-E. In a CS-E rich micro-environment in vitro lyophilisomes induced cell death by extracellular release of doxorubicin which localized to the nucleus. Immunohistochemistry identified CS-E rich stroma in a variety of solid tumors other than ovarian cancer, including breast, lung and colon cancer indicating the potential versatility of matrix therapy and the use of highly sulfated chondroitin sulfates in cancer stroma as a micro-environmental hook for targeted drug delivery. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Chimeric antigen receptor engineering: a right step in the evolution of adoptive cellular immunotherapy.

PubMed

Figueroa, Jose A; Reidy, Adair; Mirandola, Leonardo; Trotter, Kayley; Suvorava, Natallia; Figueroa, Alejandro; Konala, Venu; Aulakh, Amardeep; Littlefield, Lauren; Grizzi, Fabio; Rahman, Rakhshanda Layeequr; Jenkins, Marjorie R; Musgrove, Breeanna; Radhi, Saba; D'Cunha, Nicholas; D'Cunha, Luke N; Hermonat, Paul L; Cobos, Everardo; Chiriva-Internati, Maurizio

2015-03-01

Cancer immunotherapy comprises different therapeutic strategies that exploit the use of distinct components of the immune system, with the common goal of specifically targeting and eradicating neoplastic cells. These varied approaches include the use of specific monoclonal antibodies, checkpoint inhibitors, cytokines, therapeutic cancer vaccines and cellular anticancer strategies such as activated dendritic cell (DC) vaccines, tumor-infiltrating lymphocytes (TILs) and, more recently, genetically engineered T cells. Each one of these approaches has demonstrated promise, but their generalized success has been hindered by the paucity of specific tumor targets resulting in suboptimal tumor responses and unpredictable toxicities. This review will concentrate on recent advances on the use of engineered T cells for adoptive cellular immunotherapy (ACI) in cancer.

Making Inferences from Text: It's Vocabulary That Matters

ERIC Educational Resources Information Center

Lucas, Rebecca; Norbury, Courtenay Frazier

2015-01-01

Purpose: Many children with communication disorders have reading comprehension difficulties, and in order to target interventions effectively it is important to identify which specific components of comprehension are especially challenging. The current study explored the relationship between text-inferencing skill, autistic symptomatology, and…

Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

DTIC Science & Technology

2015-10-01

research proposed here will provide a novel insight into previously unexplored cross-talking that occurs between hedgehog -signalling and DNA...methyltransferases in prostate cancer to facilitate tumour growth and survival. Specific aims: (1) Correlate expression pattern of components of the hedgehog

Compiler writing system detail design specification. Volume 2: Component specification

NASA Technical Reports Server (NTRS)

Arthur, W. J.

1974-01-01

The logic modules and data structures composing the Meta-translator module are desribed. This module is responsible for the actual generation of the executable language compiler as a function of the input Meta-language. Machine definitions are also processed and are placed as encoded data on the compiler library data file. The transformation of intermediate language in target language object text is described.

Familiarity with interest breeds gossip: contributions of emotion, expectation, and reputation.

PubMed

Yao, Bo; Scott, Graham G; McAleer, Phil; O'Donnell, Patrick J; Sereno, Sara C

2014-01-01

Although gossip serves several important social functions, it has relatively infrequently been the topic of systematic investigation. In two experiments, we advance a cognitive-informational approach to gossip. Specifically, we sought to determine which informational components engender gossip. In Experiment 1, participants read brief passages about other people and indicated their likelihood to share this information. We manipulated target familiarity (celebrity, non-celebrity) and story interest (interesting, boring). While participants were more likely to gossip about celebrity than non-celebrity targets and interesting than boring stories, they were even more likely to gossip about celebrity targets embedded within interesting stories. In Experiment 2, we additionally probed participants' reactions to the stories concerning emotion, expectation, and reputation information conveyed. Analyses showed that while such information partially mediated target familiarity and story interest effects, only expectation and reputation accounted for the interactive pattern of gossip behavior. Our findings provide novel insights into the essential components and processing mechanisms of gossip.

Genome-wide Functional Analysis of CREB/Long-Term Memory-Dependent Transcription Reveals Distinct Basal and Memory Gene Expression Programs

PubMed Central

Lakhina, Vanisha; Arey, Rachel N.; Kaletsky, Rachel; Kauffman, Amanda; Stein, Geneva; Keyes, William; Xu, Daniel; Murphy, Coleen T.

2014-01-01

SUMMARY Induced CREB activity is a hallmark of long-term memory, but the full repertoire of CREB transcriptional targets required specifically for memory is not known in any system. To obtain a more complete picture of the mechanisms involved in memory, we combined memory training with genome-wide transcriptional analysis of C. elegans CREB mutants. This approach identified 757 significant CREB/memory-induced targets and confirmed the involvement of known memory genes from other organisms, but also suggested new mechanisms and novel components that may be conserved through mammals. CREB mediates distinct basal and memory transcriptional programs at least partially through spatial restriction of CREB activity: basal targets are regulated primarily in nonneuronal tissues, while memory targets are enriched for neuronal expression, emanating from CREB activity in AIM neurons. This suite of novel memory-associated genes will provide a platform for the discovery of orthologous mammalian long-term memory components. PMID:25611510

Familiarity with Interest Breeds Gossip: Contributions of Emotion, Expectation, and Reputation

PubMed Central

Yao, Bo; Scott, Graham G.; McAleer, Phil; O'Donnell, Patrick J.; Sereno, Sara C.

2014-01-01

Although gossip serves several important social functions, it has relatively infrequently been the topic of systematic investigation. In two experiments, we advance a cognitive-informational approach to gossip. Specifically, we sought to determine which informational components engender gossip. In Experiment 1, participants read brief passages about other people and indicated their likelihood to share this information. We manipulated target familiarity (celebrity, non-celebrity) and story interest (interesting, boring). While participants were more likely to gossip about celebrity than non-celebrity targets and interesting than boring stories, they were even more likely to gossip about celebrity targets embedded within interesting stories. In Experiment 2, we additionally probed participants' reactions to the stories concerning emotion, expectation, and reputation information conveyed. Analyses showed that while such information partially mediated target familiarity and story interest effects, only expectation and reputation accounted for the interactive pattern of gossip behavior. Our findings provide novel insights into the essential components and processing mechanisms of gossip. PMID:25119267

New generation of oral mucosal vaccines targeting dendritic cells

PubMed Central

Owen, Jennifer L.; Sahay, Bikash; Mohamadzadeh, Mansour

2013-01-01

As most infectious organisms gain entry at mucosal surfaces, there is a great deal of interest in developing vaccines that elicit effective mucosal immune responses against pathogen challenge. Targeted vaccination is one of the most effective methods available to prevent and control infectious diseases. Mucosal vaccines can offer lower costs, better accessibility, needle free delivery, and a higher capacity for mass immunizations during pandemics. Both local mucosal immunity and robust systemic responses can be achieved through mucosal vaccination. Recent progress in understanding the molecular and cellular components of the mucosal immune system have allowed for the development of a novel mucosal vaccine platform utilizing specific dendritic cell-targeting peptides and orally administered lactobacilli to elicit efficient antigen specific immune responses against infections, including B. anthracis in experimental models of disease. PMID:23835515

A nucleolar targeting signal in PML-I addresses PML to nucleolar caps in stressed or senescent cells.

PubMed

Condemine, Wilfried; Takahashi, Yuki; Le Bras, Morgane; de Thé, Hugues

2007-09-15

The promyelocytic leukemia (PML) tumour suppressor is the organiser of PML nuclear bodies, which are domains the precise functions of which are still disputed. We show that upon several types of stress, endogenous PML proteins form nucleolar caps and eventually engulf nucleolar components. Only two specific PML splice variants (PML-I and PML-IV) are efficiently targeted to the nucleolus and the abundant PML-I isoform is required for the targeting of endogenous PML proteins to this organelle. We identified a nucleolar targeting domain within the evolutionarily conserved C-terminus of PML-I. This domain contains a predicted exonuclease III fold essential for the targeting of the PML-I C-terminus to nucleolar fibrillar centres. Furthermore, spontaneous or oncogene retrieval-induced senescence is associated with the formation of very large PML nuclear bodies that initially contain nucleolar components. Later, poly-ubiquitin conjugates are found on the outer shell or within most of these senescence-associated PML bodies. Thus, unexpectedly, the scarcely studied PML-I isoform links PML bodies, nucleolus, senescence and proteolysis.

Vascular-targeted nanocarriers: design considerations and strategies for successful treatment of atherosclerosis and other vascular diseases.

PubMed

Kelley, William J; Safari, Hanieh; Lopez-Cazares, Genesis; Eniola-Adefeso, Omolola

2016-11-01

Vascular-targeted nanocarriers are an attractive option for the treatment of a number of cardiovascular diseases, as they allow for more specific delivery and increased efficacy of many small molecule drugs. However, immune clearance, limited cellular uptake, and particle-cell dynamics in blood flow can hinder nanocarrier efficacy in many applications. This review aims to investigate successful strategies for the use of vascular-targeted nanocarriers in the treatment of cardiovascular diseases such as atherosclerosis. In particular, the review will highlight strategies employed for actively targeting the components of the atherosclerotic plaque, including endothelial cells, macrophages, and platelets and passive targeting via endothelial permeability, as well as design specifications (such as size, shape, and density) aimed at enhancing the ability of nanocarriers to reach the vascular wall. WIREs Nanomed Nanobiotechnol 2016, 8:909-926. doi: 10.1002/wnan.1414 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

Human Parainfluenza Virus-3 can be Targeted by Rapidly ex vivo Expanded T-Lymphocytes

PubMed Central

McLaughlin, Lauren P.; Lang, Haili; Williams, Elizabeth; Wright, Kaylor E.; Powell, Allison; Cruz, Conrad R; Colberg-Poley, Anamaris M.; Barese, Cecilia; Hanley, Patrick J.; Bollard, Catherine M.; Keller, Michael D.

2016-01-01

Background Human Parainfluenza virus-3 (HPIV) is a common cause of respiratory infection in immunocompromised patients, and presently has no effective therapies. Virus-specific T-cell therapy has been successful for the treatment or prevention of viral infections in immunocompromised patients, but requires determination of T-cell antigens on targeted viruses. Methods HPIV3-specific T cells were expanded from peripheral blood of healthy donors using a rapid generation protocol targeting four HPIV3 proteins. Immunophenotyping was performed by flow cytometry. Viral specificity was determined by IFN-γ ELISpot, intracellular cytokine staining, and cytokine measurements from culture supernatants by Luminex assay. Cytotoxic activity was tested by 51Cr release and CD107a mobilization assays. Virus-specific T-cells targeting 6 viruses were then produced by rapid protocol, and the phenotype of HPIV3-specific T-cells was determined by immunomagnetic sorting for IFN-γ producing cells. Results HPIV3-specific T cells were expanded from 13 healthy donors. HPIV3-specific T-cells showed a CD4+ predominance (mean CD4:CD8 ratio 2.89), and demonstrated specificity for multiple HPIV3 antigens. The expanded T-cells were polyfunctional based on cytokine production, but only had a minor cytotoxic component. T cells targeting six viruses in a single product similarly showed HPIV3 specificity, with a predominant effector memory phenotype (CD3+/CD45RA-/CCR7-) in responder cells. Discussion HPIV3-specific T cells can be produced using a rapid ex vivo protocol from healthy donors and are predominantly CD4+ T-cells with Th1 activity. HPIV3 epitopes can also be successfully targeted alongside multiple other viral epitopes in production of 6-virus T-cells, without loss of HPIV3 specificity. These products may be clinically beneficial to combat HPIV3 infections by adoptive T-cell therapy in immune compromised patients. PMID:27692559

Printed Spacecraft Separation System

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

Holmans, Walter; Dehoff, Ryan

In this project Planetary Systems Corporation proposed utilizing additive manufacturing (3D printing) to manufacture a titanium spacecraft separation system for commercial and US government customers to realize a 90% reduction in the cost and energy. These savings were demonstrated via “printing-in” many of the parts and sub-assemblies into one part, thus greatly reducing the labor associated with design, procurement, assembly and calibration of mechanisms. Planetary Systems Corporation redesigned several of the components of the separation system based on additive manufacturing principles including geometric flexibility and the ability to fabricate complex designs, ability to combine multiple parts of an assembly intomore » a single component, and the ability to optimize design for specific mechanical property targets. Shock absorption was specifically targeted and requirements were established to attenuate damage to the Lightband system from shock of initiation. Planetary Systems Corporation redesigned components based on these requirements and sent the designs to Oak Ridge National Laboratory to be printed. ORNL printed the parts using the Arcam electron beam melting technology based on the desire for the parts to be fabricated from Ti-6Al-4V based on the weight and mechanical performance of the material. A second set of components was fabricated from stainless steel material on the Renishaw laser powder bed technology due to the improved geometric accuracy, surface finish, and wear resistance of the material. Planetary Systems Corporation evaluated these components and determined that 3D printing is potentially a viable method for achieving significant cost and savings metrics.« less

RNA editing in Drosophila melanogaster: new targets and functionalconsequences

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

Stapleton, Mark; Carlson, Joseph W.; Celniker, Susan E.

2006-09-05

Adenosine deaminases that act on RNA (ADARs) catalyze the site-specific conversion of adenosine to inosine in primary mRNA transcripts. These re-coding events affect coding potential, splice-sites, and stability of mature mRNAs. ADAR is an essential gene and studies in mouse, C. elegans, and Drosophila suggest its primary function is to modify adult behavior by altering signaling components in the nervous system. By comparing the sequence of isogenic cDNAs to genomic DNA, we have identified and experimentally verified 27 new targets of Drosophila ADAR. Our analyses lead us to identify new classes of genes whose transcripts are targets of ADAR includingmore » components of the actin cytoskeleton, and genes involved in ion homeostasis and signal transduction. Our results indicate that editing in Drosophila increases the diversity of the proteome, and does so in a manner that has direct functional consequences on protein function.« less

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes

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

Komatsu, Tetsuro; Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575; Will, Hans

2016-04-22

Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions asmore » well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. - Highlights: • Host nuclear antiviral factors were analyzed upon adenovirus genome delivery. • Interferon treatments fail to permit PML nuclear bodies to target adenoviral genomes. • Neither Sp100A nor B targets adenoviral genomes despite potentially opposite roles. • The nuclear DNA sensor IFI16 does not target incoming adenoviral genomes. • PHF13/SPOC1 targets neither incoming adenoviral genomes nor genome-bound protein VII.« less

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

PubMed

Ciocca, V; Darwin, C J

1999-04-01

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

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

NASA Astrophysics Data System (ADS)

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

2016-06-01

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

Genetic algorithm in the structural design of Cooke triplet lenses

NASA Astrophysics Data System (ADS)

Hazra, Lakshminarayan; Banerjee, Saswatee

1999-08-01

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

Drugs and Targets in Fibrosis

PubMed Central

Li, Xiaoyi; Zhu, Lixin; Wang, Beibei; Yuan, Meifei; Zhu, Ruixin

2017-01-01

Fibrosis contributes to the development of many diseases and many target molecules are involved in fibrosis. Currently, the majority of fibrosis treatment strategies are limited to specific diseases or organs. However, accumulating evidence demonstrates great similarities among fibroproliferative diseases, and more and more drugs are proved to be effective anti-fibrotic therapies across different diseases and organs. Here we comprehensively review the current knowledge on the pathological mechanisms of fibrosis, and divide factors mediating fibrosis progression into extracellular and intracellular groups. Furthermore, we systematically summarize both single and multiple component drugs that target fibrosis. Future directions of fibrosis drug discovery are also proposed. PMID:29218009

New generation of oral mucosal vaccines targeting dendritic cells.

PubMed

Owen, Jennifer L; Sahay, Bikash; Mohamadzadeh, Mansour

2013-12-01

As most infectious organisms gain entry at mucosal surfaces, there is a great deal of interest in developing vaccines that elicit effective mucosal immune responses against pathogen challenge. Targeted vaccination is one of the most effective methods available to prevent and control infectious diseases. Mucosal vaccines can offer lower costs, better accessibility, needle free delivery, and a higher capacity for mass immunizations during pandemics. Both local mucosal immunity and robust systemic responses can be achieved through mucosal vaccination. Recent progress in understanding the molecular and cellular components of the mucosal immune system have allowed for the development of a novel mucosal vaccine platform utilizing specific dendritic cell-targeting peptides and orally administered lactobacilli to elicit efficient antigen specific immune responses against infections, including Bacillus anthracis in experimental models of disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Male contraception: past, present and future.

PubMed

Payne, Christopher; Goldberg, Erwin

2014-01-01

Current contraceptive options available to men include withdrawal, condoms, and vasectomy, each of which has its own drawbacks. In this chapter we will describe the pros and cons for each, as well as methodological and product updates. Statistics from the U.S. Centers for Disease Control on acceptance and satisfaction will be included. Advances in vasectomy and reversal will be presented. Methods to develop new contraceptive technologies fall into two categories: hormonal and non-hormonal. Many targets and strategies have been proposed for non-hormonal male contraception within the testis. Targets include structural components in the testis, as well as enzymes, ion channels and other proteins specific to spermatozoa. Here we provide an overview of the spermatogenic mechanisms and proteins that have received research interest to date. We also discuss potential novel targets, such as ubiquitin specific proteases, that warrant greater research emphasis.

Redox signaling in the cardiomyocyte: From physiology to failure.

PubMed

Santos, Celio X C; Raza, Sadaf; Shah, Ajay M

2016-05-01

The specific effect of oxygen and reactive oxygen species (ROS) in mediating post-translational modification of protein targets has emerged as a key mechanism regulating signaling components, a process termed redox signaling. ROS act in the post-translational modification of multiple target proteins including receptors, kinases, phosphatases, ion channels and transcription factors. Both O2 and ROS are major source of electrons in redox reactions in aerobic organisms. Because the heart has the highest O2 consumption among body organs, it is not surprising that redox signaling is central to heart function and pathophysiology. In this article, we review some of the main cardiac redox signaling pathways and their roles in the cardiomyocyte and in heart failure, with particular focus on the specific molecular targets of ROS in the heart. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

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

2016-11-01

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

The Future of Tennessee: Higher Education 1987-1993.

ERIC Educational Resources Information Center

Tennessee Higher Education Commission, Nashville.

This master plan for higher education in Tennessee sketches a framework for the continued improvement of postsecondary institutions and emphasizes the critical links between higher education and other components of the state. A set of principles and achievement targets undergirding the master plan are outlined. Specific action is called for in…

Internalized compartments encapsulated nanogels for targeted drug delivery

NASA Astrophysics Data System (ADS)

Yu, Jicheng; Zhang, Yuqi; Sun, Wujin; Wang, Chao; Ranson, Davis; Ye, Yanqi; Weng, Yuyan; Gu, Zhen

2016-04-01

Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The resulting nanogels loaded with doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity in vitro. However, when treated with the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to a bare HA nanogel with DOX. This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system.Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The resulting nanogels loaded with doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity in vitro. However, when treated with the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to a bare HA nanogel with DOX. This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system. Electronic supplementary information (ESI) available: Synthesis of m-HA; synthesis of rhodamine-HA derivative; supplementary data on relative fluorescence intensity of DOX-EN-NGs on HeLa cells. See DOI: 10.1039/c5nr08895j

Method calibration of the model 13145 infrared target projectors

NASA Astrophysics Data System (ADS)

Huang, Jianxia; Gao, Yuan; Han, Ying

2014-11-01

The SBIR Model 13145 Infrared Target Projectors ( The following abbreviation Evaluation Unit ) used for characterizing the performances of infrared imaging system. Test items: SiTF, MTF, NETD, MRTD, MDTD, NPS. Infrared target projectors includes two area blackbodies, a 12 position target wheel, all reflective collimator. It provide high spatial frequency differential targets, Precision differential targets imaged by infrared imaging system. And by photoelectricity convert on simulate signal or digital signal. Applications software (IR Windows TM 2001) evaluate characterizing the performances of infrared imaging system. With regards to as a whole calibration, first differently calibration for distributed component , According to calibration specification for area blackbody to calibration area blackbody, by means of to amend error factor to calibration of all reflective collimator, radiance calibration of an infrared target projectors using the SR5000 spectral radiometer, and to analyze systematic error. With regards to as parameter of infrared imaging system, need to integrate evaluation method. According to regulation with -GJB2340-1995 General specification for military thermal imaging sets -testing parameters of infrared imaging system, the results compare with results from Optical Calibration Testing Laboratory . As a goal to real calibration performances of the Evaluation Unit.

Enzymatic single-chain antibody tagging: a universal approach to targeted molecular imaging and cell homing in cardiovascular disease.

PubMed

Ta, H T; Prabhu, S; Leitner, E; Jia, F; von Elverfeldt, D; Jackson, Katherine E; Heidt, T; Nair, A K N; Pearce, H; von Zur Muhlen, C; Wang, X; Peter, K; Hagemeyer, C E

2011-08-05

Antibody-targeted delivery of imaging agents can enhance the sensitivity and accuracy of current imaging techniques. Similarly, homing of effector cells to disease sites increases the efficacy of regenerative cell therapy while reducing the number of cells required. Currently, targeting can be achieved via chemical conjugation to specific antibodies, which typically results in the loss of antibody functionality and in severe cell damage. An ideal conjugation technique should ensure retention of antigen-binding activity and functionality of the targeted biological component. To develop a biochemically robust, highly reproducible, and site-specific coupling method using the Staphylococcus aureus sortase A enzyme for the conjugation of a single-chain antibody (scFv) to nanoparticles and cells for molecular imaging and cell homing in cardiovascular diseases. This scFv specifically binds to activated platelets, which play a pivotal role in thrombosis, atherosclerosis, and inflammation. The conjugation procedure involves chemical and enzyme-mediated coupling steps. The scFv was successfully conjugated to iron oxide particles (contrast agents for magnetic resonance imaging) and to model cells. Conjugation efficiency ranged between 50% and 70%, and bioactivity of the scFv after coupling was preserved. The targeting of scFv-coupled cells and nanoparticles to activated platelets was strong and specific as demonstrated in in vitro static adhesion assays, in a flow chamber system, in mouse intravital microscopy, and in in vivo magnetic resonance imaging of mouse carotid arteries. This unique biotechnological approach provides a versatile and broadly applicable tool for procuring targeted regenerative cell therapy and targeted molecular imaging in cardiovascular and inflammatory diseases and beyond.

Systems biology impact on antiepileptic drug discovery.

PubMed

Margineanu, Doru Georg

2012-02-01

Systems biology (SB), a recent trend in bioscience research to consider the complex interactions in biological systems from a holistic perspective, sees the disease as a disturbed network of interactions, rather than alteration of single molecular component(s). SB-relying network pharmacology replaces the prevailing focus on specific drug-receptor interaction and the corollary of rational drug design of "magic bullets", by the search for multi-target drugs that would act on biological networks as "magic shotguns". Epilepsy being a multi-factorial, polygenic and dynamic pathology, SB approach appears particularly fit and promising for antiepileptic drug (AED) discovery. In fact, long before the advent of SB, AED discovery already involved some SB-like elements. A reported SB project aimed to find out new drug targets in epilepsy relies on a relational database that integrates clinical information, recordings from deep electrodes and 3D-brain imagery with histology and molecular biology data on modified expression of specific genes in the brain regions displaying spontaneous epileptic activity. Since hitting a single target does not treat complex diseases, a proper pharmacological promiscuity might impart on an AED the merit of being multi-potent. However, multi-target drug discovery entails the complicated task of optimizing multiple activities of compounds, while having to balance drug-like properties and to control unwanted effects. Specific design tools for this new approach in drug discovery barely emerge, but computational methods making reliable in silico predictions of poly-pharmacology did appear, and their progress might be quite rapid. The current move away from reductionism into network pharmacology allows expecting that a proper integration of the intrinsic complexity of epileptic pathology in AED discovery might result in literally anti-epileptic drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Two-component signal transduction in Corynebacterium glutamicum and other corynebacteria: on the way towards stimuli and targets.

PubMed

Bott, Michael; Brocker, Melanie

2012-06-01

In bacteria, adaptation to changing environmental conditions is often mediated by two-component signal transduction systems. In the prototypical case, a specific stimulus is sensed by a membrane-bound histidine kinase and triggers autophosphorylation of a histidine residue. Subsequently, the phosphoryl group is transferred to an aspartate residue of the cognate response regulator, which then becomes active and mediates a specific response, usually by activating and/or repressing a set of target genes. In this review, we summarize the current knowledge on two-component signal transduction in Corynebacterium glutamicum. This Gram-positive soil bacterium is used for the large-scale biotechnological production of amino acids and can also be applied for the synthesis of a wide variety of other products, such as organic acids, biofuels, or proteins. Therefore, C. glutamicum has become an important model organism in industrial biotechnology and in systems biology. The type strain ATCC 13032 possesses 13 two-component systems and the role of five has been elucidated in recent years. They are involved in citrate utilization (CitAB), osmoregulation and cell wall homeostasis (MtrAB), adaptation to phosphate starvation (PhoSR), adaptation to copper stress (CopSR), and heme homeostasis (HrrSA). As C. glutamicum does not only face changing conditions in its natural environment, but also during cultivation in industrial bioreactors of up to 500 m(3) volume, adaptability can also be crucial for good performance in biotechnological production processes. Detailed knowledge on two-component signal transduction and regulatory networks therefore will contribute to both the application and the systemic understanding of C. glutamicum and related species.

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

PubMed Central

Malaguarnera, Roberta; Belfiore, Antonino

2014-01-01

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

Affibody Modified and Radiolabeled Gold-Iron Oxide Hetero-nanostructures for Tumor PET, Optical and MR Imaging

PubMed Central

Yang, Meng; Cheng, Kai; Qi, Shibo; Liu, Hongguang; Jiang, Yuxin; Jiang, Han; Li, Jinbo; Chen, Kai; Zhang, Huimao; Cheng, Zhen

2013-01-01

A highly monodispersed hetero-nanostructure with two different functional nanomaterials (gold (Au) and iron oxide (Fe3O4, IO)) within one structure was successfully developed as Affibody based trimodality nanoprobe (positron emission tomography, PET; optical imaging; and magnetic resonance imaging, MRI) for imaging of epidermal growth factor receptor (EGFR) positive tumors. Unlike other regular nanostructures with a single component, the Au-IO hetero-nanostructures (Au-IONPs) with unique chemical and physical properties have capability to combine several imaging modalities together to provide complementary information. The IO component within hetero-nanostructures serve as a T2 reporter for MRI; and gold component serve as both optical and PET reporters. Moreover, such hetero-nanoprobes could provide a robust nano-platform for surface-specific modification with both targeting molecules (anti-EGFR Affibody protein) and PET imaging reporters (radiometal 64Cu chelators) in highly efficient and reliable manner. In vitro and in vivo study showed that the resultant nanoprobe provided high specificity, sensitivity, and excellent tumor contrast for both PET and MRI imaging in the human EGFR-expressing cells and tumors. Our study data also highlighted the EGFR targeting efficiency of hetero-nanoparticles and the feasibility for their further theranostic applications. PMID:23343632

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes.

PubMed

Komatsu, Tetsuro; Will, Hans; Nagata, Kyosuke; Wodrich, Harald

2016-04-22

Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions as well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. Copyright © 2016 Elsevier Inc. All rights reserved.

Preliminary design for a reverse Brayton cycle cryogenic cooler

NASA Technical Reports Server (NTRS)

Swift, Walter L.

1993-01-01

A long life, single stage, reverse Brayton cycle cryogenic cooler is being developed for applications in space. The system is designed to provide 5 W of cooling at a temperature of 65 Kelvin with a total cycle input power of less than 200 watts. Key features of the approach include high speed, miniature turbomachines; an all metal, high performance, compact heat exchanger; and a simple, high frequency, three phase motor drive. In Phase 1, a preliminary design of the system was performed. Analyses and trade studies were used to establish the thermodynamic performance of the system and the performance specifications for individual components. Key mechanical features for components were defined and assembly layouts for the components and the system were prepared. Critical materials and processes were identified. Component and brassboard system level tests were conducted at cryogenic temperatures. The system met the cooling requirement of 5 W at 65 K. The system was also operated over a range of cooling loads from 0.5 W at 37 K to 10 W at 65 K. Input power to the system was higher than target values. The heat exchanger and inverter met or exceeded their respective performance targets. The compresssor/motor assembly was marginally below its performance target. The turboexpander met its aerodynamic efficiency target, but overall performance was below target because of excessive heat leak. The heat leak will be reduced to an acceptable value in the engineering model. The results of Phase 1 indicate that the 200 watt input power requirement can be met with state-of-the-art technology in a system which has very flexible integration requirements and negligible vibration levels.

Preliminary design for a reverse Brayton cycle cryogenic cooler

NASA Astrophysics Data System (ADS)

Swift, Walter L.

1993-12-01

A long life, single stage, reverse Brayton cycle cryogenic cooler is being developed for applications in space. The system is designed to provide 5 W of cooling at a temperature of 65 Kelvin with a total cycle input power of less than 200 watts. Key features of the approach include high speed, miniature turbomachines; an all metal, high performance, compact heat exchanger; and a simple, high frequency, three phase motor drive. In Phase 1, a preliminary design of the system was performed. Analyses and trade studies were used to establish the thermodynamic performance of the system and the performance specifications for individual components. Key mechanical features for components were defined and assembly layouts for the components and the system were prepared. Critical materials and processes were identified. Component and brassboard system level tests were conducted at cryogenic temperatures. The system met the cooling requirement of 5 W at 65 K. The system was also operated over a range of cooling loads from 0.5 W at 37 K to 10 W at 65 K. Input power to the system was higher than target values. The heat exchanger and inverter met or exceeded their respective performance targets. The compresssor/motor assembly was marginally below its performance target. The turboexpander met its aerodynamic efficiency target, but overall performance was below target because of excessive heat leak. The heat leak will be reduced to an acceptable value in the engineering model. The results of Phase 1 indicate that the 200 watt input power requirement can be met with state-of-the-art technology in a system which has very flexible integration requirements and negligible vibration levels.

An uncontrolled trial of multi-component care for first-episode psychosis: Effects on social cognition.

PubMed

Breitborde, Nicholas J K; Moe, Aubrey M; Woolverton, Cindy; Harrison-Monroe, Patricia; Bell, Emily K

2018-06-01

Growing evidence suggests that specialized, multi-component treatment programmes produce improvements in numerous outcomes among individuals with first-episode psychosis. However, these programmes often lack interventions specifically designed to address deficits in social cognition. This raises questions about the effectiveness of such programmes in addressing deficits in social cognition that accompany psychotic disorders. We investigated the effect of participation in a multi-component treatment programme on social cognition among 71 individuals with first-episode psychosis. Participants experienced gains in emotion processing, social knowledge, social perception and theory of mind. However, after controlling for multiple comparisons, these improvements were limited to theory of mind and recognition of social cues in low emotion interactions. Although our findings should be interpreted cautiously, they raise the possibility that individuals participating in multi-component treatment programmes for first-episode psychosis without interventions specifically targeting social cognition may still experience gains in social cognition. © 2017 John Wiley & Sons Australia, Ltd.

Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer

NASA Astrophysics Data System (ADS)

McGuire, Michael J.; Gray, Bethany Powell; Li, Shunzi; Cupka, Dorothy; Byers, Lauren Averett; Wu, Lei; Rezaie, Shaghayegh; Liu, Ying-Horng; Pattisapu, Naveen; Issac, James; Oyama, Tsukasa; Diao, Lixia; Heymach, John V.; Xie, Xian-Jin; Minna, John D.; Brown, Kathlynn C.

2014-03-01

Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071-40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands.

Adipocyte-derived players in hematologic tumors: useful novel targets?

PubMed

Jöhrer, Karin; Ploner, Christian; Thangavadivel, Shanmugapriya; Wuggenig, Philipp; Greil, Richard

2015-01-01

Adipocytes and their products play essential roles in tumor establishment and progression. As the main cellular component of the bone marrow, adipocytes may contribute to the development of hematologic tumors. This review summarizes experimental data on adipocytes and their interaction with various cancer cells. Special focus is set on the interactions of bone marrow adipocytes and normal and transformed cells of the hematopoietic system such as myeloma and leukemia cells. Current in vitro and in vivo data are summarized and the potential of novel therapeutic targets is critically discussed. Targeting lipid metabolism of cancer cells and adipocytes in combination with standard therapeutics might open novel therapeutic avenues in these cancer entities. Adipocyte-derived products such as free fatty acids and specific adipokines such as adiponectin may be vital anti-cancer targets in hematologic malignancies. However, available data on lipid metabolism is currently mostly referring to peripheral fat cell/cancer cell interactions and results need to be evaluated specifically for the bone marrow niche.

Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer

PubMed Central

McGuire, Michael J.; Gray, Bethany Powell; Li, Shunzi; Cupka, Dorothy; Byers, Lauren Averett; Wu, Lei; Rezaie, Shaghayegh; Liu, Ying-Horng; Pattisapu, Naveen; Issac, James; Oyama, Tsukasa; Diao, Lixia; Heymach, John V.; Xie, Xian-Jin; Minna, John D.; Brown, Kathlynn C.

2014-01-01

Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071–40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands. PMID:24670678

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

PubMed

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

2007-01-01

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

Human CD45 is an F-component-specific receptor for the staphylococcal toxin Panton-Valentine leukocidin.

PubMed

Tromp, Angelino T; Van Gent, Michiel; Abrial, Pauline; Martin, Amandine; Jansen, Joris P; De Haas, Carla J C; Van Kessel, Kok P M; Bardoel, Bart W; Kruse, Elisabeth; Bourdonnay, Emilie; Boettcher, Michael; McManus, Michael T; Day, Christopher J; Jennings, Michael P; Lina, Gérard; Vandenesch, François; Van Strijp, Jos A G; Jan Lebbink, Robert; Haas, Pieter-Jan A; Henry, Thomas; Spaan, András N

2018-05-07

The staphylococcal bi-component leukocidins Panton-Valentine leukocidin (PVL) and γ-haemolysin CB (HlgCB) target human phagocytes. Binding of the toxins' S-components to human complement C5a receptor 1 (C5aR1) contributes to cellular tropism and human specificity of PVL and HlgCB. To investigate the role of both leukocidins during infection, we developed a human C5aR1 knock-in (hC5aR1 KI ) mouse model. HlgCB, but unexpectedly not PVL, contributed to increased bacterial loads in tissues of hC5aR1 KI mice. Compared to humans, murine hC5aR1 KI neutrophils showed a reduced sensitivity to PVL, which was mediated by the toxin's F-component LukF-PV. By performing a genome-wide CRISPR-Cas9 screen, we identified CD45 as a receptor for LukF-PV. The human-specific interaction between LukF-PV and CD45 provides a molecular explanation for resistance of hC5aR1 KI mouse neutrophils to PVL and probably contributes to the lack of a PVL-mediated phenotype during infection in these mice. This study demonstrates an unsuspected role of the F-component in driving the sensitivity of human phagocytes to PVL.

Novel phage display-derived neuroblastoma-targeting peptides potentiate the effect of drug nanocarriers in preclinical settings.

PubMed

Loi, Monica; Di Paolo, Daniela; Soster, Marco; Brignole, Chiara; Bartolini, Alice; Emionite, Laura; Sun, Jessica; Becherini, Pamela; Curnis, Flavio; Petretto, Andrea; Sani, Monica; Gori, Alessandro; Milanese, Marco; Gambini, Claudio; Longhi, Renato; Cilli, Michele; Allen, Theresa M; Bussolino, Federico; Arap, Wadih; Pasqualini, Renata; Corti, Angelo; Ponzoni, Mirco; Marchiò, Serena; Pastorino, Fabio

2013-09-10

Molecular targeting of drug delivery nanocarriers is expected to improve their therapeutic index while decreasing their toxicity. Here we report the identification and characterization of novel peptide ligands specific for cells present in high-risk neuroblastoma (NB), a childhood tumor mostly refractory to current therapies. To isolate such targeting moieties, we performed combined in vitro/ex-vivo phage display screenings on NB cell lines and on tumors derived from orthotopic mouse models of human NB. By designing proper subtractive protocols, we identified phage clones specific either for the primary tumor, its metastases, or for their respective stromal components. Globally, we isolated 121 phage-displayed NB-binding peptides: 26 bound the primary tumor, 15 the metastatic mass, 57 and 23 their respective microenvironments. Of these, five phage clones were further validated for their specific binding ex-vivo to biopsies from stage IV NB patients and to NB tumors derived from mice. All five clones also targeted tumor cells and vasculature in vivo when injected into NB-bearing mice. Coupling of the corresponding targeting peptides with doxorubicin-loaded liposomes led to a significant inhibition in tumor volume and enhanced survival in preclinical NB models, thereby paving the way to their clinical development. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Use of Raman microscopy and band-target entropy minimization analysis to identify dyes in a commercial stamp. Implications for authentication and counterfeit detection.

PubMed

Widjaja, Effendi; Garland, Marc

2008-02-01

Raman microscopy was used in mapping mode to collect more than 1000 spectra in a 100 microm x 100 microm area from a commercial stamp. Band-target entropy minimization (BTEM) was then employed to unmix the mixture spectra in order to extract the pure component spectra of the samples. Three pure component spectral patterns with good signal-to-noise ratios were recovered, and their spatial distributions were determined. The three pure component spectral patterns were then identified as copper phthalocyanine blue, calcite-like material, and yellow organic dye material by comparison to known spectral libraries. The present investigation, consisting of (1) advanced curve resolution (blind-source separation) followed by (2) spectral data base matching, readily suggests extensions to authenticity and counterfeit studies of other types of commercial objects. The presence or absence of specific observable components form the basis for assessment. The present spectral analysis (BTEM) is applicable to highly overlapping spectral information. Since a priori information such as the number of components present and spectral libraries are not needed in BTEM, and since minor signals arising from trace components can be reconstructed, this analysis offers a robust approach to a wide variety of material problems involving authenticity and counterfeit issues.

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

PubMed

McGinnis, E Menton; Keil, Andreas

2011-02-09

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

A philosophy for CNS radiotracer design.

PubMed

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

2014-10-21

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

A Component-Centered Meta-Analysis of Family-Based Prevention Programs for Adolescent Substance Use

PubMed Central

Roseth, Cary J.; Fosco, Gregory M.; Lee, You-kyung; Chen, I-Chien

2016-01-01

Although research has documented the positive effects of family-based prevention programs, the field lacks specific information regarding why these programs are effective. The current study summarized the effects of family-based programs on adolescent substance use using a component-based approach to meta-analysis in which we decomposed programs into a set of key topics or components that were specifically addressed by program curricula (e.g., parental monitoring/behavior management, problem solving, positive family relations, etc.). Components were coded according to the amount of time spent on program services that targeted youth, parents, and the whole family; we also coded effect sizes across studies for each substance-related outcome. Given the nested nature of the data, we used hierarchical linear modeling to link program components (Level 2) with effect sizes (Level 1). The overall effect size across programs was .31, which did not differ by type of substance. Youth-focused components designed to encourage more positive family relationships and a positive orientation toward the future emerged as key factors predicting larger than average effect sizes. Our results suggest that, within the universe of family-based prevention, where components such as parental monitoring/behavior management are almost universal, adding or expanding certain youth-focused components may be able to enhance program efficacy. PMID:27064553

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

PubMed

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

2012-01-01

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

Exploiting CRISPR/Cas systems for biotechnology

PubMed Central

Sampson, Timothy R.; Weiss, David S.

2015-01-01

The Cas9 endonuclease is the central component of the Type II CRISPR/Cas system, a prokaryotic adaptive restriction system against invading nucleic acids, such as those originating from bacteriophages and plasmids. Recently, this RNA-directed DNA endonuclease has been harnessed to target DNA sequences of interest. Here, we review the development of Cas9 as an important tool to not only edit the genomes of a number of different prokaryotic and eukaryotic species, but also as an efficient system for site-specific transcriptional repression or activation. Additionally, a specific Cas9 protein has been observed to target an RNA substrate, suggesting that Cas9 may have the ability to be programmed to target RNA as well. Cas proteins from other CRISPR/Cas subtypes may also be exploited in this regard. Thus, CRISPR/Cas systems represent an effective and versatile biotechnological tool, which will have significant impact on future advancements in genome engineering. PMID:24323919

Exploiting CRISPR/Cas systems for biotechnology.

PubMed

Sampson, Timothy R; Weiss, David S

2014-01-01

The Cas9 endonuclease is the central component of the Type II CRISPR/Cas system, a prokaryotic adaptive restriction system against invading nucleic acids, such as those originating from bacteriophages and plasmids. Recently, this RNA-directed DNA endonuclease has been harnessed to target DNA sequences of interest. Here, we review the development of Cas9 as an important tool to not only edit the genomes of a number of different prokaryotic and eukaryotic species, but also as an efficient system for site-specific transcriptional repression or activation. Additionally, a specific Cas9 protein has been observed to target an RNA substrate, suggesting that Cas9 may have the ability to be programmed to target RNA as well. Cas proteins from other CRISPR/Cas subtypes may also be exploited in this regard. Thus, CRISPR/Cas systems represent an effective and versatile biotechnological tool, which will have significant impact on future advancements in genome engineering. © 2014 WILEY Periodicals, Inc.

Smart linkers in polymer-drug conjugates for tumor-targeted delivery.

PubMed

Chang, Minglu; Zhang, Fang; Wei, Ting; Zuo, Tiantian; Guan, Yuanyuan; Lin, Guimei; Shao, Wei

2016-01-01

To achieve effective chemotherapy, many types of drug delivery systems have been developed for the specific environments in tumor tissues. Polymer-drug conjugates are increasingly used in tumor therapy due to several significant advantages over traditional delivery systems. In the fabrication of polymer-drug conjugates, a smart linker is an important component that joins two fragments or molecules together and can be cleared by a specific stimulus, which results in targeted drug delivery and controlled release. By regulating the conjugation between the drug and the nanocarriers, stimulus-sensitive systems based on smart linkers can offer high payloads, certified stability, controlled release and targeted delivery. In this review, we summarize the current state of smart linkers (e.g. disulfide, hydrazone, peptide, azo) used recently in various polymer-drug conjugate-based delivery systems with a primary focus on their sophisticated design principles and drug delivery mechanisms as well as in vivo processes.

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).

Rapid and long-lasting learning of feature binding

PubMed Central

Yashar, Amit; Carrasco, Marisa

2016-01-01

How are features integrated (bound) into objects and how can this process be facilitated? Here we investigated the role of rapid perceptual learning in feature binding and its long-lasting effects. By isolating the contributions of individual features from their conjunctions between training and test displays, we demonstrate for the first time that training can rapidly and substantially improve feature binding. Observers trained on a conjunction search task consisting of a rapid display with one target-conjunction, then tested with a new target-conjunction. Features were the same between training and test displays. Learning transferred to the new target when its conjunction was presented as a distractor, but not when only its component features were presented in different conjunction distractors during training. Training improvement lasted for up to 16 months, but, in all conditions, it was specific to the trained target. Our findings suggest that with short training observers’ ability to bind two specific features into an object is improved, and that this learning effect can last for over a year. Moreover, our findings show that while the short-term learning effect reflects activation of presented items and their binding, long-term consolidation is task specific. PMID:27289484

Colon-targeted oral drug delivery systems: design trends and approaches.

PubMed

Amidon, Seth; Brown, Jack E; Dave, Vivek S

2015-08-01

Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

Deregulation of the COP9 signalosome-cullin-RING ubiquitin-ligase pathway: mechanisms and roles in urological cancers.

PubMed

Gummlich, Linda; Rabien, Anja; Jung, Klaus; Dubiel, Wolfgang

2013-07-01

The COP9 signalosome (CSN)-cullin-RING ubiquitin (Ub)-ligase (CRL) pathway is a prominent segment of the Ub proteasome system (UPS). It specifically ubiquitinates proteins and targets them for proteolytic elimination. As part of the UPS it maintains essential cellular processes including cell cycle progression, DNA repair, antigen processing and signal transduction. The CSN-CRL pathway consists of the CSN possessing eight subunits (CSN1-CSN8) and one CRL consisting of a cullin, a RING-domain protein and a substrate recognition subunit (SRS). In human cells approximately 250 CRLs exist each of which interacting with a specific set of substrates and the CSN. The CSN-CRL interplay determines the activity and specificity of CRL ubiquitination. The removal of the Ub-like protein Nedd8 from the CRL component cullin by the CSN (deneddylation) reduces the ubiquitinating activity and at the same time enables reassembly of CRLs in order to adapt to substrate specificity requirements. On the other hand, CRLs as well as substrates negatively influence the deneddylating activity of the CSN. In recent years evidence accumulated that deregulation of the CSN-CRL pathway can cause cancer. Here we review current knowledge on modifications of CSN and CRL components including CSN subunits, SRSs and cullins causing tumorigenesis with emphasis on urological neoplasia. The CSN-CRL pathway is a target of tumor-viruses as well as of a multitude of miRNAs. Recently evaluated miRNAs altered in urological cancers might have impact on the CSN-CRL pathway which has to be analyzed in future experiments. We propose that the pathway is a suitable target for future tumor therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Design of next generation antibody drug conjugates].

PubMed

Zhu, Gui-Dong; Fu, Yang-Xin

2013-07-01

Chemotherapy remains one of the major tools, along with surgery, radiotherapy, and more recently targeted therapy, in the war against cancer. There have appeared a plethora of highly potent cytotoxic drugs but the poor discriminability between cancerous and healthy cells of these agents limits their broader application in clinical settings. Therapeutic antibodies have emerged as an important class of biological anticancer agents, thanks to their ability in specific binding to tumor-associated antigens. While this important class of biologics can be used as single agents for the treatment of cancer through antibody-dependent cell cytotoxicity (ADCC), their therapeutical efficacy is often limited. Antitumor antibody drug conjugates (ADCs) combine the target-specificity of monoclonal antibody (mAb) and the highly active cell-killing drugs, taking advantages of the best characteristics out of both components. Thus, insufficiency of most naked mAbs in cancer therapy has been circumvented by arming the immunoglobulin with cytotoxic drugs. Here mAbs are used as vehicles to transport potent payloads to tumor cells. ADCs contain three main components: antibody, linker and cytotoxics (also frequently referred as payload). Antibodies can recognize and specifically bind to the tumor-specific antigens, leading to an antibody-assisted internalization, and payload release. While ADC has demonstrated tremendous success, a number of practical challenges limit the broader applications of this new class of anticancer therapy, including inefficient cellular uptake, low cytotoxicity, and off-target effects. This review article aims to cover recent advances in optimizing linkers with increased stability in circulation while allowing efficient payload release within tumor cells. We also attempt to provide some practical strategies in resolving the current challenges in this attractive research area, particularly to those new to the field.

Fostering Self-Regulation of Students with Learning Disabilities: Insights from 30 Years of Reading Comprehension Intervention Research

ERIC Educational Resources Information Center

Berkeley, Sheri; Larsen, Anna

2018-01-01

Thirty years of intervention research on the effects of reading comprehension strategies for students with learning disabilities was reviewed in this quantitative synthesis. Specifically, researchers targeted studies that contained self-regulated learning components. A systematic search yielded 18 studies from nine research journals that met…

Canopy gap dynamics of second-growth red spruce-northern hardwood stands in West Virginia

Treesearch

James S. Rentch; Thomas M. Schuler; Gregory J. Nowacki; Nathan R. Beane; W. Mark Ford

2010-01-01

Forest restoration requires an understanding of the natural disturbance regime of the target community and estimates of the historic range of variability of ecosystem components (composition, structure, and disturbance processes). Management prescriptions that support specific restoration activities should be consistent with these parameters. In this study, we describe...

Microfluidic Arrayed Lab-On-A-Chip for Electrochemical Capacitive Detection of DNA Hybridization Events.

PubMed

Ben-Yoav, Hadar; Dykstra, Peter H; Bentley, William E; Ghodssi, Reza

2017-01-01

A microfluidic electrochemical lab-on-a-chip (LOC) device for DNA hybridization detection has been developed. The device comprises a 3 × 3 array of microelectrodes integrated with a dual layer microfluidic valved manipulation system that provides controlled and automated capabilities for high throughput analysis of microliter volume samples. The surface of the microelectrodes is functionalized with single-stranded DNA (ssDNA) probes which enable specific detection of complementary ssDNA targets. These targets are detected by a capacitive technique which measures dielectric variation at the microelectrode-electrolyte interface due to DNA hybridization events. A quantitative analysis of the hybridization events is carried out based on a sensing modeling that includes detailed analysis of energy storage and dissipation components. By calculating these components during hybridization events the device is able to demonstrate specific and dose response sensing characteristics. The developed microfluidic LOC for DNA hybridization detection offers a technology for real-time and label-free assessment of genetic markers outside of laboratory settings, such as at the point-of-care or in-field environmental monitoring.

Beyond the usual suspects: target group- and behavior-specific factors add to a theory-based sun protection intervention for teenagers.

PubMed

Schüz, Natalie; Eid, Michael

2013-10-01

Sun protection standards among teenagers are low while sun exposure peaks in this age group. Study 1 explores predictors of adolescent protection intentions and exposure behavior. Study 2 tests the effectiveness of an intervention based on these predictors. Study 1(cross-sectional, N = 207, ages 15-18) and Study 2 (RCT, N = 253, ages 13-19) were conducted in schools. Path models were used to analyze data. Self-efficacy (β = .26, p < .001) and time perspective (β = .17, p = .014) were the strongest predictors of intentions; appearance motivation (β = .54, p < .001) and intention (β = -.18, p = .015) predicted behavior. The intervention effected changes in all predictors except self-efficacy. Changes in outcome expectancies (β = .19, p < .001) and time perspective (β = .09, p = .039) predicted changes in intention, while changes in intention (β = -.17, p = .002) and appearance motivation (β = .29, p < .001) predicted behavior changes. Target group- and behavior-specific intervention components are as important for changes in intentions and behavior as components derived from common health behavior theories.

The chemical energy unit partial oxidation reactor operation simulation modeling

NASA Astrophysics Data System (ADS)

Mrakin, A. N.; Selivanov, A. A.; Batrakov, P. A.; Sotnikov, D. G.

2018-01-01

The chemical energy unit scheme for synthesis gas, electric and heat energy production which is possible to be used both for the chemical industry on-site facilities and under field conditions is represented in the paper. The partial oxidation reactor gasification process mathematical model is described and reaction products composition and temperature determining algorithm flow diagram is shown. The developed software product verification showed good convergence of the experimental values and calculations according to the other programmes: the temperature determining relative discrepancy amounted from 4 to 5 %, while the absolute composition discrepancy ranged from 1 to 3%. The synthesis gas composition was found out practically not to depend on the supplied into the partial oxidation reactor (POR) water vapour enthalpy and compressor air pressure increase ratio. Moreover, air consumption coefficient α increase from 0.7 to 0.9 was found out to decrease synthesis gas target components (carbon and hydrogen oxides) specific yield by nearly 2 times and synthesis gas target components required ratio was revealed to be seen in the water vapour specific consumption area (from 5 to 6 kg/kg of fuel).

Natural healing-inspired collagen-targeting surgical protein glue for accelerated scarless skin regeneration.

PubMed

Jeon, Eun Young; Choi, Bong-Hyuk; Jung, Dooyup; Hwang, Byeong Hee; Cha, Hyung Joon

2017-07-01

Skin scarring after deep dermal injuries is a major clinical problem due to the current therapies limited to established scars with poor understanding of healing mechanisms. From investigation of aberrations within the extracellular matrix involved in pathophysiologic scarring, it was revealed that one of the main factors responsible for impaired healing is abnormal collagen reorganization. Here, inspired by the fundamental roles of decorin, a collagen-targeting proteoglycan, in collagen remodeling, we created a scar-preventive collagen-targeting glue consisting of a newly designed collagen-binding mussel adhesive protein and a specific glycosaminoglycan. The collagen-targeting glue specifically bound to type I collagen in a dose-dependent manner and regulated the rate and the degree of fibrillogenesis. In a rat skin excisional model, the collagen-targeting glue successfully accelerated initial wound regeneration as defined by effective reepithelialization, neovascularization, and rapid collagen synthesis. Moreover, the improved dermal collagen architecture was demonstrated by uniform size of collagen fibrils, their regular packing, and a restoration of healthy tissue component. Collectively, our natural healing-inspired collagen-targeting glue may be a promising therapeutic option for improving the healing rate with high-quality and effective scar inhibition. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pseudomonas HopU1 modulates plant immune receptor levels by blocking the interaction of their mRNAs with GRP7.

PubMed

Nicaise, Valerie; Joe, Anna; Jeong, Byeong-ryool; Korneli, Christin; Boutrot, Freddy; Westedt, Isa; Staiger, Dorothee; Alfano, James R; Zipfel, Cyril

2013-03-06

Pathogens target important components of host immunity to cause disease. The Pseudomonas syringae type III-secreted effector HopU1 is a mono-ADP-ribosyltransferase required for full virulence on Arabidopsis thaliana. HopU1 targets several RNA-binding proteins including GRP7, whose role in immunity is still unclear. Here, we show that GRP7 associates with translational components, as well as with the pattern recognition receptors FLS2 and EFR. Moreover, GRP7 binds specifically FLS2 and EFR transcripts in vivo through its RNA recognition motif. HopU1 does not affect the protein-protein associations between GRP7, FLS2 and translational components. Instead, HopU1 blocks the interaction between GRP7 and FLS2 and EFR transcripts in vivo. This inhibition correlates with reduced FLS2 protein levels upon Pseudomonas infection in a HopU1-dependent manner. Our results reveal a novel virulence strategy used by a microbial effector to interfere with host immunity.

Assessment of CAPRI predictions in rounds 3-5 shows progress in docking procedures.

PubMed

Méndez, Raúl; Leplae, Raphaël; Lensink, Marc F; Wodak, Shoshana J

2005-08-01

The current status of docking procedures for predicting protein-protein interactions starting from their three-dimensional (3D) structure is reassessed by evaluating blind predictions, performed during 2003-2004 as part of Rounds 3-5 of the community-wide experiment on Critical Assessment of PRedicted Interactions (CAPRI). Ten newly determined structures of protein-protein complexes were used as targets for these rounds. They comprised 2 enzyme-inhibitor complexes, 2 antigen-antibody complexes, 2 complexes involved in cellular signaling, 2 homo-oligomers, and a complex between 2 components of the bacterial cellulosome. For most targets, the predictors were given the experimental structures of 1 unbound and 1 bound component, with the latter in a random orientation. For some, the structure of the free component was derived from that of a related protein, requiring the use of homology modeling. In some of the targets, significant differences in conformation were displayed between the bound and unbound components, representing a major challenge for the docking procedures. For 1 target, predictions could not go to completion. In total, 1866 predictions submitted by 30 groups were evaluated. Over one-third of these groups applied completely novel docking algorithms and scoring functions, with several of them specifically addressing the challenge of dealing with side-chain and backbone flexibility. The quality of the predicted interactions was evaluated by comparison to the experimental structures of the targets, made available for the evaluation, using the well-agreed-upon criteria used previously. Twenty-four groups, which for the first time included an automatic Web server, produced predictions ranking from acceptable to highly accurate for all targets, including those where the structures of the bound and unbound forms differed substantially. These results and a brief survey of the methods used by participants of CAPRI Rounds 3-5 suggest that genuine progress in the performance of docking methods is being achieved, with CAPRI acting as the catalyst.

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

DOE PAGES

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

2018-03-08

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

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

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

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

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

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, may possess properties (i)–(iii) desired for clinical applications. PMID:26161541

Sociability and synapse subtype-specific defects in mice lacking SRPX2, a language-associated gene

PubMed Central

Cong, Qifei; Palmer, Christian R.

2018-01-01

The FoxP2 transcription factor and its target genes have been implicated in developmental brain diseases with a prominent language component, such as developmental verbal dyspraxia and specific language impairment. How FoxP2 affects neural circuitry development remains poorly understood. The sushi domain protein SRPX2 is a target of FoxP2, and mutations in SRPX2 are associated with language defects in humans. We have previously shown that SRPX2 is a synaptogenic protein that increases excitatory synapse density. Here we provide the first characterization of mice lacking the SRPX2 gene, and show that these mice exhibit defects in both neural circuitry and communication and social behaviors. Specifically, we show that mice lacking SRPX2 show a specific reduction in excitatory VGlut2 synapses in the cerebral cortex, while VGlut1 and inhibitory synapses were largely unaffected. SRPX2 KO mice also exhibit an abnormal ultrasonic vocalization ontogenetic profile in neonatal pups, and reduced preference for social novelty. These data demonstrate a functional role for SRPX2 during brain development, and further implicate FoxP2 and its targets in regulating the development of vocalization and social circuits. PMID:29920554

Surface engineered magnetic nanoparticles for specific immunotargeting of cadherin expressing cells

NASA Astrophysics Data System (ADS)

Moros, Maria; Delhaes, Flavien; Puertas, Sara; Saez, Berta; de la Fuente, Jesús M.; Grazú, Valeria; Feracci, Helene

2016-02-01

In spite of historic advances in cancer biology and recent development of sophisticated chemotherapeutics, the outlook for patients with advanced cancer is still grim. In this sense nanoparticles (NPs), through their unique physical properties, enable the development of new approaches for cancer diagnosis and treatment. Thus far the most used active targeting scheme involves NPs functionalization with antibodies specific to molecules overexpressed on cancer cell’s surface. Therefore, such active targeting relies on differences in NPs uptake kinetics rates between tumor and healthy cells. Many cancers of epithelial origin are associated with the inappropriate expression of non-epithelial cadherins (e.g. N-, P-, -11) with concomitant loss of E-cadherin. Such phenomenon named cadherin switching favors tumor development and metastasis via interactions of tumor cells with stromal components. That is why we optimized the oriented functionalization of fluorescently labelled magnetic NPs with a novel antibody specific for the extracellular domain of cadherin-11. The obtained Ab-NPs exhibited high specificity when incubated with two cell lines used as models of tumor and healthy cells. Thus, cadherin switching offers a great opportunity for the development of active targeting strategies aimed to improve the early detection and treatment of cancer.

Therapeutic targeting of regulatory T cells enhances tumor-specific CD8+ T cell responses in Epstein–Barr virus associated nasopharyngeal carcinoma

PubMed Central

Fogg, Mark; Murphy, John R.; Lorch, Jochen; Posner, Marshall; Wang, Fred

2013-01-01

Epstein–Barr virus (EBV) is associated with multiple malignancies including nasopharyngeal carcinoma (NPC). In nasopharynx cancer, CD8+ T cells specific for EBV Nuclear Antigen-1 (EBNA-1) and Latent Membrane Protein 2 (LMP2) are important components of anti-tumor immunity since both are consistently expressed in NPC. We have previously shown that EBNA-1-specific CD8+ T cell responses were suppressed in NPC patients compared to healthy controls. We now find that CD8+ T cell responses specific for LMP2 are also abnormal in NPC patients, and both EBNA-1- and LMP2-specific responses are suppressed by regulatory T cells (Treg). EBNA-1 and LMP2-specific CD8+ T cell responses, as well as immune control of EBV-infected cells in vitro, could be restored by the depletion of Tregs and by use of a clinically approved drug targeting Tregs. Thus, in vivo modulation of Tregs may be an effective means of enhancing these anti-tumor immune responses in NPC patients. PMID:23601786

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

Catterall, Simon

This final report summarizes the work carried out by the Syracuse component of a multi-institutional SciDAC grant led by USQCD. This grant supported software development for theoretical high energy physics. The Syracuse component specifically targeted the development of code for the numerical simulation of N=4 super Yang-Mills theory. The work described in the final report includes this and a summary of results achieve in exploring the structure of this theory. It also describes the personnel - students and a postdoc who were directly or indirectly involved in this project. A list of publication is also described.

Thermal Management and Reliability of Automotive Power Electronics and Electric Machines

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

Narumanchi, Sreekant V; Bennion, Kevin S; Cousineau, Justine E

Low-cost, high-performance thermal management technologies are helping meet aggressive power density, specific power, cost, and reliability targets for power electronics and electric machines. The National Renewable Energy Laboratory is working closely with numerous industry and research partners to help influence development of components that meet aggressive performance and cost targets through development and characterization of cooling technologies, and thermal characterization and improvements of passive stack materials and interfaces. Thermomechanical reliability and lifetime estimation models are important enablers for industry in cost-and time-effective design.

A mathematical analysis of multiple-target SELEX.

PubMed

Seo, Yeon-Jung; Chen, Shiliang; Nilsen-Hamilton, Marit; Levine, Howard A

2010-10-01

SELEX (Systematic Evolution of Ligands by Exponential Enrichment) is a procedure by which a mixture of nucleic acids can be fractionated with the goal of identifying those with specific biochemical activities. One combines the mixture with a specific target molecule and then separates the target-NA complex from the resulting reactions. The target-NA complex is separated from the unbound NA by mechanical means (such as by filtration), the NA is eluted from the complex, amplified by PCR (polymerase chain reaction), and the process repeated. After several rounds, one should be left with the nucleic acids that best bind to the target. The problem was first formulated mathematically in Irvine et al. (J. Mol. Biol. 222:739-761, 1991). In Levine and Nilsen-Hamilton (Comput. Biol. Chem. 31:11-25, 2007), a mathematical analysis of the process was given. In Vant-Hull et al. (J. Mol. Biol. 278:579-597, 1998), multiple target SELEX was considered. It was assumed that each target has a single nucleic acid binding site that permits occupation by no more than one nucleic acid. Here, we revisit Vant-Hull et al. (J. Mol. Biol. 278:579-597, 1998) using the same assumptions. The iteration scheme is shown to be convergent and a simplified algorithm is given. Our interest here is in the behavior of the multiple target SELEX process as a discrete "time" dynamical system. Our goal is to characterize the limiting states and their dependence on the initial distribution of nucleic acid and target fraction components. (In multiple target SELEX, we vary the target component fractions, but not their concentrations, as fixed and the initial pool of nucleic acids as a variable starting condition). Given N nucleic acids and a target consisting of M subtarget component species, there is an M × N matrix of affinities, the (i,j) entry corresponding to the affinity of the jth nucleic acid for the ith subtarget. We give a structure condition on this matrix that is equivalent to the following statement: For any initial pool of nucleic acids such that all N species are represented, the dynamical system defined by the multiple target SELEX process will converge to a unique subset of nucleic acids, each of whose concentrations depend only upon the total nucleic acid concentration, the initial fractional target distribution (both of which are assumed to be the same from round to round), and the overall limiting association constant. (The overall association constant is the equilibrium constant for the system of MN reactions when viewed as a composite single reaction). This condition is equivalent to the statement that every member of a certain family of chemical potentials at infinite target dilution can have at most one critical point. (The condition replaces the statement for single target SELEX that the dynamical system generated via the process always converges to a pool that contains only the nucleic acid that binds best to the target). This suggests that the effectiveness of multiple target SELEX as a separation procedure may not be as useful as single target SELEX unless the thermodynamic properties of these chemical potentials are well understood.

Maintaining Sufficient Nanos Is a Critical Function for Polar Granule Component in the Specification of Primordial Germ Cells

PubMed Central

Deshpande, Girish; Spady, Emma; Goodhouse, Joe; Schedl, Paul

2012-01-01

Primordial germ cells (PGC) are the precursors of germline stem cells. In Drosophila, PGC specification is thought to require transcriptional quiescence and three genes, polar granule component (pgc), nanos (nos), and germ cell less (gcl) function to downregulate Pol II transcription. While it is not understood how nos or gcl represses transcription, pgc does so by inhibiting the transcription elongation factor b (P-TEFb), which is responsible for phosphorylating Ser2 residues in the heptad repeat of the C-terminal domain (CTD) of the largest Pol II subunit. In the studies reported here, we demonstrate that nos are a critical regulatory target of pgc. We show that a substantial fraction of the PGCs in pgc embryos have greatly reduced levels of Nos protein and exhibit phenotypes characteristic of nos PGCs. Lastly, restoring germ cell–specific expression of Nos is sufficient to ameliorate the pgc phenotype. PMID:23173091

Maintaining sufficient nanos is a critical function for polar granule component in the specification of primordial germ cells.

PubMed

Deshpande, Girish; Spady, Emma; Goodhouse, Joe; Schedl, Paul

2012-11-01

Primordial germ cells (PGC) are the precursors of germline stem cells. In Drosophila, PGC specification is thought to require transcriptional quiescence and three genes, polar granule component (pgc), nanos (nos), and germ cell less (gcl) function to downregulate Pol II transcription. While it is not understood how nos or gcl represses transcription, pgc does so by inhibiting the transcription elongation factor b (P-TEFb), which is responsible for phosphorylating Ser2 residues in the heptad repeat of the C-terminal domain (CTD) of the largest Pol II subunit. In the studies reported here, we demonstrate that nos are a critical regulatory target of pgc. We show that a substantial fraction of the PGCs in pgc embryos have greatly reduced levels of Nos protein and exhibit phenotypes characteristic of nos PGCs. Lastly, restoring germ cell-specific expression of Nos is sufficient to ameliorate the pgc phenotype.

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

NASA Technical Reports Server (NTRS)

Hidalgo, Homero, Jr.

2000-01-01

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

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

PubMed

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

2011-01-01

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

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

PubMed Central

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

2012-01-01

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

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

PubMed

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

2016-02-01

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

Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer.

PubMed

Murga, Jose D; Moorji, Sameer M; Han, Amy Q; Magargal, Wells W; DiPippo, Vincent A; Olson, William C

2015-02-15

Antibody-drug conjugates (ADCs) are an emerging class of cancer therapies that have demonstrated favorable activity both as single agents and as components of combination regimens. Phase 2 testing of an ADC targeting prostate-specific membrane antigen (PSMA) in advanced prostate cancer has shown antitumor activity. The present study examined PSMA ADC used in combination with potent antiandrogens (enzalutamide and abiraterone) and other compounds. Antiproliferative activity and expression of PSMA, prostate-specific antigen and androgen receptor were evaluated in the prostate cancer cell lines LNCaP and C4-2. Cells were tested for susceptibility to antiandrogens or other inhibitors, used alone and in combination with PSMA ADC. Potential drug synergy or antagonism was evaluated using the Bliss independence method. Enzalutamide and abiraterone demonstrated robust, statistically significant synergy when combined with PSMA ADC. Largely additive activity was observed between the antiandrogens and the individual components of the ADC (free drug and unmodified antibody). Rapamycin also synergized with PSMA ADC in certain settings. Synergy was linked in part to upregulation of PSMA expression. In androgen-dependent LNCaP cells, enzalutamide and abiraterone each inhibited proliferation, upregulated PSMA expression, and synergized with PSMA ADC. In androgen-independent C4-2 cells, enzalutamide and abiraterone showed no measurable antiproliferative activity on their own but increased PSMA expression and synergized with PSMA ADC nonetheless. PSMA expression increased progressively over 3 weeks with enzalutamide and returned to baseline levels 1 week after enzalutamide removal. The findings support exploration of clinical treatment regimens that combine potent antiandrogens and PSMA-targeted therapies for prostate cancer. © 2014 Wiley Periodicals, Inc.

Plant-bacterial pathogen interactions mediated by type III effectors.

PubMed

Feng, Feng; Zhou, Jian-Min

2012-08-01

Effectors secreted by the bacterial type III system play a central role in the interaction between Gram-negative bacterial pathogens and their host plants. Recent advances in the effector studies have helped cementing several key concepts concerning bacterial pathogenesis, plant immunity, and plant-pathogen co-evolution. Type III effectors use a variety of biochemical mechanisms to target specific host proteins or DNA for pathogenesis. The identifications of their host targets led to the identification of novel components of plant innate immune system. Key modules of plant immune signaling pathways such as immune receptor complexes and MAPK cascades have emerged as a major battle ground for host-pathogen adaptation. These modules are attacked by multiple type III effectors, and some components of these modules have evolved to actively sense the effectors and trigger immunity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Targeted therapies in cancer - challenges and chances offered by newly developed techniques for protein analysis in clinical tissues

PubMed Central

Malinowsky, K; Wolff, C; Gündisch, S; Berg, D; Becker, KF

2011-01-01

In recent years, new anticancer therapies have accompanied the classical approaches of surgery and radio- and chemotherapy. These new forms of treatment aim to inhibit specific molecular targets namely altered or deregulated proteins, which offer the possibility of individualized therapies. The specificity and efficiency of these new approaches, however, bring about a number of challenges. First of all, it is essential to specifically identify and quantify protein targets in tumor tissues for the reasonable use of such targeted therapies. Additionally, it has become even more obvious in recent years that the presence of a target protein is not always sufficient to predict the outcome of targeted therapies. The deregulation of downstream signaling molecules might also play an important role in the success of such therapeutic approaches. For these reasons, the analysis of tumor-specific protein expression profiles prior to therapy has been suggested as the most effective way to predict possible therapeutic results. To further elucidate signaling networks underlying cancer development and to identify new targets, it is necessary to implement tools that allow the rapid, precise, inexpensive and simultaneous analysis of many network components while requiring only a small amount of clinical material. Reverse phase protein microarray (RPPA) is a promising technology that meets these requirements while enabling the quantitative measurement of proteins. Together with recently developed protocols for the extraction of proteins from formalin-fixed, paraffin-embedded (FFPE) tissues, RPPA may provide the means to quantify therapeutic targets and diagnostic markers in the near future and reliably screen for new protein targets. With the possibility to quantitatively analyze DNA, RNA and protein from a single FFPE tissue sample, the methods are available for integrated patient profiling at all levels of gene expression, thus allowing optimal patient stratification for individualized therapies. PMID:21197262

Soybean extracts increase cell surface ZIP4 abundance and cellular zinc levels: a potential novel strategy to enhance zinc absorption by ZIP4 targeting.

PubMed

Hashimoto, Ayako; Ohkura, Katsuma; Takahashi, Masakazu; Kizu, Kumiko; Narita, Hiroshi; Enomoto, Shuichi; Miyamae, Yusaku; Masuda, Seiji; Nagao, Masaya; Irie, Kazuhiro; Ohigashi, Hajime; Andrews, Glen K; Kambe, Taiho

2015-12-01

Dietary zinc deficiency puts human health at risk, so we explored strategies for enhancing zinc absorption. In the small intestine, the zinc transporter ZIP4 functions as an essential component of zinc absorption. Overexpression of ZIP4 protein increases zinc uptake and thereby cellular zinc levels, suggesting that food components with the ability to increase ZIP4 could potentially enhance zinc absorption via the intestine. In the present study, we used mouse Hepa cells, which regulate mouse Zip4 (mZip4) in a manner indistinguishable from that in intestinal enterocytes, to screen for suitable food components that can increase the abundance of ZIP4. Using this ZIP4-targeting strategy, two such soybean extracts were identified that were specifically able to decrease mZip4 endocytosis in response to zinc. These soybean extracts also effectively increased the abundance of apically localized mZip4 in transfected polarized Caco2 and Madin-Darby canine kidney cells and, moreover, two apically localized mZip4 acrodermatitis enteropathica mutants. Soybean components were purified from one extract and soyasaponin Bb was identified as an active component that increased both mZip4 protein abundance and zinc levels in Hepa cells. Finally, we confirmed that soyasaponin Bb is capable of enhancing cell surface endogenous human ZIP4 in human cells. Our results suggest that ZIP4 targeting may represent a new strategy to improve zinc absorption in humans. © 2015 Authors; published by Portland Press Limited.

Mapping multiple components of malaria risk for improved targeting of elimination interventions.

PubMed

Cohen, Justin M; Le Menach, Arnaud; Pothin, Emilie; Eisele, Thomas P; Gething, Peter W; Eckhoff, Philip A; Moonen, Bruno; Schapira, Allan; Smith, David L

2017-11-13

There is a long history of considering the constituent components of malaria risk and the malaria transmission cycle via the use of mathematical models, yet strategic planning in endemic countries tends not to take full advantage of available disease intelligence to tailor interventions. National malaria programmes typically make operational decisions about where to implement vector control and surveillance activities based upon simple categorizations of annual parasite incidence. With technological advances, an enormous opportunity exists to better target specific malaria interventions to the places where they will have greatest impact by mapping and evaluating metrics related to a variety of risk components, each of which describes a different facet of the transmission cycle. Here, these components and their implications for operational decision-making are reviewed. For each component, related mappable malaria metrics are also described which may be measured and evaluated by malaria programmes seeking to better understand the determinants of malaria risk. Implementing tailored programmes based on knowledge of the heterogeneous distribution of the drivers of malaria transmission rather than only consideration of traditional metrics such as case incidence has the potential to result in substantial improvements in decision-making. As programmes improve their ability to prioritize their available tools to the places where evidence suggests they will be most effective, elimination aspirations may become increasingly feasible.

Electrophysiological correlates of cross-linguistic semantic integration in hearing signers: N400 and LPC.

PubMed

Zachau, Swantje; Korpilahti, Pirjo; Hämäläinen, Jarmo A; Ervast, Leena; Heinänen, Kaisu; Suominen, Kalervo; Lehtihalmes, Matti; Leppänen, Paavo H T

2014-07-01

We explored semantic integration mechanisms in native and non-native hearing users of sign language and non-signing controls. Event-related brain potentials (ERPs) were recorded while participants performed a semantic decision task for priming lexeme pairs. Pairs were presented either within speech or across speech and sign language. Target-related ERP responses were subjected to principal component analyses (PCA), and neurocognitive basis of semantic integration processes were assessed by analyzing the N400 and the late positive complex (LPC) components in response to spoken (auditory) and signed (visual) antonymic and unrelated targets. Semantically-related effects triggered across modalities would indicate a similar tight interconnection between the signers׳ two languages like that described for spoken language bilinguals. Remarkable structural similarity of the N400 and LPC components with varying group differences between the spoken and signed targets were found. The LPC was the dominant response. The controls׳ LPC differed from the LPC of the two signing groups. It was reduced to the auditory unrelated targets and was less frontal for all the visual targets. The visual LPC was more broadly distributed in native than non-native signers and was left-lateralized for the unrelated targets in the native hearing signers only. Semantic priming effects were found for the auditory N400 in all groups, but only native hearing signers revealed a clear N400 effect to the visual targets. Surprisingly, the non-native signers revealed no semantically-related processing effect to the visual targets reflected in the N400 or the LPC; instead they appeared to rely more on visual post-lexical analyzing stages than native signers. We conclude that native and non-native signers employed different processing strategies to integrate signed and spoken semantic content. It appeared that the signers׳ semantic processing system was affected by group-specific factors like language background and/or usage. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nutrition risk screening: the interrelationship of food insecurity, food intake, and unintentional weight change among homebound elders.

PubMed

Sharkey, Joseph R

2004-01-01

Nutrition risk screening is a key component of the homedelivered meals program. To examine direct and indirect relationships among individual components of nutrition risk, path analysis was conducted on routinely collected data from 908 homebound elders who received home-delivered meals. The good fit of the model revealed that specific nutrition risk factors and indicators of nutritional risk were directly and indirectly associated with meal frequency and unintended weight change. With the heightened vulnerability for poor nutritional health among homebound elders who report food insecurity, policymakers and service providers should strengthen efforts to target individual components of nutrition risk rather than aggregate scores or categorical measures.

Differential gene expression patterns in developing sexually dimorphic rat brain regions exposed to antiandrogenic, estrogenic, or complex endocrine disruptor mixtures: glutamatergic synapses as target.

PubMed

Lichtensteiger, Walter; Bassetti-Gaille, Catherine; Faass, Oliver; Axelstad, Marta; Boberg, Julie; Christiansen, Sofie; Rehrauer, Hubert; Georgijevic, Jelena Kühn; Hass, Ulla; Kortenkamp, Andreas; Schlumpf, Margret

2015-04-01

The study addressed the question whether gene expression patterns induced by different mixtures of endocrine disrupting chemicals (EDCs) administered in a higher dose range, corresponding to 450×, 200×, and 100× high-end human exposure levels, could be characterized in developing brain with respect to endocrine activity of mixture components, and which developmental processes were preferentially targeted. Three EDC mixtures, A-Mix (anti-androgenic mixture) with 8 antiandrogenic chemicals (di-n-butylphthalate, diethylhexylphthalate, vinclozolin, prochloraz, procymidone, linuron, epoxiconazole, and DDE), E-Mix (estrogenic mixture) with 4 estrogenic chemicals (bisphenol A, 4-methylbenzylidene camphor, 2-ethylhexyl 4-methoxycinnamate, and butylparaben), a complex mixture, AEP-Mix, containing the components of A-Mix and E-Mix plus paracetamol, and paracetamol alone, were administered by oral gavage to rat dams from gestation day 7 until weaning. General developmental endpoints were not affected by EDC mixtures or paracetamol. Gene expression was analyzed on postnatal day 6, during sexual brain differentiation, by exon microarray in medial preoptic area in the high-dose group, and by real-time RT-PCR in medial preoptic area and ventromedial hypothalamus in all dose groups. Expression patterns were mixture, sex, and region specific. Effects of the analgesic drug paracetamol, which exhibits antiandrogenic activity in peripheral systems, differed from those of A-Mix. All mixtures had a strong, mixture-specific impact on genes encoding for components of excitatory glutamatergic synapses and genes controlling migration and pathfinding of glutamatergic and GABAergic neurons, as well as genes linked with increased risk of autism spectrum disorders. Because development of glutamatergic synapses is regulated by sex steroids also in hippocampus, this may represent a general target of ECD mixtures.

Crosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology.

PubMed

Zhan, Han-Xiang; Zhou, Bin; Cheng, Yu-Gang; Xu, Jian-Wei; Wang, Lei; Zhang, Guang-Yong; Hu, San-Yuan

2017-04-28

Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide. Increasing evidence has confirmed the pivotal role of stromal components in the regulation of carcinogenesis, invasion, metastasis, and therapeutic resistance in PC. Interaction between neoplastic cells and stromal cells builds a specific microenvironment, which further modulates the malignant properties of cancer cells. Instead of being a "passive bystander", stroma may play a role as a "partner in crime" in PC. However, the role of stromal components in PC is complex and requires further investigation. In this article, we review recent advances regarding the regulatory roles and mechanisms of stroma biology, especially the cellular components such as pancreatic stellate cells, macrophages, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and lymphocytes, in PC. Crosstalk between stromal cells and cancer cells is thoroughly investigated. We also review the prognostic value and molecular therapeutic targets of stroma in PC. This review may help us further understand the molecular mechanisms of stromal biology and its role in PC development and therapeutic resistance. Moreover, targeting stroma components may provide new therapeutic strategies for this stubborn disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Alterations to multisensory and unisensory integration by stimulus competition

PubMed Central

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

2011-01-01

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

Alterations to multisensory and unisensory integration by stimulus competition.

PubMed

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

2011-12-01

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

A component-centered meta-analysis of family-based prevention programs for adolescent substance use.

PubMed

Van Ryzin, Mark J; Roseth, Cary J; Fosco, Gregory M; Lee, You-Kyung; Chen, I-Chien

2016-04-01

Although research has documented the positive effects of family-based prevention programs, the field lacks specific information regarding why these programs are effective. The current study summarized the effects of family-based programs on adolescent substance use using a component-based approach to meta-analysis in which we decomposed programs into a set of key topics or components that were specifically addressed by program curricula (e.g., parental monitoring/behavior management,problem solving, positive family relations, etc.). Components were coded according to the amount of time spent on program services that targeted youth, parents, and the whole family; we also coded effect sizes across studies for each substance-related outcome. Given the nested nature of the data, we used hierarchical linear modeling to link program components (Level 2) with effect sizes (Level 1). The overall effect size across programs was .31, which did not differ by type of substance. Youth-focused components designed to encourage more positive family relationships and a positive orientation toward the future emerged as key factors predicting larger than average effect sizes. Our results suggest that, within the universe of family-based prevention, where components such as parental monitoring/behavior management are almost universal, adding or expanding certain youth-focused components may be able to enhance program efficacy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Nutrigenomics and Cancer

PubMed Central

Ardekani, Ali M.; Jabbari, Sepideh

2009-01-01

Cancer incidence is projected to increase in the future and an effectual preventive strategy is required to face this challenge. Alteration of dietary habits is potentially an effective approach for reducing cancer risk. Assessment of biological effects of a specific food or bioactive component that is linked to cancer and prediction of individual susceptibility as a function of nutrient-nutrient interactions and genetics is an essential element to evaluate the beneficiaries of dietary interventions. In general, the use of biomarkers to evaluate individuals susceptibilities to cancer must be easily accessible and reliable. However, the response of individuals to bioactive food components depends not only on the effective concentration of the bioactive food components, but also on the target tissues. This fact makes the response of individuals to food components vary from one individual to another. Nutrigenomics focuses on the understanding of interactions between genes and diet in an individual and how the response to bioactive food components is influenced by an individual's genes. Nutrients have shown to affect gene expression and to induce changes in DNA and protein molecules. Nutrigenomic approaches provide an opportunity to study how gene expression is regulated by nutrients and how nutrition affects gene variations and epigenetic events. Finding the components involved in interactions between genes and diet in an individual can potentially help identify target molecules important in preventing and/or reducing the symptoms of cancer. PMID:23407612

NF-κB as a target for oncogenic viruses

PubMed Central

Sun, Shao-Cong; Cesarman, Ethel

2013-01-01

NF-κB is a pivotal transcription factor that controls cell survival and proliferation in diverse physiological processes. The activity of NF-κB is tightly controlled through its cytoplasmic sequestration by specific inhibitors, IκBs. Various cellular stimuli induce the activation of an IκB kinase (IKK), which phosphorylates IκBs and triggers their proteasomal degradation, causing nuclear translocation of activated NF-κB. Under normal conditions, the activation of NF-κB occurs transiently, thus ensuring rapid but temporary induction of target genes. Deregulated NF-κB activation contributes to the development of various diseases, including cancers and immunological disorders. Accumulated studies demonstrate that the NF-κB signaling pathway is a target of several human oncogenic viruses, including the human T-cell leukemia virus type 1 (HTLV1), the Kaposi sarcoma-associated herpesvirus (KSHV), and the Epstein bar virus (EBV). These viruses encode specific oncoproteins that target different signaling components of the NF-κB pathway, leading to persistent activation of NF-κB. This chapter will discuss the molecular mechanisms by which NF-κB is activated by the viral oncoproteins. PMID:20845110

Identification and preclinical testing of novel antiepileptic compounds.

PubMed

Meldrum, B S

1997-01-01

Procedures for identifying novel antiepileptic drugs (AEDs) are changing and need to change more. Widespread reliance on two primary screens has led to the identification of novel compounds that resemble either phenytoin (suppressing high-frequency repetitive firing in cultured neurons and prolonging inactivation of voltage-dependent sodium channels identified by the maximal electroshock test) or benzodiazepines (potentiating the inhibitory effect of gamma-aminobutyric acid (GABA), identified by the threshold pentylenetetrazol test). Advances in molecular neurobiology have identified specific molecular targets (subunits of ion channels, neurotransmitter receptors, and transporters) and have made them available in a form permitting high-throughput screening. AEDs can be designed to interact with specific sites on the target molecules. Alternatively, the molecular screens can be used to identify active components in natural products, including folk remedies. Preclinical in vivo screens can be improved by using animals with genetic or acquired epilepsies that have similar modifications in the properties of the target molecules as do human epilepsy syndromes. Future work is likely to define molecular targets for AEDs that will block or reverse chronic epileptogenesis.

Development of an aptamer-ampicillin conjugate for treating biofilms

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

Lijuan, Cheng; Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, 410208; Xing, Yan

Biofilm formation involves the development of extracellular matrix and initially depends on adherence and tropism by flagellar movement. With the widespread development of antibiotic resistance and tolerance of biofilms, there is a growing need for novel anti-infective strategies. No currently approved medications specifically target biofilms. Aptamers are single-stranded nucleic acid molecules that may bind to their targets with high affinity and affect the target functions. We developed a bifunctional conjugate by linking an aptamer targeting bacterial flagella with ampicillin. We investigated its influence on biofilm prevention and dissolution by ultraviolet–visible spectrophotometry, inverted microscopy, and atomic force microscopy. This conjugate hadmore » distinctive antibacterial activity. Notably, the conjugate was more active than either component, and thus had a synergistic effect against biofilms.« less

Combining a synthetic spermicide with a natural trichomonacide for safe, prophylactic contraception.

PubMed

Jain, Ashish; Kumar, Lokesh; Kushwaha, Bhavana; Sharma, Monika; Pandey, Aastha; Verma, Vikas; Sharma, Vikas; Singh, Vishal; Rawat, Tara; Sharma, Vishnu L; Maikhuri, Jagdamba P; Gupta, Gopal

2014-02-01

Can a specifically acting synthetic spermicide (DSE-37) be combined with a natural microbicide (saponins) for safe, prophylactic contraception? A 1:1 (w/w) combination of DSE-37 and Sapindus saponins can target sperm and Trichomonas vaginalis precisely without any noticeable off-target effects on somatic cells at effective concentrations. Broad-spectrum vaginal agents like nonoxynol-9 (N-9) and cellulose sulfate have failed clinically as microbicides due to non-specific off-target effects, whereas agents that specifically target retroviruses have shown promise in clinical trials. DSE-37 and Sapindus saponins, respectively, specifically target human sperm and T. vaginalis in vitro. A comprehensive study of efficacy and safety was undertaken using in vitro (human cells) and in vivo (rabbit) models. The 1:1 combination of DSE-37 and Sapindus saponins was based on the in vitro spermicidal and anti-Trichomonal activities of the two components. N-9, the spermicide in clinical use, served as reference control. Free sperm thiols were fluorescently glinted to reveal differences in the targets of the test agents. On/off-target effects were evaluated in vitro against human sperm, T. vaginalis, HeLa, Vk2/E6E7, End1/E6E7 and Lactobacillus jensenii, using standard assays of drug susceptibility, cell viability, flow cytometric assessment of cell apoptosis and qPCR for expression of pro-inflammatory cytokine mRNAs. The spermicidal effect was also recorded live and free thiols on sperm were fluorescently visualized using a commercial kit. In vivo contraceptive efficacy (pregnancy/fertility rates) and safety (vaginal histopathology and in situ immune-labeling of inflammation markers VCAM-1, E-selectin and NFkB) were evaluated in rabbits. A 0.003% drug 'combination' containing 0.0015% each of DSE-37 and Sapindus saponins in physiological saline irreversibly immobilized 100% human sperm in ∼30 s and eliminated 100% T. vaginalis in 24 h, without causing any detectable toxicity to human cervical (HeLa) cells and Lactobacilli in 24-48 h, in vitro. N-9 at 0.003% exhibited lower microbicidal activity against Trichomonas but failed in spermicidal assays while causing severe toxicity to HeLa cells and Lactobacilli in 12-24 h. The 'combination' of DSE-37 and Sapindus saponins completely prevented pregnancy in rabbits at a vaginal dose of 20 mg (1% in K-Y Jelly), while application of 5% 'combination' in K-Y Jelly for 4 consecutive days caused negligible alterations in epithelial lining of rabbit vagina with only minor changes in levels of inflammation markers. N-9 at a 20 mg vaginal dose prevented pregnancy in 33% animals and a 4-day repeat application of 2% N-9 gel caused severe local toxicity to vaginal epithelium with molecular expression of acute inflammation markers. The number of animals used for the in vivo efficacy study was limited by the approval of the animal ethics committee. Anti-Trichomonal contraceptives with specifically acting synthetic component and clinically-proven safe natural component may define a new concept in empowering women to control their fertility and reproductive health. The study was funded by CSIR-Network Project 'PROGRAM' (BSC0101) and partly by the Ministry of Health and Family Welfare, Government of India (GAP0001). The funding agencies did not play any role in this study and none of the authors had any competing interest(s).

Dosage compensation proteins targeted to X chromosomes by a determinant of hermaphrodite fate.

PubMed

Dawes, H E; Berlin, D S; Lapidus, D M; Nusbaum, C; Davis, T L; Meyer, B J

1999-06-11

In many organisms, master control genes coordinately regulate sex-specific aspects of development. SDC-2 was shown to induce hermaphrodite sexual differentiation and activate X chromosome dosage compensation in Caenorhabditis elegans. To control these distinct processes, SDC-2 acts as a strong gene-specific repressor and a weaker chromosome-wide repressor. To initiate hermaphrodite development, SDC-2 associates with the promoter of the male sex-determining gene her-1 to repress its transcription. To activate dosage compensation, SDC-2 triggers assembly of a specialized protein complex exclusively on hermaphrodite X chromosomes to reduce gene expression by half. SDC-2 can localize to X chromosomes without other components of the dosage compensation complex, suggesting that SDC-2 targets dosage compensation machinery to X chromosomes.

Pointwise Partial Information Decomposition Using the Specificity and Ambiguity Lattices

NASA Astrophysics Data System (ADS)

Finn, Conor; Lizier, Joseph

2018-04-01

What are the distinct ways in which a set of predictor variables can provide information about a target variable? When does a variable provide unique information, when do variables share redundant information, and when do variables combine synergistically to provide complementary information? The redundancy lattice from the partial information decomposition of Williams and Beer provided a promising glimpse at the answer to these questions. However, this structure was constructed using a much criticised measure of redundant information, and despite sustained research, no completely satisfactory replacement measure has been proposed. In this paper, we take a different approach, applying the axiomatic derivation of the redundancy lattice to a single realisation from a set of discrete variables. To overcome the difficulty associated with signed pointwise mutual information, we apply this decomposition separately to the unsigned entropic components of pointwise mutual information which we refer to as the specificity and ambiguity. This yields a separate redundancy lattice for each component. Then based upon an operational interpretation of redundancy, we define measures of redundant specificity and ambiguity enabling us to evaluate the partial information atoms in each lattice. These atoms can be recombined to yield the sought-after multivariate information decomposition. We apply this framework to canonical examples from the literature and discuss the results and the various properties of the decomposition. In particular, the pointwise decomposition using specificity and ambiguity satisfies a chain rule over target variables, which provides new insights into the so-called two-bit-copy example.

Using auditory pre-information to solve the cocktail-party problem: electrophysiological evidence for age-specific differences.

PubMed

Getzmann, Stephan; Lewald, Jörg; Falkenstein, Michael

2014-01-01

Speech understanding in complex and dynamic listening environments requires (a) auditory scene analysis, namely auditory object formation and segregation, and (b) allocation of the attentional focus to the talker of interest. There is evidence that pre-information is actively used to facilitate these two aspects of the so-called "cocktail-party" problem. Here, a simulated multi-talker scenario was combined with electroencephalography to study scene analysis and allocation of attention in young and middle-aged adults. Sequences of short words (combinations of brief company names and stock-price values) from four talkers at different locations were simultaneously presented, and the detection of target names and the discrimination between critical target values were assessed. Immediately prior to speech sequences, auditory pre-information was provided via cues that either prepared auditory scene analysis or attentional focusing, or non-specific pre-information was given. While performance was generally better in younger than older participants, both age groups benefited from auditory pre-information. The analysis of the cue-related event-related potentials revealed age-specific differences in the use of pre-cues: Younger adults showed a pronounced N2 component, suggesting early inhibition of concurrent speech stimuli; older adults exhibited a stronger late P3 component, suggesting increased resource allocation to process the pre-information. In sum, the results argue for an age-specific utilization of auditory pre-information to improve listening in complex dynamic auditory environments.

Using auditory pre-information to solve the cocktail-party problem: electrophysiological evidence for age-specific differences

PubMed Central

Getzmann, Stephan; Lewald, Jörg; Falkenstein, Michael

2014-01-01

Speech understanding in complex and dynamic listening environments requires (a) auditory scene analysis, namely auditory object formation and segregation, and (b) allocation of the attentional focus to the talker of interest. There is evidence that pre-information is actively used to facilitate these two aspects of the so-called “cocktail-party” problem. Here, a simulated multi-talker scenario was combined with electroencephalography to study scene analysis and allocation of attention in young and middle-aged adults. Sequences of short words (combinations of brief company names and stock-price values) from four talkers at different locations were simultaneously presented, and the detection of target names and the discrimination between critical target values were assessed. Immediately prior to speech sequences, auditory pre-information was provided via cues that either prepared auditory scene analysis or attentional focusing, or non-specific pre-information was given. While performance was generally better in younger than older participants, both age groups benefited from auditory pre-information. The analysis of the cue-related event-related potentials revealed age-specific differences in the use of pre-cues: Younger adults showed a pronounced N2 component, suggesting early inhibition of concurrent speech stimuli; older adults exhibited a stronger late P3 component, suggesting increased resource allocation to process the pre-information. In sum, the results argue for an age-specific utilization of auditory pre-information to improve listening in complex dynamic auditory environments. PMID:25540608

Evolution of Abscisic Acid Synthesis and Signaling Mechanisms

PubMed Central

Hauser, Felix; Waadt, Rainer; Schroeder, Julian I.

2011-01-01

The plant hormone abscisic acid (ABA) mediates seed dormancy, controls seedling development and triggers tolerance to abiotic stresses, including drought. Core ABA signaling components consist of a recently identified group of ABA receptor proteins of the PYRABACTIN RESISTANCE (PYR)/REGULATORY COMPONENT OF ABA RECEPTOR (RCAR) family that act as negative regulators of members of the PROTEIN PHOSPHATASE 2C (PP2C) family. Inhibition of PP2C activity enables activation of SNF1-RELATED KINASE 2 (SnRK2) protein kinases, which target downstream components, including transcription factors, ion channels and NADPH oxidases. These and other components form a complex ABA signaling network. Here, an in depth analysis of the evolution of components in this ABA signaling network shows that (i) PYR/RCAR ABA receptor and ABF-type transcription factor families arose during land colonization of plants and are not found in algae and other species, (ii) ABA biosynthesis enzymes have evolved to plant- and fungal-specific forms, leading to different ABA synthesis pathways, (iii) existing stress signaling components, including PP2C phosphatases and SnRK kinases, were adapted for novel roles in this plant-specific network to respond to water limitation. In addition, evolutionarily conserved secondary structures in the PYR/RCAR ABA receptor family are visualized. PMID:21549957

Molecular targets for small-molecule modulators of circadian clocks

PubMed Central

He, Baokun; Chen, Zheng

2016-01-01

Background Circadian clocks are endogenous timing systems that regulate various aspects of mammalian metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial efforts have been dedicated to developing novel small-molecule modulators of circadian clocks. Methods Here, we review the recent progress in the identification of molecular targets of small-molecule clock modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also discuss circadian regulation of drug metabolism. Results Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these targets small molecules exert protective effects against clock-related disorders including the metabolic syndrome, immune disorders, sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics. Conclusion Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases. PMID:26750111

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

PubMed Central

Singh, Nisha; Krishnan-Sarin, Suchitra

2012-01-01

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

Intracellular Delivery System for Antibody–Peptide Drug Conjugates

PubMed Central

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

2015-01-01

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

Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts

PubMed Central

Cartellieri, M; Feldmann, A; Koristka, S; Arndt, C; Loff, S; Ehninger, A; von Bonin, M; Bejestani, E P; Ehninger, G; Bachmann, M P

2016-01-01

The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide ‘proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo. PMID:27518241

BLISTER Regulates Polycomb-Target Genes, Represses Stress-Regulated Genes and Promotes Stress Responses in Arabidopsis thaliana.

PubMed

Kleinmanns, Julia A; Schatlowski, Nicole; Heckmann, David; Schubert, Daniel

2017-01-01

HIGHLIGHTS The PRC2 interacting protein BLISTER likely acts downstream of PRC2 to silence Polycomb target genes and is a key regulator of specific stress responses in Arabidopsis . Polycomb group (PcG) proteins are key epigenetic regulators of development. The highly conserved Polycomb repressive complex 2 (PRC2) represses thousands of target genes by trimethylating H3K27 (H3K27me3). Plant specific PcG components and functions are largely unknown, however, we previously identified the plant-specific protein BLISTER (BLI) as a PRC2 interactor. BLI regulates PcG target genes and promotes cold stress resistance. To further understand the function of BLI , we analyzed the transcriptional profile of bli-1 mutants. Approximately 40% of the up-regulated genes in bli are PcG target genes, however, bli-1 mutants did not show changes in H3K27me3 levels at all tested genes, indicating that BLI regulates PcG target genes downstream of or in parallel to PRC2. Interestingly, a significant number of BLI regulated H3K27me3 target genes is regulated by the stress hormone absciscic acid (ABA). We further reveal an overrepresentation of genes responding to abiotic stresses such as drought, high salinity, or heat stress among the up-regulated genes in bli mutants. Consistently, bli mutants showed reduced desiccation stress tolerance. We conclude that the PRC2 associated protein BLI is a key regulator of stress-responsive genes in Arabidopsis : it represses ABA-responsive PcG target genes, likely downstream of PRC2, and promotes resistance to several stresses such as cold and drought.

Detection of retromer assembly in Plasmodium falciparum by immunosensing coupled to Surface Plasmon Resonance.

PubMed

Iqbal, Mohd Shameel; Siddiqui, Asim Azhar; Banerjee, Chinmoy; Nag, Shiladitya; Mazumder, Somnath; De, Rudranil; Saha, Shubhra Jyoti; Karri, Suresh Kumar; Bandyopadhyay, Uday

Retromer complex plays a crucial role in intracellular protein trafficking and is conserved throughout the eukaryotes including malaria parasite, Plasmodium falciparum, where it is partially conserved. The assembly of retromer complex in RBC stages of malarial parasite is extremely difficult to explore because of its complicated physiology, small size, and intra-erythrocytic location. Nonetheless, understanding of retromer assembly may pave new ways for the development of novel antimalarials targeting parasite-specific protein trafficking pathways. Here, we investigated the assembly of retromer complex in P. falciparum, by an immunosensing method through highly sensitive Surface Plasmon Resonance (SPR) technique. After taking leads from the bioinformatics search and literature, different interacting proteins were identified and specific antibodies were raised against them. The sensor chip was prepared by covalently linking antibody specific to one component and the whole cell lysate was passed through it in order to trap the interacting complex. Antibodies raised against other interacting components were used to detect them in the trapped complex on the SPR chip. We were able to detect three different components in the retromer complex trapped by the immobilized antibody specific against a different component on a sensor chip. The assay was reproduced and validated in a different two-component CD74-MIF system in mammalian cells. We, thus, illustrate the assembly of retromer complex in P. falciparum through a bio-sensing approach that combines SPR with immunosensing requiring a very small amount of sample from the native source. Copyright © 2018 Elsevier B.V. All rights reserved.

A philosophy for CNS radiotracer design

DOE PAGES

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

2014-10-01

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

A Philosophy for CNS Radiotracer Design

PubMed Central

2015-01-01

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

Specific effects of a calorie-based intervention on stair climbing in overweight commuters.

PubMed

Lewis, Amanda L; Eves, Frank F

2011-10-01

Point-of-choice prompts consistently increase stair climbing; a greater increase in overweight than normal weight individuals was reported in a multi-component worksite campaign. The purpose of this study is to investigate effects of a multi-component campaign, on stair climbing, in a public access setting. In an interrupted-time-series-design, baseline observations (2 weeks) preceded a 2-week point-of-choice prompt. An additional message, positioned at the top of the climb for a further 6-week period, summarised the calorific consequences of a single ascent. Inconspicuous observers recorded traveller's methods of ascent, coded by sex and weight status, twice a week between 08:00 and 09:59. At baseline, the overweight chose stairs less than normal weight individuals. The multi-component campaign targeting weight control reversed this bias, increasing stair climbing only in overweight individuals. The specificity of the effect confirms the appeal of this lifestyle activity for the overweight. The discussion focuses on how intentions to control weight may be converted into behaviour.

A Multi-mission Event-Driven Component-Based System for Support of Flight Software Development, ATLO, and Operations first used by the Mars Science Laboratory (MSL) Project

NASA Technical Reports Server (NTRS)

Dehghani, Navid; Tankenson, Michael

2006-01-01

This paper details an architectural description of the Mission Data Processing and Control System (MPCS), an event-driven, multi-mission ground data processing components providing uplink, downlink, and data management capabilities which will support the Mars Science Laboratory (MSL) project as its first target mission. MPCS is developed based on a set of small reusable components, implemented in Java, each designed with a specific function and well-defined interfaces. An industry standard messaging bus is used to transfer information among system components. Components generate standard messages which are used to capture system information, as well as triggers to support the event-driven architecture of the system. Event-driven systems are highly desirable for processing high-rate telemetry (science and engineering) data, and for supporting automation for many mission operations processes.

Antiviral drug acyclovir exhibits antitumor activity via targeting βTrCP1: Molecular docking and dynamics simulation study.

PubMed

Shafique, Shagufta; Rashid, Sajid

2017-03-01

The critical role of βTrCP1 in cancer development makes it a discerning target for the development of small drug like molecules. Currently, no inhibitor exists that is able to target its substrate binding site. Through molecular docking and dynamics simulation assays, we explored the comparative binding pattern of βTrCP1-WD40 domain with ACV and its phospho-derivatives (ACVMP, ACVDP and ACVTP). Consequently, through principal component analysis, βTrCP1-ACVTP was found to be more stable complex by obscuring a reduced conformational space than other systems. Thus based on the residual contribution and hydrogen bonding pattern, ACVTP was considered as a noteworthy inhibitor which demarcated binding in the cleft formed by βTrCP1-WD40 specific β-propeller. The outcomes of this study may provide a platform for rational design of specific and potent inhibitor against βTrCP1, with special emphasis on anticancer activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Importance of public relations in recycling strategies: principles and case studies.

PubMed

Salhofer, Stefan; Isaac, Nicole A

2002-07-01

The separate collection of waste, and especially of recyclables with specific collection systems, would not be possible without the involvement of the users. Apart from the physical installations such as collection containers, collection points, etc., the motivation of the users is an essential component. Motivation can be reinforced through public relations work. In addition to the underlying technical considerations, this paper describes the difference between communication in general and public relations and specifically examines public involvement in recycling. Through the use of examples, we look at the targeted users and typical media employed. Furthermore, we analyzes the development of public involvement. The examples show that public relations for recycling strategies relies to a great extent on attitudes, habits, and access to the target group. Thus, standardized procedures cannot be developed. For these reasons, public relation activities must be planned carefully and professionally and include an analysis of the target group, choice of media, and verification of success.

Unitary or Non-Unitary Nature of Working Memory? Evidence from Its Relation to General Fluid and Crystallized Intelligence

ERIC Educational Resources Information Center

Dang, Cai-Ping; Braeken, Johan; Ferrer, Emilio; Liu, Chang

2012-01-01

This study explored the controversy surrounding working memory: whether it is a unitary system providing general purpose resources or a more differentiated system with domain-specific sub-components. A total of 348 participants completed a set of 6 working memory tasks that systematically varied in storage target contents and type of information…

Activateable Imaging Probes Light Up Inside Cancer Cells | Center for Cancer Research

Cancer.gov

Imaging can be used to help diagnose cancer as well as monitor tumor progression and response to treatment. The field of molecular imaging focuses on techniques capable of detecting specific molecular targets associated with cancer; the agents used for molecular imaging—often called probes—are multifunctional, with components that allow them to both interact with their

Optical Neural Interfaces

PubMed Central

Warden, Melissa R.; Cardin, Jessica A.; Deisseroth, Karl

2014-01-01

Genetically encoded optical actuators and indicators have changed the landscape of neuroscience, enabling targetable control and readout of specific components of intact neural circuits in behaving animals. Here, we review the development of optical neural interfaces, focusing on hardware designed for optical control of neural activity, integrated optical control and electrical readout, and optical readout of population and single-cell neural activity in freely moving mammals. PMID:25014785

Interaction of probiotics and pathogens--benefits to human health?

PubMed

Salminen, Seppo; Nybom, Sonja; Meriluoto, Jussi; Collado, Maria Carmen; Vesterlund, Satu; El-Nezami, Hani

2010-04-01

The probiotic terminology has matured over the years and currently a unified definition has been formed. Lactic acid bacteria (LAB) and bifidobacteria have been reported to remove heavy metals, cyanotoxins and mycotoxins from aqueous solutions. The binding processes appear to be species and strain specific. The most efficient microbial species and strains in the removal of these compounds vary between components tested. However, it is of interest to note that most strains characterized until now do not bind positive components or nutrients in the diet. This has significant implications to future detoxification biotechnology development. In a similar manner, lactic acid bacteria and bifidobacteria interact directly with viruses and pathogens in food and water as well as toxin producing microbes and some toxins. This review updates information and aims to characterize these interactions in association. The target is to understand probiotic health effects and to relate the mechanisms and actions to future potential of specific probiotic bacteria on decontamination of foods and water, and diets. The same aim is targeted in characterizing the role of probiotics in inactivating pathogens and viruses of health importance to facilitate the establishment of novel means of disease risk reduction related health benefits. Copyright 2010. Published by Elsevier Ltd.

Differential Sources for 2 Neural Signatures of Target Detection: An Electrocorticography Study.

PubMed

Kam, J W Y; Szczepanski, S M; Canolty, R T; Flinker, A; Auguste, K I; Crone, N E; Kirsch, H E; Kuperman, R A; Lin, J J; Parvizi, J; Knight, R T

2018-01-01

Electrophysiology and neuroimaging provide conflicting evidence for the neural contributions to target detection. Scalp electroencephalography (EEG) studies localize the P3b event-related potential component mainly to parietal cortex, whereas neuroimaging studies report activations in both frontal and parietal cortices. We addressed this discrepancy by examining the sources that generate the target-detection process using electrocorticography (ECoG). We recorded ECoG activity from cortex in 14 patients undergoing epilepsy monitoring, as they performed an auditory or visual target-detection task. We examined target-related responses in 2 domains: high frequency band (HFB) activity and the P3b. Across tasks, we observed a greater proportion of electrodes that showed target-specific HFB power relative to P3b over frontal cortex, but their proportions over parietal cortex were comparable. Notably, there was minimal overlap in the electrodes that showed target-specific HFB and P3b activity. These results revealed that the target-detection process is characterized by at least 2 different neural markers with distinct cortical distributions. Our findings suggest that separate neural mechanisms are driving the differential patterns of activity observed in scalp EEG and neuroimaging studies, with the P3b reflecting EEG findings and HFB activity reflecting neuroimaging findings, highlighting the notion that target detection is not a unitary phenomenon. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

PubMed

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

2010-07-01

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

The balanced ideological antipathy model: explaining the effects of ideological attitudes on inter-group antipathy across the political spectrum.

PubMed

Crawford, Jarret T; Mallinas, Stephanie R; Furman, Bryan J

2015-12-01

We introduce the balanced ideological antipathy (BIA) model, which challenges assumptions that right-wing authoritarianism (RWA) and social dominance orientation (SDO) predict inter-group antipathy per se. Rather, the effects of RWA and SDO on antipathy should depend on the target's political orientation and political objectives, the specific components of RWA, and the type of antipathy expressed. Consistent with the model, two studies (N = 585) showed that the Traditionalism component of RWA positively and negatively predicted both political intolerance and prejudice toward tradition-threatening and -reaffirming groups, respectively, whereas SDO positively and negatively predicted prejudice (and to some extent political intolerance) toward hierarchy-attenuating and -enhancing groups, respectively. Critically, the Conservatism component of RWA positively predicted political intolerance (but not prejudice) toward each type of target group, suggesting it captures the anti-democratic impulse at the heart of authoritarianism. Recommendations for future research on the relationship between ideological attitudes and inter-group antipathy are discussed. © 2015 by the Society for Personality and Social Psychology, Inc.

Overview of online two-dimensional liquid chromatography based on cell membrane chromatography for screening target components from traditional Chinese medicines.

PubMed

Muhammad, Saqib; Han, Shengli; Xie, Xiaoyu; Wang, Sicen; Aziz, Muhammad Majid

2017-01-01

Cell membrane chromatography is a simple, specific, and time-saving technique for studying drug-receptor interactions, screening of active components from complex mixtures, and quality control of traditional Chinese medicines. However, the short column life, low sensitivity, low column efficiency (so cannot resolve satisfactorily mixture of compounds), low peak capacity, and inefficient in structure identification were bottleneck in its application. Combinations of cell membrane chromatography with multidimensional chromatography such as two-dimensional liquid chromatography and high sensitivity detectors like mass have significantly reduced many of the above-mentioned shortcomings. This paper provides an overview of the current advances in online two-dimensional-based cell membrane chromatography for screening target components from traditional Chinese medicines with particular emphasis on the instrumentation, preparation of cell membrane stationary phase, advantages, and disadvantages compared to alternative approaches. The last section of the review summarizes the applications of the online two-dimensional high-performance liquid chromatography based cell membrane chromatography reported since its emergence to date (2010-June 2016). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Elongated Nanoparticle Aggregates in Cancer Cells for Mechanical Destruction with Low Frequency Rotating Magnetic Field.

PubMed

Shen, Yajing; Wu, Congyu; Uyeda, Taro Q P; Plaza, Gustavo R; Liu, Bin; Han, Yu; Lesniak, Maciej S; Cheng, Yu

2017-01-01

Magnetic nanoparticles (MNPs) functionalized with targeting moieties can recognize specific cell components and induce mechanical actuation under magnetic field. Their size is adequate for reaching tumors and targeting cancer cells. However, due to the nanometric size, the force generated by MNPs is smaller than the force required for largely disrupting key components of cells. Here, we show the magnetic assembly process of the nanoparticles inside the cells, to form elongated aggregates with the size required to produce elevated mechanical forces. We synthesized iron oxide nanoparticles doped with zinc, to obtain high magnetization, and functionalized with the epidermal growth factor (EGF) peptide for targeting cancer cells. Under a low frequency rotating magnetic field at 15 Hz and 40 mT, the internalized EGF-MNPs formed elongated aggregates and generated hundreds of pN to dramatically damage the plasma and lysosomal membranes. The physical disruption, including leakage of lysosomal hydrolases into the cytosol, led to programmed cell death and necrosis. Our work provides a novel strategy of designing magnetic nanomedicines for mechanical destruction of cancer cells.

Elongated Nanoparticle Aggregates in Cancer Cells for Mechanical Destruction with Low Frequency Rotating Magnetic Field

PubMed Central

Shen, Yajing; Wu, Congyu; Uyeda, Taro Q. P.; Plaza, Gustavo R.; Liu, Bin; Han, Yu; Lesniak, Maciej S.; Cheng, Yu

2017-01-01

Magnetic nanoparticles (MNPs) functionalized with targeting moieties can recognize specific cell components and induce mechanical actuation under magnetic field. Their size is adequate for reaching tumors and targeting cancer cells. However, due to the nanometric size, the force generated by MNPs is smaller than the force required for largely disrupting key components of cells. Here, we show the magnetic assembly process of the nanoparticles inside the cells, to form elongated aggregates with the size required to produce elevated mechanical forces. We synthesized iron oxide nanoparticles doped with zinc, to obtain high magnetization, and functionalized with the epidermal growth factor (EGF) peptide for targeting cancer cells. Under a low frequency rotating magnetic field at 15 Hz and 40 mT, the internalized EGF-MNPs formed elongated aggregates and generated hundreds of pN to dramatically damage the plasma and lysosomal membranes. The physical disruption, including leakage of lysosomal hydrolases into the cytosol, led to programmed cell death and necrosis. Our work provides a novel strategy of designing magnetic nanomedicines for mechanical destruction of cancer cells. PMID:28529648

Dietary Strategies and Novel Pharmaceutical Approaches Targeting Serum ApoA-I Metabolism: A Systematic Overview

PubMed Central

Smolders, Lotte; Plat, Jogchum

2017-01-01

The incidence of CHD is still increasing, which underscores the need for new preventive and therapeutic approaches to decrease CHD risk. In this respect, increasing apoA-I concentrations may be a promising approach, especially through increasing apoA-I synthesis. This review first provides insight into current knowledge on apoA-I production, clearance, and degradation, followed by a systematic review of dietary and novel pharmacological approaches to target apoA-I metabolism. For this, a systematic search was performed to identify randomized controlled intervention studies that examined effects of whole foods and (non)nutrients on apoA-I metabolism. In addition, novel pharmacological approaches were searched for, which were specifically developed to target apoA-I metabolism. We conclude that both dietary components and pharmacological approaches can be used to increase apoA-I concentrations or functionality. For the dietary components in particular, more knowledge about the underlying mechanisms is necessary, as increasing apoA-I per se does not necessarily translate into a reduced CHD risk. PMID:28695008

Loads and loads and loads: the influence of prospective load, retrospective load, and ongoing task load in prospective memory.

PubMed

Meier, Beat; Zimmermann, Thomas D

2015-01-01

In prospective memory tasks different kinds of load can occur. Adding a prospective memory task can impose a load on ongoing task performance. Adding ongoing task load (OTL) can affect prospective memory performance. The existence of multiple target events increases prospective load (PL) and adding complexity to the to-be-remembered action increases retrospective load (RL). In two experiments, we systematically examined the effects of these different types of load on prospective memory performance. Results showed an effect of PL on costs in the ongoing task for categorical targets (Experiment 2), but not for specific targets (Experiment 1). RL and OTL both affected remembering the retrospective component of the prospective memory task. We suggest that PL can enhance costs in the ongoing task due to additional monitoring requirements. RL and OTL seem to impact the division of resources between the ongoing task and retrieval of the retrospective component, which may affect disengagement from the ongoing task. In general, the results demonstrate that the different types of load affect prospective memory differentially.

Loads and loads and loads: the influence of prospective load, retrospective load, and ongoing task load in prospective memory

PubMed Central

Meier, Beat; Zimmermann, Thomas D.

2015-01-01

In prospective memory tasks different kinds of load can occur. Adding a prospective memory task can impose a load on ongoing task performance. Adding ongoing task load (OTL) can affect prospective memory performance. The existence of multiple target events increases prospective load (PL) and adding complexity to the to-be-remembered action increases retrospective load (RL). In two experiments, we systematically examined the effects of these different types of load on prospective memory performance. Results showed an effect of PL on costs in the ongoing task for categorical targets (Experiment 2), but not for specific targets (Experiment 1). RL and OTL both affected remembering the retrospective component of the prospective memory task. We suggest that PL can enhance costs in the ongoing task due to additional monitoring requirements. RL and OTL seem to impact the division of resources between the ongoing task and retrieval of the retrospective component, which may affect disengagement from the ongoing task. In general, the results demonstrate that the different types of load affect prospective memory differentially. PMID:26082709

SFRP1 is a possible candidate for epigenetic therapy in non-small cell lung cancer.

PubMed

Taguchi, Y-H; Iwadate, Mitsuo; Umeyama, Hideaki

2016-08-12

Non-small cell lung cancer (NSCLC) remains a lethal disease despite many proposed treatments. Recent studies have indicated that epigenetic therapy, which targets epigenetic effects, might be a new therapeutic methodology for NSCLC. However, it is not clear which objects (e.g., genes) this treatment specifically targets. Secreted frizzled-related proteins (SFRPs) are promising candidates for epigenetic therapy in many cancers, but there have been no reports of SFRPs targeted by epigenetic therapy for NSCLC. This study performed a meta-analysis of reprogrammed NSCLC cell lines instead of the direct examination of epigenetic therapy treatment to identify epigenetic therapy targets. In addition, mRNA expression/promoter methylation profiles were processed by recently proposed principal component analysis based unsupervised feature extraction and categorical regression analysis based feature extraction. The Wnt/β-catenin signalling pathway was extensively enriched among 32 genes identified by feature extraction. Among the genes identified, SFRP1 was specifically indicated to target β-catenin, and thus might be targeted by epigenetic therapy in NSCLC cell lines. A histone deacetylase inhibitor might reactivate SFRP1 based upon the re-analysis of a public domain data set. Numerical computation validated the binding of SFRP1 to WNT1 to suppress Wnt signalling pathway activation in NSCLC. The meta-analysis of reprogrammed NSCLC cell lines identified SFRP1 as a promising target of epigenetic therapy for NSCLC.

Cancer-linked targets modulated by curcumin

PubMed Central

Hasima, Noor; Aggarwal, Bharat B

2012-01-01

In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting. PMID:23301199

Transgene manipulation in zebrafish by using recombinases.

PubMed

Dong, Jie; Stuart, Gary W

2004-01-01

Although much remains to be done, our results to date suggest that efficient and precise genome engineering in zebrafish will be possible in the future by using Cre recombinase and SB transposase in combination with their respective target sites. In this study, we provide the first evidence that Cre recombinase can mediate effective site-specific deletion of transgenes in zebrafish. We found that the efficiency of target site utilization could approach 100%, independent of whether the target site was provided transiently by injection or stably within an integrated transgene. Microinjection of Cre mRNA appeared to be slightly more effective for this purpose than microinjection of Cre-expressing plasmid DNA. Our work has not yet progressed to the point where SB-mediated mobilization of our transgene constructs would be observed. However, a recent report has demonstrated that SB can enhance transgenesis rates sixfold over conventional methods by efficiently mediating multiple single-copy insertion of transgenes into the zebrafish genome (Davidson et al., 2003). Therefore, it seems likely that a combined system should eventually allow both SB-mediated transgene mobilization and Cre-mediated transgene modification. Our goal is to validate methods for the precise reengineering of the zebrafish genome by using a combination of Cre-loxP and SB transposon systems. These methods can be used to delete, replace, or mobilize large pieces of DNA or to modify the genome only when and where required by the investigator. For example, it should be possible to deliver particular RNAi genes to well-expressed chromosomal loci and then exchange them easily with alternative RNAi genes for the specific suppression of alternative targets. As a nonviral vector for gene therapy, the transposon component allows for the possibility of highly efficient integration, whereas the Cre-loxP component can target the integration and/or exchange of foreign DNA into specific sites within the genome. The specificity and efficiency of this system also make it ideal for applications in which precise genome modifications are required (e.g., stock improvement). Future work should establish whether alternative recombination systems (e.g., phiC31 integrase) can improve the utility of this system. After the fish system is fully established, it would be interesting to explore its application to genome engineering in other organisms.

DGAT and triglyceride synthesis: a new target for obesity treatment?

PubMed

Chen, H C; Farese, R V

2000-07-01

Because triglycerides are considered essential for survival and their synthesis has been thought to occur through a single mechanism, inhibiting triglyceride synthesis has been largely unexplored as a possible target for obesity treatment. However, recent studies indicate that mice lacking acyl CoA:diacylglycerol acyltransferase (DGAT), a key enzyme in triglyceride synthesis, are viable and resistant to diet-induced obesity. Unexpectedly, this resistance is caused by a mechanism involving increased energy expenditure. These findings suggest that inhibiting specific components of triglyceride synthesis, such as DGAT, is feasible and may represent a novel approach to treating obesity.

Non-deterministic quantum CNOT gate with double encoding

NASA Astrophysics Data System (ADS)

Gueddana, Amor; Attia, Moez; Chatta, Rihab

2013-09-01

We define an Asymmetric Partially Polarizing Beam Splitter (APPBS) to be a linear optical component having different reflectivity (transmittance) coefficients, on the upper and the lower arms, for horizontally and vertically Polarized incident photons. Our CNOT model is composed by two APPBSs, one Half Wave Plate (HWP), two Polarizing Beam Splitters (PBSs), a Beam Splitter (BS) and a -phase rotator for specific wavelength. Control qubit operates with dual rail encoding while target qubit is based on polarization encoding. To perform CNOT operation in 4/27 of the cases, input and target incoming photons are injected with different wavelengths.

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

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

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

2016-07-05

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

A multimodal high-value curriculum affects drivers of utilization and performance on the high-value care component of the internal medicine in-training exam.

PubMed

Chau, Tom; Loertscher, Laura

2018-01-01

Background : Teaching the practice of high-value care (HVC) is an increasingly important function of graduate medical education but best practices and long-term outcomes remain unknown. Objective : Whether a multimodal curriculum designed to address specific drivers of low-value care would affect resident attitudes, skills, and performance of HVC as tested by the Internal Medicine In-Training Exam (ITE). Methods : In 2012, we performed a baseline needs assessment among internal medicine residents at a community program regarding drivers of healthcare utilization. We then created a multimodal curriculum with online interactive worksheets, lectures, and faculty buy-in to target specific skills, knowledge, and culture deficiencies. Perceived drivers of care and performance on the Internal Medicine ITE were assessed yearly through 2016. Results : Fourteen of 27 (52%) residents completed the initial needs assessment while the curriculum was eventually seen by at least 24 of 27 (89%). The ITE was taken by every resident every year. Long-term, 3-year follow-up demonstrated persistent improvement in many drivers of utilization (patient requests, reliance on subspecialists, defensive medicine, and academic curiosity) and improvement with sustained high performance on the high-value component of the ITE. Conclusion : A multimodal curriculum targeting specific drivers of low-value care can change culture and lead to sustained improvement in the practice of HVC.

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

PubMed

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

2016-12-01

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

Locally Bayesian Learning with Applications to Retrospective Revaluation and Highlighting

ERIC Educational Resources Information Center

Kruschke, John K.

2006-01-01

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

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2013-02-01

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

LED Systems Target Plant Growth

NASA Technical Reports Server (NTRS)

2010-01-01

To help develop technologies for growing edible biomass (food crops) in space, Kennedy Space Center partnered with Orbital Technologies Corporation (ORBITEC), of Madison, Wisconsin, through the Small Business Innovation Research (SBIR) program. One result of this research was the High Efficiency Lighting with Integrated Adaptive Control (HELIAC) system, components of which have been incorporated into a variety of agricultural greenhouse and consumer aquarium lighting features. The new lighting systems can be adapted to a specific plant species during a specific growth stage, allowing maximum efficiency in light absorption by all available photosynthetic tissues.

The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets.

PubMed

Wood, Steven L; Pernemalm, Maria; Crosbie, Philip A; Whetton, Anthony D

2014-05-01

Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and currently has an overall five-year survival rate of only 15%. Patients presenting with advanced stage NSCLC die within 18-months of diagnosis. Metastatic spread accounts for >70% of these deaths. Thus elucidation of the mechanistic basis of NSCLC-metastasis has potential to impact on patient quality of life and survival. Research on NSCLC metastasis has recently expanded to include non-cancer cell components of tumors-the stromal cellular compartment and extra-cellular matrix components comprising the tumor-microenvironment. Metastasis (from initial primary tumor growth through angiogenesis, intravasation, survival in the bloodstream, extravasation and metastatic growth) is an inefficient process and few released cancer cells complete the entire process. Micro-environmental interactions assist each of these steps and discovery of the mechanisms by which tumor cells co-operate with the micro-environment are uncovering key molecules providing either biomarkers or potential drug targets. The major sites of NSCLC metastasis are brain, bone, adrenal gland and the liver. The mechanistic basis of this tissue-tropism is beginning to be elucidated offering the potential to target stromal components of these tissues thus targeting therapy to the tissues affected. This review covers the principal steps involved in tumor metastasis. The role of cell-cell interactions, ECM remodeling and autocrine/paracrine signaling interactions between tumor cells and the surrounding stroma is discussed. The mechanistic basis of lung cancer metastasis to specific organs is also described. The signaling mechanisms outlined have potential to act as future drug targets minimizing lung cancer metastatic spread and morbidity. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

PubMed

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

2018-01-01

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

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

PubMed Central

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

2018-01-01

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

Prognostics for Microgrid Components

NASA Technical Reports Server (NTRS)

Saxena, Abhinav

2012-01-01

Prognostics is the science of predicting future performance and potential failures based on targeted condition monitoring. Moving away from the traditional reliability centric view, prognostics aims at detecting and quantifying the time to impending failures. This advance warning provides the opportunity to take actions that can preserve uptime, reduce cost of damage, or extend the life of the component. The talk will focus on the concepts and basics of prognostics from the viewpoint of condition-based systems health management. Differences with other techniques used in systems health management and philosophies of prognostics used in other domains will be shown. Examples relevant to micro grid systems and subsystems will be used to illustrate various types of prediction scenarios and the resources it take to set up a desired prognostic system. Specifically, the implementation results for power storage and power semiconductor components will demonstrate specific solution approaches of prognostics. The role of constituent elements of prognostics, such as model, prediction algorithms, failure threshold, run-to-failure data, requirements and specifications, and post-prognostic reasoning will be explained. A discussion on performance evaluation and performance metrics will conclude the technical discussion followed by general comments on open research problems and challenges in prognostics.

Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1–F-box interface

DOE PAGES

Gorelik, Maryna; Orlicky, Stephen; Sartori, Maria A.; ...

2016-03-14

Skp1–Cul1–F-box (SCF) E3 ligases play key roles in multiple cellular processes through ubiquitination and subsequent degradation of substrate proteins. Although Skp1 and Cul1 are invariant components of all SCF complexes, the 69 different human F-box proteins are variable substrate binding modules that determine specificity. SCF E3 ligases are activated in many cancers and inhibitors could have therapeutic potential. Here, we used phage display to develop specific ubiquitin-based inhibitors against two F-box proteins, Fbw7 and Fbw11. Unexpectedly, the ubiquitin variants bind at the interface of Skp1 and F-box proteins and inhibit ligase activity by preventing Cul1 binding to the same surface.more » Using structure-based design and phage display, we modified the initial inhibitors to generate broad-spectrum inhibitors that targeted many SCF ligases, or conversely, a highly specific inhibitor that discriminated between even the close homologs Fbw11 and Fbw1. We propose that most F-box proteins can be targeted by this approach for basic research and for potential cancer therapies.« less

Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis

PubMed Central

Xiao, Changchun; Shim, Jae-hyuck; Klüppel, Michael; Zhang, Samuel Shao-Min; Dong, Chen; Flavell, Richard A.; Fu, Xin-Yuan; Wrana, Jeffrey L.; Hogan, Brigid L.M.; Ghosh, Sankar

2003-01-01

Bone morphogenetic proteins (Bmps) are members of the transforming growth factor β (TGFβ) superfamily that play critical roles during mouse embryogenesis. Signaling by Bmp receptors is mediated mainly by Smad proteins. In this study, we show that a targeted null mutation of Ecsit, encoding a signaling intermediate of the Toll pathway, leads to reduced cell proliferation, altered epiblast patterning, impairment of mesoderm formation, and embryonic lethality at embryonic day 7.5 (E7.5), phenotypes that mimic the Bmp receptor type1a (Bmpr1a) null mutant. In addition, specific Bmp target gene expression is abolished in the absence of Ecsit. Biochemical analysis demonstrates that Ecsit associates constitutively with Smad4 and associates with Smad1 in a Bmp-inducible manner. Together with Smad1 and Smad4, Ecsit binds to the promoter of specific Bmp target genes. Finally, knock-down of Ecsit with Ecsit-specific short hairpin RNA inhibits both Bmp and Toll signaling. Therefore, these results show that Ecsit functions as an essential component in two important signal transduction pathways and establishes a novel role for Ecsit as a cofactor for Smad proteins in the Bmp signaling pathway. PMID:14633973

Substrate-Driven Mapping of the Degradome by Comparison of Sequence Logos

PubMed Central

Fuchs, Julian E.; von Grafenstein, Susanne; Huber, Roland G.; Kramer, Christian; Liedl, Klaus R.

2013-01-01

Sequence logos are frequently used to illustrate substrate preferences and specificity of proteases. Here, we employed the compiled substrates of the MEROPS database to introduce a novel metric for comparison of protease substrate preferences. The constructed similarity matrix of 62 proteases can be used to intuitively visualize similarities in protease substrate readout via principal component analysis and construction of protease specificity trees. Since our new metric is solely based on substrate data, we can engraft the protease tree including proteolytic enzymes of different evolutionary origin. Thereby, our analyses confirm pronounced overlaps in substrate recognition not only between proteases closely related on sequence basis but also between proteolytic enzymes of different evolutionary origin and catalytic type. To illustrate the applicability of our approach we analyze the distribution of targets of small molecules from the ChEMBL database in our substrate-based protease specificity trees. We observe a striking clustering of annotated targets in tree branches even though these grouped targets do not necessarily share similarity on protein sequence level. This highlights the value and applicability of knowledge acquired from peptide substrates in drug design of small molecules, e.g., for the prediction of off-target effects or drug repurposing. Consequently, our similarity metric allows to map the degradome and its associated drug target network via comparison of known substrate peptides. The substrate-driven view of protein-protein interfaces is not limited to the field of proteases but can be applied to any target class where a sufficient amount of known substrate data is available. PMID:24244149

[New idea of traditional Chinese medicine quality control based on "composition structure" theory].

PubMed

Liu, Dan; Jia, Xiaobin; Yu, Danhong

2012-03-01

On the road of the modern Chinese medicine developing internationally, there is a key issues that setting up a reasonable, accurate and be quantified quality evaluation system which is comply with the basic theory of Chinese medicine. Based on the overall understanding of the role of traditional Chinese medicine components, author suggested that the idea of "structural components" theory should be embedded into the system and thought the Chinese medicine play a multi-target, multi-channel pharmacodynamic effects founded on the specific microcosmic structural relationship between the components and the components within the group. At present, the way of Chinese pharmacopoeia checking the quality of Chinese medicine is mainly depends on controlling the single or multiple targets of ingredients. In fact, this way is out of the overall effectiveness of the Chinese medicine, so we can not thoroughly controlling the quality of Chinese medicine from the essence of the Chinese medicine. Secondly, it's only macro-structural quantity that the Chinese pharmacopoeia just controlling the less effective ingredients, this is not enough to reflect the internal microstructure of the integrity and systematic. In other words, this cannot reflect the structural components of the Chinese medicine (the essence of traditional Chinese medicine). In view of above mentioned reasons, the author propose the new idea on the quality control in the medicine that quantify the ratio structural relationship in component and the ingredients of the components, set the optimal controlling proportion between the components and ingredients. At the same time, author thought we should conduct the depth study in the micro-quantified the multi-component and multi-ingredient, in the process of studying the material basis of Chinese medicine. Therefore, it could establish a more rational basis for the Chinese medicine quality controlling system.

Target-specific porphyrin-loaded hybrid nanoparticles to improve photodynamic therapy for cancer treatment

NASA Astrophysics Data System (ADS)

Vivero-Escoto, Juan L.; Vega, Daniel L.

2017-02-01

Photodynamic therapy (PDT) has emerged as an alternative approach to chemotherapy and radiotherapy for cancer treatment. The photosensitizer (PS) is perhaps the most critical component of PDT, and continues to be an area of intense scientific research. Traditionally, PS molecules like porphyrins have dominated the field. Nevertheless, these PS agents have several disadvantages, with low water solubility, poor light absorption, and reduced selectivity for targeted tissues being some of the main drawbacks. Polysilsesquioxane (PSilQ) nanoparticles provide an interesting platform for developing PS-loaded hybrid nanocarriers. Several advantages can be foreseen by using this platform such as carrying a large payload of PS molecules; their surface and composition can be tailored to develop multifunctional systems (e.g. target-specific); and due to their small size, nanoparticles can penetrate deep into tissues and be readily internalized by cells. In this work, porphyrin-loaded PSilQ nanoparticles with a high payload of photosensitizers were synthesized, characterized, and applied in vitro. The network of this nanomaterial is formed by porphyrin-based photosensitizers chemically connected via a redox-responsive linker. Under reducing environment such as the one found in cancer cells the nanoparticles can be degraded to efficiently release single photosensitizers in the cytoplasm. The platform was further functionalized with polyethylene glycol (PEG) and folic acid as targeting ligand to improve its biocompatibility and target specificity toward cancer cells overexpressing folate receptors. The effectiveness of this porphyrin-based hybrid nanomaterial was successfully demonstrated in vitro using MDA-MB-231 breast cancer cell line.

Perceptual Learning of Object Shape

PubMed Central

Golcu, Doruk; Gilbert, Charles D.

2009-01-01

Recognition of objects is accomplished through the use of cues that depend on internal representations of familiar shapes. We used a paradigm of perceptual learning during visual search to explore what features human observers use to identify objects. Human subjects were trained to search for a target object embedded in an array of distractors, until their performance improved from near-chance levels to over 80% of trials in an object specific manner. We determined the role of specific object components in the recognition of the object as a whole by measuring the transfer of learning from the trained object to other objects sharing components with it. Depending on the geometric relationship of the trained object with untrained objects, transfer to untrained objects was observed. Novel objects that shared a component with the trained object were identified at much higher levels than those that did not, and this could be used as an indicator of which features of the object were important for recognition. Training on an object also transferred to the components of the object when these components were embedded in an array of distractors of similar complexity. These results suggest that objects are not represented in a holistic manner during learning, but that their individual components are encoded. Transfer between objects was not complete, and occurred for more than one component, regardless of how well they distinguish the object from distractors. This suggests that a joint involvement of multiple components was necessary for full performance. PMID:19864574

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer

PubMed Central

Niiro, Emiko; Morioka, Sachiko; Iwai, Kana; Yamada, Yuki; Ogawa, Kenji; Kawahara, Naoki; Kobayashi, Hiroshi

2018-01-01

Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer. PMID:29564122

Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)

PubMed Central

Ebstein, Frédéric; Keller, Martin; Paschen, Annette; Walden, Peter; Seeger, Michael; Bürger, Elke; Krüger, Elke; Schadendorf, Dirk; Kloetzel, Peter-M.; Seifert, Ulrike

2016-01-01

Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing. PMID:27143649

Molecular Pathogenesis of Chlamydia Disease Complications: Epithelial-Mesenchymal Transition and Fibrosis.

PubMed

Igietseme, Joseph U; Omosun, Yusuf; Nagy, Tamas; Stuchlik, Olga; Reed, Matthew S; He, Qing; Partin, James; Joseph, Kahaliah; Ellerson, Debra; George, Zenas; Goldstein, Jason; Eko, Francis O; Bandea, Claudiu; Pohl, Jan; Black, Carolyn M

2018-01-01

The reproductive system complications of genital chlamydial infection include fallopian tube fibrosis and tubal factor infertility. However, the molecular pathogenesis of these complications remains poorly understood. The induction of pathogenic epithelial-mesenchymal transition (EMT) through microRNA (miRNA) dysregulation was recently proposed as the pathogenic basis of chlamydial complications. Focusing on fibrogenesis, we investigated the hypothesis that chlamydia-induced fibrosis is caused by EMT-driven generation of myofibroblasts, the effector cells of fibrosis that produce excessive extracellular matrix (ECM) proteins. The results revealed that the targets of a major category of altered miRNAs during chlamydial infection are key components of the pathophysiological process of fibrogenesis; these target molecules include collagen types I, III, and IV, transforming growth factor β (TGF-β), TGF-β receptor 1 (TGF-βR1), connective tissue growth factor (CTGF), E-cadherin, SRY-box 7 (SOX7), and NFAT (nuclear factor of activated T cells) kinase dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1a (Dyrk1a). Chlamydial induction of EMT resulted in the generation of α-smooth muscle actin (α-SMA)-positive myofibroblasts that produced ECM proteins, including collagen types I and III and fibronectin. Furthermore, the inhibition of EMT prevented the generation of myofibroblasts and production of ECM proteins during chlamydial infection. These findings may provide useful avenues for targeting EMT or specific components of the EMT pathways as a therapeutic intervention strategy to prevent chlamydia-related complications. Copyright © 2017 American Society for Microbiology.

Historeceptomic Fingerprints for Drug-Like Compounds.

PubMed

Shmelkov, Evgeny; Grigoryan, Arsen; Swetnam, James; Xin, Junyang; Tivon, Doreen; Shmelkov, Sergey V; Cardozo, Timothy

2015-01-01

Most drugs exert their beneficial and adverse effects through their combined action on several different molecular targets (polypharmacology). The true molecular fingerprint of the direct action of a drug has two components: the ensemble of all the receptors upon which a drug acts and their level of expression in organs/tissues. Conversely, the fingerprint of the adverse effects of a drug may derive from its action in bystander tissues. The ensemble of targets is almost always only partially known. Here we describe an approach improving upon and integrating both components: in silico identification of a more comprehensive ensemble of targets for any drug weighted by the expression of those receptors in relevant tissues. Our system combines more than 300,000 experimentally determined bioactivity values from the ChEMBL database and 4.2 billion molecular docking scores. We integrated these scores with gene expression data for human receptors across a panel of human tissues to produce drug-specific tissue-receptor (historeceptomics) scores. A statistical model was designed to identify significant scores, which define an improved fingerprint representing the unique activity of any drug. These multi-dimensional historeceptomic fingerprints describe, in a novel, intuitive, and easy to interpret style, the holistic, in vivo picture of the mechanism of any drug's action. Valuable applications in drug discovery and personalized medicine, including the identification of molecular signatures for drugs with polypharmacologic modes of action, detection of tissue-specific adverse effects of drugs, matching molecular signatures of a disease to drugs, target identification for bioactive compounds with unknown receptors, and hypothesis generation for drug/compound phenotypes may be enabled by this approach. The system has been deployed at drugable.org for access through a user-friendly web site.

Electro-Optic Computing Architectures: Volume II. Components and System Design and Analysis

DTIC Science & Technology

1998-02-01

The objective of the Electro - Optic Computing Architecture (EOCA) program was to develop multi-function electro - optic interfaces and optical...interconnect units to enhance the performance of parallel processor systems and form the building blocks for future electro - optic computing architectures...Specifically, three multi-function interface modules were targeted for development - an Electro - Optic Interface (EOI), an Optical Interconnection Unit

Components of Task-Based Needs Analysis of the ESP Learners with the Specialization of Business and Tourism

ERIC Educational Resources Information Center

Poghosyan, Naira

2016-01-01

In the following paper we shall thoroughly analyze the target learning needs of the learners within an ESP (English for Specific Purposes) context. The main concerns of ESP have always been and remain with the needs analysis, text analysis and preparing learners to communicate effectively in the tasks prescribed by their study or work situation.…

eap Gene as novel target for specific identification of Staphylococcus aureus.

PubMed

Hussain, Muzaffar; von Eiff, Christof; Sinha, Bhanu; Joost, Insa; Herrmann, Mathias; Peters, Georg; Becker, Karsten

2008-02-01

The cell surface-associated extracellular adherence protein (Eap) mediates adherence of Staphylococcus aureus to host extracellular matrix components and inhibits inflammation, wound healing, and angiogenesis. A well-characterized collection of S. aureus and non-S. aureus staphylococcal isolates (n = 813) was tested for the presence of the Eap-encoding gene (eap) by PCR to investigate the use of the eap gene as a specific diagnostic tool for identification of S. aureus. Whereas all 597 S. aureus isolates were eap positive, this gene was not detectable in 216 non-S. aureus staphylococcal isolates comprising 47 different species and subspecies of coagulase-negative staphylococci and non-S. aureus coagulase-positive or coagulase-variable staphylococci. Furthermore, non-S. aureus isolates did not express Eap homologs, as verified on the transcriptional and protein levels. Based on these data, the sensitivity and specificity of the newly developed PCR targeting the eap gene were both 100%. Thus, the unique occurrence of Eap in S. aureus offers a promising tool particularly suitable for molecular diagnostics of this pathogen.

Kid cleaves specific mRNAs at UUACU sites to rescue the copy number of plasmid R1

PubMed Central

Pimentel, Belén; Madine, Mark A; de la Cueva-Méndez, Guillermo

2005-01-01

Stability and copy number of extra-chromosomal elements are tightly regulated in prokaryotes and eukaryotes. Toxin Kid and antitoxin Kis are the components of the parD stability system of prokaryotic plasmid R1 and they can also function in eukaryotes. In bacteria, Kid was thought to become active only in cells that lose plasmid R1 and to cleave exclusively host mRNAs at UA(A/C/U) trinucleotide sites to eliminate plasmid-free cells. Instead, we demonstrate here that Kid becomes active in plasmid-containing cells when plasmid copy number decreases, cleaving not only host- but also a specific plasmid-encoded mRNA at the longer and more specific target sequence UUACU. This specific cleavage by Kid inhibits bacterial growth and, at the same time, helps to restore the plasmid copy number. Kid targets a plasmid RNA that encodes a repressor of the synthesis of an R1 replication protein, resulting in increased plasmid DNA replication. This mechanism resembles that employed by some human herpesviruses to regulate viral amplification during infection. PMID:16163387

Process evaluation of Project WebHealth: a nondieting Web-based intervention for obesity prevention in college students.

PubMed

Dour, Colleen A; Horacek, Tanya M; Schembre, Susan M; Lohse, Barbara; Hoerr, Sharon; Kattelmann, Kendra; White, Adrienne A; Shoff, Suzanne; Phillips, Beatrice; Greene, Geoffrey

2013-01-01

To evaluate the motivational effect of the Project WebHealth study procedures and intervention components on weight-related health behavior changes in male and female college students. Process evaluation. Eight universities in the United States. Project WebHealth participants (n = 653; 29% men). Participants rated motivational effects of study procedures and intervention components. Participants were grouped into outcome-based health behavior categories based on achievement of desired targets for fruit and vegetable intake, physical activity, and/or body weight. Differences in motivation from each procedure and component were analyzed by gender- and outcome-based health behavior category. Women were generally more motivated than men. Compared to those who did not meet any target health behaviors, men with improved health outcomes (68%) were significantly more motivated by the skills to fuel the body lesson, goal setting, and research snippets. Their female counterparts (63%) were significantly more motivated by the lessons on body size and eating enjoyment, and by the suggested weekly activities. Specific study procedures and components of Project WebHealth motivated study participants to improve their weight-related health behaviors, and they differed by gender. Findings support the need for gender-tailored interventions in this population. Copyright © 2013 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.

Nanodrugs to target articular cartilage: An emerging platform for osteoarthritis therapy.

PubMed

Bottini, Massimo; Bhattacharya, Kunal; Fadeel, Bengt; Magrini, Andrea; Bottini, Nunzio; Rosato, Nicola

2016-02-01

Cartilage undergoes drastic structural changes during the development of osteoarthritis and cannot heal itself due to a defective chondrocyte response. Thus, much effort has been invested in the development of disease modifying drugs able to block key mediators within the cartilage matrix and biochemical pathways inside chondrocytes. However, the delivery of therapeutic agents into cartilage is ineffective. This has led to the use of cartilage-targeted nanodrugs to accumulate therapeutic agents into specific cartilage sub-compartments. This review will describe the nanodrugs targeted to specific components of cartilage matrix to generate drug reservoirs within the cartilage. The nanodrugs used as chondrocyte-specific gene delivery systems are also described. Although the use of cartilage-targeted nanodrugs in osteoarthritis is still in its infancy, these studies lay the foundation for the development of novel approaches for preventing the progression of cartilage breakdown and improving the quality of life of patients with osteoarthritis. Osteoarthritis is a degeneration of joint cartilage, which affects a large number of aging people. Current therapy for disease modification is often suboptimal. Recent research in nanomedicine has led to the design and use of nanodrugs with the aim to help reverse the disease process. In this comprehensive review, the authors described and discussed various nanodrugs in the hope that newer drugs could be discovered in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

Extracellular matrix components in breast cancer progression and metastasis.

PubMed

Oskarsson, Thordur

2013-08-01

The extracellular matrix (ECM) is composed of highly variable and dynamic components that regulate cell behavior. The protein composition and physical properties of the ECM govern cell fate through biochemical and biomechanical mechanisms. This requires a carefully orchestrated and thorough regulation considering that a disturbed ECM can have serious consequences and lead to pathological conditions like cancer. In breast cancer, many ECM proteins are significantly deregulated and specific matrix components promote tumor progression and metastatic spread. Intriguingly, several ECM proteins that are associated with breast cancer development, overlap substantially with a group of ECM proteins induced during the state of tissue remodeling such as mammary gland involution. Fibrillar collagens, fibronectin, hyaluronan and matricellular proteins are matrix components that are common to both involution and cancer. Moreover, some of these proteins have in recent years been identified as important constituents of metastatic niches in breast cancer. In addition, specific ECM molecules, their receptors or enzymatic modifiers are significantly involved in resistance to therapeutic intervention. Further analysis of these ECM proteins and the downstream ECM mediated signaling pathways may provide a range of possibilities to identify druggable targets against advanced breast cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.

Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies.

PubMed

Rudomanova, Valeria; Blaxall, Burns C

2017-08-01

The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gβγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gβγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gβγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gβγ-GRK2 interactions. Further, we explore the potential of GPCR-Gβγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies. Copyright © 2017 Elsevier B.V. All rights reserved.

Identifying mRNA sequence elements for target recognition by human Argonaute proteins

PubMed Central

Li, Jingjing; Kim, TaeHyung; Nutiu, Razvan; Ray, Debashish; Hughes, Timothy R.; Zhang, Zhaolei

2014-01-01

It is commonly known that mammalian microRNAs (miRNAs) guide the RNA-induced silencing complex (RISC) to target mRNAs through the seed-pairing rule. However, recent experiments that coimmunoprecipitate the Argonaute proteins (AGOs), the central catalytic component of RISC, have consistently revealed extensive AGO-associated mRNAs that lack seed complementarity with miRNAs. We herein test the hypothesis that AGO has its own binding preference within target mRNAs, independent of guide miRNAs. By systematically analyzing the data from in vivo cross-linking experiments with human AGOs, we have identified a structurally accessible and evolutionarily conserved region (∼10 nucleotides in length) that alone can accurately predict AGO–mRNA associations, independent of the presence of miRNA binding sites. Within this region, we further identified an enriched motif that was replicable on independent AGO-immunoprecipitation data sets. We used RNAcompete to enumerate the RNA-binding preference of human AGO2 to all possible 7-mer RNA sequences and validated the AGO motif in vitro. These findings reveal a novel function of AGOs as sequence-specific RNA-binding proteins, which may aid miRNAs in recognizing their targets with high specificity. PMID:24663241

Costs Of Using “Tiny Targets” to Control Glossina fuscipes fuscipes, a Vector of Gambiense Sleeping Sickness in Arua District of Uganda

PubMed Central

Shaw, Alexandra P. M.; Tirados, Inaki; Mangwiro, Clement T. N.; Esterhuizen, Johan; Lehane, Michael J.; Torr, Stephen J.; Kovacic, Vanja

2015-01-01

Introduction To evaluate the relative effectiveness of tsetse control methods, their costs need to be analysed alongside their impact on tsetse populations. Very little has been published on the costs of methods specifically targeting human African trypanosomiasis Methodology/Principal Findings In northern Uganda, a 250 km2 field trial was undertaken using small (0.5 X 0.25 m) insecticide-treated targets (“tiny targets”). Detailed cost recording accompanied every phase of the work. Costs were calculated for this operation as if managed by the Ugandan vector control services: removing purely research components of the work and applying local salaries. This calculation assumed that all resources are fully used, with no spare capacity. The full cost of the operation was assessed at USD 85.4 per km2, of which USD 55.7 or 65.2% were field costs, made up of three component activities (target deployment: 34.5%, trap monitoring: 10.6% and target maintenance: 20.1%). The remaining USD 29.7 or 34.8% of the costs were for preliminary studies and administration (tsetse surveys: 6.0%, sensitisation of local populations: 18.6% and office support: 10.2%). Targets accounted for only 12.9% of the total cost, other important cost components were labour (24.1%) and transport (34.6%). Discussion Comparison with the updated cost of historical HAT vector control projects and recent estimates indicates that this work represents a major reduction in cost levels. This is attributed not just to the low unit cost of tiny targets but also to the organisation of delivery, using local labour with bicycles or motorcycles. Sensitivity analyses were undertaken, investigating key prices and assumptions. It is believed that these costs are generalizable to other HAT foci, although in more remote areas, with denser vegetation and fewer people, costs would increase, as would be the case for other tsetse control techniques. PMID:25811956

Component deficits of visual neglect: "Magnetic" attraction of attention vs. impaired spatial working memory.

PubMed

Toba, Monica N; Rabuffetti, Marco; Duret, Christophe; Pradat-Diehl, Pascale; Gainotti, Guido; Bartolomeo, Paolo

2018-01-31

Visual neglect is a disabling consequence of right hemisphere damage, whereby patients fail to detect left-sided objects. Its precise mechanisms are debated, but there is some consensus that distinct component deficits may variously associate and interact in different patients. Here we used a touch-screen based procedure to study two putative component deficits of neglect, rightward "magnetic" attraction of attention and impaired spatial working memory, in a group of 47 right brain-damaged patients, of whom 33 had signs of left neglect. Patients performed a visual search task on three distinct conditions, whereby touched targets could (1) be tagged, (2) disappear or (3) show no change. Magnetic attraction of attention was defined as more left neglect on the tag condition than on the disappear condition, where right-sided disappeared targets could not capture patients' attention. Impaired spatial working memory should instead produce more neglect on the no change condition, where no external cue indicated that a target had already been explored, than on the tag condition. Using a specifically developed analysis algorithm, we identified significant differences of performance between the critical conditions. Neglect patients as a group performed better on the disappear condition than on the no change condition and also better in the tag condition comparing with the no change condition. No difference was found between the tag condition and the disappear condition. Some of our neglect patients had dissociated patterns of performance, with predominant magnetic attraction or impaired spatial working memory. Anatomical results issued from both grey matter analysis and fiber tracking were consistent with the typical patterns of fronto-parietal and occipito-frontal disconnection in neglect, but did not identify lesional patterns specifically associated with one or another deficit, thus suggesting the possible co-localization of attentional and working memory processes in fronto-parietal networks. These findings give support to the hypothesis of the co-occurrence of distinct cognitive deficits in visual neglect and stress the necessity of multi-component models of visuospatial disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tuning Electron Flux through Nitrogenase with Methanogen Iron Protein Homologues.

PubMed

Hiller, Caleb J; Stiebritz, Martin T; Lee, Chi Chung; Liedtke, Jasper; Hu, Yilin

2017-11-16

Nitrogenase uses a reductase component called Fe protein to deliver electrons to its catalytic partner for substrate reduction. The essential role of Fe protein in catalysis makes it an ideal target for regulating the electron flux and enzymatic activity of nitrogenase without perturbing the cofactor site. This work reports that hybrids between the Fe protein homologs of Methanosarcina acetivorans and the catalytic components of Azotobacter vinelandii can trap substrate CO through reduced electron fluxes. In addition, homology modeling/in silico docking is used to define markers for binding energy and specificity between the component proteins that correlate with the experimentally determined activities. This homologue-based approach could be further developed to allow identification or design of hybrids between homologous nitrogenase components for mechanistic investigations of nitrogenase through capture of substrates/ intermediates or for transgenic expression of nitrogenase through synthetic biology. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Co-translational protein targeting facilitates centrosomal recruitment of PCNT during centrosome maturation in vertebrates

PubMed Central

Mahe, Karan; Ou, Tingyoung; Castro, Noemi M; Christensen, Lana N; Cheung, Lee; Jiang, Xueer; Yoon, Daniel; Huang, Bo

2018-01-01

As microtubule-organizing centers of animal cells, centrosomes guide the formation of the bipolar spindle that segregates chromosomes during mitosis. At mitosis onset, centrosomes maximize microtubule-organizing activity by rapidly expanding the pericentriolar material (PCM). This process is in part driven by the large PCM protein pericentrin (PCNT), as its level increases at the PCM and helps recruit additional PCM components. However, the mechanism underlying the timely centrosomal enrichment of PCNT remains unclear. Here, we show that PCNT is delivered co-translationally to centrosomes during early mitosis by cytoplasmic dynein, as evidenced by centrosomal enrichment of PCNT mRNA, its translation near centrosomes, and requirement of intact polysomes for PCNT mRNA localization. Additionally, the microtubule minus-end regulator, ASPM, is also targeted co-translationally to mitotic spindle poles. Together, these findings suggest that co-translational targeting of cytoplasmic proteins to specific subcellular destinations may be a generalized protein targeting mechanism. PMID:29708497

Cultural differences in the primacy effect for person perception.

PubMed

Noguchi, Kenji; Kamada, Akiko; Shrira, Ilan

2014-06-01

Previous work has shown there are robust differences in how North Americans and East Asians form impressions of people. The present research examines whether the tendency to weigh initial information more heavily-the primacy effect-may be another component of these cultural differences. Specifically, we tested whether Americans would be more likely to use first impressions to guide person perception, compared to Japanese participants. In this experiment, participants read a vignette that described a target person's behaviour, then rated the target's personality. Before reading the vignette, some trait information was given to create an expectation about the target's personality. The data revealed that Americans used this initial information to guide their judgments of the target, whereas the Japanese sample based their judgments on all the information more evenly. Thus, Americans showed a stronger primacy effect in their impression formation than Japanese participants, who engaged in more data-driven processing. © 2013 International Union of Psychological Science.

Tobacco drought stress responses reveal new targets for Solanaceae crop improvement.

PubMed

Rabara, Roel C; Tripathi, Prateek; Reese, R Neil; Rushton, Deena L; Alexander, Danny; Timko, Michael P; Shen, Qingxi J; Rushton, Paul J

2015-06-30

The Solanaceae are an economically important family of plants that include tobacco (Nicotiana tabacum L.), tomato, and potato. Drought is a major cause of crop losses. We have identified major changes in physiology, metabolites, mRNA levels, and promoter activities during the tobacco response to drought. We have classified these as potential components of core responses that may be common to many plant species or responses that may be family/species-specific features of the drought stress response in tobacco or the Solanaceae. In tobacco the largest increase in any metabolite was a striking 70-fold increase in 4-hydroxy-2-oxoglutaric acid (KHG) in roots that appears to be tobacco/Solanaceae specific. KHG is poorly characterized in plants but is broken down to pyruvate and glyoxylate after the E. coli SOS response to facilitate the resumption of respiration. A similar process in tobacco would represent a mechanism to restart respiration upon water availability after drought. At the mRNA level, transcription factor gene induction by drought also showed both core and species/family specific responses. Many Group IX Subgroup 3 AP2/ERF transcription factors in tobacco appear to play roles in nicotine biosynthesis as a response to herbivory, whereas their counterparts in legume species appear to play roles in drought responses. We observed apparent Solanaceae-specific drought induction of several Group IId WRKY genes. One of these, NtWRKY69, showed ABA-independent drought stress-inducible promoter activity that moved into the leaf through the vascular tissue and then eventually into the surrounding leaf cells. We propose components of a core metabolic response to drought stress in plants and also show that some major responses to drought stress at the metabolome and transcriptome levels are family specific. We therefore propose that the observed family-specific changes in metabolism are regulated, at least in part, by family-specific changes in transcription factor activity. We also present a list of potential targets for the improvement of Solanaceae drought responses.

Recovery Act: Advanced Direct Methanol Fuel Cell for Mobile Computing

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

Fletcher, James H.; Cox, Philip; Harrington, William J

2013-09-03

ABSTRACT Project Title: Recovery Act: Advanced Direct Methanol Fuel Cell for Mobile Computing PROJECT OBJECTIVE The objective of the project was to advance portable fuel cell system technology towards the commercial targets of power density, energy density and lifetime. These targets were laid out in the DOE’s R&D roadmap to develop an advanced direct methanol fuel cell power supply that meets commercial entry requirements. Such a power supply will enable mobile computers to operate non-stop, unplugged from the wall power outlet, by using the high energy density of methanol fuel contained in a replaceable fuel cartridge. Specifically this project focusedmore » on balance-of-plant component integration and miniaturization, as well as extensive component, subassembly and integrated system durability and validation testing. This design has resulted in a pre-production power supply design and a prototype that meet the rigorous demands of consumer electronic applications. PROJECT TASKS The proposed work plan was designed to meet the project objectives, which corresponded directly with the objectives outlined in the Funding Opportunity Announcement: To engineer the fuel cell balance-of-plant and packaging to meet the needs of consumer electronic systems, specifically at power levels required for mobile computing. UNF used existing balance-of-plant component technologies developed under its current US Army CERDEC project, as well as a previous DOE project completed by PolyFuel, to further refine them to both miniaturize and integrate their functionality to increase the system power density and energy density. Benefits of UNF’s novel passive water recycling MEA (membrane electrode assembly) and the simplified system architecture it enabled formed the foundation of the design approach. The package design was hardened to address orientation independence, shock, vibration, and environmental requirements. Fuel cartridge and fuel subsystems were improved to ensure effective fuel containment. PROJECT OVERVIEW The University of North Florida (UNF), with project partner the University of Florida, recently completed the Department of Energy (DOE) project entitled “Advanced Direct Methanol Fuel Cell for Mobile Computing”. The primary objective of the project was to advance portable fuel cell system technology towards the commercial targets as laid out in the DOE R&D roadmap by developing a 20-watt, direct methanol fuel cell (DMFC), portable power supply based on the UNF innovative “passive water recovery” MEA. Extensive component, sub-system, and system development and testing was undertaken to meet the rigorous demands of the consumer electronic application. Numerous brassboard (nonpackaged) systems were developed to optimize the integration process and facilitating control algorithm development. The culmination of the development effort was a fully-integrated, DMFC, power supply (referred to as DP4). The project goals were 40 W/kg for specific power, 55 W/l for power density, and 575 Whr/l for energy density. It should be noted that the specific power and power density were for the power section only, and did not include the hybrid battery. The energy density is based on three, 200 ml, fuel cartridges, and also did not include the hybrid battery. The results show that the DP4 system configured without the methanol concentration sensor exceeded all performance goals, achieving 41.5 W/kg for specific power, 55.3 W/l for power density, and 623 Whr/l for energy density. During the project, the DOE revised its technical targets, and the definition of many of these targets, for the portable power application. With this revision, specific power, power density, specific energy (Whr/kg), and energy density are based on the total system, including fuel tank, fuel, and hybridization battery. Fuel capacity is not defined, but the same value is required for all calculations. Test data showed that the DP4 exceeded all 2011 Technical Status values; for example, the DP4 energy density was 373 Whr/l versus the DOE 2011 status of 200 Whr/l. For the DOE 2013 Technical Goals, the operation time was increased from 10 hours to 14.3 hours. Under these conditions, the DP4 closely approached or surpassed the technical targets; for example, the DP4 achieved 468 Whr/l versus the goal of 500 Whr/l. Thus, UNF has successfully met the project goals. A fully-operational, 20-watt DMFC power supply was developed based on the UNF passive water recovery MEA. The power supply meets the project performance goals and advances portable power technology towards the commercialization targets set by the DOE.« less

Targeting Mycobacterium tuberculosis Antigens to Dendritic Cells via the DC-Specific-ICAM3-Grabbing-Nonintegrin Receptor Induces Strong T-Helper 1 Immune Responses

PubMed Central

Velasquez, Lis Noelia; Stüve, Philipp; Gentilini, Maria Virginia; Swallow, Maxine; Bartel, Judith; Lycke, Nils Yngve; Barkan, Daniel; Martina, Mariana; Lujan, Hugo D.; Kalay, Hakan; van Kooyk, Yvette; Sparwasser, Tim D.; Berod, Luciana

2018-01-01

Tuberculosis remains a major global health problem and efforts to develop a more effective vaccine have been unsuccessful so far. Targeting antigens (Ags) to dendritic cells (DCs) in vivo has emerged as a new promising vaccine strategy. In this approach, Ags are delivered directly to DCs via antibodies that bind to endocytic cell-surface receptors. Here, we explored DC-specific-ICAM3-grabbing-nonintegrin (DC-SIGN) targeting as a potential vaccine against tuberculosis. For this, we made use of the hSIGN mouse model that expresses human DC-SIGN under the control of the murine CD11c promoter. We show that in vitro and in vivo delivery of anti-DC-SIGN antibodies conjugated to Ag85B and peptide 25 of Ag85B in combination with anti-CD40, the fungal cell wall component zymosan, and the cholera toxin-derived fusion protein CTA1-DD induces strong Ag-specific CD4+ T-cell responses. Improved anti-mycobacterial immunity was accompanied by increased frequencies of Ag-specific IFN-γ+ IL-2+ TNF-α+ polyfunctional CD4+ T cells in vaccinated mice compared with controls. Taken together, in this study we provide the proof of concept that the human DC-SIGN receptor can be efficiently exploited for vaccine purposes to promote immunity against mycobacterial infections. PMID:29662482

Insulation and wiring specificity of BceR-like response regulators and their target promoters in Bacillus subtilis.

PubMed

Fang, Chong; Nagy-Staroń, Anna; Grafe, Martin; Heermann, Ralf; Jung, Kirsten; Gebhard, Susanne; Mascher, Thorsten

2017-04-01

BceRS and PsdRS are paralogous two-component systems in Bacillus subtilis controlling the response to antimicrobial peptides. In the presence of extracellular bacitracin and nisin, respectively, the two response regulators (RRs) bind their target promoters, P bceA or P psdA , resulting in a strong up-regulation of target gene expression and ultimately antibiotic resistance. Despite high sequence similarity between the RRs BceR and PsdR and their known binding sites, no cross-regulation has been observed between them. We therefore investigated the specificity determinants of P bceA and P psdA that ensure the insulation of these two paralogous pathways at the RR-promoter interface. In vivo and in vitro analyses demonstrate that the regulatory regions within these two promoters contain three important elements: in addition to the known (main) binding site, we identified a linker region and a secondary binding site that are crucial for functionality. Initial binding to the high-affinity, low-specificity main binding site is a prerequisite for the subsequent highly specific binding of a second RR dimer to the low-affinity secondary binding site. In addition to this hierarchical cooperative binding, discrimination requires a competition of the two RRs for their respective binding site mediated by only slight differences in binding affinities. © 2016 John Wiley & Sons Ltd.

Targeted Delivery of LXR Agonist Using a Site-Specific Antibody-Drug Conjugate.

PubMed

Lim, Reyna K V; Yu, Shan; Cheng, Bo; Li, Sijia; Kim, Nam-Jung; Cao, Yu; Chi, Victor; Kim, Ji Young; Chatterjee, Arnab K; Schultz, Peter G; Tremblay, Matthew S; Kazane, Stephanie A

2015-11-18

Liver X receptor (LXR) agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been hindered by on-target adverse effects in the liver mediated by excessive lipogenesis. Herein, we report a novel site-specific antibody-drug conjugate (ADC) that selectively delivers a LXR agonist to monocytes/macrophages while sparing hepatocytes. The unnatural amino acid para-acetylphenylalanine (pAcF) was site-specifically incorporated into anti-CD11a IgG, which binds the α-chain component of the lymphocyte function-associated antigen 1 (LFA-1) expressed on nearly all monocytes and macrophages. An aminooxy-modified LXR agonist was conjugated to anti-CD11a IgG through a stable, cathepsin B cleavable oxime linkage to afford a chemically defined ADC. The anti-CD11a IgG-LXR agonist ADC induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro (EC50-27 nM), but had no significant effect in hepatocytes, indicating that payload delivery is CD11a-mediated. Moreover, the ADC exhibited higher-fold activation compared to a conventional synthetic LXR agonist T0901317 (Tularik) (3-fold). This novel ADC represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis.

Possible role of cochlear nonlinearity in the detection of mistuning of a harmonic component in a harmonic complex

NASA Astrophysics Data System (ADS)

Stoelinga, Christophe; Heo, Inseok; Long, Glenis; Lee, Jungmee; Lutfi, Robert; Chang, An-Chieh

2015-12-01

The human auditory system has a remarkable ability to "hear out" a wanted sound (target) in the background of unwanted sounds. One important property of sound which helps us hear-out the target is inharmonicity. When a single harmonic component of a harmonic complex is slightly mistuned, that component is heard to separate from the rest. At high harmonic numbers, where components are unresolved, the harmonic segregation effect is thought to result from detection of modulation of the time envelope (roughness cue) resulting from the mistuning. Neurophysiological research provides evidence that such envelope modulations are represented early in the auditory system, at the level of the auditory nerve. When the mistuned harmonic is a low harmonic, where components are resolved, the harmonic segregation is attributed to more centrally-located auditory processes, leading harmonic components to form a perceptual group heard separately from the mistuned component. Here we consider an alternative explanation that attributes the harmonic segregation to detection of modulation when both high and low harmonic numbers are mistuned. Specifically, we evaluate the possibility that distortion products in the cochlea generated by the mistuned component introduce detectable beating patterns for both high and low harmonic numbers. Distortion product otoacoustic emissions (DPOAEs) were measured using 3, 7, or 12-tone harmonic complexes with a fundamental frequency (F0) of 200 or 400 Hz. One of two harmonic components was mistuned at each F0: one when harmonics are expected to be resulted and the other from unresolved harmonics. Many non-harmonic DPOAEs are present whenever a harmonic component is mistuned. These non-harmonic DPOAEs are often separated by the amount of the mistuning (ΔF). This small frequency difference will generate a slow beating pattern at ΔF, because this beating is only present when a harmonic component is mistuned, it could provide a cue for behavioral detection of harmonic complex mistuning and may also be associated with the modulation of auditory nerve responses.

Modality-specificity of Selective Attention Networks.

PubMed

Stewart, Hannah J; Amitay, Sygal

2015-01-01

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

miR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage.

PubMed

Bluhm, Björn; Ehlen, Harald W A; Holzer, Tatjana; Georgieva, Veronika S; Heilig, Juliane; Pitzler, Lena; Etich, Julia; Bortecen, Toman; Frie, Christian; Probst, Kristina; Niehoff, Anja; Belluoccio, Daniele; Van den Bergen, Jocelyn; Brachvogel, Bent

2017-10-01

Cartilage originates from mesenchymal cell condensations that differentiate into chondrocytes of transient growth plate cartilage or permanent cartilage of the articular joint surface and trachea. MicroRNAs fine-tune the activation of entire signaling networks and thereby modulate complex cellular responses, but so far only limited data are available on miRNAs that regulate cartilage development. Here, we characterize a miRNA that promotes the biosynthesis of a key component in the RAF/MEK/ERK pathway in cartilage. Specifically, by transcriptome profiling we identified miR-322 to be upregulated during chondrocyte differentiation. Among the various miR-322 target genes in the RAF/MEK/ERK pathway, only Mek1 was identified as a regulated target in chondrocytes. Surprisingly, an increased concentration of miR-322 stabilizes Mek1 mRNA to raise protein levels and dampen ERK1/2 phosphorylation, while cartilage-specific inactivation of miR322 in mice linked the loss of miR-322 to decreased MEK1 levels and to increased RAF/MEK/ERK pathway activation. Such mice died perinatally due to tracheal growth restriction and respiratory failure. Hence, a single miRNA can stimulate the production of an inhibitory component of a central signaling pathway to impair cartilage development. © 2017. Published by The Company of Biologists Ltd.

SERS-fluorescence joint spectral encoded magnetic nanoprobes for multiplex cancer cell separation.

PubMed

Wang, Zhuyuan; Zong, Shenfei; Chen, Hui; Wang, Chunlei; Xu, Shuhong; Cui, Yiping

2014-11-01

A new kind of cancer cell separation method is demonstrated, using surface-enhanced Raman scattering (SERS) and fluorescence dual-encoded magnetic nanoprobes. The designed nanoprobes can realize SERS-fluorescence joint spectral encoding (SFJSE) and greatly improve the multiplexing ability. The nanoprobes have four main components, that is, the magnetic core, SERS generator, fluorescent agent, and targeting antibody. These components are assembled with a multi-layered structure to form the nanoprobes. Specifically, silica-coated magnetic nanobeads (MBs) are used as the inner core. Au core-Ag shell nanorods (Au@Ag NRs) are employed as the SERS generators and attached on the silica-coated MBs. After burying these Au@Ag NRs with another silica layer, CdTe quantum dots (QDs), that is, the fluorescent agent, are anchored onto the silica layer. Finally, antibodies are covalently linked to CdTe QDs. SFJSE is fulfilled by using different Raman molecules and QDs with different emission wavelengths. By utilizing four human cancer cell lines and one normal cell line as the model cells, the nanoprobes can specifically and simultaneously separate target cancer cells from the normal ones. This SFJSE-based method greatly facilitates the multiplex, rapid, and accurate cancer cell separation, and has a prosperous potential in high-throughput analysis and cancer diagnosis. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus

PubMed Central

Bergström, Tomas; Kann, Nina; Adamiak, Beata; Hannoun, Charles; Kindler, Eveline; Jónsdóttir, Hulda R.; Muth, Doreen; Kint, Joeri; Forlenza, Maria; Müller, Marcel A.; Drosten, Christian; Thiel, Volker; Trybala, Edward

2014-01-01

Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS–CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections. PMID:24874215

Smad ubiquitination regulatory factor-2 in the fibrotic kidney: regulation, target specificity, and functional implication.

PubMed

Tan, Ruoyun; He, Weichun; Lin, Xia; Kiss, Lawrence P; Liu, Youhua

2008-05-01

Smad ubiquitination regulatory factor-2 (Smurf2) is an E3 ubiqutin ligase that plays a pivotal role in regulating TGF-beta signaling via selectively targeting key components of the Smad pathway for degradation. In this study, we have investigated the regulation of Smurf2 expression, its target specificity, and the functional implication of its induction in the fibrotic kidney. Immunohistochemical staining revealed that Smurf2 was upregulated specifically in renal tubules of kidney biopsies from patients with various nephropathies. In vitro, Smurf2 mRNA and protein were induced in human proximal tubular epithelial cells (HKC-8) upon TGF-beta1 stimulation. Ectopic expression of Smurf2 was sufficient to reduce the steady-state levels of Smad2, but not Smad1, Smad3, Smad4, and Smad7, in HKC-8 cells. Interestingly, Smurf2 was also able to downregulate the Smad transcriptional corepressors Ski, SnoN, and TG-interacting factor. Inhibition of the proteasomal pathway prevented Smurf2-mediated downregulation of Smad2 and Smad corepressors. Functionally, overexpression of Smurf2 enhanced the transcription of the TGF-beta-responsive promoter and augmented TGF-beta1-mediated E-cadherin suppression, as well as fibronectin and type I collagen induction in HKC-8 cells. These results indicate that Smurf2 specifically targets both positive and negative Smad regulators for destruction in tubular epithelial cells, thereby providing a complex fine-tuning of TGF-beta signaling. It appears that dysregulation of Smurf2 could contribute to an aberrant TGF-beta/Smad signaling in the pathogenesis of kidney fibrosis.

Protein-RNA specificity by high-throughput principal component analysis of NMR spectra.

PubMed

Collins, Katherine M; Oregioni, Alain; Robertson, Laura E; Kelly, Geoff; Ramos, Andres

2015-03-31

Defining the RNA target selectivity of the proteins regulating mRNA metabolism is a key issue in RNA biology. Here we present a novel use of principal component analysis (PCA) to extract the RNA sequence preference of RNA binding proteins. We show that PCA can be used to compare the changes in the nuclear magnetic resonance (NMR) spectrum of a protein upon binding a set of quasi-degenerate RNAs and define the nucleobase specificity. We couple this application of PCA to an automated NMR spectra recording and processing protocol and obtain an unbiased and high-throughput NMR method for the analysis of nucleobase preference in protein-RNA interactions. We test the method on the RNA binding domains of three important regulators of RNA metabolism. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Determinants of Propranolol's Selective Effect on Loss Aversion.

PubMed

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

2015-07-01

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

Staphylococcus aureus Manipulates Innate Immunity through Own and Host-Expressed Proteases.

PubMed

Pietrocola, Giampiero; Nobile, Giulia; Rindi, Simonetta; Speziale, Pietro

2017-01-01

Neutrophils, complement system and skin collectively represent the main elements of the innate immune system, the first line of defense of the host against many common microorganisms. Bacterial pathogens have evolved strategies to counteract all these defense activities. Specifically, Staphylococcus aureus , a major human pathogen, secretes a variety of immune evasion molecules including proteases, which cleave components of the innate immune system or disrupt the integrity of extracellular matrix and intercellular connections of tissues. Additionally, S. aureus secretes proteins that can activate host zymogens which, in turn, target specific defense components. Secreted proteins can also inhibit the anti-bacterial function of neutrophils or complement system proteases, potentiating S. aureus chances of survival. Here, we review the current understanding of these proteases and modulators of host proteases in the functioning of innate immunity and describe the importance of these mechanisms in the pathology of staphylococcal diseases.

Staphylococcus aureus Manipulates Innate Immunity through Own and Host-Expressed Proteases

PubMed Central

Pietrocola, Giampiero; Nobile, Giulia; Rindi, Simonetta; Speziale, Pietro

2017-01-01

Neutrophils, complement system and skin collectively represent the main elements of the innate immune system, the first line of defense of the host against many common microorganisms. Bacterial pathogens have evolved strategies to counteract all these defense activities. Specifically, Staphylococcus aureus, a major human pathogen, secretes a variety of immune evasion molecules including proteases, which cleave components of the innate immune system or disrupt the integrity of extracellular matrix and intercellular connections of tissues. Additionally, S. aureus secretes proteins that can activate host zymogens which, in turn, target specific defense components. Secreted proteins can also inhibit the anti-bacterial function of neutrophils or complement system proteases, potentiating S. aureus chances of survival. Here, we review the current understanding of these proteases and modulators of host proteases in the functioning of innate immunity and describe the importance of these mechanisms in the pathology of staphylococcal diseases. PMID:28529927

Analyte-Triggered DNA-Probe Release from a Triplex Molecular Beacon for Nanopore Sensing.

PubMed

Guo, Bingyuan; Sheng, Yingying; Zhou, Ke; Liu, Quansheng; Liu, Lei; Wu, Hai-Chen

2018-03-26

A new nanopore sensing strategy based on triplex molecular beacon was developed for the detection of specific DNA or multivalent proteins. The sensor is composed of a triplex-forming molecular beacon and a stem-forming DNA component that is modified with a host-guest complex. Upon target DNA hybridizing with the molecular beacon loop or multivalent proteins binding to the recognition elements on the stem, the DNA probe is released and produces highly characteristic current signals when translocated through α-hemolysin. The frequency of current signatures can be used to quantify the concentrations of the target molecules. This sensing approach provides a simple, quick, and modular tool for the detection of specific macromolecules with high sensitivity and excellent selectivity. It may find useful applications in point-of-care diagnostics with a portable nanopore kit in the future. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diversity in case management modalities: the Summit model.

PubMed

Peterson, G A; Drone, I D; Munetz, M R

1997-06-01

Though ubiquitous in community mental health agencies, case management suffers from a lack of consensus regarding its definition, essential components, and appropriate application. Meaningful comparisons of various case management models await such a consensus. Global assessments of case management must be replaced by empirical studies of specific interventions with respect to the needs of specific populations. The authors describe a highly differentiated and prescriptive system of case management involving the application of more than one model of service delivery. Such a diversified and targeted system offers an opportunity to study the technology of case management in a more meaningful manner.

Epigenetics of breast cancer: modifying role of environmental and bioactive food compounds

PubMed Central

Romagnolo, Donato F.; Daniels, Kevin D.; Grunwald, Jonathan T.; Ramos, Stephan A.; Propper, Catherine R.; Selmin, Ornella I.

2017-01-01

Scope Reduced expression of tumor suppressor genes (TSG) increases the susceptibility to breast cancer. However, only a small percentage of breast tumors is related to family history and mutational inactivation of TSG. Epigenetics refers to non-mutational events that alter gene expression. Endocrine disruptors found in foods and drinking water may disrupt epigenetically hormonal regulation and increase breast cancer risk. This review centers on the working hypothesis that agonists of the aromatic hydrocarbon receptor (AHR); bisphenol A (BPA); and arsenic compounds, induce in TSG epigenetic signatures that mirror those often seen in sporadic breast tumors. Conversely, it is hypothesized that bioactive food components that target epigenetic mechanisms protect against sporadic breast cancer induced by these disruptors. Methods and results This review highlights 1) overlaps between epigenetic signatures placed in TSG by AHR-ligands, BPA, and arsenic with epigenetic alterations associated with sporadic breast tumorigenesis; and 2) potential opportunities for prevention of sporadic breast cancer with food components that target the epigenetic machinery. Conclusions Characterizing the overlap between epigenetic signatures elicited in TSG by endocrine disruptors with those observed in sporadic breast tumors may afford new strategies for breast cancer prevention with specific bioactive food components or diet. PMID:27144894

Nontechnical skill training and the use of scenarios in modern surgical education.

PubMed

Brunckhorst, Oliver; Khan, Muhammad S; Dasgupta, Prokar; Ahmed, Kamran

2017-07-01

Nontechnical skills are being increasingly recognized as a core reason of surgical errors. Combined with the changing nature of surgical training, there has therefore been an increase in nontechnical skill research in the literature. This review therefore aims to: define nontechnical skillsets, assess current training methods, explore assessment modalities and suggest future research aims. The literature demonstrates an increasing understanding of the components of nontechnical skills within surgery. This has led to a greater availability of validated training methods for its training, including the use of didactic teaching, e-learning and simulation-based scenarios. In addition, there are now various extensively validated assessment tools for nontechnical skills including NOTSS, the Oxford NOTECHS and OTAS. Finally, there is now more focus on the development of tools which target individual nontechnical skill components and an attempt to understand which of these play a greater role in specific procedures such as laparoscopic or robotic surgery. Current evidence demonstrates various training methods and tools for the training of nontechnical skills. Future research is likely to focus increasingly on individual nontechnical skill components and procedure-specific skills.

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

NASA Astrophysics Data System (ADS)

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

2016-04-01

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

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

PubMed Central

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

2016-01-01

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

[Targeted public funding for health research in the Netherlands].

PubMed

Viergever, Roderik F; Hendriks, Thom C C

2014-01-01

The Dutch government funds health research in several ways. One component of public funding consists of funding programmes issued by the Netherlands Organisation for Health Research and Development (ZonMw). The majority of ZonMw's programmes provide funding for research in specific health research areas. Such targeted funding plays an important role in addressing knowledge gaps and in generating products for which there is a need. Good governance of the allocation of targeted funding for health research requires three elements: a research agenda, an overview of the health research currently being conducted, and a transparent decision-making process regarding the distribution of funds. In this article, we describe how public funding for health research is organized in the Netherlands and how the allocation of targeted funds is governed. By describing the questions that the current model of governance raises, we take a first step towards a debate about the governance of targeted public funding for health research in the Netherlands.

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

PubMed

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

2016-12-01

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

Taking a Radical Position: Evidence for Position-Specific Radical Representations in Chinese Character Recognition Using Masked Priming ERP

PubMed Central

Su, I.-Fan; Mak, Sin-Ching Cassie; Cheung, Lai-Ying Milly; Law, Sam-Po

2012-01-01

In the investigation of orthographic representation of Chinese characters, one question that has stimulated much research is whether radicals (character components) are specified for spatial position in a character (e.g., Ding et al., 2004; Tsang and Chen, 2009). Differing from previous work, component or radical position information in this study is conceived in terms of relative frequency across different positions of characters containing it. A lexical decision task in a masked priming paradigm focusing on radicals with preferred position of occurrence was conducted. A radical position that encompasses more characters than other positions was identified to be the preferred position of a particular radical. The prime that was exposed for 96 ms might share a radical with the target in the same or different positions. Moreover, the shared radical appeared either in its preferred or non-preferred position in the target. While response latencies only revealed the effect of graphical similarity, both effects of graphical similarity and radical position preference were found in the event-related potential (ERP) results. The former effect was reflected in greater positivity in occipital P1 and greater negativity in N400 for radicals in different positions in prime and target characters. The latter effect manifested as greater negativity in occipital N170 and greater positivity in frontal P200 in the same time window elicited by radicals in their non-preferred position. Equally interesting was the reversal of the effect of radical position preference in N400 with greater negativity associated with radicals in preferred position. These findings identify the early ERP components associated with activation of position-specific radical representations in the orthographic lexicon, and reveal the change in the nature of competition from processing at the radical level to the lexical level. PMID:23024634

Messenger RNA biomarker signatures for forensic body fluid identification revealed by targeted RNA sequencing.

PubMed

Hanson, E; Ingold, S; Haas, C; Ballantyne, J

2018-05-01

The recovery of a DNA profile from the perpetrator or victim in criminal investigations can provide valuable 'source level' information for investigators. However, a DNA profile does not reveal the circumstances by which biological material was transferred. Some contextual information can be obtained by a determination of the tissue or fluid source of origin of the biological material as it is potentially indicative of some behavioral activity on behalf of the individual that resulted in its transfer from the body. Here, we sought to improve upon established RNA based methods for body fluid identification by developing a targeted multiplexed next generation mRNA sequencing assay comprising a panel of approximately equal sized gene amplicons. The multiplexed biomarker panel includes several highly specific gene targets with the necessary specificity to definitively identify most forensically relevant biological fluids and tissues (blood, semen, saliva, vaginal secretions, menstrual blood and skin). In developing the biomarker panel we evaluated 66 gene targets, with a progressive iteration of testing target combinations that exhibited optimal sensitivity and specificity using a training set of forensically relevant body fluid samples. The current assay comprises 33 targets: 6 blood, 6 semen, 6 saliva, 4 vaginal secretions, 5 menstrual blood and 6 skin markers. We demonstrate the sensitivity and specificity of the assay and the ability to identify body fluids in single source and admixed stains. A 16 sample blind test was carried out by one lab with samples provided by the other participating lab. The blinded lab correctly identified the body fluids present in 15 of the samples with the major component identified in the 16th. Various classification methods are being investigated to permit inference of the body fluid/tissue in dried physiological stains. These include the percentage of reads in a sample that are due to each of the 6 tissues/body fluids tested and inter-sample differential gene expression revealed by agglomerative hierarchical clustering. Copyright © 2018 Elsevier B.V. All rights reserved.

Insights into the molecular mechanisms of Polygonum multiflorum Thunb-induced liver injury: a computational systems toxicology approach.

PubMed

Wang, Yin-Yin; Li, Jie; Wu, Zeng-Rui; Zhang, Bo; Yang, Hong-Bin; Wang, Qin; Cai, Ying-Chun; Liu, Gui-Xia; Li, Wei-Hua; Tang, Yun

2017-05-01

An increasing number of cases of herb-induced liver injury (HILI) have been reported, presenting new clinical challenges. In this study, taking Polygonum multiflorum Thunb (PmT) as an example, we proposed a computational systems toxicology approach to explore the molecular mechanisms of HILI. First, the chemical components of PmT were extracted from 3 main TCM databases as well as the literature related to natural products. Then, the known targets were collected through data integration, and the potential compound-target interactions (CTIs) were predicted using our substructure-drug-target network-based inference (SDTNBI) method. After screening for hepatotoxicity-related genes by assessing the symptoms of HILI, a compound-target interaction network was constructed. A scoring function, namely, Ascore, was developed to estimate the toxicity of chemicals in the liver. We conducted network analysis to determine the possible mechanisms of the biphasic effects using the analysis tools, including BiNGO, pathway enrichment, organ distribution analysis and predictions of interactions with CYP450 enzymes. Among the chemical components of PmT, 54 components with good intestinal absorption were used for analysis, and 2939 CTIs were obtained. After analyzing the mRNA expression data in the BioGPS database, 1599 CTIs and 125 targets related to liver diseases were identified. In the top 15 compounds, seven with Ascore values >3000 (emodin, quercetin, apigenin, resveratrol, gallic acid, kaempferol and luteolin) were obviously associated with hepatotoxicity. The results from the pathway enrichment analysis suggest that multiple interactions between apoptosis and metabolism may underlie PmT-induced liver injury. Many of the pathways have been verified in specific compounds, such as glutathione metabolism, cytochrome P450 metabolism, and the p53 pathway, among others. Hepatitis symptoms, the perturbation of nine bile acids and yellow or tawny urine also had corresponding pathways, justifying our method. In conclusion, this computational systems toxicology method reveals possible toxic components and could be very helpful for understanding the mechanisms of HILI. In this way, the method might also facilitate the identification of novel hepatotoxic herbs.

The Csr/Rsm system of Yersinia and related pathogens: a post-transcriptional strategy for managing virulence.

PubMed

Heroven, Ann Kathrin; Böhme, Katja; Dersch, Petra

2012-04-01

This review emphasizes the function and regulation of the Csr regulatory system in the human enteropathogen Yersinia pseudotuberculosis and compares its features with the homologous Csr/Rsm systems of related pathogens. The Csr/Rsm systems of eubacteria form a complex regulatory network in which redundant non-translated Csr/Rsm-RNAs bind the RNA-binding protein CsrA/RsmA, thereby preventing its interaction with mRNA targets. The Csr system is controlled by the BarA/UvrY-type of two-component sensor-regulator systems. Apart from that, common or pathogen-specific regulators control the abundance of the Csr components. The coordinate control of virulence factors and infection-linked physiological traits by the Csr/Rsm systems helps the pathogens to adapt individually to rapidly changing conditions to which they are exposed during the different stages of an infection. As Csr/Rsm function is relevant for full virulence, it represents a target suitable for antimicrobial drug development.

Visualization of the Serratia Type VI Secretion System Reveals Unprovoked Attacks and Dynamic Assembly

PubMed Central

Gerc, Amy J.; Diepold, Andreas; Trunk, Katharina; Porter, Michael; Rickman, Colin; Armitage, Judith P.; Stanley-Wall, Nicola R.; Coulthurst, Sarah J.

2015-01-01

Summary The Type VI secretion system (T6SS) is a bacterial nanomachine that fires toxic proteins into target cells. Deployment of the T6SS represents an efficient and widespread means by which bacteria attack competitors or interact with host organisms and may be triggered by contact from an attacking neighbor cell as a defensive strategy. Here, we use the opportunist pathogen Serratia marcescens and functional fluorescent fusions of key components of the T6SS to observe different subassemblies of the machinery simultaneously and on multiple timescales in vivo. We report that the localization and dynamic behavior of each of the components examined is distinct, revealing a multi-stage and dynamic assembly process for the T6SS machinery. We also show that the T6SS can assemble and fire without needing a cell contact trigger, defining an aggressive strategy that broadens target range and suggesting that activation of the T6SS is tailored to survival in specific niches. PMID:26387948

eHealth and the use of individually tailored information: A systematic review.

PubMed

Conway, Nicholas; Webster, Clare; Smith, Blair; Wake, Deborah

2017-09-01

Tailored messages are those that specifically target individuals following an assessment of their unique characteristics. This systematic review assesses the evidence regarding the effectiveness of tailoring within eHealth interventions aimed at chronic disease management. OVID Medline/Embase databases were searched for randomised control trials, controlled clinical, trials, before -after studies, and time series analyses from inception - May 2014. Objectively measured clinical processes/outcomes were considered. Twenty-two papers were eligible for inclusion: 6/22 used fully tailored messaging and 16/22 used partially tailored messages. Two studies isolated tailoring as the active component. The remainder compared intervention with standard care. In all, 12/16 studies measuring clinical processes and 2/6 studies reporting clinical outcomes showed improvements, regardless of target group. Study quality was low and design did not allow for identification of interventions' active component. Heterogeneity precluded meta-analysis. This review has demonstrated that there is a lack of evidence to suggest that tailoring within an eHealth context confers benefit over non-tailored eHealth interventions.

Development and application of a rapid and visual loop-mediated isothermal amplification for the detection of Sporisorium scitamineum in sugarcane

PubMed Central

Su, Yachun; Yang, Yuting; Peng, Qiong; Zhou, Dinggang; Chen, Yun; Wang, Zhuqing; Xu, Liping; Que, Youxiong

2016-01-01

Smut is a fungal disease with widespread prevalence in sugarcane planting areas. Early detection and proper identification of Sporisorium scitamineum are essential in smut management practices. In the present study, four specific primers targeting the core effector Pep1 gene of S. scitamineum were designed. Optimal concentrations of Mg2+, primer and Bst DNA polymerase, the three important components of the loop-mediated isothermal amplification (LAMP) reaction system, were screened using a single factor experiment method and the L16(45) orthogonal experimental design. Hence, a LAMP system suitable for detection of S. scitamineum was established. High specificity of the LAMP method was confirmed by the assay of S. scitamineum, Fusarium moniliforme, Pestalotia ginkgo, Helminthospcrium sacchari, Fusarium oxysporum and endophytes of Yacheng05-179 and ROC22. The sensitivity of the LAMP method was equal to that of the conventional PCR targeting Pep1 gene and was 100 times higher than that of the conventional PCR assay targeting bE gene in S. scitamineum. The results suggest that this novel LAMP system has strong specificity and high sensitivity. This method not only provides technological support for the epidemic monitoring of sugarcane smut, but also provides a good case for development of similar detection technology for other plant pathogens. PMID:27035751

Targeted metabolomic profiling in rat tissues reveals sex differences.

PubMed

Ruoppolo, Margherita; Caterino, Marianna; Albano, Lucia; Pecce, Rita; Di Girolamo, Maria Grazia; Crisci, Daniela; Costanzo, Michele; Milella, Luigi; Franconi, Flavia; Campesi, Ilaria

2018-03-16

Sex differences affect several diseases and are organ-and parameter-specific. In humans and animals, sex differences also influence the metabolism and homeostasis of amino acids and fatty acids, which are linked to the onset of diseases. Thus, the use of targeted metabolite profiles in tissues represents a powerful approach to examine the intermediary metabolism and evidence for any sex differences. To clarify the sex-specific activities of liver, heart and kidney tissues, we used targeted metabolomics, linear discriminant analysis (LDA), principal component analysis (PCA), cluster analysis and linear correlation models to evaluate sex and organ-specific differences in amino acids, free carnitine and acylcarnitine levels in male and female Sprague-Dawley rats. Several intra-sex differences affect tissues, indicating that metabolite profiles in rat hearts, livers and kidneys are organ-dependent. Amino acids and carnitine levels in rat hearts, livers and kidneys are affected by sex: male and female hearts show the greatest sexual dimorphism, both qualitatively and quantitatively. Finally, multivariate analysis confirmed the influence of sex on the metabolomics profiling. Our data demonstrate that the metabolomics approach together with a multivariate approach can capture the dynamics of physiological and pathological states, which are essential for explaining the basis of the sex differences observed in physiological and pathological conditions.

HDACs and HDAC inhibitors in urothelial carcinoma - perspectives for an antineoplastic treatment.

PubMed

Pinkerneil, Maria; Hoffmann, Michèle J; Schulz, Wolfgang A; Niegisch, Günter

2017-01-11

Histone deacetylases (HDACs) influence diverse cellular processes and may contribute to tumor development and progression by multiple mechanisms. Class I HDACs are often overexpressed in cancers contributing to a genome-wide epigenetic state permitting increased proliferation, and diminished apoptosis and cell differentiation. Class IIA and IIB isoenzymes may likewise contribute to tumorigenesis as components of specific intranuclear repressor complexes or regulators of posttranslational protein modifications. As HDAC inhibitors may counteract these tumorigenic effects several of these compounds are currently tested in clinical trials. HDAC inhibitors are also considered for urothelial carcinoma, where novel therapeutic drugs are urgently required. However, only modest antineoplastic activity has been observed with isoenzyme-unspecific pan-HDAC inhibitors. Therefore, inhibition of specific HDAC isoenzymes might be more efficacious and tumor-specific. Here, we systematically review knowledge on the expression, function and suitability as therapeutic targets of the 11 classical HDACs in UC. Overall, the class I HDACs HDAC1 and HDAC2 are the most promising targets for antineoplastic treatment. In contrast, targeting HDAC8 and HDAC6 is likely to be of minor relevance in urothelial carcinoma. Class IIA HDACs like HDAC4 require further study, since their downregulation rather than upregulation could be involved in urothelial carcinoma pathogenesis.

Advanced Lithium-Ion Cell Development for NASA's Constellation Missions

NASA Technical Reports Server (NTRS)

Reid, Concha M.; Miller, Thomas B.; Manzo, Michelle A.; Mercer, Carolyn R.

2008-01-01

The Energy Storage Project of NASA s Exploration Technology Development Program is developing advanced lithium-ion batteries to meet the requirements for specific Constellation missions. NASA GRC, in conjunction with JPL and JSC, is leading efforts to develop High Energy and Ultra High Energy cells for three primary Constellation customers: Altair, Extravehicular Activities (EVA), and Lunar Surface Systems. The objective of the High Energy cell development is to enable a battery system that can operationally deliver approximately 150 Wh/kg for 2000 cycles. The Ultra High Energy cell development will enable a battery system that can operationally deliver 220 Wh/kg for 200 cycles. To accomplish these goals, cathode, electrolyte, separator, and safety components are being developed for High Energy Cells. The Ultra High Energy cell development adds lithium alloy anodes to the component development portfolio to enable much higher cell-level specific energy. The Ultra High Energy cell development is targeted for the ascent stage of Altair, which is the Lunar Lander, and for power for the Portable Life support System of the EVA Lunar spacesuit. For these missions, mass is highly critical, but only a limited number of cycles are required. The High Energy cell development is primarily targeted for Mobility Systems (rovers) for Lunar Surface Systems, however, due to the high risk nature of the Ultra High Energy cell development, the High Energy cell will also serve as a backup technology for Altair and EVA. This paper will discuss mission requirements and the goals of the material, component, and cell development efforts in further detail.

Improved GGIW-PHD filter for maneuvering non-ellipsoidal extended targets or group targets tracking based on sub-random matrices.

PubMed

Liang, Zhibing; Liu, Fuxian; Gao, Jiale

2018-01-01

For non-ellipsoidal extended targets and group targets tracking (NETT and NGTT), using an ellipsoid to approximate the target extension may not be accurate enough because of the lack of shape and orientation information. In consideration of this, we model a non-ellipsoidal extended target or target group as a combination of multiple ellipsoidal sub-objects, each represented by a random matrix. Based on these models, an improved gamma Gaussian inverse Wishart probability hypothesis density (GGIW-PHD) filter is proposed to estimate the measurement rates, kinematic states, and extension states of the sub-objects for each extended target or target group. For maneuvering NETT and NGTT, a multi-model (MM) approach based GGIW-PHD (MM-GGIW-PHD) filter is proposed. The common and the individual dynamics of the sub-objects belonging to the same extended target or target group are described by means of the combination between the overall maneuver model and the sub-object models. For the merging of updating components, an improved merging criterion and a new merging method are derived. A specific implementation of prediction partition with pseudo-likelihood method is presented. Two scenarios for non-maneuvering and maneuvering NETT and NGTT are simulated. The results demonstrate the effectiveness of the proposed algorithms.

Improved GGIW-PHD filter for maneuvering non-ellipsoidal extended targets or group targets tracking based on sub-random matrices

PubMed Central

Liu, Fuxian; Gao, Jiale

2018-01-01

For non-ellipsoidal extended targets and group targets tracking (NETT and NGTT), using an ellipsoid to approximate the target extension may not be accurate enough because of the lack of shape and orientation information. In consideration of this, we model a non-ellipsoidal extended target or target group as a combination of multiple ellipsoidal sub-objects, each represented by a random matrix. Based on these models, an improved gamma Gaussian inverse Wishart probability hypothesis density (GGIW-PHD) filter is proposed to estimate the measurement rates, kinematic states, and extension states of the sub-objects for each extended target or target group. For maneuvering NETT and NGTT, a multi-model (MM) approach based GGIW-PHD (MM-GGIW-PHD) filter is proposed. The common and the individual dynamics of the sub-objects belonging to the same extended target or target group are described by means of the combination between the overall maneuver model and the sub-object models. For the merging of updating components, an improved merging criterion and a new merging method are derived. A specific implementation of prediction partition with pseudo-likelihood method is presented. Two scenarios for non-maneuvering and maneuvering NETT and NGTT are simulated. The results demonstrate the effectiveness of the proposed algorithms. PMID:29444144

Improvement of the quantitation method for the tdh+ Vibrio parahaemolyticus in molluscan shellfish based on most-probable- number, immunomagnetic separation, and loop-mediated isothermal amplification

PubMed Central

Escalante-Maldonado, Oscar; Kayali, Ahmad Y.; Yamazaki, Wataru; Vuddhakul, Varaporn; Nakaguchi, Yoshitsugu; Nishibuchi, Mitsuaki

2015-01-01

Vibrio parahaemolyticus is a marine microorganism that can cause seafood-borne gastroenteritis in humans. The infection can be spread and has become a pandemic through the international trade of contaminated seafood. Strains carrying the tdh gene encoding the thermostable direct hemolysin (TDH) and/or the trh gene encoding the TDH-related hemolysin (TRH) are considered to be pathogenic with the former gene being the most frequently found in clinical strains. However, their distribution frequency in environmental isolates is below 1%. Thus, very sensitive methods are required for detection and quantitation of tdh+ strains in seafood. We previously reported a method to detect and quantify tdh+ V. parahaemolyticus in seafood. This method consists of three components: the most-probable-number (MPN), the immunomagnetic separation (IMS) targeting all established K antigens, and the loop-mediated isothermal amplification (LAMP) targeting the tdh gene. However, this method faces regional issues in tropical zones of the world. Technicians have difficulties in securing dependable reagents in high-temperature climates where we found MPN underestimation in samples having tdh+ strains as well as other microorganisms present at high concentrations. In the present study, we solved the underestimation problem associated with the salt polymyxin broth enrichment for the MPN component and with the immunomagnetic bead-target association for the IMS component. We also improved the supply and maintenance of the dependable reagents by introducing a dried reagent system to the LAMP component. The modified method is specific, sensitive, quick and easy and applicable regardless of the concentrations of tdh+ V. parahaemolyticus. Therefore, we conclude this modified method is useful in world tropical, sub-tropical, and temperate zones. PMID:25914681

Laser selective microablation of sensitized intracellular components within auditory receptor cells

NASA Astrophysics Data System (ADS)

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

1995-05-01

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

Method for multimodal analysis of independent source differences in schizophrenia: combining gray matter structural and auditory oddball functional data.

PubMed

Calhoun, V D; Adali, T; Giuliani, N R; Pekar, J J; Kiehl, K A; Pearlson, G D

2006-01-01

The acquisition of both structural MRI (sMRI) and functional MRI (fMRI) data for a given study is a very common practice. However, these data are typically examined in separate analyses, rather than in a combined model. We propose a novel methodology to perform independent component analysis across image modalities, specifically, gray matter images and fMRI activation images as well as a joint histogram visualization technique. Joint independent component analysis (jICA) is used to decompose a matrix with a given row consisting of an fMRI activation image resulting from auditory oddball target stimuli and an sMRI gray matter segmentation image, collected from the same individual. We analyzed data collected on a group of schizophrenia patients and healthy controls using the jICA approach. Spatially independent joint-components are estimated and resulting components were further analyzed only if they showed a significant difference between patients and controls. The main finding was that group differences in bilateral parietal and frontal as well as posterior temporal regions in gray matter were associated with bilateral temporal regions activated by the auditory oddball target stimuli. A finding of less patient gray matter and less hemodynamic activity for target detection in these bilateral anterior temporal lobe regions was consistent with previous work. An unexpected corollary to this finding was that, in the regions showing the largest group differences, gray matter concentrations were larger in patients vs. controls, suggesting that more gray matter may be related to less functional connectivity in the auditory oddball fMRI task. Hum Brain Mapp, 2005. (c) 2005 Wiley-Liss, Inc.

A Features Selection for Crops Classification

NASA Astrophysics Data System (ADS)

Liu, Yifan; Shao, Luyi; Yin, Qiang; Hong, Wen

2016-08-01

The components of the polarimetric target decomposition reflect the differences of target since they linked with the scattering properties of the target and can be imported into SVM as the classification features. The result of decomposition usually concentrate on part of the components. Selecting a combination of components can reduce the features that importing into the SVM. The features reduction can lead to less calculation and targeted classification of one target when we classify a multi-class area. In this research, we import different combinations of features into the SVM and find a better combination for classification with a data of AGRISAR.

Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway.

PubMed

Follansbee, Taylor L; Gjelsvik, Kayla J; Brann, Courtney L; McParland, Aidan L; Longhurst, Colin A; Galko, Michael J; Ganter, Geoffrey K

2017-08-30

Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans. SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a sensitized state. These findings are consistent with the observation that BMP receptor hyperactivation correlates with bone abnormalities and pain sensitization in fibrodysplasia ossificans progressiva (Kitterman et al., 2012). Because nociceptive sensitization is associated with chronic pain, these findings indicate that human BMP pathway components may represent targets for novel pain-relieving drugs. Copyright © 2017 the authors 0270-6474/17/378524-10$15.00/0.

Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway

PubMed Central

Follansbee, Taylor L.; Gjelsvik, Kayla J.; Brann, Courtney L.; McParland, Aidan L.

2017-01-01

Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans. SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a sensitized state. These findings are consistent with the observation that BMP receptor hyperactivation correlates with bone abnormalities and pain sensitization in fibrodysplasia ossificans progressiva (Kitterman et al., 2012). Because nociceptive sensitization is associated with chronic pain, these findings indicate that human BMP pathway components may represent targets for novel pain-relieving drugs. PMID:28855331

Enabling interoperability in Geoscience with GI-suite

NASA Astrophysics Data System (ADS)

Boldrini, Enrico; Papeschi, Fabrizio; Santoro, Mattia; Nativi, Stefano

2015-04-01

GI-suite is a brokering framework targeting interoperability of heterogeneous systems in the Geoscience domain. The framework is composed by different brokers each one focusing on a specific functionality: discovery, access and semantics (i.e. GI-cat, GI-axe, GI-sem). The brokering takes place between a set of heterogeneous publishing services and a set of heterogeneous consumer applications: the brokering target is represented by resources (e.g. coverages, features, or metadata information) required to seamlessly flow from the providers to the consumers. Different international and community standards are now supported by GI-suite, making possible the successful deployment of GI-suite in many international projects and initiatives (such as GEOSS, NSF BCube and several EU funded projects). As for the publisher side more than 40 standards and implementations are supported (e.g. Dublin Core, OAI-PMH, OGC W*S, Geonetwork, THREDDS Data Server, Hyrax Server, etc.). The support for each individual standard is provided by means of specific GI-suite components, called accessors. As for the consumer applications side more than 15 standards and implementations are supported (e.g. ESRI ArcGIS, Openlayers, OGC W*S, OAI-PMH clients, etc.). The support for each individual standard is provided by means of specific profiler components. The GI-suite can be used in different scenarios by different actors: - A data provider having a pre-existent data repository can deploy and configure GI-suite to broker it and making thus available its data resources through different protocols to many different users (e.g. for data discovery and/or data access) - A data consumer can use GI-suite to discover and/or access resources from a variety of publishing services that are already publishing data according to well-known standards. - A community can deploy and configure GI-suite to build a community (or project-specific) broker: GI-suite can broker a set of community related repositories and make their content available (for discovery and/or access) through specific service interfaces. The GI-conf web tool can be used to easily configure GI-suite. By enabling specific accessors and profilers, as well as many other settings, GI-suite can be tailored to the desired use scenario. Moreover, thanks to its flexible architecture, GI-suite can be easily extended to support a new standard or implementation: a Java Development Kit is available to help development of new extensions (e.g. a new accessor component).

Target Identification of Grape Seed Extract in Colorectal Cancer using Drug Affinity Responsive Target Stability (DARTS) Technique: Role of Endoplasmic Reticulum Stress Response Proteins

PubMed Central

Derry, Molly M.; Somasagara, Ranganatha; Raina, Komal; Kumar, Sushil; Gomez, Joe; Patel, Manisha; Agarwal, Rajesh; Agarwal, Chapla

2014-01-01

Various natural agents, including grape seed extract (GSE), have shown considerable chemopreventive and anti-cancer efficacy against different cancers in pre-clinical studies; however, their specific protein targets are largely unknown and thus, their clinical usefulness is marred by limited scientific evidences about their direct cellular targets. Accordingly, herein, employing, for the first time, the recently developed drug affinity responsive target stability (DARTS) technique, we aimed to profile the potential protein targets of GSE in human colorectal cancer (CRC) cells. Unlike other methods, which can cause chemical alteration of the drug components to allow for detection, this approach relies on the fact that a drug bound protein may become less susceptible to proteolysis and hence the enriched proteins can be detected by Mass Spectroscopy methods. Our results, utilizing the DARTS technique followed by examination of the spectral output by LC/MS and the MASCOT data, revealed that GSE targets endoplasmic reticulum (ER) stress response proteins resulting in overall down regulation of proteins involved in translation and that GSE also causes oxidative protein modifications, specifically on methionine amino acids residues on its protein targets. Corroborating these findings, mechanistic studies revealed that GSE indeed caused ER stress and strongly inhibited PI3k-Akt–mTOR pathway for its biological effects in CRC cells. Furthermore, bioenergetics studies indicated that GSE also interferes with glycolysis and mitochondrial metabolism in CRC cells. Together, the present study identifying GSE molecular targets in CRC cells, combined with its efficacy in vast pre-clinical CRC models, further supports its usefulness for CRC prevention and treatment. PMID:24724981

Venus Express Chemical Propulsion System - The Mars Express Legacy

NASA Astrophysics Data System (ADS)

Hunter, C. J.

2004-10-01

ESA's ambition of inter-planetary exploration using a fast-track low cost industrial programme was well achieved with Mars Express. Reusing the platform architecture for the service module and specifically the Propulsion system enabled Venus Express to benefit from several lessons learnt from the Mars Express experience. Using all existing components qualified for previous programmes, many of them commercial telecommunication spacecraft programmes with components available from stock, an industrial organisation familiar from Mars Express was able to compress the schedule to make the November 2005 launch window a realistic target. While initial inspection of the CPS schematic indicates a modified Eurostar type architecture, - a similar system using some Eurostar components - would be a fairer description. The use of many parts of the system on arrival at the destination (Mars or Venus in this case) is a departure from the usual mode of operation, where many components are used during the initial few weeks of GTO or GEO. The system modifications over the basic Eurostar system have catered for this in terms of reliability contingencies by replacing components, or providing different levels of test capability or isolation in flight. This paper aims to provide an introduction to the system, address the evolution from Eurostar, and provide an initial assessment of the success of these modifications using the Mars Express experience, and how measures have been adopted specifically for Venus Express.

Architecture, Voltage, and Components for a Turboelectric Distributed Propulsion Electric Grid

NASA Technical Reports Server (NTRS)

Armstrong, Michael J.; Blackwelder, Mark; Bollman, Andrew; Ross, Christine; Campbell, Angela; Jones, Catherine; Norman, Patrick

2015-01-01

The development of a wholly superconducting turboelectric distributed propulsion system presents unique opportunities for the aerospace industry. However, this transition from normally conducting systems to superconducting systems significantly increases the equipment complexity necessary to manage the electrical power systems. Due to the low technology readiness level (TRL) nature of all components and systems, current Turboelectric Distributed Propulsion (TeDP) technology developments are driven by an ambiguous set of system-level electrical integration standards for an airborne microgrid system (Figure 1). While multiple decades' worth of advancements are still required for concept realization, current system-level studies are necessary to focus the technology development, target specific technological shortcomings, and enable accurate prediction of concept feasibility and viability. An understanding of the performance sensitivity to operating voltages and an early definition of advantageous voltage regulation standards for unconventional airborne microgrids will allow for more accurate targeting of technology development. Propulsive power-rated microgrid systems necessitate the introduction of new aircraft distribution system voltage standards. All protection, distribution, control, power conversion, generation, and cryocooling equipment are affected by voltage regulation standards. Information on the desired operating voltage and voltage regulation is required to determine nominal and maximum currents for sizing distribution and fault isolation equipment, developing machine topologies and machine controls, and the physical attributes of all component shielding and insulation. Voltage impacts many components and system performance.

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

NASA Technical Reports Server (NTRS)

Svendsen, Robert F., Jr.

1987-01-01

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

Antigen-Specific Immune Modulation Targets mTORC1 Function To Drive Chemokine Receptor-Mediated T Cell Tolerance.

PubMed

Chen, Weirong; Wan, Xiaoxiao; Ukah, Tobechukwu K; Miller, Mindy M; Barik, Subhasis; Cattin-Roy, Alexis N; Zaghouani, Habib

2016-11-01

To contain autoimmunity, pathogenic T cells must be eliminated or diverted from reaching the target organ. Recently, we defined a novel form of T cell tolerance whereby treatment with Ag downregulates expression of the chemokine receptor CXCR3 and prevents diabetogenic Th1 cells from reaching the pancreas, leading to suppression of type 1 diabetes (T1D). This report defines the signaling events underlying Ag-induced chemokine receptor-mediated tolerance. Specifically, we show that the mammalian target of rapamycin complex 1 (mTORC1) is a major target for induction of CXCR3 downregulation and crippling of Th1 cells. Indeed, Ag administration induces upregulation of programmed death-ligand 1 on dendritic cells in a T cell-dependent manner. In return, programmed death-ligand 1 interacts with the constitutively expressed programmed death-1 on the target T cells and stimulates docking of Src homology 2 domain-containing tyrosine phosphatase 2 phosphatase to the cytoplasmic tail of programmed death-1. Active Src homology 2 domain-containing tyrosine phosphatase 2 impairs the signaling function of the PI3K/protein kinase B (AKT) pathway, leading to functional defect of mTORC1, downregulation of CXCR3 expression, and suppression of T1D. Thus, mTORC1 component of the metabolic pathway serves as a target for chemokine receptor-mediated T cell tolerance and suppression of T1D. Copyright © 2016 by The American Association of Immunologists, Inc.

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

NASA Astrophysics Data System (ADS)

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

2018-06-01

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

Active suppression after involuntary capture of attention.

PubMed

Sawaki, Risa; Luck, Steven J

2013-04-01

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

Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future.

PubMed

Chen, Ricky; Cohen, Adam L; Colman, Howard

2016-08-01

High-grade gliomas remain incurable despite current therapies, which are plagued by high morbidity and mortality. Molecular categorization of glioma subtypes using mutations in isocitrate dehydrogenase 1/2 (IDH1/2), TP53, and ATRX; codeletion of chromosomes 1p and 19q; DNA methylation; and amplification of genes such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, alpha polypeptide provides a more accurate prognostication and biologic classification than classical histopathological diagnoses, and a number of molecular markers are being incorporated in the new World Health Organization classification of gliomas. However, despite the improved understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways, these observations have so far failed to result in the successful application of targeted therapies, as has occurred in other solid tumors. To date, the only targeted therapy for gliomas approved by the US Food and Drug Administration is bevacizumab, which targets vascular endothelial growth factor. EGFR remains a dominant molecular alteration in specific glioma subtypes and represents a potentially promising target, with drugs of multiple types targeting EGFR in development including vaccines, antibody drug conjugates, and chimeric antigen receptor (CAR) T cells, despite the prior failures of EGFR tyrosine kinase inhibitors. Immune therapies under investigation include checkpoint inhibitors, vaccines against tumor-associated antigens and tumor-specific antigens, pulsed dendritic cells, heat shock protein-tumor conjugates, and CAR T cells. Mutations in the IDH1/2 genes are central to gliomagenesis in a high proportion of grade II and III gliomas, and ongoing trials are examining vaccines against IDH1, small molecular inhibitors of IDH1 and IDH2, and metabolic components including NAD+ depletion to target IDH-mutated gliomas. The central role of DNA methylation in a subset of gliomas may be targetable, but better understanding of the relation between epigenetic alterations and resulting tumor biology appears necessary. Ultimately, given the prior failure of single-agent targeted therapy in high-grade gliomas, it appears that novel combinatorial therapy or targeted drugs with immunomodulatory or epigenetic approaches will likely be necessary to successfully combat these challenging tumors.

Virus-Inspired Nanogenes Free from Man-Made Materials for Host-Specific Transfection and Bio-Aided MR Imaging.

PubMed

Zhu, Jing-Yi; Zhang, Ming-Kang; Ding, Xian-Guang; Qiu, Wen-Xiu; Yu, Wu-Yang; Feng, Jun; Zhang, Xian-Zheng

2018-05-01

Many viruses have a lipid envelope derived from the host cell membrane that contributes much to the host specificity and the cellular invasion. This study puts forward a virus-inspired technology that allows targeted genetic delivery free from man-made materials. Genetic therapeutics, metal ions, and biologically derived cell membranes are nanointegrated. Vulnerable genetic therapeutics contained in the formed "nanogene" can be well protected from unwanted attacks by blood components and enzymes. The surface envelope composed of cancer cell membrane fragments enables host-specific targeting of the nanogene to the source cancer cells and homologous tumors while effectively inhibiting recognition by macrophages. High transfection efficiency highlights the potential of this technology for practical applications. Another unique merit of this technology arises from the facile combination of special biofunction of metal ions with genetic therapy. Typically, Gd(III)-involved nanogene generates a much higher T 1 relaxation rate than the clinically used Gd magnetic resonance imaging agent and harvests the enhanced MRI contrast at tumors. This virus-inspired technology points out a distinctive new avenue for the disease-specific transport of genetic therapeutics and other biomacromolecules. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Therapeutic potential of Mediator complex subunits in metabolic diseases.

PubMed

Ranjan, Amol; Ansari, Suraiya A

2018-01-01

The multisubunit Mediator is an evolutionary conserved transcriptional coregulatory complex in eukaryotes. It is needed for the transcriptional regulation of gene expression in general as well as in a gene specific manner. Mediator complex subunits interact with different transcription factors as well as components of RNA Pol II transcription initiation complex and in doing so act as a bridge between gene specific transcription factors and general Pol II transcription machinery. Specific interaction of various Mediator subunits with nuclear receptors (NRs) and other transcription factors involved in metabolism has been reported in different studies. Evidences indicate that ligand-activated NRs recruit Mediator complex for RNA Pol II-dependent gene transcription. These NRs have been explored as therapeutic targets in different metabolic diseases; however, they show side-effects as targets due to their overlapping involvement in different signaling pathways. Here we discuss the interaction of various Mediator subunits with transcription factors involved in metabolism and whether specific interaction of these transcription factors with Mediator subunits could be potentially utilized as therapeutic strategy in a variety of metabolic diseases. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Finding pathways to national-scale land-sector sustainability.

PubMed

Gao, Lei; Bryan, Brett A

2017-04-12

The 17 Sustainable Development Goals (SDGs) and 169 targets under Agenda 2030 of the United Nations map a coherent global sustainability ambition at a level of detail general enough to garner consensus amongst nations. However, achieving the global agenda will depend heavily on successful national-scale implementation, which requires the development of effective science-driven targets tailored to specific national contexts and supported by strong national governance. Here we assess the feasibility of achieving multiple SDG targets at the national scale for the Australian land-sector. We scaled targets to three levels of ambition and two timeframes, then quantitatively explored the option space for target achievement under 648 plausible future environmental, socio-economic, technological and policy pathways using the Land-Use Trade-Offs (LUTO) integrated land systems model. We show that target achievement is very sensitive to global efforts to abate emissions, domestic land-use policy, productivity growth rate, and land-use change adoption behaviour and capacity constraints. Weaker target-setting ambition resulted in higher achievement but poorer sustainability outcomes. Accelerating land-use dynamics after 2030 changed the targets achieved by 2050, warranting a longer-term view and greater flexibility in sustainability implementation. Simultaneous achievement of multiple targets is rare owing to the complexity of sustainability target implementation and the pervasive trade-offs in resource-constrained land systems. Given that hard choices are needed, the land-sector must first address the essential food/fibre production, biodiversity and land degradation components of sustainability via specific policy pathways. It may also contribute to emissions abatement, water and energy targets by capitalizing on co-benefits. However, achieving targets relevant to the land-sector will also require substantial contributions from other sectors such as clean energy, food systems and water resource management. Nations require globally coordinated, national-scale, comprehensive, integrated, multi-sectoral analyses to support national target-setting that prioritizes efficient and effective sustainability interventions across societies, economies and environments.

Finding pathways to national-scale land-sector sustainability

NASA Astrophysics Data System (ADS)

Gao, Lei; Bryan, Brett A.

2017-04-01

The 17 Sustainable Development Goals (SDGs) and 169 targets under Agenda 2030 of the United Nations map a coherent global sustainability ambition at a level of detail general enough to garner consensus amongst nations. However, achieving the global agenda will depend heavily on successful national-scale implementation, which requires the development of effective science-driven targets tailored to specific national contexts and supported by strong national governance. Here we assess the feasibility of achieving multiple SDG targets at the national scale for the Australian land-sector. We scaled targets to three levels of ambition and two timeframes, then quantitatively explored the option space for target achievement under 648 plausible future environmental, socio-economic, technological and policy pathways using the Land-Use Trade-Offs (LUTO) integrated land systems model. We show that target achievement is very sensitive to global efforts to abate emissions, domestic land-use policy, productivity growth rate, and land-use change adoption behaviour and capacity constraints. Weaker target-setting ambition resulted in higher achievement but poorer sustainability outcomes. Accelerating land-use dynamics after 2030 changed the targets achieved by 2050, warranting a longer-term view and greater flexibility in sustainability implementation. Simultaneous achievement of multiple targets is rare owing to the complexity of sustainability target implementation and the pervasive trade-offs in resource-constrained land systems. Given that hard choices are needed, the land-sector must first address the essential food/fibre production, biodiversity and land degradation components of sustainability via specific policy pathways. It may also contribute to emissions abatement, water and energy targets by capitalizing on co-benefits. However, achieving targets relevant to the land-sector will also require substantial contributions from other sectors such as clean energy, food systems and water resource management. Nations require globally coordinated, national-scale, comprehensive, integrated, multi-sectoral analyses to support national target-setting that prioritizes efficient and effective sustainability interventions across societies, economies and environments.

Differential processing of part-to-whole and part-to-part face priming: an ERP study.

PubMed

Jemel, B; George, N; Chaby, L; Fiori, N; Renault, B

1999-04-06

We provide electrophysiological evidence supporting the hypothesis that part and whole face processing involve distinct functional mechanisms. We used a congruency judgment task and studied part-to-whole and part-to-part priming effects. Neither part-to-whole nor part-to-part conditions elicited early congruency effects on face-specific ERP components, suggesting that activation of the internal representations should occur later on. However, these components showed differential responsiveness to whole faces and isolated eyes. In addition, although late ERP components were affected when the eye targets were not associated with the prime in both conditions, their temporal and topographical features depended on the latter. These differential effects suggest the existence of distributed neural networks in the inferior temporal cortex where part and whole facial representations may be stored.

Natural variation in dauer pheromone production and sensing supports intraspecific competition in nematodes.

PubMed

Bose, Neelanjan; Meyer, Jan M; Yim, Joshua J; Mayer, Melanie G; Markov, Gabriel V; Ogawa, Akira; Schroeder, Frank C; Sommer, Ralf J

2014-07-07

Dauer formation, a major nematode survival strategy, represents a model for small-molecule regulation of metazoan development [1-10]. Free-living nematodes excrete dauer-inducing pheromones that have been assumed to target conspecifics of the same genotype [9, 11]. However, recent studies in Pristionchus pacificus revealed that the dauer pheromone of some strains affects conspecifics of other genotypes more strongly than individuals of the same genotype [12]. To elucidate the mechanistic basis for this intriguing cross-preference, we compared six P. pacificus wild isolates to determine the chemical composition of their dauer-inducing metabolomes and responses to individual pheromone components. We found that these isolates produce dauer pheromone blends of different composition and respond differently to individual pheromone components. Strikingly, there is no correlation between production of and dauer response to a specific compound in individual strains. Specifically, pheromone components that are abundantly produced by one genotype induce dauer formation in other genotypes, but not necessarily in the abundant producer. Furthermore, some genotypes respond to pheromone components they do not produce themselves. These results support a model of intraspecific competition in nematode dauer formation. Indeed, we observed intraspecific competition among sympatric strains in a novel experimental assay, suggesting a new role of small molecules in nematode ecology. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-06

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

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-09

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

Antimicrobial Peptides Targeting Gram-Positive Bacteria

PubMed Central

Malanovic, Nermina; Lohner, Karl

2016-01-01

Antimicrobial peptides (AMPs) have remarkably different structures as well as biological activity profiles, whereupon most of these peptides are supposed to kill bacteria via membrane damage. In order to understand their molecular mechanism and target cell specificity for Gram-positive bacteria, it is essential to consider the architecture of their cell envelopes. Before AMPs can interact with the cytoplasmic membrane of Gram-positive bacteria, they have to traverse the cell wall composed of wall- and lipoteichoic acids and peptidoglycan. While interaction of AMPs with peptidoglycan might rather facilitate penetration, interaction with anionic teichoic acids may act as either a trap for AMPs or a ladder for a route to the cytoplasmic membrane. Interaction with the cytoplasmic membrane frequently leads to lipid segregation affecting membrane domain organization, which affects membrane permeability, inhibits cell division processes or leads to delocalization of essential peripheral membrane proteins. Further, precursors of cell wall components, especially the highly conserved lipid II, are directly targeted by AMPs. Thereby, the peptides do not inhibit peptidoglycan synthesis via binding to proteins like common antibiotics, but form a complex with the precursor molecule, which in addition can promote pore formation and membrane disruption. Thus, the multifaceted mode of actions will make AMPs superior to antibiotics that act only on one specific target. PMID:27657092

Functional imaging reveals rapid reorganization of cortical activity after parietal inactivation in monkeys

PubMed Central

Wilke, Melanie; Kagan, Igor; Andersen, Richard A.

2012-01-01

Impairments of spatial awareness and decision making occur frequently as a consequence of parietal lesions. Here we used event-related functional MRI (fMRI) in monkeys to investigate rapid reorganization of spatial networks during reversible pharmacological inactivation of the lateral intraparietal area (LIP), which plays a role in the selection of eye movement targets. We measured fMRI activity in control and inactivation sessions while monkeys performed memory saccades to either instructed or autonomously chosen spatial locations. Inactivation caused a reduction of contralesional choices. Inactivation effects on fMRI activity were anatomically and functionally specific and mainly consisted of: (i) activity reduction in the upper bank of the superior temporal sulcus (temporal parietal occipital area) for single contralesional targets, especially in the inactivated hemisphere; and (ii) activity increase accompanying contralesional choices between bilateral targets in several frontal and parieto-temporal areas in both hemispheres. There was no overactivation for ipsilesional targets or choices in the intact hemisphere. Task-specific effects of LIP inactivation on blood oxygen level-dependent activity in the temporal parietal occipital area underline the importance of the superior temporal sulcus for spatial processing. Furthermore, our results agree only partially with the influential interhemispheric competition model of spatial neglect and suggest an additional component of interhemispheric cooperation in the compensation of neglect deficits. PMID:22562793

Necrosis Avidity: A Newly Discovered Feature of Hypericin and its Preclinical Applications in Necrosis Imaging

PubMed Central

Jiang, Binghu; Wang, Jichen; Ni, Yicheng; Chen, Feng

2013-01-01

Hypericin has been widely studied as a potent photosensitizer for photodynamic therapy in both preclinical and clinical settings. Recently, hypericin has also been discovered to have a specific avidity for necrotic tissue. This affinity is also observed in a series of radiolabeled derivatives of hypericin, including [123I]iodohypericin, [124I]iodohypericin, and [131I]iodohypericin. Hypericin, along with other necrosis-avid contrast agents, has been investigated for use in noninvasively targeting necrotic tissues in numerous disorders. Potential clinical applications of hypericin include the identification of acute myocardial infarction, evaluation of tissue viability, assessment of therapeutic responses to treatments, and interventional procedures for solid tumors. The mechanisms of necrosis avidity in hypericin remain to be fully elucidated, although several hypotheses have been suggested. In particular, it has been proposed that the necrosis avidity of hypericin is compound specific; for instance, cholesterol, phosphatidylserine, or phosphatidylethanolamine components in the phospholipid bilayer of cellular membranes may be the major targets for its observed selectivity. Further investigations are needed to identify the specific binding moiety that is responsible for the necrosis avidity of hypericin. PMID:24052807

Evaluation of Aspergillus PCR protocols for testing serum specimens.

PubMed

White, P Lewis; Mengoli, Carlo; Bretagne, Stéphane; Cuenca-Estrella, Manuel; Finnstrom, Niklas; Klingspor, Lena; Melchers, Willem J G; McCulloch, Elaine; Barnes, Rosemary A; Donnelly, J Peter; Loeffler, Juergen

2011-11-01

A panel of human serum samples spiked with various amounts of Aspergillus fumigatus genomic DNA was distributed to 23 centers within the European Aspergillus PCR Initiative to determine analytical performance of PCR. Information regarding specific methodological components and PCR performance was requested. The information provided was made anonymous, and meta-regression analysis was performed to determine any procedural factors that significantly altered PCR performance. Ninety-seven percent of protocols were able to detect a threshold of 10 genomes/ml on at least one occasion, with 83% of protocols reproducibly detecting this concentration. Sensitivity and specificity were 86.1% and 93.6%, respectively. Positive associations between sensitivity and the use of larger sample volumes, an internal control PCR, and PCR targeting the internal transcribed spacer (ITS) region were shown. Negative associations between sensitivity and the use of larger elution volumes (≥100 μl) and PCR targeting the mitochondrial genes were demonstrated. Most Aspergillus PCR protocols used to test serum generate satisfactory analytical performance. Testing serum requires less standardization, and the specific recommendations shown in this article will only improve performance.

Evaluation of Aspergillus PCR Protocols for Testing Serum Specimens▿†

PubMed Central

White, P. Lewis; Mengoli, Carlo; Bretagne, Stéphane; Cuenca-Estrella, Manuel; Finnstrom, Niklas; Klingspor, Lena; Melchers, Willem J. G.; McCulloch, Elaine; Barnes, Rosemary A.; Donnelly, J. Peter; Loeffler, Juergen

2011-01-01

A panel of human serum samples spiked with various amounts of Aspergillus fumigatus genomic DNA was distributed to 23 centers within the European Aspergillus PCR Initiative to determine analytical performance of PCR. Information regarding specific methodological components and PCR performance was requested. The information provided was made anonymous, and meta-regression analysis was performed to determine any procedural factors that significantly altered PCR performance. Ninety-seven percent of protocols were able to detect a threshold of 10 genomes/ml on at least one occasion, with 83% of protocols reproducibly detecting this concentration. Sensitivity and specificity were 86.1% and 93.6%, respectively. Positive associations between sensitivity and the use of larger sample volumes, an internal control PCR, and PCR targeting the internal transcribed spacer (ITS) region were shown. Negative associations between sensitivity and the use of larger elution volumes (≥100 μl) and PCR targeting the mitochondrial genes were demonstrated. Most Aspergillus PCR protocols used to test serum generate satisfactory analytical performance. Testing serum requires less standardization, and the specific recommendations shown in this article will only improve performance. PMID:21940479

Dissecting microRNA dysregulation in age-related macular degeneration: new targets for eye gene therapy.

PubMed

Askou, Anne Louise; Alsing, Sidsel; Holmgaard, Andreas; Bek, Toke; Corydon, Thomas J

2018-02-01

MicroRNAs (miRNAs) are key regulators of gene expression in humans. Overexpression or depletion of individual miRNAs is associated with human disease. Current knowledge suggests that the retina is influenced by miRNAs and that dysregulation of miRNAs as well as alterations in components of the miRNA biogenesis machinery are involved in retinal diseases, including age-related macular degeneration (AMD). Furthermore, recent studies have indicated that the vitreous has a specific panel of circulating miRNAs and that this panel varies according to the specific pathological stress experienced by the retinal cells. MicroRNA (miRNA) profiling indicates subtype-specific miRNA profiles for late-stage AMD highlighting the importance of proper miRNA regulation in AMD. This review will describe the function of important miRNAs involved in inflammation, oxidative stress and pathological neovascularization, the key molecular mechanisms leading to AMD, and focus on dysregulated miRNAs as potential therapeutic targets in AMD. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Floodplain sedimentology and sediment accumulation assessment – Savannah River Site

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

Yeager, Kevin M.

2016-01-03

The primary goal of the larger research program, of which this work is one component, is to restore the hydrodynamics and energy gradients of targeted Savannah River Site (SRS) streams to a condition comparable to local natural streams or rivers of similar order, and to stabilize sediment transport (net degradation/aggregation) with the assumption that the faunal components of these systems will quickly recover on their own (e.g., Pen Branch; Lakly and McArthur, 2000). This work is specifically focused on the identification of near-stream floodplain areas that exhibit sediment deposition or erosion, and the quantification of these processes over a historicalmore » time scale (last ~100 years).« less

[Analysis on "component-target-pathway" of Paeonia lactiflora in treating cardiac diseases based on data mining].

PubMed

Liu, Yang; Zhang, Fang-Bo; Tang, Shi-Huan; Wang, Ping; Li, Sen; Su, Jin; Zhou, Rong-Rong; Zhang, Jia-Qi; Sun, Hui-Feng

2018-04-01

Based on the literature review and modern application of Paeonia lactiflora in heart diseases, this article would predict the target of drug and disease by intergrative pharmacology platform of traditional Chinese medicine (TCMIP, http://www.tcmip.cn), and then explore the molecular mechanism of P. lactiflora in treatment of heart disease, providing theoretical basis and method for further studies on P. lactiflora. According to the ancient books, P. lactiflora with functions of "removing the vascular obstruction, removing the lumps, relieving pain, diuretic, nutrient qi" and other effects, have been used for many times to treat heart disease. Some prescriptions are also favored by the modern physicians nowadays. With the development of science, the chemical components that play a role in heart disease and the interrelation between these components and the body become the research hotspot. In order to further reveal the pharmacological substance base and molecular mechanism of P. lactiflora for the treatment of such diseases, TCM-IP was used to obtain multiple molecular targets and signaling pathways in treatment of heart disease. ATP1A1, a common target of drug and disease, was related to energy, and HDAC2 mainly regulated cardiomyocyte hypertrophy gene and cardiomyocyte expression. Other main drug targets such as GCK, CHUK and PRKAA2 indirectly regulated heart disease through many pathways; multiple disease-associated signaling pathways interfered with various heart diseases including coronary heart disease, myocardial ischemia and myocardial hypertrophy through influencing energy metabolism, enzyme activity and gene expression. In conclusion, P. lactiflora plays a role in protecting heart function by regulating the gene expression of cardiomyocytes directly. Meanwhile, it can indirectly intervene in other pathways of heart function, and thus participate in the treatment of heart disease. In this paper, the molecular mechanism of P. lactiflora for treatment of heart disease was in computer prediction analysis level, and the specific mechanism of action still needs further experimental verification. Copyright© by the Chinese Pharmaceutical Association.

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

PubMed

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

2017-10-27

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

Community-based pilot intervention to tackle childhood obesity: a whole-system approach.

PubMed

Vamos, E P; Lewis, E; Junghans, C; Hrobonova, E; Dunsford, E; Millett, C

2016-11-01

Go-Golborne is a pilot intervention to prevent childhood obesity in the Royal Borough of Kensington and Chelsea between 2014 and 2018. It is a multistrategy approach targeting children aged 0-16 years and their families in all settings where children live, learn and play. This paper describes the methodology and the practical steps in the development of Go-Golborne. The programme uses a quasi-experimental design for the evaluation of changes in weight status using data from the extended National Child Measurement Programme across local schools. For specific behavioural change objectives, baseline self-reported lifestyle measures will be compared against annual follow-up data over the 3-year study period. Qualitative methods will be used to explore the perceptions of stakeholders and participants and organizational change. Go-Golborne aims to mobilize everyone in the community who has a role or interest in shaping the local environment, norms and behaviours across a range of sectors. A community network of local organizations has been established to codesign all programme activities. The Steering Group of Council officers support programme implementation and environmental changes. The programme has identified six specific behaviour change objectives representing the key areas of need in Golborne and all activities in the council and the community target these objectives during specific programme phases. Key components include community capacity building, community-wide social marketing, environment and policy change and evaluation. The programme is currently at the beginning of its implementation phase with activities in the community and council targeting the first behaviour change objective. The pilot aims to test the effectiveness of this approach to support behaviour change and prevent unhealthy weight gain in children using multiple strategies. This programme will inform the development of an intervention model that defines essential programme components, accountability of partner organizations delivering obesity prevention programmes and the effective use of existing assets. Copyright © 2016 The Royal Society for Public Health. All rights reserved.

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

PubMed

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

2014-11-01

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

Modality-specificity of Selective Attention Networks

PubMed Central

Stewart, Hannah J.; Amitay, Sygal

2015-01-01

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

Method and apparatus for noble gas atom detection with isotopic selectivity

DOEpatents

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

1984-01-01

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

Linking maternal and somatic 5S rRNA types with different sequence-specific non-LTR retrotransposons

PubMed Central

Pagano, Johanna F.B.; Ensink, Wim A.; van Olst, Marina; van Leeuwen, Selina; Nehrdich, Ulrike; Zhu, Kongju; Spaink, Herman P.; Girard, Geneviève; Rauwerda, Han; Jonker, Martijs J.; Dekker, Rob J.

2017-01-01

5S rRNA is a ribosomal core component, transcribed from many gene copies organized in genomic repeats. Some eukaryotic species have two 5S rRNA types defined by their predominant expression in oogenesis or adult tissue. Our next-generation sequencing study on zebrafish egg, embryo, and adult tissue identified maternal-type 5S rRNA that is exclusively accumulated during oogenesis, replaced throughout the embryogenesis by a somatic-type, and thus virtually absent in adult somatic tissue. The maternal-type 5S rDNA contains several thousands of gene copies on chromosome 4 in tandem repeats with small intergenic regions, whereas the somatic-type is present in only 12 gene copies on chromosome 18 with large intergenic regions. The nine-nucleotide variation between the two 5S rRNA types likely affects TFIII binding and riboprotein L5 binding, probably leading to storage of maternal-type rRNA. Remarkably, these sequence differences are located exactly at the sequence-specific target site for genome integration by the 5S rRNA-specific Mutsu retrotransposon family. Thus, we could define maternal- and somatic-type MutsuDr subfamilies. Furthermore, we identified four additional maternal-type and two new somatic-type MutsuDr subfamilies, each with their own target sequence. This target-site specificity, frequently intact maternal-type retrotransposon elements, plus specific presence of Mutsu retrotransposon RNA and piRNA in egg and adult tissue, suggest an involvement of retrotransposons in achieving the differential copy number of the two types of 5S rDNA loci. PMID:28003516

Comparative Analysis of Predicted Plastid-Targeted Proteomes of Sequenced Higher Plant Genomes

PubMed Central

Schaeffer, Scott; Harper, Artemus; Raja, Rajani; Jaiswal, Pankaj; Dhingra, Amit

2014-01-01

Plastids are actively involved in numerous plant processes critical to growth, development and adaptation. They play a primary role in photosynthesis, pigment and monoterpene synthesis, gravity sensing, starch and fatty acid synthesis, as well as oil, and protein storage. We applied two complementary methods to analyze the recently published apple genome (Malus × domestica) to identify putative plastid-targeted proteins, the first using TargetP and the second using a custom workflow utilizing a set of predictive programs. Apple shares roughly 40% of its 10,492 putative plastid-targeted proteins with that of the Arabidopsis (Arabidopsis thaliana) plastid-targeted proteome as identified by the Chloroplast 2010 project and ∼57% of its entire proteome with Arabidopsis. This suggests that the plastid-targeted proteomes between apple and Arabidopsis are different, and interestingly alludes to the presence of differential targeting of homologs between the two species. Co-expression analysis of 2,224 genes encoding putative plastid-targeted apple proteins suggests that they play a role in plant developmental and intermediary metabolism. Further, an inter-specific comparison of Arabidopsis, Prunus persica (Peach), Malus × domestica (Apple), Populus trichocarpa (Black cottonwood), Fragaria vesca (Woodland Strawberry), Solanum lycopersicum (Tomato) and Vitis vinifera (Grapevine) also identified a large number of novel species-specific plastid-targeted proteins. This analysis also revealed the presence of alternatively targeted homologs across species. Two separate analyses revealed that a small subset of proteins, one representing 289 protein clusters and the other 737 unique protein sequences, are conserved between seven plastid-targeted angiosperm proteomes. Majority of the novel proteins were annotated to play roles in stress response, transport, catabolic processes, and cellular component organization. Our results suggest that the current state of knowledge regarding plastid biology, preferentially based on model systems is deficient. New plant genomes are expected to enable the identification of potentially new plastid-targeted proteins that will aid in studying novel roles of plastids. PMID:25393533

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

PubMed

Grubert, Anna; Eimer, Martin

2013-10-01

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

Animal models of ulcerative colitis and their application in drug research

PubMed Central

Low, Daren; Nguyen, Deanna D; Mizoguchi, Emiko

2013-01-01

The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn’s disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed. PMID:24250223

Development of germ-line-specific CRISPR-Cas9 systems to improve the production of heritable gene modifications in Arabidopsis

PubMed Central

Mao, Yanfei; Zhang, Zhengjing; Feng, Zhengyan; Wei, Pengliang; Zhang, Hui; Botella, José Ramón; Zhu, Jian-Kang

2017-01-01

Summary The Streptococcus-derived CRISPR/Cas9 system is being widely used to perform targeted gene modifications in plants. This customized endonuclease system has two components, the single-guide RNA (sgRNA) for target DNA recognition and the CRISPR-associated protein 9 (Cas9) for DNA cleavage. Ubiquitously expressed CRISPR/Cas9 systems (UC) generate targeted gene modifications with high efficiency but only those produced in reproductive cells are transmitted to the next generation. We report the design and characterization of a germ-line-specific Cas9 system (GSC) for Arabidopsis gene modification in male gametocytes, constructed using a SPOROCYTELESS (SPL) genomic expression cassette. Four loci in two endogenous genes were targeted by both systems for comparative analysis. Mutations generated by the GSC system were rare in T1 plants but were abundant (30%) in the T2 generation. The vast majority (70%) of the T2 mutant population generated using the UC system were chimeras while the newly developed GSC system produced only 29% chimeras, with 70% of the T2 mutants being heterozygous. Analysis of two loci in the T2 population showed that the abundance of heritable gene mutations was 37% higher in the GSC system compared to the UC system and the level of polymorphism of the mutations was also dramatically increased with the GSC system. Two additional systems based on germ-line-specific promoters (pDD45-GT and pLAT52-GT) were also tested, and one of them was capable of generating heritable homozygous T1 mutant plants. Our results suggest that future application of the described GSC system will facilitate the screening for targeted gene modifications, especially lethal mutations in the T2 population. PMID:26360626

Literature evidence in open targets - a target validation platform.

PubMed

Kafkas, Şenay; Dunham, Ian; McEntyre, Johanna

2017-06-06

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

A transcriptional dynamic network during Arabidopsis thaliana pollen development.

PubMed

Wang, Jigang; Qiu, Xiaojie; Li, Yuhua; Deng, Youping; Shi, Tieliu

2011-01-01

To understand transcriptional regulatory networks (TRNs), especially the coordinated dynamic regulation between transcription factors (TFs) and their corresponding target genes during development, computational approaches would represent significant advances in the genome-wide expression analysis. The major challenges for the experiments include monitoring the time-specific TFs' activities and identifying the dynamic regulatory relationships between TFs and their target genes, both of which are currently not yet available at the large scale. However, various methods have been proposed to computationally estimate those activities and regulations. During the past decade, significant progresses have been made towards understanding pollen development at each development stage under the molecular level, yet the regulatory mechanisms that control the dynamic pollen development processes remain largely unknown. Here, we adopt Networks Component Analysis (NCA) to identify TF activities over time course, and infer their regulatory relationships based on the coexpression of TFs and their target genes during pollen development. We carried out meta-analysis by integrating several sets of gene expression data related to Arabidopsis thaliana pollen development (stages range from UNM, BCP, TCP, HP to 0.5 hr pollen tube and 4 hr pollen tube). We constructed a regulatory network, including 19 TFs, 101 target genes and 319 regulatory interactions. The computationally estimated TF activities were well correlated to their coordinated genes' expressions during the development process. We clustered the expression of their target genes in the context of regulatory influences, and inferred new regulatory relationships between those TFs and their target genes, such as transcription factor WRKY34, which was identified that specifically expressed in pollen, and regulated several new target genes. Our finding facilitates the interpretation of the expression patterns with more biological relevancy, since the clusters corresponding to the activity of specific TF or the combination of TFs suggest the coordinated regulation of TFs to their target genes. Through integrating different resources, we constructed a dynamic regulatory network of Arabidopsis thaliana during pollen development with gene coexpression and NCA. The network illustrated the relationships between the TFs' activities and their target genes' expression, as well as the interactions between TFs, which provide new insight into the molecular mechanisms that control the pollen development.

Cramer-Rao Lower Bound Evaluation for Linear Frequency Modulation Based Active Radar Networks Operating in a Rice Fading Environment.

PubMed

Shi, Chenguang; Salous, Sana; Wang, Fei; Zhou, Jianjiang

2016-12-06

This paper investigates the joint target parameter (delay and Doppler) estimation performance of linear frequency modulation (LFM)-based radar networks in a Rice fading environment. The active radar networks are composed of multiple radar transmitters and multichannel receivers placed on moving platforms. First, the log-likelihood function of the received signal for a Rician target is derived, where the received signal scattered off the target comprises of dominant scatterer (DS) component and weak isotropic scatterers (WIS) components. Then, the analytically closed-form expressions of the Cramer-Rao lower bounds (CRLBs) on the Cartesian coordinates of target position and velocity are calculated, which can be adopted as a performance metric to access the target parameter estimation accuracy for LFM-based radar network systems in a Rice fading environment. It is found that the cumulative Fisher information matrix (FIM) is a linear combination of both DS component and WIS components, and it also demonstrates that the joint CRLB is a function of signal-to-noise ratio (SNR), target's radar cross section (RCS) and transmitted waveform parameters, as well as the relative geometry between the target and the radar network architectures. Finally, numerical results are provided to indicate that the joint target parameter estimation performance of active radar networks can be significantly improved with the exploitation of DS component.

Hospital protocols for targeted glycemic control: Development, implementation, and models for cost justification.

PubMed

Magee, Michelle F

2007-05-15

Evolving elements of best practices for providing targeted glycemic control in the hospital setting, clinical performance measurement, basal-bolus plus correction-dose insulin regimens, components of standardized subcutaneous (s.c.) insulin order sets, and strategies for implementation and cost justification of glycemic control initiatives are discussed. Best practices for targeted glycemic control should address accurate documentation of hyperglycemia, initial patient assessment, management plan, target blood glucose range, blood glucose monitoring frequency, maintenance of glycemic control, criteria for glucose management consultations, and standardized insulin order sets and protocols. Establishing clinical performance measures, including desirable processes and outcomes, can help ensure the success of targeted hospital glycemic control initiatives. The basal-bolus plus correction-dose regimen for insulin administration will be used to mimic the normal physiologic pattern of endogenous insulin secretion. Standardized insulin order sets and protocols are being used to minimize the risk of error in insulin therapy. Components of standardized s.c. insulin order sets include specification of the hyperglycemia diagnosis, finger stick blood glucose monitoring frequency and timing, target blood glucose concentration range, cutoff values for excessively high or low blood glucose concentrations that warrant alerting the physician, basal and prandial or nutritional (i.e., bolus) insulin, correction doses, hypoglycemia treatment, and perioperative or procedural dosage adjustments. The endorsement of hospital administrators and key physician and nursing leaders is needed for glycemic control initiatives. Initiatives may be cost justified on the basis of the billings for clinical diabetes management services and/or the return- on-investment accrued to reductions in hospital length of stay, readmissions, and accurate documentation and coding of unrecognized or uncontrolled diabetes, and diabetes complications. Standardized insulin order sets and protocols may minimize risk of insulin errors. The endorsement of these protocols by administrators, physicians, nurses, and pharmacists is also needed for success.

Limited role of phonology in reading Chinese two-character compounds: evidence from an ERP study.

PubMed

Wong, A W-K; Wu, Y; Chen, H-C

2014-01-03

This study investigates the role of phonology in reading logographic Chinese. Specifically, whether phonological information is obligatorily activated in reading Chinese two-character compounds was examined using the masked-priming paradigm with event-related potential (ERP) recordings. Twenty-two native Cantonese Chinese speakers participated in a lexical decision experiment. The targets were visually presented Chinese two-character strings and the participants were asked to judge whether the target in each trial was a legitimate compound word in Chinese. Each target was preceded by a briefly presented word prime. The prime and target shared an identical constituent character in the Character-related condition, a syllable in the Syllable-related condition, were semantically related in the Semantic-related condition, and were unrelated (both phonologically and semantically) in the control condition. The prime–target relationship was manipulated to probe the effects of word-form (i.e., character- or syllable-relatedness) and word-semantic relatedness on phonological (as indexed by an N250 ERP component) and semantic (as indexed by an N400 ERP component) processing. Significant and comparable facilitation effects in reaction time, relative to the control, were observed in the Character-related and the Semantic-related conditions. Furthermore, a significant reduction in ERP amplitudes (N250), relative to the control, was obtained in the Character-related condition in the time window of 150-250 ms post target. In addition, attenuation in ERP amplitudes was found in the Semantic-related condition in the window of 250-500 ms (N400). However, no significant results (neither behavioral nor ERP) were found in the Syllable-related condition. These results suggest that phonological activation is not mandatory and the role of phonology is minimal at best in reading Chinese two-character compounds.

Modeling patterns of anatomical deformations in prostate patients undergoing radiation therapy with an endorectal balloon

NASA Astrophysics Data System (ADS)

Brion, Eliott; Richter, Christian; Macq, Benoit; Stützer, Kristin; Exner, Florian; Troost, Esther; Hölscher, Tobias; Bondar, Luiza

2017-03-01

External beam radiation therapy (EBRT) treats cancer by delivering daily fractions of radiation to a target volume. For prostate cancer, the target undergoes day-to-day variations in position, volume, and shape. For stereotactic photon and for proton EBRT, endorectal balloons (ERBs) can be used to limit variations. To date, patterns of non-rigid variations for patients with ERB have not been modeled. We extracted and modeled the patient-specific patterns of variations, using regularly acquired CT-images, non-rigid point cloud registration, and principal component analysis (PCA). For each patient, a non-rigid point-set registration method, called Coherent Point Drift, (CPD) was used to automatically generate landmark correspondences between all target shapes. To ensure accurate registrations, we tested and validated CPD by identifying parameter values leading to the smallest registration errors (surface matching error 0.13+/-0.09 mm). PCA demonstrated that 88+/-3.2% of the target motion could be explained using only 4 principal modes. The most dominant component of target motion is a squeezing and stretching in the anterior-posterior and superior-inferior directions. A PCA model of daily landmark displacements, generated using 6 to 10 CT-scans, could explain well the target motion for the CT-scans not included in the model (modeling error decreased from 1.83+/-0.8 mm for 6 CT-scans to 1.6+/-0.7 mm for 10 CT-scans). PCA modeling error was smaller than the naive approximation by the mean shape (approximation error 2.66+/-0.59 mm). Future work will investigate the use of the PCA-model to improve the accuracy of EBRT techniques that are highly susceptible to anatomical variations such as, proton therapy

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

NASA Technical Reports Server (NTRS)

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

1994-01-01

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

Financial Stress and Behavioral Health in Military Servicemembers: Risk, Resilience, Mechanisms and Targets for Intervention

DTIC Science & Technology

2016-02-29

aware that notwithstanding any other provision of law, no person shall be subject to any penalty for falling to comply with a collection of information ...mail.mil Barbara A . Thompson Director, Office of Family Readiness Policy Office of the Secretary of Defense Military Community and Family Policy...occurring across the nation during any particular time. This occurs within a specific family and community setting and has a developmental component

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

DTIC Science & Technology

2010-01-01

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

The exosome component Rrp6 is required for RNA polymerase II termination at specific targets of the Nrd1-Nab3 pathway.

PubMed

Fox, Melanie J; Gao, Hongyu; Smith-Kinnaman, Whitney R; Liu, Yunlong; Mosley, Amber L

2015-01-01

The exosome and its nuclear specific subunit Rrp6 form a 3'-5' exonuclease complex that regulates diverse aspects of RNA biology including 3' end processing and degradation of a variety of noncoding RNAs (ncRNAs) and unstable transcripts. Known targets of the nuclear exosome include short (<1000 bp) RNAPII transcripts such as small noncoding RNAs (snRNAs), cryptic unstable transcripts (CUTs), and some stable unannotated transcripts (SUTs) that are terminated by an Nrd1, Nab3, and Sen1 (NNS) dependent mechanism. NNS-dependent termination is coupled to RNA 3' end processing and/or degradation by the Rrp6/exosome in yeast. Recent work suggests Nrd1 is necessary for transcriptome surveillance, regulating promoter directionality and suppressing antisense transcription independently of, or prior to, Rrp6 activity. It remains unclear whether Rrp6 is directly involved in termination; however, Rrp6 has been implicated in the 3' end processing and degradation of ncRNA transcripts including CUTs. To determine the role of Rrp6 in NNS termination globally, we performed RNA sequencing (RNA-Seq) on total RNA and perform ChIP-exo analysis of RNA Polymerase II (RNAPII) localization. Deletion of RRP6 promotes hyper-elongation of multiple NNS-dependent transcripts resulting from both improperly processed 3' RNA ends and faulty transcript termination at specific target genes. The defects in RNAPII termination cause transcriptome-wide changes in mRNA expression through transcription interference and/or antisense repression, similar to previously reported effects of depleting Nrd1 from the nucleus. Elongated transcripts were identified within all classes of known NNS targets with the largest changes in transcription termination occurring at CUTs. Interestingly, the extended transcripts that we have detected in our studies show remarkable similarity to Nrd1-unterminated transcripts at many locations, suggesting that Rrp6 acts with the NNS complex globally to promote transcription termination in addition to 3' end RNA processing and/or degradation at specific targets.

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 phage could be endocytosed by cancer cells in culture.

Sex Steroid Signaling: Implications for Lung Diseases

PubMed Central

Sathish, Venkatachalem; Martin, Yvette N.; Prakash, Y.S.

2015-01-01

There is increasing recognition that the sex hormones (estrogen, progesterone, and testosterone) have biological and pathophysiological actions in peripheral, non-reproductive organs, including the lung. Clinically, sex differences in the incidence, morbidity and mortality of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, lung cancer and pulmonary hypertension have been noted, although intrinsic sex differences vs. the roles of sex steroids are still not well-understood. Accordingly, it becomes important to ask the following questions: 1) Which sex steroids are involved? 2) How do they affect different components of the lung under normal circumstances? 3) How does sex steroid signaling change in or contribute to lung disease, and in this regard, are sex steroids detrimental or beneficial? As our understanding of sex steroid signaling in the lung improves, it is important to consider whether such information can be used to develop new therapeutic strategies to target lung diseases, perhaps in both sexes or in a sex-specific manner. In this review, we focus on the basics of sex steroid signaling, and the current state of knowledge regarding how they influence structure and function of specific lung components across the life span and in the context of some important lung diseases. We then summarize the potential for sex steroids as useful biomarkers and therapeutic targets in these lung diseases as a basis for future translational research in the area of gender and individualized medicine. PMID:25595323

Adolescents' social environment and depression: social networks, extracurricular activity, and family relationship influences.

PubMed

Mason, Michael J; Schmidt, Christopher; Abraham, Anisha; Walker, Leslie; Tercyak, Kenneth

2009-12-01

The present study examined components of adolescents' social environment (social network, extracurricular activities, and family relationships) in association with depression. A total of 332 adolescents presenting for a routine medical check-up were self-assessed for social network risk (i.e., smoking habits of best male and female friends), extracurricular activity level (i.e., participation in organized sports teams, clubs, etc.), family relationship quality (i.e., cohesion and conflict), and symptoms of depression (i.e., minimal, mild, moderate/severe). Results of a forward linear regression modeling indicate that social environment components were associated with a significant proportion of the variance in adolescent depression (Adjusted R (2) = .177, p < or = .05). Specifically, adolescent females (beta = .166, p < .01) and those having more smokers in their social network (beta = .107, p < .05) presented with significantly greater depression symptoms. Conversely, adolescents who engaged in more extracurricular activities (beta = -.118, p < .05) and experienced higher quality family relationships (beta = -.368, p < .001) presented with significantly lower depressive symptoms. These findings highlight the important role that the social environment plays in adolescent depression, as well as yields new insights into socially-based intervention targets that may ameliorate adolescent depression. These intervention targets may be gender-specific, include positive social network skills training, increase adolescents' engagement in organized activities, and attend to the quality of their family relationships.

Isolation of recombinant antibodies directed against surface proteins of Clostridium difficile.

PubMed

Shirvan, Ali Nazari; Aitken, Robert

2016-01-01

Clostridium difficile has emerged as an increasingly important nosocomial pathogen and the prime causative agent of antibiotic-associated diarrhoea and pseudomembranous colitis in humans. In addition to toxins A and B, immunological studies using antisera from patients infected with C. difficile have shown that a number of other bacterial factors contribute to the pathogenesis, including surface proteins, which are responsible for adhesion, motility and other interactions with the human host. In this study, various clostridial targets, including FliC, FliD and cell wall protein 66, were expressed and purified. Phage antibody display yielded a large panel of specific recombinant antibodies, which were expressed, purified and characterised. Reactions of the recombinant antibodies with their targets were detected by enzyme-linked immunosorbent assay; and Western blotting suggested that linear rather than conformational epitopes were recognised. Binding of the recombinant antibodies to surface-layer proteins and their components showed strain specificity, with good recognition of proteins from C. difficile 630. However, no reaction was observed for strain R20291-a representative of the 027 ribotype. Binding of the recombinant antibodies to C. difficile M120 extracts indicated that a component of a surface-layer protein of this strain might possess immunoglobulin-binding activities. The recombinant antibodies against FliC and FliD proteins were able to inhibit bacterial motility. Copyright © 2016. Published by Elsevier Editora Ltda.

Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh.

PubMed

Aktar, Amena; Rahman, M Arifur; Afrin, Sadia; Akter, Aklima; Uddin, Taher; Yasmin, Tahirah; Sami, Md Israk Nur; Dash, Pinki; Jahan, Sultana Rownok; Chowdhury, Fahima; Khan, Ashraful I; LaRocque, Regina C; Charles, Richelle C; Bhuiyan, Taufiqur Rahman; Mandlik, Anjali; Kelly, Meagan; Kováč, Pavol; Xu, Peng; Calderwood, Stephen B; Harris, Jason B; Qadri, Firdausi; Ryan, Edward T

2018-04-01

The mediators of protection against cholera, a severe dehydrating illness of humans caused by Vibrio cholerae, are unknown. We have previously shown that plasma IgA as well as memory B IgG cells targeting lipopolysaccharide (LPS) of Vibrio cholerae O1 correlate with protection against V. cholerae O1 infection among household contacts of cholera patients. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of LPS. Therefore, we prospectively followed household contacts of cholera patients to determine whether OSP-specific immune responses present at the time of enrollment are associated with protection against V. cholerae infection. In this study, we enrolled two hundred forty two household contacts of one hundred fifty index patients who were infected with Vibrio cholerae. We determined OSP-specific memory B cells and plasma IgA, IgG and IgM antibody responses on study entry (day 2). The presence of OSP-specific plasma IgA, IgM, and IgG antibody responses on study entry were associated with a decrease in the risk of infection in household contacts (IgA, p = 0.015; IgM, p = 0.01, and IgG, p = 0.024). In addition, the presence of OSP-specific IgG memory B cell responses in peripheral blood on study entry was also associated with a decreased risk of infection (44% reduction; 95% CI: 31.1 to 99.8) in contacts. No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cell responses. These results suggest that immune responses that target OSP, both in plasma and memory responses, may be important in mediating protection against infection with V. cholerae O1.

Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh

PubMed Central

Aktar, Amena; Rahman, M. Arifur; Afrin, Sadia; Akter, Aklima; Uddin, Taher; Yasmin, Tahirah; Sami, Md. Israk Nur; Dash, Pinki; Jahan, Sultana Rownok; Chowdhury, Fahima; Khan, Ashraful I.; LaRocque, Regina C.; Charles, Richelle C.; Bhuiyan, Taufiqur Rahman; Mandlik, Anjali; Kelly, Meagan; Kováč, Pavol; Xu, Peng; Calderwood, Stephen B.; Harris, Jason B.; Ryan, Edward T.

2018-01-01

Background The mediators of protection against cholera, a severe dehydrating illness of humans caused by Vibrio cholerae, are unknown. We have previously shown that plasma IgA as well as memory B IgG cells targeting lipopolysaccharide (LPS) of Vibrio cholerae O1 correlate with protection against V. cholerae O1 infection among household contacts of cholera patients. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of LPS. Therefore, we prospectively followed household contacts of cholera patients to determine whether OSP-specific immune responses present at the time of enrollment are associated with protection against V. cholerae infection. Methodology In this study, we enrolled two hundred forty two household contacts of one hundred fifty index patients who were infected with Vibrio cholerae. We determined OSP-specific memory B cells and plasma IgA, IgG and IgM antibody responses on study entry (day 2). Principle findings The presence of OSP-specific plasma IgA, IgM, and IgG antibody responses on study entry were associated with a decrease in the risk of infection in household contacts (IgA, p = 0.015; IgM, p = 0.01, and IgG, p = 0.024). In addition, the presence of OSP-specific IgG memory B cell responses in peripheral blood on study entry was also associated with a decreased risk of infection (44% reduction; 95% CI: 31.1 to 99.8) in contacts. No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cell responses. Conclusion These results suggest that immune responses that target OSP, both in plasma and memory responses, may be important in mediating protection against infection with V. cholerae O1. PMID:29684006

Regulation of expression, activity and localization of fungal chitin synthases

PubMed Central

Rogg, Luise E.; Fortwendel, Jarrod R.; Juvvadi, Praveen R.; Steinbach, William J.

2013-01-01

The fungal cell wall represents an attractive target for pharmacologic inhibition, as many of the components are fungal-specific. Though targeted inhibition of β-glucan synthesis is effective treatment for certain fungal infections, the ability of the cell wall to dynamically compensate via the cell wall integrity pathway may limit overall efficacy. To date, chitin synthesis inhibitors have not been successfully deployed in the clinical setting. Fungal chitin synthesis is a complex and highly regulated process. Regulation of chitin synthesis occurs on multiple levels, thus targeting of these regulatory pathways may represent an exciting alternative approach. A variety of signaling pathways have been implicated in chitin synthase regulation, at both transcriptional and post-transcriptional levels. Recent research suggests that localization of chitin synthases likely represents a major regulatory mechanism. However, much of the regulatory machinery is not necessarily shared among different chitin synthases. Thus, an in depth understanding of the precise roles of each protein in cell wall maintenance and repair will be essential to identifying the most likely therapeutic targets. PMID:21526913

Genomic identification of direct target genes of LEAFY

PubMed Central

William, Dilusha A.; Su, Yanhui; Smith, Michael R.; Lu, Meina; Baldwin, Don A.; Wagner, Doris

2004-01-01

The switch from vegetative to reproductive development in plants necessitates a switch in the developmental program of the descendents of the stem cells in the shoot apical meristem. Genetic and molecular investigations have demonstrated that the plant-specific transcription factor and meristem identity regulator LEAFY (LFY) controls this developmental transition by inducing expression of a second transcription factor, APETALA1, and by regulating the expression of additional, as yet unknown, genes. Here we show that the additional LFY targets include the APETALA1-related factor, CAULI-FLOWER, as well as three transcription factors and two putative signal transduction pathway components. These genes are up-regulated by LFY even when protein synthesis is inhibited and, hence, appear to be direct targets of LFY. Supporting this conclusion, cis-regulatory regions upstream of these genes are bound by LFY in vivo. The newly identified LFY targets likely initiate the transcriptional changes that are required for the switch from vegetative to reproductive development in Arabidopsis. PMID:14736918

Bombyx mori and Aedes aegypti form multi-functional immune complexes that integrate pattern recognition, melanization, coagulants, and hemocyte recruitment

PubMed Central

Phillips, Dennis R.

2017-01-01

The innate immune system of insects responds to wounding and pathogens by mobilizing multiple pathways that provide both systemic and localized protection. Key localized responses in hemolymph include melanization, coagulation, and hemocyte encapsulation, which synergistically seal wounds and envelop and destroy pathogens. To be effective, these pathways require a targeted deposition of their components to provide protection without compromising the host. Extensive research has identified a large number of the effectors that comprise these responses, but questions remain regarding their post-translational processing, function, and targeting. Here, we used mass spectrometry to demonstrate the integration of pathogen recognition proteins, coagulants, and melanization components into stable, high-mass, multi-functional Immune Complexes (ICs) in Bombyx mori and Aedes aegypti. Essential proteins common to both include phenoloxidases, apolipophorins, serine protease homologs, and a serine protease that promotes hemocyte recruitment through cytokine activation. Pattern recognition proteins included C-type Lectins in B. mori, while A. aegypti contained a protein homologous to Plasmodium-resistant LRIM1 from Anopheles gambiae. We also found that the B. mori IC is stabilized by extensive transglutaminase-catalyzed cross-linking of multiple components. The melanization inhibitor Egf1.0, from the parasitoid wasp Microplitis demolitor, blocked inclusion of specific components into the IC and also inhibited transglutaminase activity. Our results show how coagulants, melanization components, and hemocytes can be recruited to a wound surface or pathogen, provide insight into the mechanism by which a parasitoid evades this immune response, and suggest that insects as diverse as Lepidoptera and Diptera utilize similar defensive mechanisms. PMID:28199361

Bombyx mori and Aedes aegypti form multi-functional immune complexes that integrate pattern recognition, melanization, coagulants, and hemocyte recruitment.

PubMed

Phillips, Dennis R; Clark, Kevin D

2017-01-01

The innate immune system of insects responds to wounding and pathogens by mobilizing multiple pathways that provide both systemic and localized protection. Key localized responses in hemolymph include melanization, coagulation, and hemocyte encapsulation, which synergistically seal wounds and envelop and destroy pathogens. To be effective, these pathways require a targeted deposition of their components to provide protection without compromising the host. Extensive research has identified a large number of the effectors that comprise these responses, but questions remain regarding their post-translational processing, function, and targeting. Here, we used mass spectrometry to demonstrate the integration of pathogen recognition proteins, coagulants, and melanization components into stable, high-mass, multi-functional Immune Complexes (ICs) in Bombyx mori and Aedes aegypti. Essential proteins common to both include phenoloxidases, apolipophorins, serine protease homologs, and a serine protease that promotes hemocyte recruitment through cytokine activation. Pattern recognition proteins included C-type Lectins in B. mori, while A. aegypti contained a protein homologous to Plasmodium-resistant LRIM1 from Anopheles gambiae. We also found that the B. mori IC is stabilized by extensive transglutaminase-catalyzed cross-linking of multiple components. The melanization inhibitor Egf1.0, from the parasitoid wasp Microplitis demolitor, blocked inclusion of specific components into the IC and also inhibited transglutaminase activity. Our results show how coagulants, melanization components, and hemocytes can be recruited to a wound surface or pathogen, provide insight into the mechanism by which a parasitoid evades this immune response, and suggest that insects as diverse as Lepidoptera and Diptera utilize similar defensive mechanisms.

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

PubMed

Straube, Andreas; Aicher, Bernhard; Fiebich, Bernd L; Haag, Gunther

2011-03-31

Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.As an example the fixed-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

PubMed Central

2011-01-01

Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies. PMID:21453539

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

PubMed

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

2003-02-21

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

Animal models of drug addiction.

PubMed

García Pardo, María Pilar; Roger Sánchez, Concepción; De la Rubia Ortí, José Enrique; Aguilar Calpe, María Asunción

2017-09-29

The development of animal models of drug reward and addiction is an essential factor for progress in understanding the biological basis of this disorder and for the identification of new therapeutic targets. Depending on the component of reward to be studied, one type of animal model or another may be used. There are models of reinforcement based on the primary hedonic effect produced by the consumption of the addictive substance, such as the self-administration (SA) and intracranial self-stimulation (ICSS) paradigms, and there are models based on the component of reward related to associative learning and cognitive ability to make predictions about obtaining reward in the future, such as the conditioned place preference (CPP) paradigm. In recent years these models have incorporated methodological modifications to study extinction, reinstatement and reconsolidation processes, or to model specific aspects of addictive behavior such as motivation to consume drugs, compulsive consumption or drug seeking under punishment situations. There are also models that link different reinforcement components or model voluntary motivation to consume (two-bottle choice, or drinking in the dark tests). In short, innovations in these models allow progress in scientific knowledge regarding the different aspects that lead individuals to consume a drug and develop compulsive consumption, providing a target for future treatments of addiction.

School-Based First Aid Training Programs: A Systematic Review.

PubMed

Reveruzzi, Bianca; Buckley, Lisa; Sheehan, Mary

2016-04-01

This review examines the breadth of first aid training delivered to school students and the components that are age appropriate to adolescents. Eligible studies included school-based first aid interventions targeting students aged between 10 and 18 years. Online databases were searched, for peer-reviewed publications available as at August 2014. A total of 20 journal articles were relevant to the review. Research supported programs with longer durations (3 hours or more). Most programs taught resuscitation alone and few included content that was context-specific and relevant to the target group. The training experience of the facilitator did not appear to impact on student outcomes. Incorporating both practical and didactic components was found to be an important factor in delivering material and facilitating the retention of knowledge. Educational resources and facilitator training were found to be common features of effective programs. The review supports first aid in school curriculum and provides details of key components pertinent to design of school-based first aid programs. The findings suggest that first aid training may have benefits wider than the uptake and retention of knowledge and skills. There is a need for future research, particularly randomized controlled trials to aid in identifying best practice approaches. © 2016, American School Health Association.

Designing polymers with sugar-based advantages for bioactive delivery applications.

PubMed

Zhang, Yingyue; Chan, Jennifer W; Moretti, Alysha; Uhrich, Kathryn E

2015-12-10

Sugar-based polymers have been extensively explored as a means to increase drug delivery systems' biocompatibility and biodegradation. Here,we review he use of sugar-based polymers for drug delivery applications, with a particular focus on the utility of the sugar component(s) to provide benefits for drug targeting and stimuli responsive systems. Specifically, numerous synthetic methods have been developed to reliably modify naturally-occurring polysaccharides, conjugate sugar moieties to synthetic polymer scaffolds to generate glycopolymers, and utilize sugars as a multifunctional building block to develop sugar-linked polymers. The design of sugar-based polymer systems has tremendous implications on both the physiological and biological properties imparted by the saccharide units and are unique from synthetic polymers. These features include the ability of glycopolymers to preferentially target various cell types and tissues through receptor interactions, exhibit bioadhesion for prolonged residence time, and be rapidly recognized and internalized by cancer cells. Also discussed are the distinct stimuli-sensitive properties of saccharide-modified polymers to mediate drug release under desired conditions. Saccharide-based systems with inherent pH- and temperature-sensitive properties, as well as enzyme-cleavable polysaccharides for targeted bioactive delivery, are covered. Overall, this work emphasizes inherent benefits of sugar-containing polymer systems for bioactive delivery.

Comparative statistical component analysis of transgenic, cyanophycin-producing potatoes in greenhouse and field trials.

PubMed

Schmidt, Kerstin; Schmidtke, Jörg; Mast, Yvonne; Waldvogel, Eva; Wohlleben, Wolfgang; Klemke, Friederike; Lockau, Wolfgang; Hausmann, Tina; Hühns, Maja; Broer, Inge

2017-08-01

Potatoes are a promising system for industrial production of the biopolymer cyanophycin as a second compound in addition to starch. To assess the efficiency in the field, we analysed the stability of the system, specifically its sensitivity to environmental factors. Field and greenhouse trials with transgenic potatoes (two independent events) were carried out for three years. The influence of environmental factors was measured and target compounds in the transgenic plants (cyanophycin, amino acids) were analysed for differences to control plants. Furthermore, non-target parameters (starch content, number, weight and size of tubers) were analysed for equivalence with control plants. The huge amount of data received was handled using modern statistical approaches to model the correlation between influencing environmental factors (year of cultivation, nitrogen fertilization, origin of plants, greenhouse or field cultivation) and key components (starch, amino acids, cyanophycin) and agronomic characteristics. General linear models were used for modelling, and standard effect sizes were applied to compare conventional and genetically modified plants. Altogether, the field trials prove that significant cyanophycin production is possible without reduction of starch content. Non-target compound composition seems to be equivalent under varying environmental conditions. Additionally, a quick test to measure cyanophycin content gives similar results compared to the extensive enzymatic test. This work facilitates the commercial cultivation of cyanophycin potatoes.

TRAC based sensing for autonomous rendezvous

NASA Technical Reports Server (NTRS)

Everett, Louis J.; Monford, Leo

1991-01-01

The Targeting Reflective Alignment Concept (TRAC) sensor is to be used in an effort to support an Autonomous Rendezvous and Docking (AR&D) flight experiment. The TRAC sensor uses a fixed-focus, fixed-iris CCD camera and a target that is a combination of active and passive components. The system experiment is anticipated to fly in 1994 using two Commercial Experiment Transporters (COMET's). The requirements for the sensor are: bearing error less than or equal to 0.075 deg; bearing error rate less than 0.3 deg/sec; attitude error less than 0.5 deg.; and attitude rate error less than 2.0 deg/sec. The range requirement depends on the range and the range rate of the vehicle. The active component of the target is several 'kilo-bright' LED's that can emit 2500 millicandela with 40 milliwatts of input power. Flashing the lights in a known pattern eliminates background illumination. The system should be able to rendezvous from 300 meters all the way to capture. A question that arose during the presentation: What is the life time of the LED's and their sensitivity to radiation? The LED's should be manufactured to Military Specifications, coated with silicon dioxide, and all other space qualified precautions should be taken. The LED's will not be on all the time so they should easily last the two-year mission.

bicoid RNA localization requires specific binding of an endosomal sorting complex

PubMed Central

Irion, Uwe; St Johnston, Daniel

2007-01-01

Summary paragraph: bicoid mRNA localises to the anterior of the Drosophila egg, where it is translated to form a morphogen gradient of Bicoid protein that patterns the head and thorax of the embryo. Although bicoid was the first identified localised cytoplasmic determinant1-4, little is known about how the mRNA is coupled to the microtubule-dependent transport pathway that targets it to the anterior, and it has been proposed that it is recognised by a complex of many redundant proteins, each of which binds to the localisation element in its 3'UTR with little or no specificity5. Indeed, the only known RNA-binding protein that co-localises with bicoid mRNA is Staufen, which binds non-specifically to dsRNA in vitro6, 7. Here we show that mutants in all subunits of the ESCRT-II complex (Vps22, Vps25 and Vps36) abolish the final Staufen-dependent step in bcd RNA localisation. ESCRT-II is a highly conserved component of the pathway that sorts ubiquitinated endosomal proteins into internal vesicles8, 9, and functions as a tumour-suppressor by removing activated receptors from the cytoplasm10, 11. However, the role of ESCRT-II in bicoid localisation appears to be independent of endosomal sorting, because mutations in ESCRT-I and III components have no effect of the targeting of bicoid mRNA. Instead, Vps36 functions by binding directly and specifically to stem-loop V of the bicoid 3'UTR through its N-terminal GLUE domain12, making it the first example of a sequence specific RNA-binding protein that recognises the bicoid localisation signal. Furthermore, Vps36 localises to the anterior of the oocyte in a bicoid mRNA-dependent manner, and is required for the subsequent recruitment of Staufen to the bicoid complex. This novel function of ESCRT-II as an RNA-binding complex is conserved in vertebrates, and may explain some of its roles that are independent of endosomal sorting. PMID:17268469

Method To Identify Specific Inhibiutors Of Imp Dehydrogenase

DOEpatents

Collart, Frank R.; Huberman, Eliezer

2000-11-28

This invention relates to methods to identify specific inhibitors of the purine nucleotide synthesis enzyme, IMP dehydrogenase (IMPDH). IMPDH is an essential enzyme found in all free-living organisms from humans to bacteria and is an important therapeutic target. The invention allows the identification of specific inhibitors of any IMPDH enzyme which can be expressed in a functional form in a recombinant host cell. A variety of eukaryotic or prokaryotic host systems commonly used for the expression of recombinant proteins are suitable for the practice of the invention. The methods are amenable to high throughput systems for the screening of inhibitors generated by combinatorial chemistry or other methods such as antisense molecule production. Utilization of exogenous guanosine as a control component of the methods allows for the identification of inhibitors specific for IMPDH rather than other causes of decreased cell proliferation.

Empathic competencies in violent offenders☆

PubMed Central

Seidel, Eva-Maria; Pfabigan, Daniela Melitta; Keckeis, Katinka; Wucherer, Anna Maria; Jahn, Thomas; Lamm, Claus; Derntl, Birgit

2013-01-01

Violent offending has often been associated with a lack of empathy, but experimental investigations are rare. The present study aimed at clarifying whether violent offenders show a general empathy deficit or specific deficits regarding the separate subcomponents. To this end, we assessed three core components of empathy (emotion recognition, perspective taking, affective responsiveness) as well as skin conductance response (SCR) in a sample of 30 male violent offenders and 30 healthy male controls. Data analysis revealed reduced accuracy in violent offenders compared to healthy controls only in emotion recognition, and that a high number of violent assaults was associated with decreased accuracy in perspective taking for angry scenes. SCR data showed reduced physiological responses in the offender group specifically for fear and disgust stimuli during emotion recognition and perspective taking. In addition, higher psychopathy scores in the violent offender group were associated with reduced accuracy in affective responsiveness. This is the first study to show that mainly emotion recognition is deficient in violent offenders whereas the other components of empathy are rather unaffected. This divergent impact of violent offending on the subcomponents of empathy suggests that all three empathy components can be targeted by therapeutic interventions separately. PMID:24035702

Lectin conjugates as biospecific contrast agents for MRI. Coupling of Lycopersicon esculentum agglutinin to linear water-soluble DTPA-loaded oligomers.

PubMed

Pashkunova-Martic, Irena; Kremser, Christian; Galanski, Markus; Schluga, Petra; Arion, Vladimir; Debbage, Paul; Jaschke, Werner; Keppler, Bernhard

2011-06-01

Magnetic resonance imaging (MRI) requires synthesis of contrast media bearing targeting groups and numerous gadolinium chelating groups generating high relaxivity. This paper explores the results of linking the gadolinium chelates to the targeting group, a protein molecule, via various types of linkers. Polycondensates of diethylenetriaminepentaacetic acid (DTPA) with either diols or diamines were synthesised and coupled to the targeting group, a lectin (Lycopersicon esculentum agglutinin, tomato lectin) which binds with high affinity to specific oligosaccharide configurations in the endothelial glycocalyx. The polycondensates bear up to four carboxylic groups per constitutive unit. Gd-chelate bonds are created through dative interactions with the unshared pair of electrons on each oxygen and nitrogen atom on DTPA. This is mandatory for complexation of Gd(III) and avoidance of the severe toxicity of free gadolinium ions. The polymer-DTPA compounds were characterised by (1)H NMR and mass spectrometry. The final lectin-DTPA-polycondensate conjugates were purified by fast protein liquid chromatography (FPLC). The capacity for specific binding was assessed, and the MRI properties were examined in order to evaluate the use of these oligomers as components of selective perfusional contrast agents.

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

NASA Astrophysics Data System (ADS)

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

2013-11-01

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

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

NASA Astrophysics Data System (ADS)

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

2014-03-01

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

Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs) α/γ

PubMed Central

Moldes-Anaya, Angel; Sæther, Thomas; Uhlig, Silvio; Nebb, Hilde I.; Larsen, Terje; Eilertsen, Hans C.; Paulsen, Steinar M.

2017-01-01

The peroxisome proliferator-activated receptors (PPARs) function as ligand-activated transcription factors that convert signals in the form of lipids to physiological responses through the activation of metabolic target genes. Due to their key roles in lipid and carbohydrate metabolism, the PPARs are important drug targets. However, for several of the PPAR drugs currently in use, adverse side effects have been reported. In an effort to identify compounds from marine organisms that may serve as molecular scaffolds for the development of novel and safer PPAR-targeting drugs, we performed a bioassay-guided screening of organic extracts made from organisms supplied by the Norwegian Biobank of Arctic Marine Organisms (Marbank). Among several interesting hits, we identified two poorly described isomeric oxo-fatty acids from the microalgae Chaetoceros karianus for which we provide the first evidence that they might display dual specificity towards human PPARα and PPARγ. Principal component analysis showed that C. karianus stood out from other Chaetoceros species, both with respect to the metabolic profile and the PPAR activity. The isolation of these compounds holds the potential of uncovering a PPAR pharmacophore with tunable activity and specificity. PMID:28587091

NEuclid: a long-range tilt-immune homodyne interferometer

NASA Astrophysics Data System (ADS)

Bradshaw, M. J.; Speake, C. C.

2017-11-01

The new Easy to Use Compact Laser Interferometric Device (nEUCLID) is a polarisation-based homodyne interferometer with substantially unequal arms that is tolerant to target mirror tilt. The design has no active components, uses standard optical components of 25 mm diameter, has a working distance of 706 mm and a reference arm-length of 21 mm. nEUCLID optics have a footprint of 210 x 190 x 180 mm, and has a tolerance to target mirror tilt of +/- 0.5 degrees, made possible by a novel new retro-reflector design [1]. nEUCLID was built to a set of specifications laid down by Airbus Defence and Space, who required a lowmass, low-power device to measure displacement with nanometre accuracy for space applications. At the University of Birmingham we have previously built a smaller, more compact tilt-insensitive homodyne interferometer - the EUCLID [2, 3, 4] - which has a working distance of 6 mm, a working range of +/- 3 mm, and a tilt range of +/- 1° [2]. We created a new optical design to allow a much larger working distance to be achieved (as discussed in Section II) and used this in a new interferometer - the nEUCLID. Section II describes the interferometer in detail; how nEUCLID is tilt insensitive, and the optical configuration. Section III states the design specifications from Airbus Defence and Space and the components used in the final design. The output interference pattern from nEUCLID, and how it has been corrected with a meniscus lens, is also discussed. In Section IV we discuss the results demonstrating the tilt immunity range, and the sensitivity of the device. Section V describes several potential applications of nEUCLID, and Section VI draws together our conclusions.

Localization and Sub-Cellular Shuttling of HTLV-1 Tax with the miRNA Machinery

PubMed Central

Van Duyne, Rachel; Guendel, Irene; Klase, Zachary; Narayanan, Aarthi; Coley, William; Jaworski, Elizabeth; Roman, Jessica; Popratiloff, Anastas; Mahieux, Renaud; Kehn-Hall, Kylene; Kashanchi, Fatah

2012-01-01

The innate ability of the human cell to silence endogenous retroviruses through RNA sequences encoding microRNAs, suggests that the cellular RNAi machinery is a major means by which the host mounts a defense response against present day retroviruses. Indeed, cellular miRNAs target and hybridize to specific sequences of both HTLV-1 and HIV-1 viral transcripts. However, much like the variety of host immune responses to retroviral infection, the virus itself contains mechanisms that assist in the evasion of viral inhibition through control of the cellular RNAi pathway. Retroviruses can hijack both the enzymatic and catalytic components of the RNAi pathway, in some cases to produce novel viral miRNAs that can either assist in active viral infection or promote a latent state. Here, we show that HTLV-1 Tax contributes to the dysregulation of the RNAi pathway by altering the expression of key components of this pathway. A survey of uninfected and HTLV-1 infected cells revealed that Drosha protein is present at lower levels in all HTLV-1 infected cell lines and in infected primary cells, while other components such as DGCR8 were not dramatically altered. We show colocalization of Tax and Drosha in the nucleus in vitro as well as coimmunoprecipitation in the presence of proteasome inhibitors, indicating that Tax interacts with Drosha and may target it to specific areas of the cell, namely, the proteasome. In the presence of Tax we observed a prevention of primary miRNA cleavage by Drosha. Finally, the changes in cellular miRNA expression in HTLV-1 infected cells can be mimicked by the add back of Drosha or the addition of antagomiRs against the cellular miRNAs which are downregulated by the virus. PMID:22808228

Auto Code Generation for Simulink-Based Attitude Determination Control System

NASA Technical Reports Server (NTRS)

MolinaFraticelli, Jose Carlos

2012-01-01

This paper details the work done to auto generate C code from a Simulink-Based Attitude Determination Control System (ADCS) to be used in target platforms. NASA Marshall Engineers have developed an ADCS Simulink simulation to be used as a component for the flight software of a satellite. This generated code can be used for carrying out Hardware in the loop testing of components for a satellite in a convenient manner with easily tunable parameters. Due to the nature of the embedded hardware components such as microcontrollers, this simulation code cannot be used directly, as it is, on the target platform and must first be converted into C code; this process is known as auto code generation. In order to generate C code from this simulation; it must be modified to follow specific standards set in place by the auto code generation process. Some of these modifications include changing certain simulation models into their atomic representations which can bring new complications into the simulation. The execution order of these models can change based on these modifications. Great care must be taken in order to maintain a working simulation that can also be used for auto code generation. After modifying the ADCS simulation for the auto code generation process, it is shown that the difference between the output data of the former and that of the latter is between acceptable bounds. Thus, it can be said that the process is a success since all the output requirements are met. Based on these results, it can be argued that this generated C code can be effectively used by any desired platform as long as it follows the specific memory requirements established in the Simulink Model.

An electrophysiological investigation of reinforcement effects in attention deficit/hyperactivity disorder: Dissociating cue sensitivity from down-stream effects on target engagement and performance.

PubMed

Chronaki, Georgia; Soltesz, Fruzsina; Benikos, Nicholas; Sonuga-Barke, Edmund J S

2017-12-01

Neural hypo-sensitivity to cues predicting positive reinforcement has been observed in ADHD using the Monetary Incentive Delay (MID) task. Here we report the first study using an electrophysiological analogue of this task to distinguish between (i) cue related anticipation of reinforcement and downstream effects on (ii) target engagement and (iii) performance in a clinical sample of adolescents with ADHD and controls. Thirty-one controls and 32 adolescents with ADHD aged 10-16 years performed the electrophysiological (e)-MID task - in which preparatory cues signal whether a response to an upcoming target will be reinforced or not - under three conditions; positive reinforcement, negative reinforcement (response cost) and no consequence (neutral). We extracted values for both cue-related potentials known to be, both, associated with response preparation and modulated by reinforcement (Cue P3 and Cue CNV) and target-related potentials (target P3) and compared these between ADHD and controls. ADHD and controls did not differ on cue-related components on neutral trials. Against expectation, adolescents with ADHD displayed Cue P3 and Cue CNV reinforcement-related enhancement (versus neutral trials) compared to controls. ADHD individuals displayed smaller target P3 amplitudes and slower and more variable performance - but effects were not modulated by reinforcement contingencies. When age, IQ and conduct problems were controlled effects were marginally significant but the pattern of results did not change. ADHD was associated with hypersensitivity to positive (and marginally negative) reinforcement reflected on components often thought to be associated with response preparation - however these did not translate into improved attention to targets. In the case of ADHD, upregulated CNV may be a specific marker of hyper-arousal rather than an enhancement of anticipatory attention to upcoming targets. Future studies should examine the effects of age, IQ and conduct problems on reinforcement sensitivity in ADHD. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription.

PubMed

Portnoy, Victoria; Lin, Szu Hua Sharon; Li, Kathy H; Burlingame, Alma; Hu, Zheng-Hui; Li, Hao; Li, Long-Cheng

2016-03-01

Small activating RNAs (saRNAs) targeting specific promoter regions are able to stimulate gene expression at the transcriptional level, a phenomenon known as RNA activation (RNAa). It is known that RNAa depends on Ago2 and is associated with epigenetic changes at the target promoters. However, the precise molecular mechanism of RNAa remains elusive. Using human CDKN1A (p21) as a model gene, we characterized the molecular nature of RNAa. We show that saRNAs guide Ago2 to and associate with target promoters. saRNA-loaded Ago2 facilitates the assembly of an RNA-induced transcriptional activation (RITA) complex, which, in addition to saRNA-Ago2 complex, includes RHA and CTR9, the latter being a component of the PAF1 complex. RITA interacts with RNA polymerase II to stimulate transcription initiation and productive elongation, accompanied by monoubiquitination of histone 2B. Our results establish the existence of a cellular RNA-guided genome-targeting and transcriptional activation mechanism and provide important new mechanistic insights into the RNAa process.

An eHealth Intervention to Promote Physical Activity and Social Network of Single, Chronically Impaired Older Adults: Adaptation of an Existing Intervention Using Intervention Mapping

PubMed Central

Peels, Denise A; Berendsen, Brenda AJ; Bolman, Catherine AW; Lechner, Lilian

2017-01-01

Background Especially for single older adults with chronic diseases, physical inactivity and a poor social network are regarded as serious threats to their health and independence. The Active Plus intervention is an automated computer-tailored eHealth intervention that has been proven effective to promote physical activity (PA) in the general population of adults older than 50 years. Objective The aim of this study was to report on the methods and results of the systematic adaptation of Active Plus to the wishes and needs of the subgroup of single people older than 65 years who have one or more chronic diseases, as this specific target population may encounter specific challenges regarding PA and social network. Methods The Intervention Mapping (IM) protocol was used to systematically adapt the existing intervention to optimally suit this specific target population. A literature study was performed, and quantitative as well as qualitative data were derived from health care professionals (by questionnaires, n=10) and the target population (by focus group interviews, n=14), which were then systematically integrated into the adapted intervention. Results As the health problems and the targeted behavior are largely the same in the original and adapted intervention, the outcome of the needs assessment was that the performance objectives remained the same. As found in the literature study and in data derived from health professionals and focus groups, the relative importance and operationalization of the relevant psychosocial determinants related to these objectives are different from the original intervention, resulting in a refinement of the change objectives to optimally fit the specific target population. This refinement also resulted in changes in the practical applications, program components, intervention materials, and the evaluation and implementation strategy for the subgroup of single, chronically impaired older adults. Conclusions This study demonstrates that the adaptation of an existing intervention is an intensive process in which adopting the IM protocol is an invaluable tool. The study provides a broad insight in adapting interventions aimed at single older adults with a chronic disease. It is concluded that even when the new target population is a sizable segment of the original target population, the adapted intervention still needs considerable changes to optimally fit the needs and situational differences of the narrower target population. PMID:29170146

Relationships between drought, heat and air humidity responses revealed by transcriptome-metabolome co-analysis.

PubMed

Georgii, Elisabeth; Jin, Ming; Zhao, Jin; Kanawati, Basem; Schmitt-Kopplin, Philippe; Albert, Andreas; Winkler, J Barbro; Schäffner, Anton R

2017-07-10

Elevated temperature and reduced water availability are frequently linked abiotic stresses that may provoke distinct as well as interacting molecular responses. Based on non-targeted metabolomic and transcriptomic measurements from Arabidopsis rosettes, this study aims at a systematic elucidation of relevant components in different drought and heat scenarios as well as relationships between molecular players of stress response. In combined drought-heat stress, the majority of single stress responses are maintained. However, interaction effects between drought and heat can be discovered as well; these relate to protein folding, flavonoid biosynthesis and growth inhibition, which are enhanced, reduced or specifically induced in combined stress, respectively. Heat stress experiments with and without supplementation of air humidity for maintenance of vapor pressure deficit suggest that decreased relative air humidity due to elevated temperature is an important component of heat stress, specifically being responsible for hormone-related responses to water deprivation. Remarkably, this "dry air effect" is the primary trigger of the metabolomic response to heat. In contrast, the transcriptomic response has a substantial temperature component exceeding the dry air component and including up-regulation of many transcription factors and protein folding-related genes. Data level integration independent of prior knowledge on pathways and condition labels reveals shared drought and heat responses between transcriptome and metabolome, biomarker candidates and co-regulation between genes and metabolic compounds, suggesting novel players in abiotic stress response pathways. Drought and heat stress interact both at transcript and at metabolite response level. A comprehensive, non-targeted view of this interaction as well as non-interacting processes is important to be taken into account when improving tolerance to abiotic stresses in breeding programs. Transcriptome and metabolome may respond with different extent to individual stress components. Their contrasting behavior in response to temperature stress highlights that the protein folding machinery effectively shields the metabolism from stress. Disentangling the complex relationships between transcriptome and metabolome in response to stress is an enormous challenge. As demonstrated by case studies with supporting evidence from additional data, the large dataset provided in this study may assist in determining linked genetic and metabolic features as candidates for future mechanistic analyses.

An olfactory cocktail party: figure-ground segregation of odorants in rodents.

PubMed

Rokni, Dan; Hemmelder, Vivian; Kapoor, Vikrant; Murthy, Venkatesh N

2014-09-01

In odorant-rich environments, animals must be able to detect specific odorants of interest against variable backgrounds. However, studies have found that both humans and rodents are poor at analyzing the components of odorant mixtures, suggesting that olfaction is a synthetic sense in which mixtures are perceived holistically. We found that mice could be easily trained to detect target odorants embedded in unpredictable and variable mixtures. To relate the behavioral performance to neural representation, we imaged the responses of olfactory bulb glomeruli to individual odors in mice expressing the Ca(2+) indicator GCaMP3 in olfactory receptor neurons. The difficulty of segregating the target from the background depended strongly on the extent of overlap between the glomerular responses to target and background odors. Our study indicates that the olfactory system has powerful analytic abilities that are constrained by the limits of combinatorial neural representation of odorants at the level of the olfactory receptors.

Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells

PubMed Central

Tam, Wai Leong; Lu, Haihui; Buikhuisen, Joyce; Soh, Boon Seng; Lim, Elgene; Reinhardt, Ferenc; Wu, Zhenhua Jeremy; Krall, Jordan A.; Bierie, Brian; Guo, Wenjun; Chen, Xi; Liu, Xiaole Shirley; Brown, Myles; Lim, Bing; Weinberg, Robert A.

2014-01-01

SUMMARY The epithelial-mesenchymal transition program becomes activated during malignant progression and can enrich for cancer stem cells (CSCs). We report that inhibition of protein kinase C α (PKCα) specifically targets CSCs, but has little effect on non-CSCs. The formation of CSCs from non-stem cells involves a shift from EGFR to PDGFR signaling, and results in the PKCα-dependent activation of FRA1. We identified an AP-1 molecular switch in which c-FOS and FRA1 are preferentially utilized in non-CSCs and CSCs, respectively. PKCα and FRA1 expression is associated with the aggressive triple-negative breast cancers and the depletion of FRA1 results in a mesenchymal-epithelial transition. Hence, identifying molecular features that shift between cell states can be exploited to target signaling components critical to CSCs. PMID:24029232

Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells.

PubMed

Tam, Wai Leong; Lu, Haihui; Buikhuisen, Joyce; Soh, Boon Seng; Lim, Elgene; Reinhardt, Ferenc; Wu, Zhenhua Jeremy; Krall, Jordan A; Bierie, Brian; Guo, Wenjun; Chen, Xi; Liu, Xiaole Shirley; Brown, Myles; Lim, Bing; Weinberg, Robert A

2013-09-09

The epithelial-mesenchymal transition program becomes activated during malignant progression and can enrich for cancer stem cells (CSCs). We report that inhibition of protein kinase C α (PKCα) specifically targets CSCs but has little effect on non-CSCs. The formation of CSCs from non-stem cells involves a shift from EGFR to PDGFR signaling and results in the PKCα-dependent activation of FRA1. We identified an AP-1 molecular switch in which c-FOS and FRA1 are preferentially utilized in non-CSCs and CSCs, respectively. PKCα and FRA1 expression is associated with the aggressive triple-negative breast cancers, and the depletion of FRA1 results in a mesenchymal-epithelial transition. Hence, identifying molecular features that shift between cell states can be exploited to target signaling components critical to CSCs. Copyright © 2013 Elsevier Inc. All rights reserved.

Quantification of false positive reduction in nucleic acid purification on hemorrhagic fever DNA.

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

James, Conrad D.; Pohl, Kenneth Roy; Derzon, Mark Steven

2006-11-01

Columbia University has developed a sensitive highly multiplexed system for genetic identification of nucleic acid targets. The primary obstacle to implementing this technology is the high rate of false positives due to high levels of unbound reporters that remain within the system after hybridization. The ability to distinguish between free reporters and reporters bound to targets limits the use of this technology. We previously demonstrated a new electrokinetic method for binary separation of kb pair long DNA molecules and oligonucleotides. The purpose of this project 99864 is to take these previous demonstrations and further develop the technique and hardware formore » field use. Specifically, our objective was to implement separation in a heterogeneous sample (containing target DNA and background oligo), to perform the separation in a flow-based device, and to develop all of the components necessary for field testing a breadboard prototype system.« less

Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways

PubMed Central

Rhind, Nicholas; Russell, Paul

2010-01-01

SUMMARY Recent work on the mechanisms of DNA damage and replication cell cycle checkpoints has revealed great similarity between the checkpoint pathways of organisms as diverse as yeasts, flies and humans. However, there are differences in the ways these organisms regulate their cell cycles. To connect the conserved checkpoint pathways with various cell cycle targets requires an adaptable link that can target different cell cycle components in different organisms. The Chk1 and Cds1 protein kinases, downstream effectors in the checkpoint pathways, seem to play just such roles. Perhaps more surprisingly, the two kinases not only have different targets in different organisms but also seem to respond to different signals in different organisms. So, whereas in fission yeast Chk1 is required for the DNA damage checkpoint and Cds1 is specifically involved in the replication checkpoint, their roles seem to be shuffled in metazoans. PMID:11058076

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

PubMed

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

2015-09-15

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

Face Aging Effect Simulation Using Hidden Factor Analysis Joint Sparse Representation.

PubMed

Yang, Hongyu; Huang, Di; Wang, Yunhong; Wang, Heng; Tang, Yuanyan

2016-06-01

Face aging simulation has received rising investigations nowadays, whereas it still remains a challenge to generate convincing and natural age-progressed face images. In this paper, we present a novel approach to such an issue using hidden factor analysis joint sparse representation. In contrast to the majority of tasks in the literature that integrally handle the facial texture, the proposed aging approach separately models the person-specific facial properties that tend to be stable in a relatively long period and the age-specific clues that gradually change over time. It then transforms the age component to a target age group via sparse reconstruction, yielding aging effects, which is finally combined with the identity component to achieve the aged face. Experiments are carried out on three face aging databases, and the results achieved clearly demonstrate the effectiveness and robustness of the proposed method in rendering a face with aging effects. In addition, a series of evaluations prove its validity with respect to identity preservation and aging effect generation.

Determinants of propranolol’s selective effect on loss aversion

PubMed Central

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

2015-01-01

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

Molecular defects leading to human complement component C6 deficiency in an African-American family

PubMed Central

Zhu, Z-B; Totemchokchyakarn, K; Atkinson, T P; Volanakis, J E

1998-01-01

Complement component C6 deficiency (C6D) was diagnosed in a 16-year-old African-American male with meningococcal meningitis. The patient's father and two brothers also had C6D, but gave no history of meningitis or other neisserial infection. By using exon-specific polymerase chain reaction (PCR)/single-strand conformation polymorphism as a screening step and nucleotide sequencing of target exons, we determined that the proband was a compound heterozygote for two C6 gene mutations. The first, 1195delC located in exon 7, is a novel mutation, while the second, 1936delG in exon 12, has been described before to cause C6D in an unrelated African-American individual. Both mutations result in premature termination codons and C6 null alleles. Allele-specific PCR indicated that the proband's two brothers also inherited the 1195delC mutation from their heterozygous mother and the 1936delG mutation from their homozygous father. PMID:9472666

Evaluating contribution of ionic, osmotic and oxidative stress components towards salinity tolerance in barley

PubMed Central

2014-01-01

Background Salinity tolerance is a physiologically multi-faceted trait attributed to multiple mechanisms. Three barley (Hordeum vulgare) varieties contrasting in their salinity tolerance were used to assess the relative contribution of ionic, osmotic and oxidative stress components towards overall salinity stress tolerance in this species, both at the whole-plant and cellular levels. In addition, transcriptional changes in the gene expression profile were studied for key genes mediating plant ionic and oxidative homeostasis (NHX; RBOH; SOD; AHA and GORK), to compare a contribution of transcriptional and post-translational factors towards the specific components of salinity tolerance. Results Our major findings are two-fold. First, plant tissue tolerance was a dominating component that has determined the overall plant responses to salinity, with root K+ retention ability and reduced sensitivity to stress-induced hydroxyl radical production being the main contributing tolerance mechanisms. Second, it was not possible to infer which cultivars were salinity tolerant based solely on expression profiling of candidate genes at one specific time point. For the genes studied and the time point selected that transcriptional changes in the expression of these specific genes had a small role for barley’s adaptive responses to salinity. Conclusions For better tissue tolerance, sodium sequestration, K+ retention and resistance to oxidative stress all appeared to be crucial. Because these traits are highly interrelated, it is suggested that a major progress in crop breeding for salinity tolerance can be achieved only if these complementary traits are targeted at the same time. This study also highlights the essentiality of post translational modifications in plant adaptive responses to salinity. PMID:24774965

Adolescent transformations of behavioral and neural processes as potential targets for prevention.

PubMed

Eldreth, Dana; Hardin, Michael G; Pavletic, Nevia; Ernst, Monique

2013-06-01

Adolescence is a transitional period in development that is marked by a distinct, typical behavioral profile of high rates of exploration, novelty-seeking, and emotional lability. While these behaviors generally assist the adolescent transition to independence, they can also confer vulnerability for excessive risk-taking and psychopathology, particularly in the context of specific environmental or genetic influences. As prevention research depends on the identification of targets of vulnerability, the following review will discuss the interplay among motivational systems including reward-related, avoidance-related, and regulatory processes in typical and atypical adolescent development. Each set of processes will be discussed in relation to their underlying neural correlates and distinct developmental trajectories. Evidence suggests that typical adolescent behavior and the risk for atypical development are mediated by heightened adolescent responsiveness of reward-related and avoidance-related systems under specific conditions, concurrent with poor modulation by immature regulatory processes. Finally, we will propose strategies to exploit heightened reward processing to reinforce inhibitory control, which is an essential component of regulatory processes in prevention interventions.

TNF-induced target cell killing by CTL activated through cross-presentation.

PubMed

Wohlleber, Dirk; Kashkar, Hamid; Gärtner, Katja; Frings, Marianne K; Odenthal, Margarete; Hegenbarth, Silke; Börner, Carolin; Arnold, Bernd; Hämmerling, Günter; Nieswandt, Bernd; van Rooijen, Nico; Limmer, Andreas; Cederbrant, Karin; Heikenwalder, Mathias; Pasparakis, Manolis; Protzer, Ulrike; Dienes, Hans-Peter; Kurts, Christian; Krönke, Martin; Knolle, Percy A

2012-09-27

Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF), which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Mining Naïve Rabbit Antibody Repertoires by Phage Display for Monoclonal Antibodies of Therapeutic Utility.

PubMed

Peng, Haiyong; Nerreter, Thomas; Chang, Jing; Qi, Junpeng; Li, Xiuling; Karunadharma, Pabalu; Martinez, Gustavo J; Fallahi, Mohammad; Soden, Jo; Freeth, Jim; Beerli, Roger R; Grawunder, Ulf; Hudecek, Michael; Rader, Christoph

2017-09-15

Owing to their high affinities and specificities, rabbit monoclonal antibodies (mAbs) have demonstrated value and potential primarily as basic research and diagnostic reagents, but, in some cases, also as therapeutics. To accelerate access to rabbit mAbs bypassing immunization, we generated a large naïve rabbit antibody repertoire represented by a phage display library encompassing >10 billion independent antibodies in chimeric rabbit/human Fab format and validated it by next-generation sequencing. Panels of rabbit mAbs selected from this library against two emerging cancer targets, ROR1 and ROR2, revealed high diversity, affinity, and specificity. Moreover, ROR1- and ROR2-targeting rabbit mAbs demonstrated therapeutic utility as components of chimeric antigen receptor-engineered T cells, further corroborating the value of the naïve rabbit antibody library as a rich and virtually unlimited source of rabbit mAbs. Copyright © 2017 Elsevier Ltd. All rights reserved.

From Bits and Pieces to Whole Phage to Nanomachines: Pathogen Detection Using Bacteriophages.

PubMed

Anany, H; Chou, Y; Cucic, S; Derda, R; Evoy, S; Griffiths, M W

2017-02-28

The innate specificity of bacteriophages toward their hosts makes them excellent candidates for the development of detection assays. They can be used in many ways to detect pathogens, and each has its own advantages and disadvantages. Whole bacteriophages can carry reporter genes to alter the phenotype of the target. Bacteriophages can act as staining agents or the progeny of the infection process can be detected, which further increases the sensitivity of the detection assay. Compared with whole-phage particles, use of phage components as probes offers other advantages: for example, smaller probe size to enhance binding activity, phage structures that can be engineered for better affinity, as well as specificity, binding properties, and robustness. When no natural binding with the target exists, phages can be used as vehicles to identify new protein-ligand interactions necessary for diagnostics. This review comprehensively summarizes many uses of phages as detection tools and points the way toward how phage-based technologies may be improved.

Adults with dyslexia demonstrate space-based and object-based covert attention deficits: shifting attention to the periphery and shifting attention between objects in the left visual field.

PubMed

Buchholz, Judy; Aimola Davies, Anne

2005-02-01

Performance on a covert visual attention task is compared between a group of adults with developmental dyslexia (specifically phonological difficulties) and a group of age and IQ matched controls. The group with dyslexia were generally slower to detect validly-cued targets. Costs of shifting attention toward the periphery when the target was invalidly cued were significantly higher for the group with dyslexia, while costs associated with shifts toward the fovea tended to be lower. Higher costs were also shown by the group with dyslexia for up-down shifts of attention in the periphery. A visual field processing difference was found, in that the group with dyslexia showed higher costs associated with shifting attention between objects in they LVF. These findings indicate that these adults with dyslexia have difficulty in both the space-based and the object-based components of covert visual attention, and more specifically to stimuli located in the periphery.

Detection of adulterated murine components in meat products by TaqMan© real-time PCR.

PubMed

Fang, Xin; Zhang, Chi

2016-02-01

Using murine meat to substitute mutton has been identified as a new type of meat fraud in China, yet no detection method for murine species has been reported. Here, three kinds of rodent were used as target species to establish a murine-specific real-time PCR method of detection. The mitochondrial cytochrome b gene (cytb) of each target was sequenced and a TaqMan probe was designed based on the cytb. Simultaneously, an internal positive control (IPC) plasmid along with its respective probe were designed to monitor the PCR reaction. As a result, the duplex real-time PCR system was verified to be specific. The limit of detection (LOD) was lower than 1 pg of DNA per reaction and 0.1% murine contamination in meat mixtures. Standard curves were generated for a quantitative analysis. Thus, this study provided a new tool to control the quality of meat products for official and third-party laboratories. Copyright © 2015. Published by Elsevier Ltd.

Design of a homogeneous multifunctional supported lipid membrane on layer-by-layer coated microcarriers.

PubMed

Göse, Martin; Pescador, Paula; Reibetanz, Uta

2015-03-09

Key challenges in the development of drug delivery systems are the prevention of serum compartment interaction and the targeted delivery of the cargo. Layer-by-Layer microcarriers offer many advantages due to various options in drug assembly and multifunctional design. Surface modification with a supported lipid membrane enhances biocompatibility, drug protection ability, and specific functionality. However, the integration of functionalized lipids strongly influences the membrane formation and is often accompanied by submicrometer irregularities: The accessibility of underlying polymers to serum components may change the carrier's properties and enhances the susceptibility to opsonization. Therefore, the formation of a tightly assembled multifunctional lipid membrane has been emphasized. A phosphatidylserine/phosphatidylcholine (POPS/POPC) bilayer equipped with phosphatidylethanolamine-polyethylene glycol-biotin (PE-PEG-Biotin) was used to facilitate a biotin/streptavidin binding site for a variable attachment of an additional function, such as antibodies for specific targeting. Thus, a prefunctionalized carrier where only the outer functionality needs to be replaced without disturbing the underlying structure could be created.

The PPARγ2 A/B-Domain Plays a Gene-Specific Role in Transactivation and Cofactor Recruitment

PubMed Central

Bugge, Anne; Grøntved, Lars; Aagaard, Mads M.; Borup, Rehannah; Mandrup, Susanne

2009-01-01

We have previously shown that adenoviral expression of peroxisome proliferator-activated receptors (PPARs) leads to rapid establishment of transcriptionally active complexes and activation of target gene expression within 5–8 h after transduction. Here we have used the adenoviral delivery system combined with expression array analysis to identify novel putative PPARγ target genes in murine fibroblasts and to determine the role of the A/B-domain in PPARγ-mediated transactivation of genomic target genes. Of the 257 genes found to be induced by PPARγ2 expression, only 25 displayed A/B-domain dependency, i.e. significantly reduced induction in the cells expressing the truncated PPARγ lacking the A/B-domain (PPARγCDE). Nine of the 25 A/B-domain-dependent genes were involved in lipid storage, and in line with this, triglyceride accumulation was considerably decreased in the cells expressing PPARγCDE compared with cells expressing full-length PPARγ2. Using chromatin immunoprecipitation, we demonstrate that PPARγ binding to genomic target sites and recruitment of the mediator component TRAP220/MED1/PBP/DRIP205 is not affected by the deletion of the A/B-domain. By contrast, the PPARγ-mediated cAMP response element-binding protein (CREB)-binding protein (CBP) and p300 recruitment to A/B-domain-dependent target genes is compromised by deletion of the A/B-domain. These results indicate that the A/B-domain of PPARγ2 is specifically involved in the recruitment or stabilization of CBP- and p300-containing cofactor complexes to a subset of target genes. PMID:19282365

Free Extracellular miRNA Functionally Targets Cells by Transfecting Exosomes from Their Companion Cells.

PubMed

Bryniarski, Krzysztof; Ptak, Wlodzimierz; Martin, Emilia; Nazimek, Katarzyna; Szczepanik, Marian; Sanak, Marek; Askenase, Philip W

2015-01-01

Lymph node and spleen cells of mice doubly immunized by epicutaneous and intravenous hapten application produce a suppressive component that inhibits the action of the effector T cells that mediate contact sensitivity reactions. We recently re-investigated this phenomenon in an immunological system. CD8+ T lymphocyte-derived exosomes transferred suppressive miR-150 to the effector T cells antigen-specifically due to exosome surface coat of antibody light chains made by B1a lymphocytes. Extracellular RNA (exRNA) is protected from plasma RNases by carriage in exosomes or by chaperones. Exosome transfer of functional RNA to target cells is well described, whereas the mechanism of transfer of exRNA free of exosomes remains unclear. In the current study we describe extracellular miR-150, extracted from exosomes, yet still able to mediate antigen-specific suppression. We have determined that this was due to miR-150 association with antibody-coated exosomes produced by B1a cell companions of the effector T cells, which resulted in antigen-specific suppression of their function. Thus functional cell targeting by free exRNA can proceed by transfecting companion cell exosomes that then transfer RNA cargo to the acceptor cells. This contrasts with the classical view on release of RNA-containing exosomes from the multivesicular bodies for subsequent intercellular targeting. This new alternate pathway for transfer of exRNA between cells has distinct biological and immunological significance, and since most human blood exRNA is not in exosomes may be relevant to evaluation and treatment of diseases.

Free Extracellular miRNA Functionally Targets Cells by Transfecting Exosomes from Their Companion Cells

PubMed Central

Bryniarski, Krzysztof; Ptak, Wlodzimierz; Martin, Emilia; Nazimek, Katarzyna; Szczepanik, Marian; Sanak, Marek; Askenase, Philip W.

2015-01-01

Lymph node and spleen cells of mice doubly immunized by epicutaneous and intravenous hapten application produce a suppressive component that inhibits the action of the effector T cells that mediate contact sensitivity reactions. We recently re-investigated this phenomenon in an immunological system. CD8+ T lymphocyte-derived exosomes transferred suppressive miR-150 to the effector T cells antigen-specifically due to exosome surface coat of antibody light chains made by B1a lymphocytes. Extracellular RNA (exRNA) is protected from plasma RNases by carriage in exosomes or by chaperones. Exosome transfer of functional RNA to target cells is well described, whereas the mechanism of transfer of exRNA free of exosomes remains unclear. In the current study we describe extracellular miR-150, extracted from exosomes, yet still able to mediate antigen-specific suppression. We have determined that this was due to miR-150 association with antibody-coated exosomes produced by B1a cell companions of the effector T cells, which resulted in antigen-specific suppression of their function. Thus functional cell targeting by free exRNA can proceed by transfecting companion cell exosomes that then transfer RNA cargo to the acceptor cells. This contrasts with the classical view on release of RNA-containing exosomes from the multivesicular bodies for subsequent intercellular targeting. This new alternate pathway for transfer of exRNA between cells has distinct biological and immunological significance, and since most human blood exRNA is not in exosomes may be relevant to evaluation and treatment of diseases. PMID:25923429

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

NASA Astrophysics Data System (ADS)

Dao, KinhLuan Lenny D.

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

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

PubMed

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

2014-09-01

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

MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex

PubMed Central

Kyle, Stephanie M.; Saha, Pradip K.; Brown, Hannah M.; Chan, Lawrence C.; Justice, Monica J.

2016-01-01

Rett syndrome (RTT; OMIM 312750), a progressive neurological disorder, is caused by mutations in methyl-CpG-binding protein 2 (MECP2; OMIM 300005), a ubiquitously expressed factor. A genetic suppressor screen designed to identify therapeutic targets surprisingly revealed that downregulation of the cholesterol biosynthesis pathway improves neurological phenotypes in Mecp2 mutant mice. Here, we show that MeCP2 plays a direct role in regulating lipid metabolism. Mecp2 deletion in mice results in a host of severe metabolic defects caused by lipid accumulation, including insulin resistance, fatty liver, perturbed energy utilization, and adipose inflammation by macrophage infiltration. We show that MeCP2 regulates lipid homeostasis by anchoring the repressor complex containing NCoR1 and HDAC3 to its lipogenesis targets in hepatocytes. Consistently, we find that liver targeted deletion of Mecp2 causes fatty liver disease and dyslipidemia similar to HDAC3 liver-specific deletion. These findings position MeCP2 as a novel component in metabolic homeostasis. Rett syndrome patients also show signs of peripheral dyslipidemia; thus, together these data suggest that RTT should be classified as a neurological disorder with systemic metabolic components. We previously showed that treatment of Mecp2 mice with statin drugs alleviated motor symptoms and improved health and longevity. Lipid metabolism is a highly treatable target; therefore, our results shed light on new metabolic pathways for treatment of Rett syndrome. PMID:27288453

New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation.

PubMed

Wang, Xin; Feng, Shaozhen; Fan, Jinjin; Li, Xiaoyan; Wen, Qiong; Luo, Ning

2016-09-15

Smad3 is a critical signaling protein in renal fibrosis. Proteolysis targeting chimeric molecules (PROTACs) are small molecules designed to degrade target proteins via ubiquitination. They have three components: (1) a recognition motif for E3 ligase; (2) a linker; and (3) a ligand for the target protein. We aimed to design a new PROTAC to prevent renal fibrosis by targeting Smad3 proteins and using hydroxylated pentapeptide of hypoxia-inducible factor-1α as the recognition motif for von Hippel-Lindau (VHL) ubiquitin ligase (E3). Computer-aided drug design was used to find a specific ligand targeting Smad3. Surface plasmon resonance (SPR) was used to verify and optimize screening results. Synthesized PROTAC was validated by two-stage mass spectrometry. The PROTAC's specificity for VHL (E3 ligase) was proved with two human renal carcinoma cell lines, 786-0 (VHL(-)) and ACHN (VHL(+)), and its anti-fibrosis effect was tested in renal fibrosis cell models. Thirteen small molecular compounds (SMCs) were obtained from the Enamine library using GLIDE molecular docking program. SPR results showed that #8 SMC (EN300-72284) combined best with Smad3 (KD=4.547×10(-5)M). Mass spectrometry showed that synthesized PROTAC had the correct peptide molecular weights. Western blot showed Smad3 was degraded by PROTAC with whole-cell lysate of ACHN but not 786-0. Degradation, but not ubiquitination, of Smad3 was inhibited by proteasome inhibitor MG132. The upregulation of fibronectin and Collagen I induced by TGF-β1 in both renal fibroblast and mesangial cells were inhibited by PROTAC. The new PROTAC might prevent renal fibrosis by targeting Smad3 for ubiquitination and degradation. Copyright © 2016 Elsevier Inc. All rights reserved.

Innovation processes in technologies for the processing of refractory mineral raw materials

NASA Astrophysics Data System (ADS)

Chanturiya, V. A.

2008-12-01

Analysis of the grade of mineral resources of Russia and other countries shows that end products that are competitive in terms of both technological and environmental criteria in the world market can only be obtained by the development and implementation of progressive technologies based on the up-to-date achievements of fundamental sciences. The essence of modern innovation processes in technologies developed in Russia for the complex and comprehensive processing of refractory raw materials with a complex composition is ascertained. These processes include (i) radiometric methods of concentration of valuable components, (ii) high-energy methods of disintegration of highly dispersed mineral components, and (iii) electrochemical methods of water conditioning to obtain target products for solving specific technological problems.

Investigation of the functional role of CSLD proteins in plant cell wall deposition

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

Nielsen, Erik Etlar

The overall goal of this research proposal was to characterize the molecular machinery responsible for polarized secretion of cell wall components in Arabidopsis thaliana. We have used the polarized expansion that occurs during root hair cell growth to identify membrane trafficking pathways involved in polarized secretion of cell wall components to the expanding tips of these cells, and we have recently shown that CSLD3 is preferentially targeted to the apical plasma membranes in root hair cells, where it plays essential roles during cell wall deposition in these cells. The specific aims of the project are designed to answer the followingmore » objective: Identification of the cell wall polysaccharide class that CSLD proteins synthesize.« less

Clinical review: Extracorporeal blood purification in severe sepsis

PubMed Central

Venkataraman, Ramesh; Subramanian, Sanjay; Kellum, John A

2003-01-01

Sepsis and septic shock are the leading causes of acute renal failure, multiple organ system dysfunction, and death in the intensive care unit. The pathogenesis of sepsis is complex and comprises a mosaic of interconnected pathways. Several attempts to improve patient outcomes by targeting specific components of this network have been unsuccessful. For these reasons, the ideal immunomodulating strategy would be one that restores immunologic stability rather than blindly inhibiting or stimulating one or another component of this complex network. Hence, the recent focus of immunomodulatory therapy in sepsis has shifted to nonspecific methods of influencing the entire inflammatory response without suppressing it. Here, we discuss the various modalities of extracorporeal blood purification, the existing evidence, and future prospects. PMID:12720560

The relationship between social status and the components of agency.

PubMed

Louvet, Eva; Cambon, Laurent; Milhabet, Isabelle; Rohmer, Odile

2018-02-20

Building on the two fundamental dimensions of social judgment distinguishing communion from agency, the purpose of the present work was to show that the strength of the relationship between social status and agency depends on specific components at issue: assertiveness, competence, and effort. Four experimental studies were conducted using two complementary paradigms. In Studies 1 and 2, we manipulated social status, and participants had to rate the target on competence, assertiveness, and effort. In Studies 3 and 4, we reversed the design. Results consistently showed that social status was primarily related to assertiveness, somewhat related to competence, and only slightly related to effort. The present research provides a better understanding of how the dimensions of social judgment are used to explain differences in social status.

The use of multisensor data for robotic applications

NASA Technical Reports Server (NTRS)

Abidi, M. A.; Gonzalez, R. C.

1990-01-01

The feasibility of realistic autonomous space manipulation tasks using multisensory information is shown through two experiments involving a fluid interchange system and a module interchange system. In both cases, autonomous location of the mating element, autonomous location of the guiding light target, mating, and demating of the system were performed. Specifically, vision-driven techniques were implemented to determine the arbitrary two-dimensional position and orientation of the mating elements as well as the arbitrary three-dimensional position and orientation of the light targets. The robotic system was also equipped with a force/torque sensor that continuously monitored the six components of force and torque exerted on the end effector. Using vision, force, torque, proximity, and touch sensors, the two experiments were completed successfully and autonomously.

Analysis of low molecular weight metabolites in tea using mass spectrometry-based analytical methods.

PubMed

Fraser, Karl; Harrison, Scott J; Lane, Geoff A; Otter, Don E; Hemar, Yacine; Quek, Siew-Young; Rasmussen, Susanne

2014-01-01

Tea is the second most consumed beverage in the world after water and there are numerous reported health benefits as a result of consuming tea, such as reducing the risk of cardiovascular disease and many types of cancer. Thus, there is much interest in the chemical composition of teas, for example; defining components responsible for contributing to reported health benefits; defining quality characteristics such as product flavor; and monitoring for pesticide residues to comply with food safety import/export requirements. Covered in this review are some of the latest developments in mass spectrometry-based analytical techniques for measuring and characterizing low molecular weight components of tea, in particular primary and secondary metabolites. The methodology; more specifically the chromatography and detection mechanisms used in both targeted and non-targeted studies, and their main advantages and disadvantages are discussed. Finally, we comment on the latest techniques that are likely to have significant benefit to analysts in the future, not merely in the area of tea research, but in the analytical chemistry of low molecular weight compounds in general.

Improving the Dynamic Characteristics of Body-in-White Structure Using Structural Optimization

PubMed Central

Yahaya Rashid, Aizzat S.; Mohamed Haris, Sallehuddin; Alias, Anuar

2014-01-01

The dynamic behavior of a body-in-white (BIW) structure has significant influence on the noise, vibration, and harshness (NVH) and crashworthiness of a car. Therefore, by improving the dynamic characteristics of BIW, problems and failures associated with resonance and fatigue can be prevented. The design objectives attempt to improve the existing torsion and bending modes by using structural optimization subjected to dynamic load without compromising other factors such as mass and stiffness of the structure. The natural frequency of the design was modified by identifying and reinforcing the structure at critical locations. These crucial points are first identified by topology optimization using mass and natural frequencies as the design variables. The individual components obtained from the analysis go through a size optimization step to find their target thickness of the structure. The thickness of affected regions of the components will be modified according to the analysis. The results of both optimization steps suggest several design modifications to achieve the target vibration specifications without compromising the stiffness of the structure. A method of combining both optimization approaches is proposed to improve the design modification process. PMID:25101312

Posture and Locomotion Coupling: A Target for Rehabilitation Interventions in Persons with Parkinson's Disease

PubMed Central

Mille, Marie-Laure; Creath, Robert A.; Prettyman, Michelle G.; Johnson Hilliard, Marjorie; Martinez, Katherine M.; MacKinnon, Colum D.; Rogers, Mark W.

2012-01-01

Disorders of posture, balance, and gait are debilitating motor manifestations of advancing Parkinson's disease requiring rehabilitation intervention. These problems often reflect difficulties with coupling or sequencing posture and locomotion during complex whole body movements linked with falls. Considerable progress has been made with demonstrating the effectiveness of exercise interventions for individuals with Parkinson's disease. However, gaps remain in the evidence base for specific interventions and the optimal content of exercise interventions. Using a conceptual theoretical framework and experimental findings, this perspective and review advances the viewpoint that rehabilitation interventions focused on separate or isolated components of posture, balance, or gait may limit the effectiveness of current clinical practices. It is argued that treatment effectiveness may be improved by directly targeting posture and locomotion coupling problems as causal factors contributing to balance and gait dysfunction. This approach may help advance current clinical practice and improve outcomes in rehabilitation for persons with Parkinson's disease. “. . .postural activity should be regarded as a function in its own right and not merely as a component of movement. . .” James Purdon Martin PMID:22295253

The Speed of Serial Attention Shifts in Visual Search: Evidence from the N2pc Component.

PubMed

Grubert, Anna; Eimer, Martin

2016-02-01

Finding target objects among distractors in visual search display is often assumed to be based on sequential movements of attention between different objects. However, the speed of such serial attention shifts is still under dispute. We employed a search task that encouraged the successive allocation of attention to two target objects in the same search display and measured N2pc components to determine how fast attention moved between these objects. Each display contained one digit in a known color (fixed-color target) and another digit whose color changed unpredictably across trials (variable-color target) together with two gray distractor digits. Participants' task was to find the fixed-color digit and compare its numerical value with that of the variable-color digit. N2pc components to fixed-color targets preceded N2pc components to variable-color digits, demonstrating that these two targets were indeed selected in a fixed serial order. The N2pc to variable-color digits emerged approximately 60 msec after the N2pc to fixed-color digits, which shows that attention can be reallocated very rapidly between different target objects in the visual field. When search display durations were increased, thereby relaxing the temporal demands on serial selection, the two N2pc components to fixed-color and variable-color targets were elicited within 90 msec of each other. Results demonstrate that sequential shifts of attention between different target locations can operate very rapidly at speeds that are in line with the assumptions of serial selection models of visual search.

A novel albumin nanocomplex containing both small interfering RNA and gold nanorods for synergetic anticancer therapy

NASA Astrophysics Data System (ADS)

Choi, Jin-Ha; Hwang, Hai-Jin; Shin, Seung Won; Choi, Jeong-Woo; Um, Soong Ho; Oh, Byung-Keun

2015-05-01

Therapeutic nanocomplexes have been extensively developed for the effective treatment of aggressive cancers because of their outstanding versatility, easy manipulation, and low cytotoxicity. In this study, we describe the synthesis of a novel bovine serum albumin (BSA)-based nanocomplex harboring both Bcl-2-specific small interfering RNA (siRNA) and gold (Au) nanorods (siRNA and rods encapsulated in BSA; SREB) with the aim of developing a targeted breast cancer therapeutic. The SREB complexes contained 2 × 105 siRNA molecules and eight Au nanorods per BSA complex and were successively functionalized with polyethylene glycol (PEG) and anti-ErbB-2 antibodies to facilitate active targeting. The synergetic therapeutic activity originating from the two components effectively induced cell death (~80% reduction in viability compared with control cells) in target breast cancer cells after a single dose of laser irradiation. Intracellular SREB nanocomplex decomposition by proteolytic enzymes resulted in simultaneous RNA interference and thermal ablation, thus leading to apoptosis in the targeted cancer cells. Moreover, these therapeutic effects were sustained for approximately 72 hours. The intrinsic biocompatibility, multifunctionality, and potent in vitro anticancer properties of these SREB nanocomplexes indicate that they have great therapeutic potential for in vivo targeted cancer therapy, in addition to other areas of nanomedicine.Therapeutic nanocomplexes have been extensively developed for the effective treatment of aggressive cancers because of their outstanding versatility, easy manipulation, and low cytotoxicity. In this study, we describe the synthesis of a novel bovine serum albumin (BSA)-based nanocomplex harboring both Bcl-2-specific small interfering RNA (siRNA) and gold (Au) nanorods (siRNA and rods encapsulated in BSA; SREB) with the aim of developing a targeted breast cancer therapeutic. The SREB complexes contained 2 × 105 siRNA molecules and eight Au nanorods per BSA complex and were successively functionalized with polyethylene glycol (PEG) and anti-ErbB-2 antibodies to facilitate active targeting. The synergetic therapeutic activity originating from the two components effectively induced cell death (~80% reduction in viability compared with control cells) in target breast cancer cells after a single dose of laser irradiation. Intracellular SREB nanocomplex decomposition by proteolytic enzymes resulted in simultaneous RNA interference and thermal ablation, thus leading to apoptosis in the targeted cancer cells. Moreover, these therapeutic effects were sustained for approximately 72 hours. The intrinsic biocompatibility, multifunctionality, and potent in vitro anticancer properties of these SREB nanocomplexes indicate that they have great therapeutic potential for in vivo targeted cancer therapy, in addition to other areas of nanomedicine. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr00211g

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

PubMed

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

2017-03-01

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

In trans paired nicking triggers seamless genome editing without double-stranded DNA cutting.

PubMed

Chen, Xiaoyu; Janssen, Josephine M; Liu, Jin; Maggio, Ignazio; 't Jong, Anke E J; Mikkers, Harald M M; Gonçalves, Manuel A F V

2017-09-22

Precise genome editing involves homologous recombination between donor DNA and chromosomal sequences subjected to double-stranded DNA breaks made by programmable nucleases. Ideally, genome editing should be efficient, specific, and accurate. However, besides constituting potential translocation-initiating lesions, double-stranded DNA breaks (targeted or otherwise) are mostly repaired through unpredictable and mutagenic non-homologous recombination processes. Here, we report that the coordinated formation of paired single-stranded DNA breaks, or nicks, at donor plasmids and chromosomal target sites by RNA-guided nucleases based on CRISPR-Cas9 components, triggers seamless homology-directed gene targeting of large genetic payloads in human cells, including pluripotent stem cells. Importantly, in addition to significantly reducing the mutagenicity of the genome modification procedure, this in trans paired nicking strategy achieves multiplexed, single-step, gene targeting, and yields higher frequencies of accurately edited cells when compared to the standard double-stranded DNA break-dependent approach.CRISPR-Cas9-based gene editing involves double-strand breaks at target sequences, which are often repaired by mutagenic non-homologous end-joining. Here the authors use Cas9 nickases to generate coordinated single-strand breaks in donor and target DNA for precise homology-directed gene editing.

Cramer-Rao Lower Bound Evaluation for Linear Frequency Modulation Based Active Radar Networks Operating in a Rice Fading Environment

PubMed Central

Shi, Chenguang; Salous, Sana; Wang, Fei; Zhou, Jianjiang

2016-01-01

This paper investigates the joint target parameter (delay and Doppler) estimation performance of linear frequency modulation (LFM)-based radar networks in a Rice fading environment. The active radar networks are composed of multiple radar transmitters and multichannel receivers placed on moving platforms. First, the log-likelihood function of the received signal for a Rician target is derived, where the received signal scattered off the target comprises of dominant scatterer (DS) component and weak isotropic scatterers (WIS) components. Then, the analytically closed-form expressions of the Cramer-Rao lower bounds (CRLBs) on the Cartesian coordinates of target position and velocity are calculated, which can be adopted as a performance metric to access the target parameter estimation accuracy for LFM-based radar network systems in a Rice fading environment. It is found that the cumulative Fisher information matrix (FIM) is a linear combination of both DS component and WIS components, and it also demonstrates that the joint CRLB is a function of signal-to-noise ratio (SNR), target’s radar cross section (RCS) and transmitted waveform parameters, as well as the relative geometry between the target and the radar network architectures. Finally, numerical results are provided to indicate that the joint target parameter estimation performance of active radar networks can be significantly improved with the exploitation of DS component. PMID:27929433

A principal components analysis of dynamic spatial memory biases.

PubMed

Motes, Michael A; Hubbard, Timothy L; Courtney, Jon R; Rypma, Bart

2008-09-01

Research has shown that spatial memory for moving targets is often biased in the direction of implied momentum and implied gravity, suggesting that representations of the subjective experiences of these physical principles contribute to such biases. The present study examined the association between these spatial memory biases. Observers viewed targets that moved horizontally from left to right before disappearing or viewed briefly shown stationary targets. After a target disappeared, observers indicated the vanishing position of the target. Principal components analysis revealed that biases along the horizontal axis of motion loaded on separate components from biases along the vertical axis orthogonal to motion. The findings support the hypothesis that implied momentum and implied gravity biases have unique influences on spatial memory. (c) 2008 APA, all rights reserved.

Applicability of IHE/Continua components for PHR systems: learning from experiences.

PubMed

Urbauer, Philipp; Sauermann, Stefan; Frohner, Matthias; Forjan, Mathias; Pohn, Birgit; Mense, Alexander

2015-04-01

Capturing personal health data using smartphones, PCs or other devices, and the reuse of the data in personal health records (PHR) is becoming more and more attractive for modern health-conscious populations. This paper analyses interoperability specifications targeting standards-based communication of computer systems and personal health devices (e.g. blood pressure monitor) in healthcare from initiatives like Integrating the Healthcare Enterprise (IHE) and Continua Health Alliance driven by industry and healthcare professionals. Furthermore it identifies certain contradictions and gaps in the specifications and suggests possible solutions. Despite these shortcomings, the specifications allow fully functional implementations of PHR systems. Henceforth, both big business and small and medium-sized enterprises (SMEs) can actively contribute to the widespread use of large-scale interoperable PHR systems. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

PubMed

Sek, Aleksander; Moore, Brian C J

2003-05-01

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

Harnessing the Power of Influence: Why the Marine Corps Needs to Combine Information Operations and Public Affairs

DTIC Science & Technology

2012-05-06

was becoming a key component of the U.S. economy . “At the same time, it is becoming a vulnerable target in both war and peacetime.”4 He further...greater degree of access which complicates the matter with instant access to the global information grid ( GIG ). Specifically, smart phones have...other associated services and National Security Systems. Also called GIG . (This term and its definition are provided for information and are proposed

The selective recognition of antibody IgY for digestive system cancers.

PubMed

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

1997-01-01

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

A sensitive and quantitative element-tagged immunoassay with ICPMS detection.

PubMed

Baranov, Vladimir I; Quinn, Zoë; Bandura, Dmitry R; Tanner, Scott D

2002-04-01

We report a set of novel immunoassays in which proteins of interest can be detected using specific element-tagged antibodies. These immunoassays are directly coupled with an inductively coupled plasma mass spectrometer (ICPMS) to quantify the elemental (in this work, metal) component of the reacted tagged antibodies. It is demonstrated that these methods can detect levels of target proteins as low as 0.1-0.5 ng/mL and yield a linear response to protein concentration over 3 orders of magnitude.

Photovoltaic energy converter as a chipscale high efficiency power source for implanted active microelectronic devices.

PubMed

Hwang, N-J; Patterson, W R; Song, Y-K; Atay, T; Nurmikko, A V

2004-01-01

We report the development of a microscale photovoltaic energy converter which has been designed and implemented to deliver power to CMOS-based microelectronic chips. The design targets the delivery of voltages on the order of 3V with power levels in excess of 10 mW. The geometry of the prototype device, which has been fabricated and tested, is specifically designed for coupling to an optical fiber, to facilitate remote power delivery in implantable component environment.

CRISPR: From Prokaryotic Immune Systems to Plant Genome Editing Tools.

PubMed

Bandyopadhyay, Anindya; Mazumdar, Shamik; Yin, Xiaojia; Quick, William Paul

2017-01-01

The clustered regularly interspaced short palindromic repeats (CRISPR) system is a prokaryotic adaptive immune system that has the ability to identify specific locations on the bacteriophage (phage) genome to create breaks in it, and internalize the phage genome fragments in its own genome as CRISPR arrays for memory-dependent resistance. Although CRISPR has been used in the dairy industry for a long time, it recently gained importance in the field of genome editing because of its ability to precisely target locations in a genome. This system has further been modified to locate and target any region of a genome of choice due to modifications in the components of the system. By changing the nucleotide sequence of the 20-nucleotide target sequence in the guide RNA, targeting any location is possible. It has found an application in the modification of plant genomes with its ability to generate mutations and insertions, thus helping to create new varieties of plants. With the ability to introduce specific sequences into the plant genome after cleavage by the CRISPR system and subsequent DNA repair through homology-directed repair (HDR), CRISPR ensures that genome editing can be successfully applied in plants, thus generating stronger and more improved traits. Also, the use of the CRISPR editing system can generate plants that are transgene-free and have mutations that are stably inherited, thus helping to circumvent current GMO regulations.

[Lectins from Sambucus nigra L inflorescences: isolation and investigation of biological activity using procaryotic test-systems].

PubMed

Karpova, I S; Korets'ka, N V; Pal'chykovs'ka, L H; Nehruts'ka, V V

2007-01-01

Isolation of lectins from extracts of the Sambucus nigra inflorescences and of pollen material have been performed using isoelectric focusing without carrier ampholytes (autofocusing). Fractions active in agglutination tests with different carbohydrate specificity were subjected to SDS-PAGE. The major lectin found in whole inflores-cences was GalNAc specific and is proposed to be a heterotetramer with subunits of about 30 and 33 kDa. It was called SNAflu-I. At least two other lectins were present in the pollen material and supposed to consist of identical subunits. Major positively charged lectin was Glc/Man specific with subunit of 26 kDa and called SNApol-I. Other pollen component (SNApol-II) was Gal specific with subunit of about 20 kDa. In order to elucidate cell targets sensitive for the S. nigra lectin's activity the combined effects of the lectins and transcriptional of phenazine origin on B. subtilis cells growth have been studied. Only SNApol-I demonstrated the antagonistic activity against these inhibitors in vivo. This lectin but not the SNAflu-I can also inhibit transcription in vitro. It is supposed that lectins from the same source may act in different directions on cell metabolism. Particularly one of the common targets may be the DNA-dependent synthesis of RNA.

The Use of Matrix Training to Promote Generative Language with Children with Autism

ERIC Educational Resources Information Center

Frampton, Sarah E.; Wymer, Sarah C.; Hansen, Bethany; Shillingsburg, M. Alice

2016-01-01

Matrix training consists of planning instruction by arranging components of desired skills across 2 axes. After training with diagonal targets that each combine 2 unique skill components, responses to nondiagonal targets, consisting of novel combinations of the components, may emerge. A multiple-probe design across participants was used to…

77 FR 48570 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Order Approving a Proposed Rule...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-14

... Underlying Securities) of the NASDAQ Options Market rules.\\11\\ Additionally, the Target Component's and the...\\ Additionally, the Target Component's and the Benchmark Component's trading volume (in all markets in which the...-Regulatory Organizations; The NASDAQ Stock Market LLC; Order Approving a Proposed Rule Change Relating to the...

Linking maternal and somatic 5S rRNA types with different sequence-specific non-LTR retrotransposons.

PubMed

Locati, Mauro D; Pagano, Johanna F B; Ensink, Wim A; van Olst, Marina; van Leeuwen, Selina; Nehrdich, Ulrike; Zhu, Kongju; Spaink, Herman P; Girard, Geneviève; Rauwerda, Han; Jonker, Martijs J; Dekker, Rob J; Breit, Timo M

2017-04-01

5S rRNA is a ribosomal core component, transcribed from many gene copies organized in genomic repeats. Some eukaryotic species have two 5S rRNA types defined by their predominant expression in oogenesis or adult tissue. Our next-generation sequencing study on zebrafish egg, embryo, and adult tissue identified maternal-type 5S rRNA that is exclusively accumulated during oogenesis, replaced throughout the embryogenesis by a somatic-type, and thus virtually absent in adult somatic tissue. The maternal-type 5S rDNA contains several thousands of gene copies on chromosome 4 in tandem repeats with small intergenic regions, whereas the somatic-type is present in only 12 gene copies on chromosome 18 with large intergenic regions. The nine-nucleotide variation between the two 5S rRNA types likely affects TFIII binding and riboprotein L5 binding, probably leading to storage of maternal-type rRNA. Remarkably, these sequence differences are located exactly at the sequence-specific target site for genome integration by the 5S rRNA-specific Mutsu retrotransposon family. Thus, we could define maternal- and somatic-type MutsuDr subfamilies. Furthermore, we identified four additional maternal-type and two new somatic-type MutsuDr subfamilies, each with their own target sequence. This target-site specificity, frequently intact maternal-type retrotransposon elements, plus specific presence of Mutsu retrotransposon RNA and piRNA in egg and adult tissue, suggest an involvement of retrotransposons in achieving the differential copy number of the two types of 5S rDNA loci. © 2017 Locati et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Phenolic-enriched foods: sources and processing for enhanced health benefits.

PubMed

McDougall, Gordon J

2017-05-01

Polyphenols are ubiquitous secondary products present in many plant foods. Their intake has been associated with health benefits ranging from reduced incidence of CVD, diabetes and cancers to improved neurodegenerative outcomes. Major dietary sources include beverages such as coffee, teas and foods such as chocolate. Fruits are also major sources and berries in particular are a palatable source of a diverse range of polyphenol components. There are a number of ways that polyphenol uptake could be increased and healthier polyphenol-rich foods could be produced with specific compositions to target-specific health effects. Firstly, we could exploit the genetic diversity of plants (with a focus on berries) to select varieties that have enhanced levels of specific polyphenols implicated in disease mitigation (e.g. anthocyanins, tannins or flavonols). Working with variation induced by environmental and agronomic factors, modern molecular breeding techniques could exploit natural variation and beneficially alter polyphenol content and composition, although this could be relatively long term. Alternatively, we could employ a synthetic biology approach and design new plants that overexpress certain genes or re-deploy more metabolic effort into specific polyphenols. However, such 'polyphenol-plus' fruit could prove unpalatable as polyphenols contribute to sensorial properties (e.g. astringency of tannins). However, if the aim was to produce a polyphenol as a pharmaceutical then 'lifting' biosynthetic pathways from plants and expressing them in microbial vectors may be a feasible option. Secondly, we could design processing methods to enhance the polyphenolic composition or content of foods. Fermentation of teas, cocoa beans and grapes, or roasting of cocoa and coffee beans has long been used and can massively influence polyphenol composition and potential bioactivity. Simple methods such as milling, heat treatment, pasteurisation or juicing (v. pureeing) can have notable effects on polyphenol profiles and novel extraction methods bring new opportunities. Encapsulation methods can protect specific polyphenols during digestion and increase their delivery in the gastrointestinal tract to target-specific health effects. Lastly we could examine reformulation of products to alter polyphenol content or composition. Enhancing staple apple or citrus juices with berry juices could double polyphenol levels and provide specific polyphenol components. Reformulation of foods with polyphenol-rich factions recovered from 'wastes' could increase polyphenol intake, alter product acceptability, improve shelf life and prevent food spoilage. Finally, co-formulation of foods can influence bioavailability and potential bioactivity of certain polyphenols. Within the constraints that certain polyphenols can interfere with drug effectiveness through altered metabolism, this provides another avenue to enhance polyphenol intake and potential effectiveness. In conclusion, these approaches could be developed separately or in combination to produce foods with enhanced levels of phenolic components that are effective against specific disease conditions.

Detection and quantification of angiogenesis in experimental valve disease with integrin-targeted nanoparticles and 19-fluorine MRI/MRS

PubMed Central

Waters, Emily A; Chen, Junjie; Allen, John S; Zhang, Huiying; Lanza, Gregory M; Wickline, Samuel A

2008-01-01

Background Angiogenesis is a critical early feature of atherosclerotic plaque development and may also feature prominently in the pathogenesis of aortic valve stenosis. It has been shown that MRI can detect and quantify specific molecules of interest expressed in cardiovascular disease and cancer by measuring the unique fluorine signature of appropriately targeted perfluorocarbon (PFC) nanoparticles. In this study, we demonstrated specific binding of ανβ3 integrin targeted nanoparticles to neovasculature in a rabbit model of aortic valve disease. We also showed that fluorine MRI could be used to detect and quantify the development of neovasculature in the excised aortic valve leaflets. Methods New Zealand White rabbits consumed a cholesterol diet for ~180 days and developed aortic valve thickening, inflammation, and angiogenesis mimicking early human aortic valve disease. Rabbits (n = 7) were treated with ανβ3 integrin targeted PFC nanoparticles or control untargeted PFC nanoparticles (n = 6). Competitive inhibition in vivo of nanoparticle binding (n = 4) was tested by pretreatment with targeted nonfluorinated nanoparticles followed 2 hours later by targeted PFC nanoparticles. 2 hours after treatment, aortic valves were excised and 19F MRS was performed at 11.7T. Integrated 19F spectral peaks were compared using a one-way ANOVA and Hsu's MCB (multiple comparisons with the best) post hoc t test. In 3 additional rabbits treated with ανβ3 integrin targeted PFC nanoparticles, 19F spectroscopy was performed on a 3.0T clinical scanner. The presence of angiogenesis was confirmed by immunohistochemistry. Results Valves of rabbits treated with targeted PFC nanoparticles had 220% more fluorine signal than valves of rabbits treated with untargeted PFC nanoparticles (p < 0.001). Pretreatment of rabbits with targeted oil-based nonsignaling nanoparticles reduced the fluorine signal by 42% due to competitive inhibition, to a level not significantly different from control animals. Nanoparticles were successfully detected in all samples scanned at 3.0T. PECAM endothelial staining and ανβ3 integrin staining revealed the presence of neovasculature within the valve leaflets. Conclusion Integrin-targeted PFC nanoparticles specifically detect early angiogenesis in sclerotic aortic valves of cholesterol fed rabbits. These techniques may be useful for assessing atherosclerotic components of preclinical aortic valve disease in patients and could assist in defining efficacy of medical therapies. PMID:18817557

Scaling of Ion Thrusters to Low Power

NASA Technical Reports Server (NTRS)

Patterson, Michael J.; Grisnik, Stanley P.; Soulas, George C.

1998-01-01

Analyses were conducted to examine ion thruster scaling relationships in detail to determine performance limits, and lifetime expectations for thruster input power levels below 0.5 kW. This was motivated by mission analyses indicating the potential advantages of high performance, high specific impulse systems for small spacecraft. The design and development status of a 0.1-0.3 kW prototype small thruster and its components are discussed. Performance goals include thruster efficiencies on the order of 40% to 54% over a specific impulse range of 2000 to 3000 seconds, with a lifetime in excess of 8000 hours at full power. Thruster technologies required to achieve the performance and lifetime targets are identified.

Configurations of a two-tiered amplified gene expression system in adenoviral vectors designed to improve the specificity of in vivo prostate cancer imaging

PubMed Central

Sato, M; Figueiredo, ML; Burton, JB; Johnson, M; Chen, M; Powell, R; Gambhir, SS; Carey, M; Wu, L

2009-01-01

Effective treatment for recurrent, disseminated prostate cancer is notably limited. We have developed adenoviral vectors with a prostate-specific two-step transcriptional amplification (TSTA) system that would express therapeutic genes at a robust level to target metastatic disease. The TSTA system employs the prostate-specific antigen (PSA) promoter/enhancer to drive a potent synthetic activator, which in turn activates the expression of the therapeutic gene. In this study, we explored different configurations of this bipartite system and discovered that physical separation of the two TSTA components into E1 and E3 regions of adenovirus was able to enhance androgen regulation and cell-discriminatory expression. The TSTA vectors that express imaging reporter genes were assessed by noninvasive imaging technologies in animal models. The improved selectivity of the E1E3 configured vector was reflected in silenced ectopic expression in the lung. Significantly, the enhanced specificity of the E1E3 vector enabled the detection of lung metastasis of prostate cancer. An E1E3 TSTA vector that expresses the herpes simplex virus thymidine kinase gene can effectively direct positron emission tomography (PET) imaging of the tumor. The prostate-targeted gene delivery vectors with robust and cell-specific expression capability will advance the development of safe and effective imaging guided therapy for recurrent metastatic stages of prostate cancer. PMID:18305574

Evidence that family 35 carbohydrate binding modules display conserved specificity but divergent function

PubMed Central

Montanier, Cedric; van Bueren, Alicia Lammerts; Dumon, Claire; Flint, James E.; Correia, Marcia A.; Prates, Jose A.; Firbank, Susan J.; Lewis, Richard J.; Grondin, Gilles G.; Ghinet, Mariana G.; Gloster, Tracey M.; Herve, Cecile; Knox, J. Paul; Talbot, Brian G.; Turkenburg, Johan P.; Kerovuo, Janne; Brzezinski, Ryszard; Fontes, Carlos M. G. A.; Davies, Gideon J.; Boraston, Alisdair B.; Gilbert, Harry J.

2009-01-01

Enzymes that hydrolyze complex carbohydrates play important roles in numerous biological processes that result in the maintenance of marine and terrestrial life. These enzymes often contain noncatalytic carbohydrate binding modules (CBMs) that have important substrate-targeting functions. In general, there is a tight correlation between the ligands recognized by bacterial CBMs and the substrate specificity of the appended catalytic modules. Through high-resolution structural studies, we demonstrate that the architecture of the ligand binding sites of 4 distinct family 35 CBMs (CBM35s), appended to 3 plant cell wall hydrolases and the exo-β-d-glucosaminidase CsxA, which contributes to the detoxification and metabolism of an antibacterial fungal polysaccharide, is highly conserved and imparts specificity for glucuronic acid and/or Δ4,5-anhydrogalaturonic acid (Δ4,5-GalA). Δ4,5-GalA is released from pectin by the action of pectate lyases and as such acts as a signature molecule for plant cell wall degradation. Thus, the CBM35s appended to the 3 plant cell wall hydrolases, rather than targeting the substrates of the cognate catalytic modules, direct their appended enzymes to regions of the plant that are being actively degraded. Significantly, the CBM35 component of CsxA anchors the enzyme to the bacterial cell wall via its capacity to bind uronic acid sugars. This latter observation reveals an unusual mechanism for bacterial cell wall enzyme attachment. This report shows that the biological role of CBM35s is not dictated solely by their carbohydrate specificities but also by the context of their target ligands. PMID:19218457

Specific Synergist for Neonicotinoid Insecticides: IPPA08, a cis-Neonicotinoid Compound with a Unique Oxabridged Substructure.

PubMed

Bao, Haibo; Shao, Xusheng; Zhang, Yixi; Deng, Yayun; Xu, Xiaoyong; Liu, Zewen; Li, Zhong

2016-06-29

Insecticide synergists are key components to increase the control efficacy and reduce active ingredient use. Here, we describe a novel insecticide synergist with activity specific for insecticidal neonicotinoids. The synergist IPPA08, a cis configuration neonicotinoid compound with a unique oxabridged substructure, could increase the toxicity of most neonicotinoid insecticides belonging to the Insecticide Resistance Action Committee (IRAC) 4A subgroup against a range of insect species, although IPPA08 itself was almost inactive to insects at synergistic concentrations. Unfortunately, similar effects were observed on the honey bee (Apis mellifera) and the brown planthopper (Nilaparvata lugens), resistant to imidacloprid. IPPA08 did not show any effects on toxicity of insecticides with different targets, which made us define it as a neonicotinoid-specific synergist. Unlike most insecticide synergists, by inhibition of activities of detoxification enzymes, IPPA08 showed no effects on enzyme activities. The results revealed that IPPA08 worked as a synergist through a distinct way. Although the modulating insect nicotinic acetylcholine receptors (nAChRs, targets of neonicotinoid insecticides) were supposed as a possible mode of action for IPPA08 as a neonicotinoid-specific synergist, direct evidence is needed in further studies. In insect pest control, IPPA08 acts as a target synergist to increase neonicotinoid toxicity and reduce the amount of neonicotinoid used. Combinations of IPPA08 and insecticidal neonicotinoids may be developed into new insecticide formulations. In summary, combining an active ingredient with a "custom" synergist appears to be a very promising approach for the development of effective new insecticide products.

Stimulus-to-matching-stimulus interval influences N1, P2, and P3b in an equiprobable Go/NoGo task.

PubMed

Steiner, Genevieve Z; Barry, Robert J; Gonsalvez, Craig J

2014-10-01

Previous research has shown that as the stimulus-to-matching-stimulus interval (including the target-to-target interval, TTI, and nontarget-to-nontarget interval, NNI) increases, the amplitude of the P300 ERP component increases systematically. Here, we extended previous P300 research and explored TTI and NNI effects on the various ERP components elicited in an auditory equiprobable Go/NoGo task. We also examined whether a similar mechanism was underpinning interval effects in early ERP components (e.g., N1). Thirty participants completed a specially-designed variable-ISI equiprobable task whilst their EEG activity was recorded. Component amplitudes were extracted using temporal PCA with unrestricted Varimax rotation. As expected, N1, P2, and P3b amplitudes increased as TTI and NNI increased, however, Processing Negativity (PN) and Slow Wave (SW) did not show the same systematic change with interval increments. To determine the origin of interval effects in sequential processing, a multiple regression analysis was conducted on each ERP component including stimulus type, interval, and all preceding components as predictors. These analyses showed that matching-stimulus interval predicted N1, P3b, and weakly predicted P2, but not PN or SW; SW was determined by P3b only. These results suggest that N1, P3b, and to some extent, P2, are affected by a similar temporal mechanism. However, the dissimilar pattern of results obtained for sequential ERP components indicates that matching-stimulus intervals are not affecting all aspects of stimulus processing. This argues against a global mechanism, such as a pathway-specific refractory effect, and suggests that stimulus processing is occurring in parallel pathways, some of which are not affected by temporal manipulations of matching-stimulus interval. Copyright © 2014 Elsevier B.V. All rights reserved.

Digestive proteolysis in the Colorado potato beetle, Leptinotarsa decemlineata: Activity-based profiling and imaging of a multipeptidase network.

PubMed

Srp, Jaroslav; Nussbaumerová, Martina; Horn, Martin; Mareš, Michael

2016-11-01

The Colorado potato beetle (CPB), Leptinotarsa decemlineata, is a major pest of potato plants, and its digestive system is a promising target for development of pest control strategies. This work focuses on functional proteomic analysis of the digestive proteolytic enzymes expressed in the CPB gut. We identified a set of peptidases using imaging with specific activity-based probes and activity profiling with selective substrates and inhibitors. The secreted luminal peptidases were classified as: (i) endopeptidases of cathepsin D, cathepsin L, and trypsin types and (ii) exopeptidases with aminopeptidase (cathepsin H), carboxypeptidase (serine carboxypeptidase, prolyl carboxypeptidase), and carboxydipeptidase (cathepsin B) activities. The proteolytic arsenal also includes non-luminal peptidases with prolyl oligopeptidase and metalloaminopeptidase activities. Our results indicate that the CPB gut employs a multienzyme network of peptidases with complementary specificities to efficiently degrade ingested proteins. This proteolytic system functions in both CPB larvae and adults and is controlled mainly by cysteine and aspartic peptidases and supported by serine and metallopeptidases. The component enzymes identified here are potential targets for inhibitors with tailored specificities that could be engineered into potato plants to confer resistance to CPB. Copyright © 2016 Elsevier Ltd. All rights reserved.

Specificity determinants for Cry insecticidal proteins: Insights from their mode of action.

PubMed

Jurat-Fuentes, Juan Luis; Crickmore, Neil

2017-01-01

Insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) are used as active components of biopesticides and as plant incorporated protectants in transgenic crops. One of the most relevant attributes of these Bt protein-based insecticidal technologies is their high specificity, which assures lack of detrimental effects on non-target insects, vertebrates and the environment. The identification of specificity determinants in Bt insecticidal proteins could guide risk assessment for novel insecticidal proteins currently considered for commercialization. In this work we review the available data on specificity determinants of crystal (Cry) insecticidal proteins as the Bt toxins most well characterized and used in transgenic crops. The multi-step mode of action of the Cry insecticidal proteins allows various factors to potentially affect specificity determination and here we define seven levels that could influence specificity. The relative relevance of each of these determinants on efficacy of transgenic crops producing Cry insecticidal proteins is also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Multispectral and Textural Properties and Diversity of Soils in Gusev Crater and Meridiani Planum from Mars Exploration Rover Pancam and MI Data

NASA Astrophysics Data System (ADS)

Bell, J. F.; Fraeman, A. A.; Grossman, L.; Herkenhoff, K. E.; Sullivan, R. J.; Mer/Athena Science Team

2010-12-01

The Mars Exploration Rovers Spirit and Opportunity have enabled more than six and a half years of detailed, in situ field study of two specific landing sites and traverse paths within Gusev crater and Meridiani Planum, respectively. Much of the study has relied on high-resolution, multispectral imaging of fine-grained regolith components--the dust, sand, cobbles, clasts, and other components collectively referred to as "soil"--at both sites using the rovers' Panoramic Camera (Pancam) and Microscopic Imager (MI) imaging systems. As of early September 2010, the Pancam systems have acquired more than 1300 and 1000 "13 filter" multispectral imaging sequences of surfaces in Gusev and Meridiani, respectively, with each sequence consisting of co-located images at 11 unique narrowband wavelengths between 430 nm and 1009 nm and having a maximum spatial resolution of about 500 microns per pixel. The MI systems have acquired more than 5900 and 6500 monochromatic images, respectively, at about 31 microns per pixel scale. Pancam multispectral image cubes are calibrated to radiance factor (I/F, where I is the measured radiance and π*F is the incident solar irradiance) using observations of the onboard calibration targets, and then corrected to relative reflectance (assuming Lambertian photometric behavior) for comparison with laboratory rock and mineral measurements. Specifically, Pancam spectra can be used to detect the possible presence of some iron-bearing minerals (e.g., some ferric oxides/oxyhydroxides and pyroxenes) as well as structural water or OH in some hydrated alteration products, providing important inputs on the choice of targets for more quantitative compositional and mineralogic follow-up using the rover's other in situ and remote sensing analysis tools. Pancam 11-band spectra are being analyzed using a variety of standard as well as specifically-tailored analysis methods, including color ratio and band depth parameterizations, spectral similarity and principal components clustering, and simple visual inspection based on correlations with false color unit boundaries and textural variations seen in both Pancam and MI imaging. Approximately 20 distinct spectral classes of fine-grained surface components were identified at each site based on these methods. In this presentation we describe these spectral classes, their geologic and textural context and distribution based on supporting high-res MI and other Pancam imaging, and their potential compositional/mineralogic interpretations based on a variety of rover data sets.

Improved neovascularization and wound repair by targeting human basic fibroblast growth factor (bFGF) to fibrin.

PubMed

Zhao, Wenxue; Han, Qianqian; Lin, Hang; Gao, Yuan; Sun, Wenjie; Zhao, Yannan; Wang, Bin; Chen, Bing; Xiao, Zhifeng; Dai, Jianwu

2008-10-01

Targeted therapy is a new generation of therapeutics, where two critical factors are involved. One is the particular molecular target, and the other is the specific target-binding drug. In this work, the fibrin, a main component of plasma clot at wound sites, was used as the target for human bFGF, aiming to improve therapeutic neovascularization and wound repair. To endow bFGF with fibrin-targeting ability, a fibrin-binding peptide Kringle1 (K1), derived from human plasminogen, was fused to human bFGF. The recombinant K1bFGF showed high fibrin and plasma-clot-binding ability. When applied to the wound sites with plasma clots, K1bFGF induced robust neovascularization and improved wound healing. To extend the application of K1bFGF to other cases where no plasma clots exist, we developed a fibrin-scaffold/K1bFGF system. This system could induce localized neovascularization by delivery of K1bFGF in a sustained and site-targeting manner, and provide a microenvironment promoting cell growth and tissue regeneration. In summary, we successfully used the pathologic environment fibrin clot as the target for bFGF, and based on which bFGF was designed into a targeting agent by introduction of a fibrin-binding peptide. This provides a potential approach to improve therapeutic neovascularization and wound repair.

Real Time Intelligent Target Detection and Analysis with Machine Vision

NASA Technical Reports Server (NTRS)

Howard, Ayanna; Padgett, Curtis; Brown, Kenneth

2000-01-01

We present an algorithm for detecting a specified set of targets for an Automatic Target Recognition (ATR) application. ATR involves processing images for detecting, classifying, and tracking targets embedded in a background scene. We address the problem of discriminating between targets and nontarget objects in a scene by evaluating 40x40 image blocks belonging to an image. Each image block is first projected onto a set of templates specifically designed to separate images of targets embedded in a typical background scene from those background images without targets. These filters are found using directed principal component analysis which maximally separates the two groups. The projected images are then clustered into one of n classes based on a minimum distance to a set of n cluster prototypes. These cluster prototypes have previously been identified using a modified clustering algorithm based on prior sensed data. Each projected image pattern is then fed into the associated cluster's trained neural network for classification. A detailed description of our algorithm will be given in this paper. We outline our methodology for designing the templates, describe our modified clustering algorithm, and provide details on the neural network classifiers. Evaluation of the overall algorithm demonstrates that our detection rates approach 96% with a false positive rate of less than 0.03%.

Sensitization to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal): experience in a Flemish case series.

PubMed

Ebo, D G; Faber, M; Sabato, V; Leysen, J; Gadisseur, A; Bridts, C H; De Clerck, L S

2013-01-01

Recent observations have disclosed that the galactose-alpha (1,3)-galactose (alpha-gal) moiety of non-primate glycoproteins can constitute a target for meat allergy. To describe adults with allergic reactions to mammalian meat, dairy products and gelatin. To investigate whether patients could demonstrate sensitization to activated recombinant human coagulation factor VII ectapog alpha that is produced in baby hamster kidney cells. Ten adults with mammalian meat, dairy products and gelatin allergies were examined using quantification of specific IgE and/or skin prick test for red meat, milk, milk components, gelatin, cetuximab and eptacog alpha. Most patients demonstrate quite typical clinical histories and serological profiles, with anti-alpha-gal titers varying from less than 1% to over 25% of total serum IgE. All patients demonstrate negative sIgE for gelatin, except the patient with a genuine gelatin allergy. All patients also demonstrated a negative sIgE to recombinant milk components casein, lactalbumin and lactoglobulin. Specific IgE to eptacog was positive in 5 out of the 9 patients sensitized to alpha-gal and none of the 10 control individuals. This series confirms the importance of the alpha-gal carbohydrate moiety as a potential target for allergy to mammalian meat, dairy products and gelatin (oral, topical or parenteral) in a Flemish population of meat allergic adults. It also confirms in vitro tests to mammalian meat generally to be more reliable than mammalian meat skin tests, but that diagnosis can benefit from skin testing with cetuximab. Specific IgE to gelatin is far too insensitive to diagnose alphaa-gal related gelatin allergy. IgE binding studies indicate a potential risk of alpha-gal-containing human recombinant proteins produced in mammalians.

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

PubMed

Brydges, Christopher R; Barceló, Francisco

2018-01-01

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

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

PubMed Central

Brydges, Christopher R.; Barceló, Francisco

2018-01-01

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

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

PubMed

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

2010-09-13

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

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

PubMed Central

2010-01-01

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

Chloroquine derivatives block the translocation pores and inhibit cellular entry of Clostridium botulinum C2 toxin and Bacillus anthracis lethal toxin.

PubMed

Kreidler, Anna-Maria; Benz, Roland; Barth, Holger

2017-03-01

The pathogenic bacteria Clostridium botulinum and Bacillus anthracis produce the binary protein toxins C2 and lethal toxin (LT), respectively. These toxins consist of a binding/transport (B 7 ) component that delivers the separate enzyme (A) component into the cytosol of target cells where it modifies its specific substrate and causes cell death. The B 7 components of C2 toxin and LT, C2IIa and PA 63 , respectively, are ring-shaped heptamers that bind to their cellular receptors and form complexes with their A components C2I and lethal factor (LF), respectively. After receptor-mediated endocytosis of the toxin complexes, C2IIa and PA 63 insert into the membranes of acidified endosomes and form trans-membrane pores through which C2I and LF translocate across endosomal membranes into the cytosol. C2IIa and PA 63 also form channels in planar bilayer membranes, and we used this approach earlier to identify chloroquine as a potent blocker of C2IIa and PA 63 pores. Here, a series of chloroquine derivatives was investigated to identify more efficient toxin inhibitors with less toxic side effects. Chloroquine, primaquine, quinacrine, and fluphenazine blocked C2IIa and PA 63 pores in planar lipid bilayers and in membranes of living epithelial cells and macrophages, thereby preventing the pH-dependent membrane transport of the A components into the cytosol and protecting cells from intoxication with C2 toxin and LT. These potent inhibitors of toxin entry underline the central role of the translocation pores for cellular uptake of binary bacterial toxins and as relevant drug targets, and might be lead compounds for novel pharmacological strategies against severe enteric diseases and anthrax.

Pain-Related Rumination, But Not Magnification or Helplessness, Mediates Race and Sex Differences in Experimental Pain.

PubMed

Meints, Samantha M; Stout, Madison; Abplanalp, Samuel; Hirsh, Adam T

2017-03-01

Compared with white individuals and men, black individuals and women show a lower tolerance for experimental pain stimuli. Previous studies suggest that pain catastrophizing is important in this context, but little is known about which components of catastrophizing contribute to these race and sex differences. The purpose of the current study was to examine the individual components of catastrophizing (rumination, magnification, and helplessness) as candidate mediators of race and sex differences in experimental pain tolerance. Healthy undergraduates (N = 172, 74% female, 43.2% black) participated in a cold pressor task and completed a situation-specific version of the Pain Catastrophizing Scale. Black and female participants showed a lower pain tolerance than white (P < .01, d = .70) and male (P < .01, d = .55) participants, respectively. Multiple mediation analyses indicated that these race and sex differences were mediated by the rumination component of catastrophizing (indirect effect = -7.13, 95% confidence interval (CI), -16.20 to -1.96, and 5.75, 95% CI, .81-15.57, respectively) but not by the magnification (95% CI, -2.91 to 3.65 and -1.54 to 1.85, respectively) or helplessness (95% CI, -5.53 to 3.31 and -.72 to 5.38, respectively) components. This study provides new information about race and sex differences in pain and suggests that treatments targeting the rumination component of catastrophizing may help mitigate pain-related disparities. This study suggests that differences in pain-related rumination, but not magnification or helplessness, are important contributors to race and sex differences in the pain experience. Interventions that target this maladaptive cognitive style may help reduce disparities in pain. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

PubMed Central

Pi, Fengmei; Zhao, Zhengyi; Chelikani, Venkata; Yoder, Kristine; Kvaratskhelia, Mamuka

2016-01-01

The intracellular parasitic nature of viruses and the emergence of antiviral drug resistance necessitate the development of new potent antiviral drugs. Recently, a method for developing potent inhibitory drugs by targeting biological machines with high stoichiometry and a sequential-action mechanism was described. Inspired by this finding, we reviewed the development of antiviral drugs targeting viral DNA-packaging motors. Inhibiting multisubunit targets with sequential actions resembles breaking one bulb in a series of Christmas lights, which turns off the entire string. Indeed, studies on viral DNA packaging might lead to the development of new antiviral drugs. Recent elucidation of the mechanism of the viral double-stranded DNA (dsDNA)-packaging motor with sequential one-way revolving motion will promote the development of potent antiviral drugs with high specificity and efficiency. Traditionally, biomotors have been classified into two categories: linear and rotation motors. Recently discovered was a third type of biomotor, including the viral DNA-packaging motor, beside the bacterial DNA translocases, that uses a revolving mechanism without rotation. By analogy, rotation resembles the Earth's rotation on its own axis, while revolving resembles the Earth's revolving around the Sun (see animations at http://rnanano.osu.edu/movie.html). Herein, we review the structures of viral dsDNA-packaging motors, the stoichiometries of motor components, and the motion mechanisms of the motors. All viral dsDNA-packaging motors, including those of dsDNA/dsRNA bacteriophages, adenoviruses, poxviruses, herpesviruses, mimiviruses, megaviruses, pandoraviruses, and pithoviruses, contain a high-stoichiometry machine composed of multiple components that work cooperatively and sequentially. Thus, it is an ideal target for potent drug development based on the power function of the stoichiometries of target complexes that work sequentially. PMID:27356896

77 FR 38347 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing of Proposed Rule...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-27

... Component of the Alpha Pair. To calculate the daily total return today of a Target Component or a Benchmark... Benchmark Component, respectively, would be subtracted from today's closing market price for the Target...''). The Price Difference would be added to any declared dividend, if today were an ``ex-dividend'' date...

Protein-anchoring therapy to target extracellular matrix proteins to their physiological destinations.

PubMed

Ito, Mikako; Ohno, Kinji

2018-02-20

Endplate acetylcholinesterase (AChE) deficiency is a form of congenital myasthenic syndrome (CMS) caused by mutations in COLQ, which encodes collagen Q (ColQ). ColQ is an extracellular matrix (ECM) protein that anchors AChE to the synaptic basal lamina. Biglycan, encoded by BGN, is another ECM protein that binds to the dystrophin-associated protein complex (DAPC) on skeletal muscle, which links the actin cytoskeleton and ECM proteins to stabilize the sarcolemma during repeated muscle contractions. Upregulation of biglycan stabilizes the DPAC. Gene therapy can potentially ameliorate any disease that can be recapitulated in cultured cells. However, the difficulty of tissue-specific and developmental stage-specific regulated expression of transgenes, as well as the difficulty of introducing a transgene into all cells in a specific tissue, prevents us from successfully applying gene therapy to many human diseases. In contrast to intracellular proteins, an ECM protein is anchored to the target tissue via its specific binding affinity for protein(s) expressed on the cell surface within the target tissue. Exploiting this unique feature of ECM proteins, we developed protein-anchoring therapy in which a transgene product expressed even in remote tissues can be delivered and anchored to a target tissue using specific binding signals. We demonstrate the application of protein-anchoring therapy to two disease models. First, intravenous administration of adeno-associated virus (AAV) serotype 8-COLQ to Colq-deficient mice, resulting in specific anchoring of ectopically expressed ColQ-AChE at the NMJ, markedly improved motor functions, synaptic transmission, and the ultrastructure of the neuromuscular junction (NMJ). In the second example, Mdx mice, a model for Duchenne muscular dystrophy, were intravenously injected with AAV8-BGN. The treatment ameliorated motor deficits, mitigated muscle histopathologies, decreased plasma creatine kinase activities, and upregulated expression of utrophin and DAPC component proteins. We propose that protein-anchoring therapy could be applied to hereditary/acquired defects in ECM and secreted proteins, as well as therapeutic overexpression of such factors. Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

What works to increase attendance for diabetic retinopathy screening? An evidence synthesis and economic analysis.

PubMed

Lawrenson, John G; Graham-Rowe, Ella; Lorencatto, Fabiana; Rice, Stephen; Bunce, Catey; Francis, Jill J; Burr, Jennifer M; Aluko, Patricia; Vale, Luke; Peto, Tunde; Presseau, Justin; Ivers, Noah M; Grimshaw, Jeremy M

2018-05-01

Diabetic retinopathy screening (DRS) is effective but uptake is suboptimal. To determine the effectiveness of quality improvement (QI) interventions for DRS attendance; describe the interventions in terms of QI components and behaviour change techniques (BCTs); identify theoretical determinants of attendance; investigate coherence between BCTs identified in interventions and determinants of attendance; and determine the cost-effectiveness of QI components and BCTs for improving DRS. Phase 1 - systematic review of randomised controlled trials (RCTs) evaluating interventions to increase DRS attendance (The Cochrane Library, MEDLINE, EMBASE and trials registers to February 2017) and coding intervention content to classify QI components and BCTs. Phase 2 - review of studies reporting factors influencing attendance, coded to theoretical domains (MEDLINE, EMBASE, PsycINFO and sources of grey literature to March 2016). Phase 3 - mapping BCTs (phase 1) to theoretical domains (phase 2) and an economic evaluation to determine the cost-effectiveness of BCTs or QI components. Phase 1 - 7277 studies were screened, of which 66 RCTs were included in the review. Interventions were multifaceted and targeted patients, health-care professionals (HCPs) or health-care systems. Overall, interventions increased DRS attendance by 12% [risk difference (RD) 0.12, 95% confidence interval (CI) 0.10 to 0.14] compared with usual care, with substantial heterogeneity in effect size. Both DRS-targeted and general QI interventions were effective, particularly when baseline attendance levels were low. All commonly used QI components and BCTs were associated with significant improvements, particularly in those with poor attendance. Higher effect estimates were observed in subgroup analyses for the BCTs of 'goal setting (outcome, i.e. consequences)' (RD 0.26, 95% CI 0.16 to 0.36) and 'feedback on outcomes (consequences) of behaviour' (RD 0.22, 95% CI 0.15 to 0.29) in interventions targeting patients and of 'restructuring the social environment' (RD 0.19, 95% CI 0.12 to 0.26) and 'credible source' (RD 0.16, 95% CI 0.08 to 0.24) in interventions targeting HCPs. Phase 2 - 3457 studies were screened, of which 65 non-randomised studies were included in the review. The following theoretical domains were likely to influence attendance: 'environmental context and resources', 'social influences', 'knowledge', 'memory, attention and decision processes', 'beliefs about consequences' and 'emotions'. Phase 3 - mapping identified that interventions included BCTs targeting important barriers to/enablers of DRS attendance. However, BCTs targeting emotional factors around DRS were under-represented. QI components were unlikely to be cost-effective whereas BCTs with a high probability (≥ 0.975) of being cost-effective at a societal willingness-to-pay threshold of £20,000 per QALY included 'goal-setting (outcome)', 'feedback on outcomes of behaviour', 'social support' and 'information about health consequences'. Cost-effectiveness increased when DRS attendance was lower and with longer screening intervals. Quality improvement/BCT coding was dependent on descriptions of intervention content in primary sources; methods for the identification of coherence of BCTs require improvement. Randomised controlled trial evidence indicates that QI interventions incorporating specific BCT components are associated with meaningful improvements in DRS attendance compared with usual care. Interventions generally used appropriate BCTs that target important barriers to screening attendance, with a high probability of being cost-effective. Research is needed to optimise BCTs or BCT combinations that seek to improve DRS attendance at an acceptable cost. BCTs targeting emotional factors represent a missed opportunity to improve attendance and should be tested in future studies. This study is registered as PROSPERO CRD42016044157 and PROSPERO CRD42016032990. The National Institute for Health Research Health Technology Assessment programme.

Sex steroid signaling: implications for lung diseases.

PubMed

Sathish, Venkatachalem; Martin, Yvette N; Prakash, Y S

2015-06-01

There is increasing recognition that sex hormones (estrogen, progesterone, and testosterone) have biological and pathophysiological actions in peripheral, non-reproductive organs, including the lung. Clinically, sex differences in the incidence, morbidity and mortality of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, lung cancer and pulmonary hypertension have been noted, although intrinsic sex differences vs. the roles of sex steroids are still not well-understood. Accordingly, it becomes important to ask the following questions: 1) Which sex steroids are involved? 2) How do they affect different components of the lung under normal circumstances? 3) How does sex steroid signaling change in or contribute to lung disease, and in this regard, are sex steroids detrimental or beneficial? As our understanding of sex steroid signaling in the lung improves, it is important to consider whether such information can be used to develop new therapeutic strategies to target lung diseases, perhaps in both sexes or in a sex-specific manner. In this review, we focus on the basics of sex steroid signaling, and the current state of knowledge regarding how they influence structure and function of specific lung components across the life span and in the context of some important lung diseases. We then summarize the potential for sex steroids as useful biomarkers and therapeutic targets in these lung diseases as a basis for future translational research in the area of gender and individualized medicine. Copyright © 2015 Elsevier Inc. All rights reserved.

A Paper-Based Device for Performing Loop-Mediated Isothermal Amplification with Real-Time Simultaneous Detection of Multiple DNA Targets.

PubMed

Seok, Youngung; Joung, Hyou-Arm; Byun, Ju-Young; Jeon, Hyo-Sung; Shin, Su Jeong; Kim, Sanghyo; Shin, Young-Beom; Han, Hyung Soo; Kim, Min-Gon

2017-01-01

Paper-based diagnostic devices have many advantages as a one of the multiple diagnostic test platforms for point-of-care (POC) testing because they have simplicity, portability, and cost-effectiveness. However, despite high sensitivity and specificity of nucleic acid testing (NAT), the development of NAT based on a paper platform has not progressed as much as the others because various specific conditions for nucleic acid amplification reactions such as pH, buffer components, and temperature, inhibitions from technical differences of paper-based device. Here, we propose a paper-based device for performing loop-mediated isothermal amplification (LAMP) with real-time simultaneous detection of multiple DNA targets. We determined the optimal chemical components to enable dry conditions for the LAMP reaction without lyophilization or other techniques. We also devised the simple paper device structure by sequentially stacking functional layers, and employed a newly discovered property of hydroxynaphthol blue fluorescence to analyze real-time LAMP signals in the paper device. This proposed platform allowed analysis of three different meningitis DNA samples in a single device with single-step operation. This LAMP-based multiple diagnostic device has potential for real-time analysis with quantitative detection of 10 2 -10 5 copies of genomic DNA. Furthermore, we propose the transformation of DNA amplification devices to a simple and affordable paper system approach with great potential for realizing a paper-based NAT system for POC testing.

A Paper-Based Device for Performing Loop-Mediated Isothermal Amplification with Real-Time Simultaneous Detection of Multiple DNA Targets

PubMed Central

Seok, Youngung; Joung, Hyou-Arm; Byun, Ju-Young; Jeon, Hyo-Sung; Shin, Su Jeong; Kim, Sanghyo; Shin, Young-Beom; Han, Hyung Soo; Kim, Min-Gon

2017-01-01

Paper-based diagnostic devices have many advantages as a one of the multiple diagnostic test platforms for point-of-care (POC) testing because they have simplicity, portability, and cost-effectiveness. However, despite high sensitivity and specificity of nucleic acid testing (NAT), the development of NAT based on a paper platform has not progressed as much as the others because various specific conditions for nucleic acid amplification reactions such as pH, buffer components, and temperature, inhibitions from technical differences of paper-based device. Here, we propose a paper-based device for performing loop-mediated isothermal amplification (LAMP) with real-time simultaneous detection of multiple DNA targets. We determined the optimal chemical components to enable dry conditions for the LAMP reaction without lyophilization or other techniques. We also devised the simple paper device structure by sequentially stacking functional layers, and employed a newly discovered property of hydroxynaphthol blue fluorescence to analyze real-time LAMP signals in the paper device. This proposed platform allowed analysis of three different meningitis DNA samples in a single device with single-step operation. This LAMP-based multiple diagnostic device has potential for real-time analysis with quantitative detection of 102-105 copies of genomic DNA. Furthermore, we propose the transformation of DNA amplification devices to a simple and affordable paper system approach with great potential for realizing a paper-based NAT system for POC testing. PMID:28740546

Epizoic communities of prokaryotes on healthy and diseased scleractinian corals in Lingayen Gulf, Philippines.

PubMed

Arboleda, Mark; Reichardt, Wolfgang

2009-01-01

In search for microbiological indicators of coral health and coral diseases, community profiles of coral-associated epizoic prokaryotes were investigated because of their dual potential as a source of coral pathogens and their antagonists. In pairwise samples of visually healthy and diseased coral specimens from Bolinao Bay (Pangasinan, Philippines), mixed biofilm communities of ectoderm- and mucus-colonizing epizoic prokaryotes were compared using fluorescent in situ hybridization (FISH). Oligonucleotide probes targeted 13 phylotypes representing the main taxonomic groups of marine prokaryotes. Coral taxa tended to show specific community profiles. An attempt to separate the profiles of healthy and diseased specimens by applying principal component analysis (PCA) to a (nonselective) collection of corals (affected by various diseases) proved unsuccessful. On the other hand, separate PCA clusters were obtained from healthy and diseased corals belonging to a single species (Pocillopora damicornis) only. This cluster formation was dominated by principal component 1 with the genus Vibrio accounting for 18%. At the same time, reef-site-specific clusters were formed as well. At a reef site exposed to pollution from intensive fish cage (Chanos chanos) farming, healthy P. damicornis were mainly (93%) colonized by unicellular cyanobacteria. The formal calculation of diversity parameters suggested that evenness in particular was driven by both health status and reef site location. Despite the low resolution of taxonomic levels achieved with FISH probes targeting only large phylotype groups, significant differences between healthy and diseased corals and also between polluted and nonpolluted reef sites were observed.

Systems Perturbation Analysis of a Large-Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics

PubMed Central

Puniya, Bhanwar Lal; Allen, Laura; Hochfelder, Colleen; Majumder, Mahbubul; Helikar, Tomáš

2016-01-01

Dysregulation in signal transduction pathways can lead to a variety of complex disorders, including cancer. Computational approaches such as network analysis are important tools to understand system dynamics as well as to identify critical components that could be further explored as therapeutic targets. Here, we performed perturbation analysis of a large-scale signal transduction model in extracellular environments that stimulate cell death, growth, motility, and quiescence. Each of the model’s components was perturbed under both loss-of-function and gain-of-function mutations. Using 1,300 simulations under both types of perturbations across various extracellular conditions, we identified the most and least influential components based on the magnitude of their influence on the rest of the system. Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins. The most influential components under all environmental conditions were enriched with several biological processes. The inositol pathway was found as most influential under inactivating perturbations, whereas the kinase and small lung cancer pathways were identified as the most influential under activating perturbations. The most influential components were enriched with essential genes and druggable proteins. Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network. Additionally, the systemic perturbation analysis of the model revealed a network motif of most influential components which affect each other. Furthermore, our analysis predicted novel combinations of cancer drug targets with various effects on other most influential components. We found that the combinatorial perturbation consisting of PI3K inactivation and overactivation of IP3R1 can lead to increased activity levels of apoptosis-related components and tumor-suppressor genes, suggesting that this combinatorial perturbation may lead to a better target for decreasing cell proliferation and inducing apoptosis. Finally, our approach shows a potential to identify and prioritize therapeutic targets through systemic perturbation analysis of large-scale computational models of signal transduction. Although some components of the presented computational results have been validated against independent gene expression data sets, more laboratory experiments are warranted to more comprehensively validate the presented results. PMID:26904540

N400-like responses to three-chord harmonic sequences with unexpected out of key endings: scalp topography, cortical sources, and perspectives for a clinical use.

PubMed

Bonfiglio, Luca; Virgillito, Alessandra; Magrini, Massimo; Piarulli, Andrea; Bergamasco, Massimo; Barcaro, Umberto; Rossi, Bruno; Salvetti, Ovidio; Carboncini, Maria Chiara

2015-03-01

A series of ERP components, each provided with both a precise timing with respect to stimulation and a specific cortical localization, reflects the temporal succession of processing stages of music information. This makes the musical stimulus potentially usable to probe residual brain functions in non-communicating patients with disorders of consciousness. In an attempt to find a simple stimulation protocol that was suitable for use in a clinical setting, the purpose of this study was to verify whether a minimum-length musical stimulus, provided with a definite music-syntactic connotation, was still able to elicit musical ERPs in a group of eight healthy subjects. The stimulus was composed of the minimum number of chords necessary and sufficient to enable the subject to predict a plausible closure of the sequence (priming) and, at the same time, to provide him/her with the closing chord of the sequence (target), either congruous (probable closing) or not (improbable closing) to the tonal context. The subject's task was to discriminate and recognize the irregular targets. The components that were expected to be elicited, in this experimental situation, were ERAN, N5, P600/LPC. Conversely, in addition to these former components, we unexpectedly observed a N400-like component. To determine whether this component was a real N400, we submitted our data to a sLORETA analysis in order to identify its cortical generators. Irregular chords showed higher current densities with respect to regular ones on the right-sided medial and superior temporal gyri, superior and inferior parietal lobules, fusiform and parahippocampal gyri, and on the bilateral posterior cingulate cortex. In particular, the N400-like wave seems to share with the word-primed music-elicited N400 certain generators that are located in cortical areas BA 21/37 and BA 22. This suggests that even chord-primed chord targets can convey extra-musical meanings and that, consequently, they might be useful in assessing residual higher-order information-processing capabilities in non-communicating patients with disorders of consciousness.

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

PubMed

Shin, Eunsam; Chong, Sang Chul

2016-12-01

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

Targeting of insect epicuticular lipids by the entomopathogenic fungus Beauveria bassiana: hydrocarbon oxidation within the context of a host-pathogen interaction

PubMed Central

Pedrini, Nicolás; Ortiz-Urquiza, Almudena; Huarte-Bonnet, Carla; Zhang, Shizhu; Keyhani, Nemat O.

2013-01-01

Broad host range entomopathogenic fungi such as Beauveria bassiana attack insect hosts via attachment to cuticular substrata and the production of enzymes for the degradation and penetration of insect cuticle. The outermost epicuticular layer consists of a complex mixture of non-polar lipids including hydrocarbons, fatty acids, and wax esters. Long chain hydrocarbons are major components of the outer waxy layer of diverse insect species, where they serve to protect against desiccation and microbial parasites, and as recognition molecules or as a platform for semiochemicals. Insect pathogenic fungi have evolved mechanisms for overcoming this barrier, likely with sets of lipid degrading enzymes with overlapping substrate specificities. Alkanes and fatty acids are substrates for a specific subset of fungal cytochrome P450 monooxygenases involved in insect hydrocarbon degradation. These enzymes activate alkanes by terminal oxidation to alcohols, which are further oxidized by alcohol and aldehyde dehydrogenases, whose products can enter β-oxidation pathways. B. bassiana contains at least 83 genes coding for cytochrome P450s (CYP), a subset of which are involved in hydrocarbon oxidation, and several of which represent new CYP subfamilies/families. Expression data indicated differential induction by alkanes and insect lipids and four CYP proteins have been partially characterized after heterologous expression in yeast. Gene knockouts revealed a phenotype for only one (cyp52X1) out of six genes examined to date. CYP52X1 oxidizes long chain fatty acids and participates in the degradation of specific epicuticular lipid components needed for breaching the insect waxy layer. Examining the hydrocarbon oxidizing CYP repertoire of pathogens involved in insect epicuticle degradation can lead to the characterization of enzymes with novel substrate specificities. Pathogen targeting may also represent an important co-evolutionary process regarding insect cuticular hydrocarbon synthesis. PMID:23422735

Sarcopenia in Alcoholic Liver Disease: Clinical and Molecular Advances.

PubMed

Dasarathy, Jaividhya; McCullough, Arthur J; Dasarathy, Srinivasan

2017-08-01

Despite advances in treatment of alcohol use disorders that focus on increasing abstinence and reducing recidivism, alcoholic liver disease (ALD) is projected to be the major cause of cirrhosis and its complications. Malnutrition is recognized as the most frequent complication in ALD, and despite the high clinical significance, there are no effective therapies to reverse malnutrition in ALD. Malnutrition is a relatively imprecise term, and sarcopenia or skeletal muscle loss, the major component of malnutrition, is primarily responsible for the adverse clinical consequences in patients with liver disease. It is, therefore, critical to define the specific abnormality (sarcopenia) rather than malnutrition in ALD, so that therapies targeting sarcopenia can be developed. Skeletal muscle mass is maintained by a balance between protein synthesis and proteolysis. Both direct effects of ethanol (EtOH) and its metabolites on the skeletal muscle and the consequences of liver disease result in disturbed proteostasis (protein homeostasis) and consequent sarcopenia. Once cirrhosis develops in patients with ALD, abstinence is unlikely to be effective in completely reversing sarcopenia, as other contributors including hyperammonemia, hormonal, and cytokine abnormalities aggravate sarcopenia and maintain a state of anabolic resistance initiated by EtOH. Cirrhosis is also a state of accelerated starvation, with increased gluconeogenesis that requires amino acid diversion from signaling and substrate functions. Novel therapeutic options are being recognized that are likely to supplant the current "deficiency replacement" approach and instead focus on specific molecular perturbations, given the increasing availability of small molecules that can target specific signaling components. Myostatin antagonists, leucine supplementation, and mitochondrial protective agents are currently in various stages of evaluation in preclinical studies to prevent and reverse sarcopenia, in cirrhosis in general, and ALD, specifically. Translation of these data to human studies and clinical application requires priority for allocation of resources. Copyright © 2017 by the Research Society on Alcoholism.

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

PubMed Central

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

2011-01-01

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

[The Functional Role of Exosomes in Cancer Biology and Their Potential as Biomarkers and Therapeutic Targets of Cancer].

PubMed

Naito, Yutaka; Yoshioka, Yusuke; Ochiya, Takahiro

2015-06-01

Intercellular communication plays an important role in the regulation of various cellular events. In particular, cancer cells and the surrounding cells communicate with each other, and this intercellular communication triggers cancer initiation and progression through the secretion of molecules, including growth factors and cytokines. Recent advances in cancer biology have indicated that small membrane vesicles, termed exosomes, also serve as regulatory agents in intercellular communications. Exosomes contain functional cellular components, including proteins and microRNAs (miRNAs), and they transfer these components to recipient cells. This exosome-mediated intercellular communication leads to increased growth, invasion, and metastasis of cancer. Thus, researchers regard exosomes as important cues to understanding the molecular mechanisms of cancer biology. Indeed, several lines of evidence have demonstrated that exosomes can explain multiple aspects of cancer biology. In addition, increasing evidence suggests that exosomes and their specific molecules are also attractive for use as biomarkers and therapeutic targets in cancer. Recent reports showed the efficacy of a novel diagnosis by detecting component molecules of cancer-derived exosomes, including miRNAs and membrane proteins. Furthermore, clinical trials that test the application of exosomes for cancer therapy have already been reported. From these points of view, we will summarize experimental data that support the role of exosomes in cancer progression and the potential of exosomes for use in novel diagnostic and therapeutic approaches for cancer.

Extracting binaural information from simultaneous targets and distractors: Effects of amplitude modulation and asynchronous envelopes

PubMed Central

Stellmack, Mark A.; Byrne, Andrew J.; Viemeister, Neal F.

2010-01-01

When different components of a stimulus carry different binaural information, processing of binaural information in a target component is often affected. The present experiments examine whether such interference is affected by amplitude modulation and the relative phase of modulation of the target and distractors. In all experiments, listeners attempted to discriminate interaural time differences of a target stimulus in the presence of distractor stimuli with ITD=0. In Experiment 1, modulation of the distractors but not the target reduced interference between components. In Experiment 2, synthesized musical notes exhibited little binaural interference when there were slight asynchronies between different streams of notes (31 or 62 ms). The remaining experiments suggested that the reduction in binaural interference in the previous experiments was due neither to the complex spectra of the synthesized notes nor to greater detectability of the target in the presence of modulated distractors. These data suggest that this interference is reduced when components are modulated in ways that result in the target appearing briefly in isolation, not because of segregation cues. These data also suggest that modulation and asynchronies between modulators that might be encountered in real-world listening situations are adequate to reduce binaural interference to inconsequential levels. PMID:20815459

Chess players' eye movements reveal rapid recognition of complex visual patterns: Evidence from a chess-related visual search task.

PubMed

Sheridan, Heather; Reingold, Eyal M

2017-03-01

To explore the perceptual component of chess expertise, we monitored the eye movements of expert and novice chess players during a chess-related visual search task that tested anecdotal reports that a key differentiator of chess skill is the ability to visualize the complex moves of the knight piece. Specifically, chess players viewed an array of four minimized chessboards, and they rapidly searched for the target board that allowed a knight piece to reach a target square in three moves. On each trial, there was only one target board (i.e., the "Yes" board), and for the remaining "lure" boards, the knight's path was blocked on either the first move (the "Easy No" board) or the second move (i.e., "the Difficult No" board). As evidence that chess experts can rapidly differentiate complex chess-related visual patterns, the experts (but not the novices) showed longer first-fixation durations on the "Yes" board relative to the "Difficult No" board. Moreover, as hypothesized, the task strongly differentiated chess skill: Reaction times were more than four times faster for the experts relative to novices, and reaction times were correlated with within-group measures of expertise (i.e., official chess ratings, number of hours of practice). These results indicate that a key component of chess expertise is the ability to rapidly recognize complex visual patterns.

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

PubMed

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

2016-05-06

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

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

PubMed Central

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

2016-01-01

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

Vulnerability of animal trade networks to the spread of infectious diseases: a methodological approach applied to evaluation and emergency control strategies in cattle, France, 2005.

PubMed

Rautureau, S; Dufour, B; Durand, B

2011-04-01

Besides farming, trade of livestock is a major component of agricultural economy. However, the networks generated by live animal movements are the major support for the propagation of infectious agents between farms, and their structure strongly affects how fast a disease may spread. Structural characteristics may thus be indicators of network vulnerability to the spread of infectious disease. The method proposed here is based upon the analysis of specific subnetworks: the giant strongly connected components (GSCs). Their existence, size and geographic extent are used to assess network vulnerability. Their disappearance when targeted nodes are removed allows studying how network vulnerability may be controlled under emergency conditions. The method was applied to the cattle trade network in France, 2005. Giant strongly connected components were present and widely spread all over the country in yearly, monthly and weekly networks. Among several tested approaches, the most efficient way to make GSCs disappear was based on the ranking of nodes by decreasing betweenness centrality (the proportion of shortest paths between nodes on which a specific node lies). Giant strongly connected components disappearance was obtained after removal of <1% of network nodes. Under emergency conditions, suspending animal trade activities in a small subset of holdings may thus allow to control the spread of an infectious disease through the animal trade network. Nodes representing markets and dealers were widely affected by these simulated control measures. This confirms their importance as 'hubs' for infectious diseases spread. Besides emergency conditions, specific sensitization and preventive measures should be dedicated to this population. © 2010 Blackwell Verlag GmbH.

Evaluating robustness in rank-based risk assessments of freshwater ecosystems

USGS Publications Warehouse

Mattson, K.M.; Angermeier, Paul

2007-01-01

Conservation planning aims to protect biodiversity by sustainng the natural physical, chemical, and biological processes within representative ecosystems. Often data to measure these components are inadequate or unavailable. The impact of human activities on ecosystem processes complicates integrity assessments and might alter ecosystem organization at multiple spatial scales. Freshwater conservation targets, such as populations and communities, are influenced by both intrinsic aquatic properties and the surrounding landscape, and locally collected data might not accurately reflect potential impacts. We suggest that changes in five major biotic drivers—energy sources, physical habitat, flow regime, water quality, and biotic interactions—might be used as surrogates to inform conservation planners of the ecological integrity of freshwater ecosystems. Threats to freshwater systems might be evaluated based on their impact to these drivers to provide an overview of potential risk to conservation targets. We developed a risk-based protocol, the Ecological Risk Index (ERI), to identify watersheds with least/most risk to conservation targets. Our protocol combines risk-based components, specifically the frequency and severity of human-induced stressors, with biotic drivers and mappable land- and water-use data to provide a summary of relative risk to watersheds. We illustrate application of our protocol with a case study of the upper Tennessee River basin, USA. Differences in risk patterns among the major drainages in the basin reflect dominant land uses, such as mining and agriculture. A principal components analysis showed that localized, moderately severe threats accounted for most of the threat composition differences among our watersheds. We also found that the relative importance of threats is sensitive to the spatial grain of the analysis. Our case study demonstrates that the ERI is useful for evaluating the frequency and severity of ecosystemwide risk, which can inform local and regional conservation planning.

Components of Motor Deficiencies in ADHD and Possible Interventions.

PubMed

Dahan, Anat; Ryder, Chen Hanna; Reiner, Miriam

2018-05-15

There is a growing body of evidence pointing at several types of motor abnormalities found in attention-deficit/hyperactivity disorder (ADHD). In this article we review findings stemming from different paradigms, and suggest an interweaving approach to the different stages involved in the motor regulation process. We start by reviewing various aspects of motor abnormalities found in ADHD and related brain mechanisms. Then, we classify reported motor impairments associated with ADHD, into four classes of motor stages: Attention to the task, motion preparation, motion execution and motion monitoring. Motor abnormalities and corresponding neural activations are analyzed in the context of each of the four identified motor patterns, along with the interactions among them and with other systems. Given the specifications and models of the role of the four motor impairments in ADHD, we ask what treatments correspond to the identified motor impairments. We analyze therapeutic interventions targeting motor difficulties most commonly experienced among individuals with ADHD; first, Neurofeedback training and EMG-biofeedback. As some of the identified components of attention, planning and monitoring have been shown to be linked to abnormal oscillation patterns in the brain, we examine neurofeedback interventions aimed to address these types of oscillations: Theta/beta frequency training and SCP neurofeedback targeted at elevating the CNV component. Additionally we discuss EMG-Biofeedback interventions targeted at feedback on motor activity. Further we review physical activity and motor interventions aimed at improving motor difficulties, associated with ADHD. These kinds of interventions are shown to be helpful not only in aspects of physical ability, but also in enhancing cognition and executive functioning. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

MS2 bacteriophage as a delivery vessel of porphyrins for photodynamic therapy

NASA Astrophysics Data System (ADS)

Cohen, Brian A.; Kaloyeros, Alain E.; Bergkvist, Magnus

2011-02-01

Challenges associated with photodynamic therapy (PDT) include the packaging and site-specific delivery of therapeutic agents to the tissue of interest. Nanoscale encapsulation of PDT agents inside targeted virus capsids is a novel concept for packaging and site-specific targeting. The icosahedral MS2 bacteriophage is one potential candidate for such a packaging-system. MS2 has a porous capsid with an exterior diameter of ~28 nm where the pores allow small molecules access to the capsid interior. Furthermore, MS2 presents suitable residues on the exterior capsid for conjugation of targeting ligands. Initial work by the present investigators has successfully demonstrated RNA-based self-packaging of a heterocyclic PDT agent (meso-tetrakis(para-N-trimethylanilinium)porphine, TMAP) into the MS2 capsid. Packaging photoactive compounds in confined spaces could result in energy transfer between the molecules upon photoactivation, which could in turn reduce the production of radical oxygen species (ROS). ROS are key components in photodynamic therapy, and a reduced production could negatively impact the efficacy of PDT treatment. Here, findings are presented from an investigation of ROS generation of TMAP encapsulated within the MS2 capsid compared to free TMAP in solution. Monitoring of ROS production upon photoactivation via a specific singlet oxygen assay revealed the impact on ROS generation between packaged porphyrins as compared to free porphyrin in an aqueous solution. Follow on work will study the ability of MS2-packaged porphyrins to generate ROS in vitro and subsequent cytotoxic effects on cells in culture.

Insights into Atherosclerosis Using Nanotechnology

PubMed Central

Linton, MacRae F.; Fazio, Sergio; Haselton, Frederick R.

2010-01-01

A developing forefront in vascular disease research is the application of nanotechnology, the engineering of devices at the molecular scale, for diagnostic and therapeutic applications in atherosclerosis. Promising research in this field over the past decade has resulted in the preclinical validation of nanoscale devices that target cellular and molecular components of the atherosclerotic plaque, including one of its prominent cell types, the macrophage. Nanoscale contrast agents targeting constituents of plaque biology have been adapted for application in multiple imaging modalities, leading toward more detailed diagnostic readouts, whereas nanoscale drug delivery devices can be tailored for site-specific therapeutic activity. This review highlights recent progress in utilizing nanotechnology for the clinical management of atherosclerosis, drawing upon recent preclinical studies relevant to diagnosis and treatment of the plaque and promising future applications. PMID:20425261

PARP13 and RNA regulation in immunity and cancer

PubMed Central

Todorova, Tanya; Bock, Florian; Chang, Paul

2015-01-01

Posttranscriptional regulation of RNA is an important mechanism for activating and resolving cellular stress responses. Poly(ADP-ribose) Polymerase-13 (PARP13), also known as ZC3HAV1 and Zinc-finger Antiviral Protein (ZAP), is an RNA-binding protein that regulates the stability, and translation of specific mRNAs, and modulates the miRNA silencing pathway to globally impact miRNA targets. These functions of PARP13 are important components of the cellular response to stress. In addition, the ability of PARP13 to restrict oncogenic viruses and to repress the pro-survival cytokine receptor TRAILR4 suggests that it can be protective against malignant transformation and cancer development. The relevance of PARP13 to human health and disease make it a promising therapeutic target. PMID:25851173

Designing Trojan Horses | Center for Cancer Research

Cancer.gov

Waging battle against cancer cells without inflicting damage on normal tissue has long been a goal for cancer treatment. A new type of drug called immunotoxins may help make this goal a reality. Much like the Greeks used a wooden horse to get soldiers inside the gates of Troy, immunotoxins use clever genetic engineering to get a lethal toxin inside cancer cells. Each immunotoxin consists of two components an antibody and a toxin that are fused together. The custom-designed antibody acts as a homing signal, seeking out a specific target present on the surface of cancer cells. When the antibody binds its target, the whole immunotoxin is brought inside the cell. Unwittingly, the cancer cell has exposed itself to a powerful poison, a mistake that will likely condemn it to death.

EU Development of High Heat Flux Components

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

Linke, J.; Lorenzetto, P.; Majerus, P.

2005-04-15

The development of plasma facing components for next step fusion devices in Europe is strongly focused to ITER. Here a wide spectrum of different design options for the divertor target and the first wall have been investigated with tungsten, CFC, and beryllium armor. Electron beam simulation experiments have been used to determine the performance of high heat flux components under ITER specific thermal loads. Beside thermal fatigue loads with power density levels up to 20 MWm{sup -2}, off-normal events are a serious concern for the lifetime of plasma facing components. These phenomena are expected to occur on a time scalemore » of a few milliseconds (plasma disruptions) or several hundred milliseconds (vertical displacement events) and have been identified as a major source for the production of neutron activated metallic or tritium enriched carbon dust which is of serious importance from a safety point of view.The irradiation induced material degradation is another critical concern for future D-T-burning fusion devices. In ITER the integrated neutron fluence to the first wall and the divertor armour will remain in the order of 1 dpa and 0.7 dpa, respectively. This value is low compared to future commercial fusion reactors; nevertheless, a nonnegligible degradation of the materials has been detected, both for mechanical and thermal properties, in particular for the thermal conductivity of carbon based materials. Beside the degradation of individual material properties, the high heat flux performance of actively cooled plasma facing components has been investigated under ITER specific thermal and neutron loads.« less

Knowing where is different from knowing what: Distinct response time profiles and accuracy effects for target location, orientation, and color probability.

PubMed

Jabar, Syaheed B; Filipowicz, Alex; Anderson, Britt

2017-11-01

When a location is cued, targets appearing at that location are detected more quickly. When a target feature is cued, targets bearing that feature are detected more quickly. These attentional cueing effects are only superficially similar. More detailed analyses find distinct temporal and accuracy profiles for the two different types of cues. This pattern parallels work with probability manipulations, where both feature and spatial probability are known to affect detection accuracy and reaction times. However, little has been done by way of comparing these effects. Are probability manipulations on space and features distinct? In a series of five experiments, we systematically varied spatial probability and feature probability along two dimensions (orientation or color). In addition, we decomposed response times into initiation and movement components. Targets appearing at the probable location were reported more quickly and more accurately regardless of whether the report was based on orientation or color. On the other hand, when either color probability or orientation probability was manipulated, response time and accuracy improvements were specific for that probable feature dimension. Decomposition of the response time benefits demonstrated that spatial probability only affected initiation times, whereas manipulations of feature probability affected both initiation and movement times. As detection was made more difficult, the two effects further diverged, with spatial probability disproportionally affecting initiation times and feature probability disproportionately affecting accuracy. In conclusion, all manipulations of probability, whether spatial or featural, affect detection. However, only feature probability affects perceptual precision, and precision effects are specific to the probable attribute.

Target selection biases from recent experience transfer across effectors.

PubMed

Moher, Jeff; Song, Joo-Hyun

2016-02-01

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

Bio-chemo-mechanical models of vascular mechanics

PubMed Central

Kim, Jungsil; Wagenseil, Jessica E.

2014-01-01

Models of vascular mechanics are necessary to predict the response of an artery under a variety of loads, for complex geometries, and in pathological adaptation. Classic constitutive models for arteries are phenomenological and the fitted parameters are not associated with physical components of the wall. Recently, microstructurally-linked models have been developed that associate structural information about the wall components with tissue-level mechanics. Microstructurally-linked models are useful for correlating changes in specific components with pathological outcomes, so that targeted treatments may be developed to prevent or reverse the physical changes. However, most treatments, and many causes, of vascular disease have chemical components. Chemical signaling within cells, between cells, and between cells and matrix constituents affects the biology and mechanics of the arterial wall in the short- and long-term. Hence, bio-chemo-mechanical models that include chemical signaling are critical for robust models of vascular mechanics. This review summarizes bio-mechanical and bio-chemo-mechanical models with a focus on large elastic arteries. We provide applications of these models and challenges for future work. PMID:25465618

Phospholipase D2 Mediates Survival Signaling through Direct Regulation of Akt in Glioblastoma Cells*♦

PubMed Central

Bruntz, Ronald C.; Taylor, Harry E.; Lindsley, Craig W.; Brown, H. Alex

2014-01-01

The lack of innovative drug targets for glioblastoma multiforme (GBM) limits patient survival to approximately 1 year following diagnosis. The pro-survival kinase Akt provides an ideal target for the treatment of GBM as Akt signaling is frequently activated in this cancer type. However, the central role of Akt in physiological processes limits its potential as a therapeutic target. In this report, we show that the lipid-metabolizing enzyme phospholipase D (PLD) is a novel regulator of Akt in GBM. Studies using a combination of small molecule PLD inhibitors and siRNA knockdowns establish phosphatidic acid, the product of the PLD reaction, as an essential component for the membrane recruitment and activation of Akt. Inhibition of PLD enzymatic activity and subsequent Akt activation decreases GBM cell viability by specifically inhibiting autophagic flux. We propose a mechanism whereby phosphorylation of beclin1 by Akt prevents binding of Rubicon (RUN domain cysteine-rich domain containing beclin1-interacting protein), an interaction known to inhibit autophagic flux. These findings provide a novel framework through which Akt inhibition can be achieved without directly targeting the kinase. PMID:24257753

A Light Harvesting Complex-Like Protein in Maintenance of Photosynthetic Components in Chlamydomonas1[OPEN

PubMed Central

Zhao, Lei; Cheng, Dongmei; Huang, Xiahe; Chen, Mei; Xing, Jiale; Gao, Liyan; Li, Lingyu; Wang, Yale; Peng, Lianwei; Wang, Yingchun

2017-01-01

Using a genetic approach, we have identified and characterized a novel protein, named Msf1 (Maintenance factor for photosystem I), that is required for the maintenance of specific components of the photosynthetic apparatus in the green alga Chlamydomonas reinhardtii. Msf1 belongs to the superfamily of light-harvesting complex proteins with three transmembrane domains and consensus chlorophyll-binding sites. Loss of Msf1 leads to reduced accumulation of photosystem I and chlorophyll-binding proteins/complexes. Msf1is a component of a thylakoid complex containing key enzymes of the tetrapyrrole biosynthetic pathway, thus revealing a possible link between Msf1 and chlorophyll biosynthesis. Protein interaction assays and greening experiments demonstrate that Msf1 interacts with Copper target homolog1 (CHL27B) and accumulates concomitantly with chlorophyll in Chlamydomonas, implying that chlorophyll stabilizes Msf1. Contrary to other light-harvesting complex-like genes, the expression of Msf1 is not stimulated by high-light stress, but its protein level increases significantly under heat shock, iron and copper limitation, as well as in stationary cells. Based on these results, we propose that Msf1 is required for the maintenance of photosystem I and specific protein-chlorophyll complexes especially under certain stress conditions. PMID:28637830

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

PubMed

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

2015-01-01

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

Collateral damage control in cancer therapy: defining the stem identity in gliomas.

PubMed

Hsieh, David

2011-01-01

The discovery of discrete functional components in cancer systems advocates a paradigm shift in therapeutic design towards the targeted destruction of critical cellular constituents that fuel tumorigenic potential. In astrocytomas, malignant growth can be propagated and sustained by glioma stem cells (GSCs) endowed with highly efficient clonogenic and tumor initiation capacities. Given their disproportionate oncogenic contribution, GSCs are often considered the optimal targets for curative treatment because their eradication may subvert the refractory nature of GBMs. However, the close affinity of GSCs and normal neural stem cells (NSCs) is a cautionary note for off-target effects of GSC-based therapies. In fact, many parallels can be drawn between GSC and NSC functions, which ostensibly rely on a communal collection of stem cell-promoting transcription factors (TFs). Only through rigorous scrutiny of nuances in the stemness program of GSCs and NSCs may we clarify the pathogenic mechanisms of stemness factors and reveal processes exploited by cancer cells to co-opt stem cell traits. Importantly, discerning the specific requirements for GSC and NSC maintenance may be an essential requisite when assessing molecular targets for discriminatory targeting of GSCs with minimal sequelae.

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

NASA Astrophysics Data System (ADS)

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

2016-02-01

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

A Nanoparticle Carrying the p53 Gene Targets Tumors Including Cancer Stem Cells, Sensitizes Glioblastoma to Chemotherapy and Improves Survival

PubMed Central

2015-01-01

Temozolomide (TMZ)-resistance in glioblastoma multiforme (GBM) has been linked to upregulation of O6-methylguanine-DNA methyltransferase (MGMT). Wild-type (wt) p53 was previously shown to down-modulate MGMT. However, p53 therapy for GBM is limited by lack of efficient delivery across the blood brain barrier (BBB). We have developed a systemic nanodelivery platform (scL) for tumor-specific targeting (primary and metastatic), which is currently in multiple clinical trials. This self-assembling nanocomplex is formed by simple mixing of the components in a defined order and a specific ratio. Here, we demonstrate that scL crosses the BBB and efficiently targets GBM, as well as cancer stem cells (CSCs), which have been implicated in recurrence and treatment resistance in many human cancers. Moreover, systemic delivery of scL-p53 down-modulates MGMT and induces apoptosis in intracranial GBM xenografts. The combination of scL-p53 and TMZ increased the antitumor efficacy of TMZ with enhanced survival benefit in a mouse model of highly TMZ-resistant GBM. scL-p53 also sensitized both CSCs and bulk tumor cells to TMZ, increasing apoptosis. These results suggest that combining scL-p53 with standard TMZ treatment could be a more effective therapy for GBM. PMID:24811110

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

PubMed

Fisher, Lawrence; Tang, Tricia; Polonsky, William

2017-04-01

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

Functionality of In vitro Reconstituted Group II Intron RmInt1-Derived Ribonucleoprotein Particles.

PubMed

Molina-Sánchez, Maria D; García-Rodríguez, Fernando M; Toro, Nicolás

2016-01-01

The functional unit of mobile group II introns is a ribonucleoprotein particle (RNP) consisting of the intron-encoded protein (IEP) and the excised intron RNA. The IEP has reverse transcriptase activity but also promotes RNA splicing, and the RNA-protein complex triggers site-specific DNA insertion by reverse splicing, in a process called retrohoming. In vitro reconstituted ribonucleoprotein complexes from the Lactococcus lactis group II intron Ll.LtrB, which produce a double strand break, have recently been studied as a means of developing group II intron-based gene targeting methods for higher organisms. The Sinorhizobium meliloti group II intron RmInt1 is an efficient mobile retroelement, the dispersal of which appears to be linked to transient single-stranded DNA during replication. The RmInt1IEP lacks the endonuclease domain (En) and cannot cut the bottom strand to generate the 3' end to initiate reverse transcription. We used an Escherichia coli expression system to produce soluble and active RmInt1 IEP and reconstituted RNPs with purified components in vitro . The RNPs generated were functional and reverse-spliced into a single-stranded DNA target. This work constitutes the starting point for the use of group II introns lacking DNA endonuclease domain-derived RNPs for highly specific gene targeting methods.

Functionality of In vitro Reconstituted Group II Intron RmInt1-Derived Ribonucleoprotein Particles

PubMed Central

Molina-Sánchez, Maria D.; García-Rodríguez, Fernando M.; Toro, Nicolás

2016-01-01

The functional unit of mobile group II introns is a ribonucleoprotein particle (RNP) consisting of the intron-encoded protein (IEP) and the excised intron RNA. The IEP has reverse transcriptase activity but also promotes RNA splicing, and the RNA-protein complex triggers site-specific DNA insertion by reverse splicing, in a process called retrohoming. In vitro reconstituted ribonucleoprotein complexes from the Lactococcus lactis group II intron Ll.LtrB, which produce a double strand break, have recently been studied as a means of developing group II intron-based gene targeting methods for higher organisms. The Sinorhizobium meliloti group II intron RmInt1 is an efficient mobile retroelement, the dispersal of which appears to be linked to transient single-stranded DNA during replication. The RmInt1IEP lacks the endonuclease domain (En) and cannot cut the bottom strand to generate the 3′ end to initiate reverse transcription. We used an Escherichia coli expression system to produce soluble and active RmInt1 IEP and reconstituted RNPs with purified components in vitro. The RNPs generated were functional and reverse-spliced into a single-stranded DNA target. This work constitutes the starting point for the use of group II introns lacking DNA endonuclease domain-derived RNPs for highly specific gene targeting methods. PMID:27730127

Data-driven signal-resolving approaches of infrared spectra to explore the macroscopic and microscopic spatial distribution of organic and inorganic compounds in plant.

PubMed

Chen, Jian-bo; Sun, Su-qin; Zhou, Qun

2015-07-01

The nondestructive and label-free infrared (IR) spectroscopy is a direct tool to characterize the spatial distribution of organic and inorganic compounds in plant. Since plant samples are usually complex mixtures, signal-resolving methods are necessary to find the spectral features of compounds of interest in the signal-overlapped IR spectra. In this research, two approaches using existing data-driven signal-resolving methods are proposed to interpret the IR spectra of plant samples. If the number of spectra is small, "tri-step identification" can enhance the spectral resolution to separate and identify the overlapped bands. First, the envelope bands of the original spectrum are interpreted according to the spectra-structure correlations. Then the spectrum is differentiated to resolve the underlying peaks in each envelope band. Finally, two-dimensional correlation spectroscopy is used to enhance the spectral resolution further. For a large number of spectra, "tri-step decomposition" can resolve the spectra by multivariate methods to obtain the structural and semi-quantitative information about the chemical components. Principal component analysis is used first to explore the existing signal types without any prior knowledge. Then the spectra are decomposed by self-modeling curve resolution methods to estimate the spectra and contents of significant chemical components. At last, targeted methods such as partial least squares target can explore the content profiles of specific components sensitively. As an example, the macroscopic and microscopic distribution of eugenol and calcium oxalate in the bud of clove is studied.

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.

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

PubMed

Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R; Redmond, T Michael; Boye, Sanford L; Hauswirth, William W; Ding, Xi-Qin

2016-12-01

Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 -/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

Geometric shapes inversion method of space targets by ISAR image segmentation

NASA Astrophysics Data System (ADS)

Huo, Chao-ying; Xing, Xiao-yu; Yin, Hong-cheng; Li, Chen-guang; Zeng, Xiang-yun; Xu, Gao-gui

2017-11-01

The geometric shape of target is an effective characteristic in the process of space targets recognition. This paper proposed a method of shape inversion of space target based on components segmentation from ISAR image. The Radon transformation, Hough transformation, K-means clustering, triangulation will be introduced into ISAR image processing. Firstly, we use Radon transformation and edge detection to extract space target's main body spindle and solar panel spindle from ISAR image. Then the targets' main body, solar panel, rectangular and circular antenna are segmented from ISAR image based on image detection theory. Finally, the sizes of every structural component are computed. The effectiveness of this method is verified using typical targets' simulation data.

Engineered Hybrid Nanoparticles for On-Demand Diagnostics and Therapeutics.

PubMed

Nguyen, Kim Truc; Zhao, Yanli

2015-12-15

Together with the simultaneous development of nanomaterials and molecular biology, the bionano interface brings about various applications of hybrid nanoparticles in nanomedicine. The hybrid nanoparticles not only present properties of the individual components but also show synergistic effects for specialized applications. Thus, the development of advanced hybrid nanoparticles for targeted and on-demand diagnostics and therapeutics of diseases has rapidly become a hot research topic in nanomedicine. The research focus is to fabricate novel classes of programmable hybrid nanoparticles that are precisely engineered to maximize drug concentrations in diseased cells, leading to enhanced efficacy and reduced side effects of chemotherapy for the disease treatment. In particular, the hybrid nanoparticle platforms can simultaneously target diseased cells, enable the location to be imaged by optical methods, and release therapeutic drugs to the diseased cells by command. This Account specially discusses the rational fabrication of integrated hybrid nanoparticles and their applications in diagnostics and therapeutics. For diagnostics applications, hybrid nanoparticles can be utilized as imaging agents that enable detailed visualization at the molecular level. By the use of suitable targeting ligands incorporated on the nanoparticles, targeted optical imaging may be feasible with improved performance. Novel imaging techniques such as multiphoton excitation and photoacoustic imaging using near-infrared light have been developed using the intrinsic properties of particular nanoparticles. The use of longer-wavelength excitation sources allows deeper penetration into the human body for disease diagnostics and at the same time reduces the adverse effects on normal tissues. Furthermore, multimodal imaging techniques have been achieved by combining several types of components in nanoparticles, offering higher accuracy and better spatial views, with the aim of detecting life-threatening diseases before symptoms appear. For therapeutics applications, various nanoparticle-based treatment methods such as photodynamic therapy, drug delivery, and gene delivery have been developed. The intrinsic ability of organic nanoparticles to generate reactive oxygen species has been utilized for photodynamic therapy, and mesoporous silica nanoparticles have been widely used for drug loading and controlled delivery. Herein, the development of controlled-release systems that can specifically deliver drug molecules to target cells and release then upon triggering is highlighted. By control of the release of loaded drug molecules at precise sites (e.g., cancer cells or malignant tumors), side effects of the drugs are minimized. This approach provides better control and higher efficacy of drugs in the human body. Future personalized medicine is also feasible through gene delivery methods. Specific DNA/RNA-carrying nanoparticles are able to deliver them to target cells to obtain desired properties. This development may create an evolution in current medicine, leading to more personalized healthcare systems that can reduce the population screening process and also the duration of drug evaluation. Furthermore, nanoparticles can be incorporated with various components that can be used for simultaneous diagnostics and therapeutics. These multifunctional theranostic nanoparticles enable real-time monitoring of treatment process for more efficient therapy.

Spherical Nucleic Acids as Intracellular Agents for Nucleic Acid Based Therapeutics

NASA Astrophysics Data System (ADS)

Hao, Liangliang

Recent functional discoveries on the noncoding sequences of human genome and transcriptome could lead to revolutionary treatment modalities because the noncoding RNAs (ncRNAs) can be applied as therapeutic agents to manipulate disease-causing genes. To date few nucleic acid-based therapeutics have been translated into the clinic due to challenges in the delivery of the oligonucleotide agents in an effective, cell specific, and non-toxic fashion. Unmodified oligonucleotide agents are destroyed rapidly in biological fluids by enzymatic degradation and have difficulty crossing the plasma membrane without the aid of transfection reagents, which often cause inflammatory, cytotoxic, or immunogenic side effects. Spherical nucleic acids (SNAs), nanoparticles consisting of densely organized and highly oriented oligonucleotides, pose one possible solution to circumventing these problems in both the antisense and RNA interference (RNAi) pathways. The unique three dimensional architecture of SNAs protects the bioactive oligonucleotides from unspecific degradation during delivery and supports their targeting of class A scavenger receptors and endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. Owing to their unique structure, SNAs are able to cross cell membranes and regulate target genes expression as a single entity, without triggering the cellular innate immune response. Herein, my thesis has focused on understanding the interactions between SNAs and cellular components and developing SNA-based nanostructures to improve therapeutic capabilities. Specifically, I developed a novel SNA-based, nanoscale agent for delivery of therapeutic oligonucleotides to manipulate microRNAs (miRNAs), the endogenous post-transcriptional gene regulators. I investigated the role of SNAs involving miRNAs in anti-cancer or anti-inflammation responses in cells and in in vivo murine disease models via systemic injection. Furthermore, I explored using different strategies to construct novel SNA-based nanomaterials with desired properties and applying targeting moieties to the SNA platform to achieve cell type specific gene regulation effects. Due to the flexibility of the SNA approach, the SNA platform can potentially be applied to many genetic disorders through tailored target specificities.

Caveolin1 Identifies a Specific Subpopulation of Cerebral Cortex Callosal Projection Neurons (CPN) Including Dual Projecting Cortical Callosal/Frontal Projection Neurons (CPN/FPN)

PubMed Central

2018-01-01

Abstract The neocortex is composed of many distinct subtypes of neurons that must form precise subtype-specific connections to enable the cortex to perform complex functions. Callosal projection neurons (CPN) are the broad population of commissural neurons that connect the cerebral hemispheres via the corpus callosum (CC). Currently, how the remarkable diversity of CPN subtypes and connectivity is specified, and how they differentiate to form highly precise and specific circuits, are largely unknown. We identify in mouse that the lipid-bound scaffolding domain protein Caveolin 1 (CAV1) is specifically expressed by a unique subpopulation of Layer V CPN that maintain dual ipsilateral frontal projections to premotor cortex. CAV1 is expressed by over 80% of these dual projecting callosal/frontal projection neurons (CPN/FPN), with expression peaking early postnatally as axonal and dendritic targets are being reached and refined. CAV1 is localized to the soma and dendrites of CPN/FPN, a unique population of neurons that shares information both between hemispheres and with premotor cortex, suggesting function during postmitotic development and refinement of these neurons, rather than in their specification. Consistent with this, we find that Cav1 function is not necessary for the early specification of CPN/FPN, or for projecting to their dual axonal targets. CPN subtype-specific expression of Cav1 identifies and characterizes a first molecular component that distinguishes this functionally unique projection neuron population, a population that expands in primates, and is prototypical of additional dual and higher-order projection neuron subtypes. PMID:29379878

Therapeutic targeting of regulatory T cells enhances tumor-specific CD8+ T cell responses in Epstein–Barr virus associated nasopharyngeal carcinoma

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

Fogg, Mark; Murphy, John R.; Lorch, Jochen

Epstein–Barr virus (EBV) is associated with multiple malignancies including nasopharyngeal carcinoma (NPC). In nasopharynx cancer, CD8+ T cells specific for EBV Nuclear Antigen-1 (EBNA-1) and Latent Membrane Protein 2 (LMP2) are important components of anti-tumor immunity since both are consistently expressed in NPC. We have previously shown that EBNA-1-specific CD8+ T cell responses were suppressed in NPC patients compared to healthy controls. We now find that CD8+ T cell responses specific for LMP2 are also abnormal in NPC patients, and both EBNA-1- and LMP2-specific responses are suppressed by regulatory T cells (Treg). EBNA-1 and LMP2-specific CD8+ T cell responses, asmore » well as immune control of EBV-infected cells in vitro, could be restored by the depletion of Tregs and by use of a clinically approved drug targeting Tregs. Thus, in vivo modulation of Tregs may be an effective means of enhancing these anti-tumor immune responses in NPC patients. - Highlights: • Viral proteins are tumor antigens in Epstein–Barr virus associated Nasopharyngeal Carcinoma. • CD8+ T cell responses against EBV proteins EBNA-1 and LMP2 are suppressed in NPC patients. • T regulatory cells are responsible for suppressing EBV immunity in NPC patients. • Depletion of Tregs with Ontak can rescue EBV-specific CD8+ T cell responses in NPC patients. • This clinically approved drug may be effective for enhancing anti-tumor immunity in NPC patients.« less

An eHealth Intervention to Promote Physical Activity and Social Network of Single, Chronically Impaired Older Adults: Adaptation of an Existing Intervention Using Intervention Mapping.

PubMed

Boekhout, Janet M; Peels, Denise A; Berendsen, Brenda Aj; Bolman, Catherine Aw; Lechner, Lilian

2017-11-23

Especially for single older adults with chronic diseases, physical inactivity and a poor social network are regarded as serious threats to their health and independence. The Active Plus intervention is an automated computer-tailored eHealth intervention that has been proven effective to promote physical activity (PA) in the general population of adults older than 50 years. The aim of this study was to report on the methods and results of the systematic adaptation of Active Plus to the wishes and needs of the subgroup of single people older than 65 years who have one or more chronic diseases, as this specific target population may encounter specific challenges regarding PA and social network. The Intervention Mapping (IM) protocol was used to systematically adapt the existing intervention to optimally suit this specific target population. A literature study was performed, and quantitative as well as qualitative data were derived from health care professionals (by questionnaires, n=10) and the target population (by focus group interviews, n=14), which were then systematically integrated into the adapted intervention. As the health problems and the targeted behavior are largely the same in the original and adapted intervention, the outcome of the needs assessment was that the performance objectives remained the same. As found in the literature study and in data derived from health professionals and focus groups, the relative importance and operationalization of the relevant psychosocial determinants related to these objectives are different from the original intervention, resulting in a refinement of the change objectives to optimally fit the specific target population. This refinement also resulted in changes in the practical applications, program components, intervention materials, and the evaluation and implementation strategy for the subgroup of single, chronically impaired older adults. This study demonstrates that the adaptation of an existing intervention is an intensive process in which adopting the IM protocol is an invaluable tool. The study provides a broad insight in adapting interventions aimed at single older adults with a chronic disease. It is concluded that even when the new target population is a sizable segment of the original target population, the adapted intervention still needs considerable changes to optimally fit the needs and situational differences of the narrower target population. ©Janet M Boekhout, Denise A Peels, Brenda AJ Berendsen, Catherine AW Bolman, Lilian Lechner. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 23.11.2017.

SRY, like HMG1, recognizes sharp angles in DNA.

PubMed Central

Ferrari, S; Harley, V R; Pontiggia, A; Goodfellow, P N; Lovell-Badge, R; Bianchi, M E

1992-01-01

HMG boxes are DNA binding domains present in chromatin proteins, general transcription factors for nucleolar and mitochondrial RNA polymerases, and gene- and tissue-specific transcriptional regulators. The HMG boxes of HMG1, an abundant component of chromatin, interact specifically with four-way junctions, DNA structures that are cross-shaped and contain angles of approximately 60 and 120 degrees between their arms. We show here also that the HMG box of SRY, the protein that determines the expression of male-specific genes in humans, recognizes four-way junction DNAs irrespective of their sequence. In addition, when SRY binds to linear duplex DNA containing its specific target AACAAAG, it produces a sharp bend. Therefore, the interaction between HMG boxes and DNA appears to be predominantly structure-specific. The production of the recognition of a kink in DNA can serve several distinct functions, such as the repair of DNA lesions, the folding of DNA segments with bound transcriptional factors into productive complexes or the wrapping of DNA in chromatin. Images PMID:1425584

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

PubMed

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

2014-12-01

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

A content analysis of preconception health education materials: characteristics, strategies, and clinical-behavioral components.

PubMed

Levis, Denise M; Westbrook, Kyresa

2013-01-01

Many health organizations and practitioners in the United States promote preconception health (PCH) to consumers. However, summaries and evaluations of PCH promotional activities are limited. We conducted a content analysis of PCH health education materials collected from local-, state-, national-, and federal-level partners by using an existing database of partners, outreach to maternal and child health organizations, and a snowball sampling technique. Not applicable. Not applicable. Thirty-two materials were included for analysis, based on inclusion/exclusion criteria. A codebook guided coding of materials' characteristics (type, authorship, language, cost), use of marketing and behavioral strategies to reach the target population (target audience, message framing, call to action), and inclusion of PCH subject matter (clinical-behavioral components). The self-assessment of PCH behaviors was the most common material (28%) to appear in the sample. Most materials broadly targeted women, and there was a near-equal distribution in targeting by pregnancy planning status segments (planners and nonplanners). "Practicing PCH benefits the baby's health" was the most common message frame used. Materials contained a wide range of clinical-behavioral components. Strategic targeting of subgroups of consumers is an important but overlooked strategy. More research is needed around PCH components, in terms of packaging and increasing motivation, which could guide use and placement of clinical-behavioral components within promotional materials.

High-throughput chinmedomics-based prediction of effective components and targets from herbal medicine AS1350

PubMed Central

Liu, Qi; Zhang, Aihua; Wang, Liang; Yan, Guangli; Zhao, Hongwei; Sun, Hui; Zou, Shiyu; Han, Jinwei; Ma, Chung Wah; Kong, Ling; Zhou, Xiaohang; Nan, Yang; Wang, Xijun

2016-01-01

This work was designed to explore the effective components and targets of herbal medicine AS1350 and its effect on “Kidney-Yang Deficiency Syndrome” (KYDS) based on a chinmedomics strategy which is capable of directly discovering and predicting the effective components, and potential targets, of herbal medicine. Serum samples were analysed by UPLC-MS combined with pattern recognition analysis to identify the biomarkers related to the therapeutic effects. Interestingly, the effectiveness of AS1350 against KYDS was proved by the chinmedomics method and regulated the biomarkers and targeting of metabolic disorders. Some 48 marker metabolites associated with alpha-linolenic acid metabolism, fatty acid metabolism, sphingolipids metabolism, phospholipid metabolism, steroid hormone biosynthesis, and amino acid metabolism were identified. The correlation coefficient between the constituents in vivo and the changes of marker metabolites were calculated by PCMS software and the potential effective constituents of AS1350 were also confirmed. By using chinmedomics technology, the components in AS1350 protecting against KYDS by re-balancing metabolic disorders of fatty acid metabolism, lipid metabolism, steroid hormone biosynthesis, etc. were deduced. These data indicated that the phenotypic characterisations of AS1350 altering the metabolic signatures of KYDS were multi-component, multi-pathway, multi-target, and overall regulation in nature. PMID:27910928

Aging and involuntary attention capture: electrophysiological evidence for preserved attentional control with advanced age.

PubMed

Lien, Mei-Ching; Gemperle, Alison; Ruthruff, Eric

2011-03-01

The present study examined whether people become more susceptible to capture by salient objects as they age. Participants searched a target display for a letter in a specific color and indicated its identity. In Experiment 1, this target display was preceded by a non-informative cue display containing one target-color box, one ignored-color box, and two white boxes. On half of the trials, this cue display also contained a salient-but-irrelevant abrupt onset. To assess capture by the target-color cue, we used the N2pc component of the event-related potential, thought to reflect attentional allocation to the left or right visual field. The target-color box in the cue display produced a substantial N2pc effect for younger adults and, most importantly, this effect was not diminished by the presence of an abrupt onset. Therefore, the abrupt onset was unable to capture attention away from the target-color cue. Critically, older adults demonstrated the same resistance to capture by the abrupt onset. Experiment 2 extended these findings to irrelevant color singleton cues. Thus, we argue that the ability to attend to relevant stimuli and resist capture by salient-but-irrelevant stimuli is preserved with advancing age. (c) 2011 APA, all rights reserved.

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

PubMed Central

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

2015-01-01

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

Engineering synthetic TAL effectors with orthogonal target sites

PubMed Central

Garg, Abhishek; Lohmueller, Jason J.; Silver, Pamela A.; Armel, Thomas Z.

2012-01-01

The ability to engineer biological circuits that process and respond to complex cellular signals has the potential to impact many areas of biology and medicine. Transcriptional activator-like effectors (TALEs) have emerged as an attractive component for engineering these circuits, as TALEs can be designed de novo to target a given DNA sequence. Currently, however, the use of TALEs is limited by degeneracy in the site-specific manner by which they recognize DNA. Here, we propose an algorithm to computationally address this problem. We apply our algorithm to design 180 TALEs targeting 20 bp cognate binding sites that are at least 3 nt mismatches away from all 20 bp sequences in putative 2 kb human promoter regions. We generated eight of these synthetic TALE activators and showed that each is able to activate transcription from a targeted reporter. Importantly, we show that these proteins do not activate synthetic reporters containing mismatches similar to those present in the genome nor a set of endogenous genes predicted to be the most likely targets in vivo. Finally, we generated and characterized TALE repressors comprised of our orthogonal DNA binding domains and further combined them with shRNAs to accomplish near complete repression of target gene expression. PMID:22581776

The vascular endothelium in diabetes--a therapeutic target?

PubMed

Mather, Kieren J

2013-03-01

Insulin resistance affects the vascular endothelium, and contributes to systemic insulin resistance by directly impairing the actions of insulin to redistribute blood flow as part of its normal actions driving muscle glucose uptake. Impaired vascular function is a component of the insulin resistance syndrome, and is a feature of type 2 diabetes. On this basis, the vascular endothelium has emerged as a therapeutic target where the intent is to improve systemic metabolic state by improving vascular function. We review the available literature presenting studies in humans, evaluating the effects of metabolically targeted and vascular targeted therapies on insulin action and systemic metabolism. Therapies that improve systemic insulin resistance exert strong concurrent effects to improve vascular function and vascular insulin action. RAS-acting agents and statins have widely recognized beneficial effects on vascular function but have not uniformly produced the hoped-for metabolic benefits. These observations support the notion that systemic metabolic benefits can arise from therapies targeted at the endothelium, but improving vascular insulin action does not result from all treatments that improve endothelium-dependent vasodilation. A better understanding of the mechanisms of insulin's actions in the vascular wall will advance our understanding of the specificity of these responses, and allow us to better target the vasculature for metabolic benefits.

Development of germ-line-specific CRISPR-Cas9 systems to improve the production of heritable gene modifications in Arabidopsis.

PubMed

Mao, Yanfei; Zhang, Zhengjing; Feng, Zhengyan; Wei, Pengliang; Zhang, Hui; Botella, José Ramón; Zhu, Jian-Kang

2016-02-01

The Streptococcus-derived CRISPR/Cas9 system is being widely used to perform targeted gene modifications in plants. This customized endonuclease system has two components, the single-guide RNA (sgRNA) for target DNA recognition and the CRISPR-associated protein 9 (Cas9) for DNA cleavage. Ubiquitously expressed CRISPR/Cas9 systems (UC) generate targeted gene modifications with high efficiency but only those produced in reproductive cells are transmitted to the next generation. We report the design and characterization of a germ-line-specific Cas9 system (GSC) for Arabidopsis gene modification in male gametocytes, constructed using a SPOROCYTELESS (SPL) genomic expression cassette. Four loci in two endogenous genes were targeted by both systems for comparative analysis. Mutations generated by the GSC system were rare in T1 plants but were abundant (30%) in the T2 generation. The vast majority (70%) of the T2 mutant population generated using the UC system were chimeras while the newly developed GSC system produced only 29% chimeras, with 70% of the T2 mutants being heterozygous. Analysis of two loci in the T2 population showed that the abundance of heritable gene mutations was 37% higher in the GSC system compared to the UC system and the level of polymorphism of the mutations was also dramatically increased with the GSC system. Two additional systems based on germ-line-specific promoters (pDD45-GT and pLAT52-GT) were also tested, and one of them was capable of generating heritable homozygous T1 mutant plants. Our results suggest that future application of the described GSC system will facilitate the screening for targeted gene modifications, especially lethal mutations in the T2 population. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Identifying the control structure of multijoint coordination during pistol shooting.

PubMed

Scholz, J P; Schöner, G; Latash, M L

2000-12-01

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

The relationship between operative and radiographic acetabular component orientation: which factors influence resultant cup orientation?

PubMed

Grammatopoulos, G; Pandit, H G; da Assunção, R; McLardy-Smith, P; De Smet, K A; Gill, H S; Murray, D W

2014-10-01

There is great variability in acetabular component orientation following hip replacement. The aims of this study were to compare the component orientation at impaction with the orientation measured on post-operative radiographs and identify factors that influence the difference between the two. A total of 67 hip replacements (52 total hip replacements and 15 hip resurfacings) were prospectively studied. Intra-operatively, the orientation of the acetabular component after impaction relative to the operating table was measured using a validated stereo-photogrammetry protocol. Post-operatively, the radiographic orientation was measured; the mean inclination/anteversion was 43° (sd 6°)/ 19° (sd 7°). A simulated radiographic orientation was calculated based on how the orientation would have appeared had an on-table radiograph been taken intra-operatively. The mean difference between radiographic and intra-operative inclination/anteversion was 5° (sd 5°)/ -8° (sd 8°). The mean difference between simulated radiographic and intra-operative inclination/anteversion, which quantifies the effect of the different way acetabular orientation is measured, was 3°/-6° (sd 2°). The mean difference between radiographic and simulated radiographic orientation inclination/anteversion, which is a manifestation of the change in pelvic position between component impaction and radiograph, was 1°/-2° (sd 7°). This study demonstrated that in order to achieve a specific radiographic orientation target, surgeons should implant the acetabular component 5° less inclined and 8° more anteverted than their target. Great variability (2 sd about ± 15°) in the post-operative radiographic cup orientation was seen. The two equally contributing causes for this are variability in the orientation at which the cup is implanted, and the change in pelvic position between impaction and post-operative radiograph. ©2014 The British Editorial Society of Bone & Joint Surgery.

Splicing-factor alterations in cancers

PubMed Central

Anczuków, Olga; Krainer, Adrian R.

2016-01-01

Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators. PMID:27530828

Directed therapies in lung cancer: new hope?

PubMed

Parente Lamelas, Isaura; Abal Arca, José; Fírvida Pérez, José Luis

2012-10-01

Lung cancer (LC) is a serious health problem due to its high incidence and mortality. Surgery is the most effective therapeutic strategy in this type of tumor, but in recent years new drugs are being investigated that target specific components of the tumor cells, improving survival in patients with advanced disease and relapse. We present a review of individualized treatments in LC, particularly therapies that inhibit epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) and anaplastic lymphoma kinase (ALK). Copyright © 2011 SEPAR. Published by Elsevier España, S.L. All rights reserved.

On-orbit point spread function estimation for THEOS imaging system

NASA Astrophysics Data System (ADS)

Khetkeeree, Suphongsa; Liangrocapart, Sompong

2018-03-01

In this paper, we present two approaches for net Point Spread Function (net-PSF) estimation of Thailand Earth Observation System (THEOS) imaging system. In the first approach, we estimate the net- PSF by employing the specification information of the satellite. The analytic model of the net- PSF based on the simple model of push-broom imaging system. This model consists of a scanner, optical system, detector and electronics system. The mathematical PSF model of each component is demonstrated in spatial domain. In the second approach, the specific target images from THEOS imaging system are analyzed to determine the net-PSF. For panchromatic imaging system, the images of the checkerboard target at Salon de Provence airport are used to analysis the net-PSF by slant-edge method. For multispectral imaging system, the new man-made targets are proposed. It is a pier bridge in Lamchabang, Chonburi, Thailand. This place has had a lot of bridges which have several width sizes and orientation. The pulse method is used to analysis the images of this bridge for estimating the net-PSF. Finally, the Full Width at Half Maximums (FWHMs) of the net-PSF of both approaches is compared. The results show that both approaches coincide and all Modulation Transfer Functions (MTFs) at Nyquist of both approaches are better than the requirement. However, the FWHM of multispectral system more deviate than panchromatic system, because the targets are not specially constructed for estimating the characteristics of the satellite imaging system.

A model system for pathogen detection using a two-component bacteriophage/bioluminescent signal amplification assay

NASA Astrophysics Data System (ADS)

Bright, Nathan G.; Carroll, Richard J.; Applegate, Bruce M.

2004-03-01

Microbial contamination has become a mounting concern the last decade due to an increased emphasis of minimally processed food products specifically produce, and the recognition of foodborne pathogens such as Campylobacter jejuni, Escherichia coli O157:H7, and Listeria monocytogenes. This research investigates a detection approach utilizing bacteriophage pathogen specificity coupled with a bacterial bioluminescent bioreporter utilizing the quorum sensing molecule from Vibrio fischeri, N-(3-oxohexanoyl)-homoserine lactone (3-oxo-C6-HSL). The 3-oxo-C6-HSL molecules diffuse out of the target cell after infection and induce bioluminescence from a population of 3-oxo-C6-HSL bioreporters (ROLux). E. coli phage M13, a well-characterized bacteriophage, offers a model system testing the use of bacteriophage for pathogen detection through cell-to-cell communication via a LuxR/3-oxo-C6-HSL system. Simulated temperate phage assays tested functionality of the ROLux reporter and production of 3-oxo-C6-HSL by various test strains. These assays showed detection limits of 102cfu after 24 hours in a varietry of detection formats. Assays incorporating the bacteriophage M13-luxI with the ROLux reporter and a known population of target cells were subsequently developed and have shown consistent detection limits of 105cfu target organisms. Measurable light response from high concentrations of target cells was almost immediate, suggesting an enrichment step to further improve detection limits and reduce assay time.

Nonspecific Organelle-Targeting Strategy with Core-Shell Nanoparticles of Varied Lipid Components/Ratios.

PubMed

Zhang, Lu; Sun, Jiashu; Wang, Yilian; Wang, Jiancheng; Shi, Xinghua; Hu, Guoqing

2016-07-19

We report a nonspecific organelle-targeting strategy through one-step microfluidic fabrication and screening of a library of surface charge- and lipid components/ratios-varied lipid shell-polymer core nanoparticles. Different from the common strategy relying on the use of organelle-targeted moieties conjugated onto the surface of nanoparticles, here, we program the distribution of hybrid nanoparticles in lysosomes or mitochondria by tuning the lipid components/ratios in shell. Hybrid nanoparticles with 60% 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 20% 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) can intracellularly target mitochondria in both in vitro and in vivo models. While replacing DOPE with the same amount of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the nanoparticles do not show mitochondrial targeting, indicating an incremental effect of cationic and fusogenic lipids on lysosomal escape which is further studied by molecular dynamics simulations. This work unveils the lipid-regulated subcellular distribution of hybrid nanoparticles in which target moieties and complex synthetic steps are avoided.

Identification of Buried Objects in GPR Using Amplitude Modulated Signals Extracted from Multiresolution Monogenic Signal Analysis

PubMed Central

Qiao, Lihong; Qin, Yao; Ren, Xiaozhen; Wang, Qifu

2015-01-01

It is necessary to detect the target reflections in ground penetrating radar (GPR) images, so that surface metal targets can be identified successfully. In order to accurately locate buried metal objects, a novel method called the Multiresolution Monogenic Signal Analysis (MMSA) system is applied in ground penetrating radar (GPR) images. This process includes four steps. First the image is decomposed by the MMSA to extract the amplitude component of the B-scan image. The amplitude component enhances the target reflection and suppresses the direct wave and reflective wave to a large extent. Then we use the region of interest extraction method to locate the genuine target reflections from spurious reflections by calculating the normalized variance of the amplitude component. To find the apexes of the targets, a Hough transform is used in the restricted area. Finally, we estimate the horizontal and vertical position of the target. In terms of buried object detection, the proposed system exhibits promising performance, as shown in the experimental results. PMID:26690146

Additive Manufacturing of Wind Turbine Molds

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

Post, Brian; Richardson, Bradley; Lloyd, Peter

The objective of this project was to explore the utility of Big Area Additive Manufacturing (BAAM) for low cost manufacturing of wind turbine molds. Engineers at Oak Ridge National Laboratory (ORNL) and TPI Composites (TPI) collaborated to design and manufacture a printed mold that can be used for resin infusion of wind turbine components. Specific focus was on required material properties (operating temperatures and pressures, coefficient of thermal expansion (CTE), thermal conductivity), surface finish (accuracy and coatings) and system integration (integrated vacuum ports, and heating element). The project began with a simple proof of principle components, targeting surface coatings andmore » material properties for printing a small section (approximately 4’ x 4’ x 2’) of a mold. Next, the second phase scaled up and integrated with the objective of capturing all of the necessary components (integrated heating to accelerate cure time, and vacuum, sealing) for resin infusion on a mold of significant size (8’ x 20’ x 6’).« less

Comparative Analysis of Argonaute-dependent Small RNA Pathways in Drosophila

PubMed Central

Zhou, Rui; Hotta, Ikuko; Denli, Ahmet M.; Hong, Pengyu; Perrimon, Norbert; Hannon, Gregory J.

2008-01-01

Summary The specificity of RNAi pathways is determined by several classes of small RNAs, which include siRNAs, piRNAs, endo-siRNAs, and microRNAs (miRNAs). These small RNAs are invariably incorporated into large Argonaute (Ago)-containing effector complexes known as RNA-induced silencing complexes (RISCs), which they guide to silencing targets. Both genetic and biochemical strategies have yielded conserved molecular components of small RNA biogenesis and effector machineries. However, given the complexity of these pathways, there are likely to be additional components and regulators that remain to be uncovered. We have undertaken a comparative and comprehensive RNAi screen to identify genes that impact three major Ago-dependent small RNA pathways that operate in Drosophila S2 cells. We identify subsets of candidates that act positively or negatively in siRNA, endo-siRNA and miRNA pathways. Our studies indicate that many components are shared among all three Argonaute-dependent silencing pathways, though each is also impacted by discrete sets of genes. PMID:19026789

Examining the Sustainability of an Evidence-Based Preschool Curriculum: The REDI Program

PubMed Central

Sanford DeRousie, Rebecca M.; Bierman, Karen L.

2011-01-01

This study examined the extent to which an evidence-based preschool curriculum (Head Start REDI) was sustained by 20 teachers during the year following a randomized controlled efficacy trial, when teachers were no longer required by the research project to implement the curriculum. Two quantitative measures of sustainability (teacher ratings, REDI coach ratings) and a qualitative measure (teacher interview) were collected and compared. Sustainability varied by the specific curriculum component, with higher rates of sustainability for the social-emotional component (Preschool PATHS) than for the language and literacy components. Estimates of sustainability were affected by the method of measurement, with REDI coach ratings and qualitative teacher interviews more closely aligned than teacher ratings. Responses from qualitative interviews identified the main factors that teachers thought affected sustainability. Teacher responses suggest that efforts to promote sustainability are best targeted at reducing barriers, such as competing demands, rather than simply highlighting the benefits of the new curriculum. PMID:22408287

A STUDY TO EVALUATE THE LEVELS OF DIOXIN-LIKE ...

EPA Pesticide Factsheets

The Environmental Protection Agency (EPA), in cooperation with USDA and the US Food and Drug Administration (FDA), has undertaken a program to study the presence of dioxin-like compounds in animal feeds. Two phases of this program have been completed, and this paper reports on the third phase. The first phase was a study on the mass balance of dioxins in lactating cows. The objective of that study was to quantify the role feeds play in total dairy cow exposures. The second phase of the program involved the collections and measurement of dioxins in minor feed components. Dioxins in specific targeted animal feed components of interest, including animal and plant byproducts were measured. The third phase involved sampling of total mixed dairy feeds and feed components from dairy facilities around the United States, and measuring for dioxin-like compounds. Lorber, M; Ferrario, J; Byrne, C; Greene, C; Cyrus, A. 2004. A Study to Evaluate the Levels of Dioxin-Like Compounds in Dairy Feeds in the United States. Organohalogen Compounds 66: 1958-1965. journal articles