Effects of Pre-Existing Target Structure on the Formation of Large Craters

NASA Technical Reports Server (NTRS)

Barnouin-Jha, O. S.; Cintala, M. J.; Crawford, D. A.

2003-01-01

The shapes of large-scale craters and the mechanics responsible for melt generation are influenced by broad and small-scale structures present in a target prior to impact. For example, well-developed systems of fractures often create craters that appear square in outline, good examples being Meteor Crater, AZ and the square craters of 433 Eros. Pre-broken target material also affects melt generation. Kieffer has shown how the shock wave generated in Coconino sandstone at Meteor crater created reverberations which, in combination with the natural target heterogeneity present, created peaks and troughs in pressure and compressed density as individual grains collided to produce a range of shock mineralogies and melts within neighboring samples. In this study, we further explore how pre-existing target structure influences various aspects of the cratering process. We combine experimental and numerical techniques to explore the connection between the scales of the impact generated shock wave and the pre-existing target structure. We focus on the propagation of shock waves in coarse, granular media, emphasizing its consequences on excavation, crater growth, ejecta production, cratering efficiency, melt generation, and crater shape. As a baseline, we present a first series of results for idealized targets where the particles are all identical in size and possess the same shock impedance. We will also present a few results, whereby we increase the complexities of the target properties by varying the grain size, strength, impedance and frictional properties. In addition, we investigate the origin and implications of reverberations that are created by the presence of physical and chemical heterogeneity in a target.

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

PubMed

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

2013-11-01

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

Why Agricultural Educators Remain in the Classroom

ERIC Educational Resources Information Center

Crutchfield, Nina; Ritz, Rudy; Burris, Scott

2013-01-01

The purpose of this study was to identify and describe factors that are related to agricultural educator career retention and to explore the relationships between work engagement, work-life balance, occupational commitment, and personal and career factors as related to the decision to remain in the teaching profession. The target population for…

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting.

PubMed

Zhu, Charles; Sempkowski, Michelle; Holleran, Timothy; Linz, Thomas; Bertalan, Thomas; Josefsson, Anders; Bruchertseifer, Frank; Morgenstern, Alfred; Sofou, Stavroula

2017-06-01

Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with α-particle emitters. This is mostly due to the α-particles' relatively short range (≤100 μm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of α-particles against solid tumors, we designed non-targeted, non-internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly-diffusive forms of the encapsulated α-particle generator Actinium-225 ( 225 Ac) resulting in more homogeneous distributions of the α-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400 μm-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing 225 Ac-loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of α-particle emitters, independent of cell-targeting. Copyright © 2017 Elsevier Ltd. All rights reserved.

Captured metagenomics: large-scale targeting of genes based on ‘sequence capture’ reveals functional diversity in soils

PubMed Central

Manoharan, Lokeshwaran; Kushwaha, Sandeep K.; Hedlund, Katarina; Ahrén, Dag

2015-01-01

Microbial enzyme diversity is a key to understand many ecosystem processes. Whole metagenome sequencing (WMG) obtains information on functional genes, but it is costly and inefficient due to large amount of sequencing that is required. In this study, we have applied a captured metagenomics technique for functional genes in soil microorganisms, as an alternative to WMG. Large-scale targeting of functional genes, coding for enzymes related to organic matter degradation, was applied to two agricultural soil communities through captured metagenomics. Captured metagenomics uses custom-designed, hybridization-based oligonucleotide probes that enrich functional genes of interest in metagenomic libraries where only probe-bound DNA fragments are sequenced. The captured metagenomes were highly enriched with targeted genes while maintaining their target diversity and their taxonomic distribution correlated well with the traditional ribosomal sequencing. The captured metagenomes were highly enriched with genes related to organic matter degradation; at least five times more than similar, publicly available soil WMG projects. This target enrichment technique also preserves the functional representation of the soils, thereby facilitating comparative metagenomics projects. Here, we present the first study that applies the captured metagenomics approach in large scale, and this novel method allows deep investigations of central ecosystem processes by studying functional gene abundances. PMID:26490729

Large-scale 3D simulations of ICF and HEDP targets

NASA Astrophysics Data System (ADS)

Marinak, Michael M.

2000-10-01

The radiation hydrodynamics code HYDRA continues to be developed and applied to 3D simulations of a variety of targets for both inertial confinement fusion (ICF) and high energy density physics. Several packages have been added enabling this code to perform ICF target simulations with similar accuracy as two-dimensional codes of long-time historical use. These include a laser ray trace and deposition package, a heavy ion deposition package, implicit Monte Carlo photonics, and non-LTE opacities, derived from XSN or the linearized response matrix approach.(R. More, T. Kato, Phys. Rev. Lett. 81, 814 (1998), S. Libby, F. Graziani, R. More, T. Kato, Proceedings of the 13th International Conference on Laser Interactions and Related Plasma Phenomena, (AIP, New York, 1997).) LTE opacities can also be calculated for arbitrary mixtures online by combining tabular values generated by different opacity codes. Thermonuclear burn, charged particle transport, neutron energy deposition, electron-ion coupling and conduction, and multigroup radiation diffusion packages are also installed. HYDRA can employ ALE hydrodynamics; a number of grid motion algorithms are available. Multi-material flows are resolved using material interface reconstruction. Results from large-scale simulations run on up to 1680 processors, using a combination of massively parallel processing and symmetric multiprocessing, will be described. A large solid angle simulation of Rayleigh-Taylor instability growth in a NIF ignition capsule has resolved simultaneously the full spectrum of the most dangerous modes that grow from surface roughness. Simulations of a NIF hohlraum illuminated with the initial 96 beam configuration have also been performed. The effect of the hohlraum’s 3D intrinsic drive asymmetry on the capsule implosion will be considered. We will also discuss results from a Nova experiment in which a copper sphere is crushed by a planar shock. Several interacting hydrodynamic instabilities, including

Formulation design for target delivery of iron nanoparticles to TCE zones.

PubMed

Wang, Ziheng; Acosta, Edgar

2013-12-01

Nanoparticles of zero-valent iron (NZVI) are effective reducing agents for some dense non-aqueous phase liquid (DNAPL) contaminants such as trichloroethylene (TCE). However, target delivery of iron nanoparticles to DNAPL zones in the aquifer remains an elusive feature for NZVI technologies. This work discusses three strategies to deliver iron nanoparticles to DNAPL zones. To this end, iron oxide nanoparticles coated with oleate (OL) ions were used as stable analogs for NZVI. The OL-coated iron oxide nanoparticles are rendered lipophilic via (a) the addition of CaCl2, (b) acidification, or (c) the addition of a cationic surfactant, benzethonium chloride (BC). Mixtures of OL and BC show promise as a target delivery strategy due to the high stability of the nanoparticles in water, and their preferential partition into TCE in batch experiments. Column tests show that while the OL-BC coated iron oxide nanoparticles remain largely mobile in TCE-free columns, a large fraction of these particles are retained in TCE-contaminated columns, confirming the effectiveness of this target delivery strategy. © 2013.

The striking similarities between standard, distractor-free, and target-free recognition

PubMed Central

Dobbins, Ian G.

2012-01-01

It is often assumed that observers seek to maximize correct responding during recognition testing by actively adjusting a decision criterion. However, early research by Wallace (Journal of Experimental Psychology: Human Learning and Memory 4:441–452, 1978) suggested that recognition rates for studied items remained similar, regardless of whether or not the tests contained distractor items. We extended these findings across three experiments, addressing whether detection rates or observer confidence changed when participants were presented standard tests (targets and distractors) versus “pure-list” tests (lists composed entirely of targets or distractors). Even when observers were made aware of the composition of the pure-list test, the endorsement rates and confidence patterns remained largely similar to those observed during standard testing, suggesting that observers are typically not striving to maximize the likelihood of success across the test. We discuss the implications for decision models that assume a likelihood ratio versus a strength decision axis, as well as the implications for prior findings demonstrating large criterion shifts using target probability manipulations. PMID:21476108

Targeting Stable Rotors to Treat Atrial Fibrillation.

PubMed

Narayan, Sanjiv M; Krummen, David E

2012-09-01

Therapy for atrial fibrillation (AF) remains suboptimal, in large part because its mechanisms are unclear. While pulmonary vein ectopy may trigger AF, it remains uncertain how AF, once triggered, is actually sustained. Recent discoveries show that human AF is maintained by a small number of rotors or focal sources. AF sources are widely distributed in patient-specific locations, often remote from pulmonary veins and in the right atrium and stable for prolonged periods of time. In a multicentre experience, brief targeted ablation at sources (focal impulse and rotor modulation [FIRM]) terminated AF predominantly to sinus rhythm prior to pulmonary vein isolation and eliminated AF on rigorous followup. This review summarises the evidence for stable rotors and focal sources of human AF and their clinical role as ablation targets to eliminate paroxysmal, persistent and long-standing persistent AF.

Large protein as a potential target for use in rabies diagnostics.

PubMed

Santos Katz, I S; Dias, M H; Lima, I F; Chaves, L B; Ribeiro, O G; Scheffer, K C; Iwai, L K

Rabies is a zoonotic viral disease that remains a serious threat to public health worldwide. The rabies lyssavirus (RABV) genome encodes five structural proteins, multifunctional and significant for pathogenicity. The large protein (L) presents well-conserved genomic regions, which may be a good alternative to generate informative datasets for development of new methods for rabies diagnosis. This paper describes the development of a technique for the identification of L protein in several RABV strains from different hosts, demonstrating that MS-based proteomics is a potential method for antigen identification and a good alternative for rabies diagnosis.

Guidelines for the recognition of cemetery remains in Greece.

PubMed

Eliopoulos, Constantine; Moraitis, Konstantinos; Reyes, Federico; Spiliopoulou, Chara; Manolis, Sotiris

2011-06-01

Forensic pathologists frequently consult anthropologists for the identification of skeletonized human remains. These remains may be the result of criminal activity or remains that were unearthed because of erosion, or during construction projects. In some cases, human remains that had been previously buried in a cemetery may be the subject of a forensic investigation. Early recognition of cemetery remains prevents unnecessary efforts and conserves precious resources. One of the key characteristics of cemetery remains is the presence of embalmed tissue. However, there are countries where embalming is not a common practice, and other clues must be sought for identifying previously buried remains. Current funerary customs in Greece and, in particular, the tradition of exhumations result in a large number of misplaced human remains. The present study presents examples of cemetery remains from Greece and offers guidelines for recognizing changes on skeletal remains that may be indicative of a cemetery origin. Location of discovery, condition of the remains, and the types of associated artifacts are all factors that aid forensic anthropologists in identifying cemetery remains.

Large-Angle Scattering of Multi-GeV Muons on Thin Lead Targets

NASA Astrophysics Data System (ADS)

Longhin, A.; Paoloni, A.; Pupilli, F.

2015-10-01

The probability of large-angle scattering for multi-GeV muons in lead targets with a thickness of O(10 - 1) radiation lengths is studied. The new estimates presented here are based both on simulation programs (GEANT4 libraries) and theoretical calculations. In order to validate the results provided by simulation, a comparison is drawn with experimental data from the literature. This study is particularly relevant when applied to muons originating from νμ CC interactions of CNGS beam neutrinos. In that circumstance the process under study represents the dominant background for the νμ → ντ search in the τ→ μ channel for the OPERA experiment at LNGS. Finally we also investigate, in the CNGS context, possible contributions from the muon photo-nuclear process which might in principle also produce a large-angle muon scattering signature in the detector.

Large area thermal target board: An improvement to environmental effects and system parameters characterization

NASA Astrophysics Data System (ADS)

Watkins, Wendell R.; Bean, Brent L.; Munding, Peter D.

1994-06-01

Recent field tests have provided excellent opportunities to use a new characterization tool associated with the Mobile Imaging Spectroscopy Laboratory (MISL) of the Battlefield Environment Directorate, formerly the U.S. Army Atmospheric Sciences Laboratory. The MISL large area (1.8 by 1.8 m, uniform temperature, thermal target) was used for characterization and isolation of phenomena which impact target contrast. By viewing the target board from closeup and distant ranges simultaneously with the MISL thermal imagers, the inherent scene content could be calibrated and the degrading effects of atmospheric propagation could be isolated. The target board is equipped with several spatial frequency bar patterns, but only the largest 3.5-cycle full area bar pattern was used for the distant range of 1.6 km. The quantities measured with the target board include the inherent background change, the contrast transmission, and the atmospheric modulation transfer function. The MISL target board has a unique design which makes it lightweight with near perfect transition between the hot and cold portions of the bar pattern. The heated portion of the target is an elongated rectangular even which is tilted back at a 30 deg angle to form a 1.8 by 1.8 m square when viewed from the front. The cold bars we positioned in front of the heated oven surface and can be oriented in either the vertical or horizontal direction. The oven is mounted on a lightweight trailer for one- or two-man positioning. An attached metal and canvas structure is used to shield the entire target from both solar loading and cooling winds. The target board has a thin aluminum sheet front surface which is insulated from the oven's heating structure.

Laser backscattered from partially convex targets of large sizes in random media for E-wave polarization.

PubMed

El-Ocla, Hosam

2006-08-01

The characteristics of a radar cross section (RCS) of partially convex targets with large sizes up to five wavelengths in free space and random media are studied. The nature of the incident wave is an important factor in remote sensing and radar detection applications. I investigate the effects of beam wave incidence on the performance of RCS, drawing on the method I used in a previous study on plane-wave incidence. A beam wave can be considered a plane wave if the target size is smaller than the beam width. Therefore, to have a beam wave with a limited spot on the target, the target size should be larger than the beam width (assuming E-wave incidence wave polarization. The effects of the target configuration, random medium parameters, and the beam width on the laser RCS and the enhancement in the radar cross section are numerically analyzed, resulting in the possibility of having some sort of control over radar detection using beam wave incidence.

Large-angle production of charged pions with incident pion beams on nuclear targets

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

Apollonio, M.; Chimenti, P.; Giannini, G.

2009-12-15

Measurements of the double-differential {pi}{sup {+-}} production cross section in the range of momentum 100{<=}p{<=}800 MeV/c and angle 0.35{<=}{theta}{<=}2.15 rad using {pi}{sup {+-}} beams incident on beryllium, aluminum, carbon, copper, tin, tantalum, and lead targets are presented. The data were taken with the large-acceptance hadron production (HARP) detector in the T9 beam line of the CERN Proton Synchrotron. The secondary pions were produced by beams in a momentum range from 3 to 12.9GeV/c hitting a solid target with a thickness of 5% of a nuclear interaction length. The tracking and identification of the produced particles was performed using a small-radiusmore » cylindrical time projection chamber placed inside a solenoidal magnet. Incident particles were identified by an elaborate system of beam detectors. Results are obtained for the double-differential cross sections d{sup 2}{sigma}/dp d{theta} at six incident-beam momenta. Data at 3,5,8, and 12GeV/c are available for all targets, while additional data at 8.9 and 12.9GeV/c were taken in positive particle beams on Be and Al targets, respectively. The measurements are compared with several generators of GEANT4 and the MARS Monte Carlo simulation.« less

High-resolution inverse synthetic aperture radar imaging for large rotation angle targets based on segmented processing algorithm

NASA Astrophysics Data System (ADS)

Chen, Hao; Zhang, Xinggan; Bai, Yechao; Tang, Lan

2017-01-01

In inverse synthetic aperture radar (ISAR) imaging, the migration through resolution cells (MTRCs) will occur when the rotation angle of the moving target is large, thereby degrading image resolution. To solve this problem, an ISAR imaging method based on segmented preprocessing is proposed. In this method, the echoes of large rotating target are divided into several small segments, and every segment can generate a low-resolution image without MTRCs. Then, each low-resolution image is rotated back to the original position. After image registration and phase compensation, a high-resolution image can be obtained. Simulation and real experiments show that the proposed algorithm can deal with the radar system with different range and cross-range resolutions and significantly compensate the MTRCs.

Temozolomide nanoparticles for targeted glioblastoma therapy.

PubMed

Fang, Chen; Wang, Kui; Stephen, Zachary R; Mu, Qingxin; Kievit, Forrest M; Chiu, Daniel T; Press, Oliver W; Zhang, Miqin

2015-04-01

Glioblastoma (GBM) is a deadly and debilitating brain tumor with an abysmal prognosis. The standard therapy for GBM is surgery followed by radiation and chemotherapy with Temozolomide (TMZ). Treatment of GBMs remains a challenge, largely because of the fast degradation of TMZ, the inability to deliver an effective dose of TMZ to tumors, and a lack of target specificity that may cause systemic toxicity. Here, we present a simple method for synthesizing a nanoparticle-based carrier that can protect TMZ from rapid degradation in physiological solutions and can specifically deliver them to GBM cells through the mediation of a tumor-targeting peptide chlorotoxin (CTX). Our nanoparticle, namely NP-TMZ-CTX, had a hydrodynamic size of <100 nm, exhibited sustained stability in cell culture media for up to 2 weeks, and could accommodate stable drug loading. TMZ bound to nanoparticles showed a much higher stability at physiological pH, with a half-life 7-fold greater than that of free TMZ. NP-TMZ-CTX was able to target GBM cells and achieved 2-6-fold higher uptake and a 50-90% reduction of IC50 72 h post-treatment as compared to nontargeted NP-TMZ. NP-TMZ-CTX showed great promise in its ability to deliver a large therapeutic dose of TMZ to GBM cells and could serve as a template for targeted delivery of other therapeutics.

Development and Evaluation of a Parallel Reaction Monitoring Strategy for Large-Scale Targeted Metabolomics Quantification.

PubMed

Zhou, Juntuo; Liu, Huiying; Liu, Yang; Liu, Jia; Zhao, Xuyang; Yin, Yuxin

2016-04-19

Recent advances in mass spectrometers which have yielded higher resolution and faster scanning speeds have expanded their application in metabolomics of diverse diseases. Using a quadrupole-Orbitrap LC-MS system, we developed an efficient large-scale quantitative method targeting 237 metabolites involved in various metabolic pathways using scheduled, parallel reaction monitoring (PRM). We assessed the dynamic range, linearity, reproducibility, and system suitability of the PRM assay by measuring concentration curves, biological samples, and clinical serum samples. The quantification performances of PRM and MS1-based assays in Q-Exactive were compared, and the MRM assay in QTRAP 6500 was also compared. The PRM assay monitoring 237 polar metabolites showed greater reproducibility and quantitative accuracy than MS1-based quantification and also showed greater flexibility in postacquisition assay refinement than the MRM assay in QTRAP 6500. We present a workflow for convenient PRM data processing using Skyline software which is free of charge. In this study we have established a reliable PRM methodology on a quadrupole-Orbitrap platform for evaluation of large-scale targeted metabolomics, which provides a new choice for basic and clinical metabolomics study.

Integrated DNA/RNA targeted genomic profiling of diffuse large B-cell lymphoma using a clinical assay.

PubMed

Intlekofer, Andrew M; Joffe, Erel; Batlevi, Connie L; Hilden, Patrick; He, Jie; Seshan, Venkatraman E; Zelenetz, Andrew D; Palomba, M Lia; Moskowitz, Craig H; Portlock, Carol; Straus, David J; Noy, Ariela; Horwitz, Steven M; Gerecitano, John F; Moskowitz, Alison; Hamlin, Paul; Matasar, Matthew J; Kumar, Anita; van den Brink, Marcel R; Knapp, Kristina M; Pichardo, Janine D; Nahas, Michelle K; Trabucco, Sally E; Mughal, Tariq; Copeland, Amanda R; Papaemmanuil, Elli; Moarii, Mathai; Levine, Ross L; Dogan, Ahmet; Miller, Vincent A; Younes, Anas

2018-06-12

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target.

High-efficiency targeted editing of large viral genomes by RNA-guided nucleases.

PubMed

Bi, Yanwei; Sun, Le; Gao, Dandan; Ding, Chen; Li, Zhihua; Li, Yadong; Cun, Wei; Li, Qihan

2014-05-01

A facile and efficient method for the precise editing of large viral genomes is required for the selection of attenuated vaccine strains and the construction of gene therapy vectors. The type II prokaryotic CRISPR-Cas (clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)) RNA-guided nuclease system can be introduced into host cells during viral replication. The CRISPR-Cas9 system robustly stimulates targeted double-stranded breaks in the genomes of DNA viruses, where the non-homologous end joining (NHEJ) and homology-directed repair (HDR) pathways can be exploited to introduce site-specific indels or insert heterologous genes with high frequency. Furthermore, CRISPR-Cas9 can specifically inhibit the replication of the original virus, thereby significantly increasing the abundance of the recombinant virus among progeny virus. As a result, purified recombinant virus can be obtained with only a single round of selection. In this study, we used recombinant adenovirus and type I herpes simplex virus as examples to demonstrate that the CRISPR-Cas9 system is a valuable tool for editing the genomes of large DNA viruses.

High-Efficiency Targeted Editing of Large Viral Genomes by RNA-Guided Nucleases

PubMed Central

Gao, Dandan; Ding, Chen; Li, Zhihua; Li, Yadong; Cun, Wei; Li, Qihan

2014-01-01

A facile and efficient method for the precise editing of large viral genomes is required for the selection of attenuated vaccine strains and the construction of gene therapy vectors. The type II prokaryotic CRISPR-Cas (clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)) RNA-guided nuclease system can be introduced into host cells during viral replication. The CRISPR-Cas9 system robustly stimulates targeted double-stranded breaks in the genomes of DNA viruses, where the non-homologous end joining (NHEJ) and homology-directed repair (HDR) pathways can be exploited to introduce site-specific indels or insert heterologous genes with high frequency. Furthermore, CRISPR-Cas9 can specifically inhibit the replication of the original virus, thereby significantly increasing the abundance of the recombinant virus among progeny virus. As a result, purified recombinant virus can be obtained with only a single round of selection. In this study, we used recombinant adenovirus and type I herpes simplex virus as examples to demonstrate that the CRISPR-Cas9 system is a valuable tool for editing the genomes of large DNA viruses. PMID:24788700

Impact of target mRNA structure on siRNA silencing efficiency: A large-scale study.

PubMed

Gredell, Joseph A; Berger, Angela K; Walton, S Patrick

2008-07-01

The selection of active siRNAs is generally based on identifying siRNAs with certain sequence and structural properties. However, the efficiency of RNA interference has also been shown to depend on the structure of the target mRNA, primarily through studies using exogenous transcripts with well-defined secondary structures in the vicinity of the target sequence. While these studies provide a means for examining the impact of target sequence and structure independently, the predicted secondary structures for these transcripts are often not reflective of structures that form in full-length, native mRNAs where interactions can occur between relatively remote segments of the mRNAs. Here, using a combination of experimental results and analysis of a large dataset, we demonstrate that the accessibility of certain local target structures on the mRNA is an important determinant in the gene silencing ability of siRNAs. siRNAs targeting the enhanced green fluorescent protein were chosen using a minimal siRNA selection algorithm followed by classification based on the predicted minimum free energy structures of the target transcripts. Transfection into HeLa and HepG2 cells revealed that siRNAs targeting regions of the mRNA predicted to have unpaired 5'- and 3'-ends resulted in greater gene silencing than regions predicted to have other types of secondary structure. These results were confirmed by analysis of gene silencing data from previously published siRNAs, which showed that mRNA target regions unpaired at either the 5'-end or 3'-end were silenced, on average, approximately 10% more strongly than target regions unpaired in the center or primarily paired throughout. We found this effect to be independent of the structure of the siRNA guide strand. Taken together, these results suggest minimal requirements for nucleation of hybridization between the siRNA guide strand and mRNA and that both mRNA and guide strand structure should be considered when choosing candidate si

Impact of target mRNA structure on siRNA silencing efficiency: a large-scale study

PubMed Central

Gredell, Joseph A.; Berger, Angela K.; Walton, S. Patrick

2009-01-01

The selection of active siRNAs is generally based on identifying siRNAs with certain sequence and structural properties. However, the efficiency of RNA interference has also been shown to depend on the structure of the target mRNA, primarily through studies using exogenous transcripts with well-defined secondary structures in the vicinity of the target sequence. While these studies provide a means for examining the impact of target sequence and structure independently, the predicted secondary structures for these transcripts are often not reflective of structures that form in full-length, native mRNAs where interactions can occur between relatively remote segments of the mRNAs. Here, using a combination of experimental results and analysis of a large dataset, we demonstrate that the accessibility of certain local target structures on the mRNA is an important determinant in the gene silencing ability of siRNAs. siRNAs targeting the enhanced green fluorescent protein were chosen using a minimal siRNA selection algorithm followed by classification based on the predicted minimum free energy structures of the target transcripts. Transfection into HeLa and HepG2 cells revealed that siRNAs targeting regions of the mRNA predicted to have unpaired 5’- and 3’-ends resulted in greater gene silencing than regions predicted to have other types of secondary structure. These results were confirmed by analysis of gene silencing data from previously published siRNAs, which showed that mRNA target regions unpaired at either the 5’-end or 3’-end were silenced, on average, ~10% more strongly than target regions unpaired in the center or primarily paired throughout. We found this effect to be independent of the structure of the siRNA guide strand. Taken together, these results suggest minimal requirements for nucleation of hybridization between the siRNA guide strand and mRNA and that both mRNA and guide strand structure should be considered when choosing candidate siRNAs. PMID

Automated selected reaction monitoring data analysis workflow for large-scale targeted proteomic studies.

PubMed

Surinova, Silvia; Hüttenhain, Ruth; Chang, Ching-Yun; Espona, Lucia; Vitek, Olga; Aebersold, Ruedi

2013-08-01

Targeted proteomics based on selected reaction monitoring (SRM) mass spectrometry is commonly used for accurate and reproducible quantification of protein analytes in complex biological mixtures. Strictly hypothesis-driven, SRM assays quantify each targeted protein by collecting measurements on its peptide fragment ions, called transitions. To achieve sensitive and accurate quantitative results, experimental design and data analysis must consistently account for the variability of the quantified transitions. This consistency is especially important in large experiments, which increasingly require profiling up to hundreds of proteins over hundreds of samples. Here we describe a robust and automated workflow for the analysis of large quantitative SRM data sets that integrates data processing, statistical protein identification and quantification, and dissemination of the results. The integrated workflow combines three software tools: mProphet for peptide identification via probabilistic scoring; SRMstats for protein significance analysis with linear mixed-effect models; and PASSEL, a public repository for storage, retrieval and query of SRM data. The input requirements for the protocol are files with SRM traces in mzXML format, and a file with a list of transitions in a text tab-separated format. The protocol is especially suited for data with heavy isotope-labeled peptide internal standards. We demonstrate the protocol on a clinical data set in which the abundances of 35 biomarker candidates were profiled in 83 blood plasma samples of subjects with ovarian cancer or benign ovarian tumors. The time frame to realize the protocol is 1-2 weeks, depending on the number of replicates used in the experiment.

Recent advances quantifying the large wood dynamics in river basins: New methods and remaining challenges

NASA Astrophysics Data System (ADS)

Ruiz-Villanueva, Virginia; Piégay, Hervé; Gurnell, Angela A.; Marston, Richard A.; Stoffel, Markus

2016-09-01

Large wood is an important physical component of woodland rivers and significantly influences river morphology. It is also a key component of stream ecosystems. However, large wood is also a source of risk for human activities as it may damage infrastructure, block river channels, and induce flooding. Therefore, the analysis and quantification of large wood and its mobility are crucial for understanding and managing wood in rivers. As the amount of large-wood-related studies by researchers, river managers, and stakeholders increases, documentation of commonly used and newly available techniques and their effectiveness has also become increasingly relevant as well. Important data and knowledge have been obtained from the application of very different approaches and have generated a significant body of valuable information representative of different environments. This review brings a comprehensive qualitative and quantitative summary of recent advances regarding the different processes involved in large wood dynamics in fluvial systems including wood budgeting and wood mechanics. First, some key definitions and concepts are introduced. Second, advances in quantifying large wood dynamics are reviewed; in particular, how measurements and modeling can be combined to integrate our understanding of how large wood moves through and is retained within river systems. Throughout, we present a quantitative and integrated meta-analysis compiled from different studies and geographical regions. Finally, we conclude by highlighting areas of particular research importance and their likely future trajectories, and we consider a particularly underresearched area so as to stress the future challenges for large wood research.

Joint Stability in Total Knee Arthroplasty: What Is the Target for a Stable Knee?

PubMed

Wright, Timothy M

2017-02-01

Instability remains a common cause of failure in total knee arthroplasty. Although approaches for surgical treatment of instability exist, the target for initial stability remains elusive, increasing the likelihood that failures will persist because adequate stability is not restored when performing the primary arthroplasty. Although the mechanisms that stabilize the knee joint-contact between the articular surfaces, ligamentous constraints, and muscle forces-are well-defined, their relative importance and the interplay among them throughout functions of daily living are poorly understood. The problem is exacerbated by the complex multiplanar motions that occur across the joint and the large variations in these motions across the population, suggesting that stability targets may need to be patient-specific.

Large Dog Relinquishment to Two Municipal Facilities in New York City and Washington, D.C.: Identifying Targets for Intervention

PubMed Central

Weiss, Emily; Slater, Margaret; Garrison, Laurie; Drain, Natasha; Dolan, Emily; Scarlett, Janet M.; Zawistowski, Stephen L.

2014-01-01

Simple Summary While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other-sized dogs in most animal shelters in the United States. We hypothesized that one way to increase the lives saved with regard to large dogs in shelters is to keep them home in the first place when possible. Our research is the first to collect data in New York City and Washington, D.C., identifying the process leading to the owner relinquishment of large dogs. We found that targets for interventions to decrease large dog relinquishment are likely different in each community. Abstract While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other sized dogs in most animal shelters in the United States. We hypothesized one way to increase the lives saved with respect to these large dogs is to keep them home when possible. In order to develop solutions to decrease relinquishment, a survey was developed to learn more about the reasons owners relinquish large dogs. The survey was administered to owners relinquishing their dogs at two large municipal facilities, one in New York City and one in Washington, D.C. There were 157 responses between the two facilities. We found both significant similarities and differences between respondents and their dogs from the two cities. We identified opportunities to potentially support future relinquishers and found that targets for interventions are likely different in each community. PMID:26480315

Advances in large, transportable, highly spin-polarized, solid HD targets operable in the frozen-spin mode in a 1-4K temperature environment

NASA Astrophysics Data System (ADS)

Lewis, Aaron Paul

The development of large, portable highly spin-polarized solid HD targets has been in progress at Syracuse University for the past 5 years. These targets are scheduled for deployment at Brookhaven National Laboratory, bearing the acronym SPHICE (Spin-Polarized Hydrogen Ice), for studies of the electro-magnetic spin structure of the nucleus via scattering of polarized gammas from the HD polarized protons and deuterons. The target work has just reached the milestone demonstration of the complete system, including polarization of triple targets containing 4 moles of solid HD, aging of these targets so that they retain their polarization for months under storage at a temperature of 1.3K and in an 8 Tesla field, and for at least a week at operational conditions of 1.3K and 0.7 Tesla in an in-beam cryostat. Cold-transfers of the polarized targets to a storage cryostat have been successfully carried out, and the storage cryostat has been trucked from Syracuse to BNL with one polarized target, sufficient to test the in-beam operations there. The complete system is presented here, with emphasis on innovations for engagement and disengagement of multiple targets, a solution to the challenge of attaining sufficiently strong RF fields in the large volume probe coils at acceptable power dissipation in the cables, and the polarization production and monitoring in the highly inhomogeneous magnetic fields owing to the multiple targets and the large dimensions of the targets. In this first multiple target production and extraction-to-storage cycle, air-ice accumulation in the dilution refrigerator due to repetitive use of cold sliding o-ring seals resulted in a rupture of one of the inserted targets, and a consequent partial thermal short from a solid HD ice bridge. The o-ring fault was cured with double evacuatable o-ring seals, and the air-ice was successfully cleaned out. However, the refrigerator operating base temperature was substantially higher than that normally obtained

Speed-up of the volumetric method of moments for the approximate RCS of large arbitrary-shaped dielectric targets

NASA Astrophysics Data System (ADS)

Moreno, Javier; Somolinos, Álvaro; Romero, Gustavo; González, Iván; Cátedra, Felipe

2017-08-01

A method for the rigorous computation of the electromagnetic scattering of large dielectric volumes is presented. One goal is to simplify the analysis of large dielectric targets with translational symmetries taken advantage of their Toeplitz symmetry. Then, the matrix-fill stage of the Method of Moments is efficiently obtained because the number of coupling terms to compute is reduced. The Multilevel Fast Multipole Method is applied to solve the problem. Structured meshes are obtained efficiently to approximate the dielectric volumes. The regular mesh grid is achieved by using parallelepipeds whose centres have been identified as internal to the target. The ray casting algorithm is used to classify the parallelepiped centres. It may become a bottleneck when too many points are evaluated in volumes defined by parametric surfaces, so a hierarchical algorithm is proposed to minimize the number of evaluations. Measurements and analytical results are included for validation purposes.

Multimodal Hierarchical Imaging of Serial Sections for Finding Specific Cellular Targets within Large Volumes

PubMed Central

Wacker, Irene U.; Veith, Lisa; Spomer, Waldemar; Hofmann, Andreas; Thaler, Marlene; Hillmer, Stefan; Gengenbach, Ulrich; Schröder, Rasmus R.

2018-01-01

Targeting specific cells at ultrastructural resolution within a mixed cell population or a tissue can be achieved by hierarchical imaging using a combination of light and electron microscopy. Samples embedded in resin are sectioned into arrays consisting of ribbons of hundreds of ultrathin sections and deposited on pieces of silicon wafer or conductively coated coverslips. Arrays are imaged at low resolution using a digital consumer like smartphone camera or light microscope (LM) for a rapid large area overview, or a wide field fluorescence microscope (fluorescence light microscopy (FLM)) after labeling with fluorophores. After post-staining with heavy metals, arrays are imaged in a scanning electron microscope (SEM). Selection of targets is possible from 3D reconstructions generated by FLM or from 3D reconstructions made from the SEM image stacks at intermediate resolution if no fluorescent markers are available. For ultrastructural analysis, selected targets are finally recorded in the SEM at high-resolution (a few nanometer image pixels). A ribbon-handling tool that can be retrofitted to any ultramicrotome is demonstrated. It helps with array production and substrate removal from the sectioning knife boat. A software platform that allows automated imaging of arrays in the SEM is discussed. Compared to other methods generating large volume EM data, such as serial block-face SEM (SBF-SEM) or focused ion beam SEM (FIB-SEM), this approach has two major advantages: (1) The resin-embedded sample is conserved, albeit in a sliced-up version. It can be stained in different ways and imaged with different resolutions. (2) As the sections can be post-stained, it is not necessary to use samples strongly block-stained with heavy metals to introduce contrast for SEM imaging or render the tissue blocks conductive. This makes the method applicable to a wide variety of materials and biological questions. Particularly prefixed materials e.g., from biopsy banks and pathology labs

Generalizing Evidence From Randomized Clinical Trials to Target Populations

PubMed Central

Cole, Stephen R.; Stuart, Elizabeth A.

2010-01-01

Properly planned and conducted randomized clinical trials remain susceptible to a lack of external validity. The authors illustrate a model-based method to standardize observed trial results to a specified target population using a seminal human immunodeficiency virus (HIV) treatment trial, and they provide Monte Carlo simulation evidence supporting the method. The example trial enrolled 1,156 HIV-infected adult men and women in the United States in 1996, randomly assigned 577 to a highly active antiretroviral therapy and 579 to a largely ineffective combination therapy, and followed participants for 52 weeks. The target population was US people infected with HIV in 2006, as estimated by the Centers for Disease Control and Prevention. Results from the trial apply, albeit muted by 12%, to the target population, under the assumption that the authors have measured and correctly modeled the determinants of selection that reflect heterogeneity in the treatment effect. In simulations with a heterogeneous treatment effect, a conventional intent-to-treat estimate was biased with poor confidence limit coverage, but the proposed estimate was largely unbiased with appropriate confidence limit coverage. The proposed method standardizes observed trial results to a specified target population and thereby provides information regarding the generalizability of trial results. PMID:20547574

Targeting dendritic cells--why bother?

PubMed

Kreutz, Martin; Tacken, Paul J; Figdor, Carl G

2013-04-11

Vaccination is among the most efficient forms of immunotherapy. Although sometimes inducing lifelong protective B-cell responses, T-cell-mediated immunity remains challenging. Targeting antigen to dendritic cells (DCs) is an extensively explored concept aimed at improving cellular immunity. The identification of various DC subsets with distinct functional characteristics now allows for the fine-tuning of targeting strategies. Although some of these DC subsets are regarded as superior for (cross-) priming of naive T cells, controversies still remain about which subset represents the best target for immunotherapy. Because targeting the antigen alone may not be sufficient to obtain effective T-cell responses, delivery systems have been developed to target multiple vaccine components to DCs. In this Perspective, we discuss the pros and cons of targeting DCs: if targeting is beneficial at all and which vaccine vehicles and immunization routes represent promising strategies to reach and activate DCs.

Large-Scale Off-Target Identification Using Fast and Accurate Dual Regularized One-Class Collaborative Filtering and Its Application to Drug Repurposing.

PubMed

Lim, Hansaim; Poleksic, Aleksandar; Yao, Yuan; Tong, Hanghang; He, Di; Zhuang, Luke; Meng, Patrick; Xie, Lei

2016-10-01

Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting their capability for large-scale off-target identification. In addition, the performances of most machine learning based algorithms have been mainly evaluated to predict off-target interactions in the same gene family for hundreds of chemicals. It is not clear how these algorithms perform in terms of detecting off-targets across gene families on a proteome scale. Here, we are presenting a fast and accurate off-target prediction method, REMAP, which is based on a dual regularized one-class collaborative filtering algorithm, to explore continuous chemical space, protein space, and their interactome on a large scale. When tested in a reliable, extensive, and cross-gene family benchmark, REMAP outperforms the state-of-the-art methods. Furthermore, REMAP is highly scalable. It can screen a dataset of 200 thousands chemicals against 20 thousands proteins within 2 hours. Using the reconstructed genome-wide target profile as the fingerprint of a chemical compound, we predicted that seven FDA-approved drugs can be repurposed as novel anti-cancer therapies. The anti-cancer activity of six of them is supported by experimental evidences. Thus, REMAP is a valuable addition to the existing in silico toolbox for drug target identification, drug repurposing, phenotypic screening, and

Large-Scale Off-Target Identification Using Fast and Accurate Dual Regularized One-Class Collaborative Filtering and Its Application to Drug Repurposing

PubMed Central

Poleksic, Aleksandar; Yao, Yuan; Tong, Hanghang; Meng, Patrick; Xie, Lei

2016-01-01

Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting their capability for large-scale off-target identification. In addition, the performances of most machine learning based algorithms have been mainly evaluated to predict off-target interactions in the same gene family for hundreds of chemicals. It is not clear how these algorithms perform in terms of detecting off-targets across gene families on a proteome scale. Here, we are presenting a fast and accurate off-target prediction method, REMAP, which is based on a dual regularized one-class collaborative filtering algorithm, to explore continuous chemical space, protein space, and their interactome on a large scale. When tested in a reliable, extensive, and cross-gene family benchmark, REMAP outperforms the state-of-the-art methods. Furthermore, REMAP is highly scalable. It can screen a dataset of 200 thousands chemicals against 20 thousands proteins within 2 hours. Using the reconstructed genome-wide target profile as the fingerprint of a chemical compound, we predicted that seven FDA-approved drugs can be repurposed as novel anti-cancer therapies. The anti-cancer activity of six of them is supported by experimental evidences. Thus, REMAP is a valuable addition to the existing in silico toolbox for drug target identification, drug repurposing, phenotypic screening, and

SDSS-III Baryon Oscillation Spectroscopic Survey data release 12: Galaxy target selection and large-scale structure catalogues

DOE PAGES

Reid, Beth; Ho, Shirley; Padmanabhan, Nikhil; ...

2015-11-17

The Baryon Oscillation Spectroscopic Survey (BOSS), part of the Sloan Digital Sky Survey (SDSS) III project, has provided the largest survey of galaxy redshifts available to date, in terms of both the number of galaxy redshifts measured by a single survey, and the effective cosmological volume covered. Key to analysing the clustering of these data to provide cosmological measurements is understanding the detailed properties of this sample. Potential issues include variations in the target catalogue caused by changes either in the targeting algorithm or properties of the data used, the pattern of spectroscopic observations, the spatial distribution of targets formore » which redshifts were not obtained, and variations in the target sky density due to observational systematics. We document here the target selection algorithms used to create the galaxy samples that comprise BOSS. We also present the algorithms used to create large-scale structure catalogues for the final Data Release (DR12) samples and the associated random catalogues that quantify the survey mask. The algorithms are an evolution of those used by the BOSS team to construct catalogues from earlier data, and have been designed to accurately quantify the galaxy sample. Furthermore, the code used, designated mksample, is released with this paper.« less

Chemotherapy remains an essential element of personalized care for persons with lung cancers

PubMed Central

Hellmann, M. D.; Li, B. T.; Chaft, J. E.; Kris, M. G.

2016-01-01

Molecularly targeted and immunotherapies have improved the care of patients with lung cancers. These successes have rallied calls to replace or avoid chemotherapy. Yet, even in this era of precision medicine and exciting advances, cytotoxic chemotherapies remain an essential component of lung cancer treatment. In the setting of locoregional disease, chemotherapy is the only systemic therapy thus far proven to enhance curability when combined with surgery or radiation. In the metastatic setting, chemotherapy can improve the length and quality of life in many patients. Chemotherapy remains the mainstay of care for individuals whose cancers with oncogenic drivers have acquired resistance to targeted agents. Chemotherapy also has the potential to modulate the immune system to enhance the effectiveness of immune checkpoint inhibitors. In this context, chemotherapy should be framed as a critical component of the armamentarium available for optimizing cancer care rather than an unfortunate anachronism. We examine the role of chemotherapy with precision medicine in the current care of patients with lung cancers, as well as opportunities for future integration in combinations with targeted agents, angiogenesis inhibitors, immunotherapies, and antibody drug conjugates. PMID:27456296

Benchmark of four popular virtual screening programs: construction of the active/decoy dataset remains a major determinant of measured performance.

PubMed

Chaput, Ludovic; Martinez-Sanz, Juan; Saettel, Nicolas; Mouawad, Liliane

2016-01-01

In a structure-based virtual screening, the choice of the docking program is essential for the success of a hit identification. Benchmarks are meant to help in guiding this choice, especially when undertaken on a large variety of protein targets. Here, the performance of four popular virtual screening programs, Gold, Glide, Surflex and FlexX, is compared using the Directory of Useful Decoys-Enhanced database (DUD-E), which includes 102 targets with an average of 224 ligands per target and 50 decoys per ligand, generated to avoid biases in the benchmarking. Then, a relationship between these program performances and the properties of the targets or the small molecules was investigated. The comparison was based on two metrics, with three different parameters each. The BEDROC scores with α = 80.5, indicated that, on the overall database, Glide succeeded (score > 0.5) for 30 targets, Gold for 27, FlexX for 14 and Surflex for 11. The performance did not depend on the hydrophobicity nor the openness of the protein cavities, neither on the families to which the proteins belong. However, despite the care in the construction of the DUD-E database, the small differences that remain between the actives and the decoys likely explain the successes of Gold, Surflex and FlexX. Moreover, the similarity between the actives of a target and its crystal structure ligand seems to be at the basis of the good performance of Glide. When all targets with significant biases are removed from the benchmarking, a subset of 47 targets remains, for which Glide succeeded for only 5 targets, Gold for 4 and FlexX and Surflex for 2. The performance dramatic drop of all four programs when the biases are removed shows that we should beware of virtual screening benchmarks, because good performances may be due to wrong reasons. Therefore, benchmarking would hardly provide guidelines for virtual screening experiments, despite the tendency that is maintained, i.e., Glide and Gold display better

Molecular targeting agents in cancer therapy: science and society.

PubMed

Shaikh, Asim Jamal

2012-01-01

The inception of targeted agents has revolutionized the cancer therapy paradigm, both for physicians and patients. A large number of molecular targeted agents for cancer therapy are currently available for clinical use today. Many more are in making, but there are issues that remain to be resolved for the scientific as well as social community before the recommendation of their widespread use in may clinical scenarios can be done, one such issue being cost and cost effectiveness, others being resistance and lack of sustained efficacy. With the current knowledge about available targeted agents, the growing knowledge of intricate molecular pathways and unfolding of wider spectrum of molecular targets that can really matter in the disease control, calls for only the just use of the agents available now, drug companies need to make a serious attempt to reduce the cost of the agents. Research should focus on agents that show sustained responses in preclinical data. More needs to be done in laboratories and by the pharmaceutical industries, before we can truly claim to have entered a new era of targeted therapy in cancer care.

Bar coded retroreflective target

DOEpatents

Vann, Charles S.

2000-01-01

This small, inexpensive, non-contact laser sensor can detect the location of a retroreflective target in a relatively large volume and up to six degrees of position. The tracker's laser beam is formed into a plane of light which is swept across the space of interest. When the beam illuminates the retroreflector, some of the light returns to the tracker. The intensity, angle, and time of the return beam is measured to calculate the three dimensional location of the target. With three retroreflectors on the target, the locations of three points on the target are measured, enabling the calculation of all six degrees of target position. Until now, devices for three-dimensional tracking of objects in a large volume have been heavy, large, and very expensive. Because of the simplicity and unique characteristics of this tracker, it is capable of three-dimensional tracking of one to several objects in a large volume, yet it is compact, light-weight, and relatively inexpensive. Alternatively, a tracker produces a diverging laser beam which is directed towards a fixed position, and senses when a retroreflective target enters the fixed field of view. An optically bar coded target can be read by the tracker to provide information about the target. The target can be formed of a ball lens with a bar code on one end. As the target moves through the field, the ball lens causes the laser beam to scan across the bar code.

Targeted PET imaging strategy to differentiate malignant from inflamed lymph nodes in diffuse large B-cell lymphoma

PubMed Central

Salloum, Darin; Carney, Brandon; Brand, Christian; Kossatz, Susanne; Sadique, Ahmad; Lewis, Jason S.; Weber, Wolfgang A.; Wendel, Hans-Guido; Reiner, Thomas

2017-01-01

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. DLBCL exhibits highly aggressive and systemic progression into multiple tissues in patients, particularly in lymph nodes. Whole-body 18F-fluodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging has an essential role in diagnosing DLBCL in the clinic; however, [18F]FDG-PET often faces difficulty in differentiating malignant tissues from certain nonmalignant tissues with high glucose uptake. We have developed a PET imaging strategy for DLBCL that targets poly[ADP ribose] polymerase 1 (PARP1), the expression of which has been found to be much higher in DLBCL than in healthy tissues. In a syngeneic DLBCL mouse model, this PARP1-targeted PET imaging approach allowed us to discriminate between malignant and inflamed lymph nodes, whereas [18F]FDG-PET failed to do so. Our PARP1-targeted PET imaging approach may be an attractive addition to the current PET imaging strategy to differentiate inflammation from malignancy in DLBCL. PMID:28827325

Comparison of large-angle production of charged pions with incident protons on cylindrical long and short targets

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

Apollonio, M.; Chimenti, P.; Giannini, G.

2009-12-15

The HARP Collaboration has presented measurements of the double-differential {pi}{sup {+-}} production cross section in the range of momentum 100 MeV/c{<=}p{<=}800 MeV/c and angle 0.35 rad{<=}{theta}{<=}2.15 rad with proton beams hitting thin nuclear targets. In many applications the extrapolation to long targets is necessary. In this article the analysis of data taken with long (one interaction length) solid cylindrical targets made of carbon, tantalum, and lead is presented. The data were taken with the large-acceptance HARP detector in the T9 beam line of the CERN proton synchrotron. The secondary pions were produced by beams of protons with momenta of 5,more » 8, and 12GeV/c. The tracking and identification of the produced particles were performed using a small-radius cylindrical time projection chamber placed inside a solenoidal magnet. Incident protons were identified by an elaborate system of beam detectors. Results are obtained for the double-differential yields per target nucleon d{sup 2}{sigma}/dpd{theta}. The measurements are compared with predictions of the MARS and GEANT4 Monte Carlo simulations.« less

Integrative Analysis Reveals an Outcome-associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B-cell Lymphoma

PubMed Central

Monti, Stefano; Chapuy, Bjoern; Takeyama, Kunihiko; Rodig, Scott J; Hao, Yangsheng; Yeda, Kelly T.; Inguilizian, Haig; Mermel, Craig; Curie, Treeve; Dogan, Ahmed; Kutok, Jeffery L; Beroukim, Rameen; Neuberg, Donna; Habermann, Thomas; Getz, Gad; Kung, Andrew L; Golub, Todd R; Shipp, Margaret A

2013-01-01

Summary Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease with a high proliferation rate. By integrating copy number data with transcriptional profiles and performing pathway analysis in primary DLBCLs, we identified a comprehensive set of copy number alterations (CNAs) that decreased p53 activity and perturbed cell cycle regulation. Primary tumors either had multiple complementary alterations of p53 and cell cycle components or largely lacked these lesions. DLBCLs with p53 and cell cycle pathway CNAs had decreased abundance of p53 target transcripts and increased expression of E2F target genes and the Ki67 proliferation marker. CNAs of the CDKN2A-TP53-RB-E2F axis provide a structural basis for increased proliferation in DLBCL, predict outcome with current therapy and suggest targeted treatment approaches. PMID:22975378

A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation.

PubMed

Artemov, Artem; Aliper, Alexander; Korzinkin, Michael; Lezhnina, Ksenia; Jellen, Leslie; Zhukov, Nikolay; Roumiantsev, Sergey; Gaifullin, Nurshat; Zhavoronkov, Alex; Borisov, Nicolas; Buzdin, Anton

2015-10-06

A new generation of anticancer therapeutics called target drugs has quickly developed in the 21st century. These drugs are tailored to inhibit cancer cell growth, proliferation, and viability by specific interactions with one or a few target proteins. However, despite formally known molecular targets for every "target" drug, patient response to treatment remains largely individual and unpredictable. Choosing the most effective personalized treatment remains a major challenge in oncology and is still largely trial and error. Here we present a novel approach for predicting target drug efficacy based on the gene expression signature of the individual tumor sample(s). The enclosed bioinformatic algorithm detects activation of intracellular regulatory pathways in the tumor in comparison to the corresponding normal tissues. According to the nature of the molecular targets of a drug, it predicts whether the drug can prevent cancer growth and survival in each individual case by blocking the abnormally activated tumor-promoting pathways or by reinforcing internal tumor suppressor cascades. To validate the method, we compared the distribution of predicted drug efficacy scores for five drugs (Sorafenib, Bevacizumab, Cetuximab, Sorafenib, Imatinib, Sunitinib) and seven cancer types (Clear Cell Renal Cell Carcinoma, Colon cancer, Lung adenocarcinoma, non-Hodgkin Lymphoma, Thyroid cancer and Sarcoma) with the available clinical trials data for the respective cancer types and drugs. The percent of responders to a drug treatment correlated significantly (Pearson's correlation 0.77 p = 0.023) with the percent of tumors showing high drug scores calculated with the current algorithm.

Discovery of functional monoclonal antibodies targeting G-protein-coupled receptors and ion channels.

PubMed

Wilkinson, Trevor C I

2016-06-15

The development of recombinant antibody therapeutics is a significant area of growth in the pharmaceutical industry with almost 50 approved monoclonal antibodies on the market in the US and Europe. Despite this growth, however, certain classes of important molecular targets have remained intractable to therapeutic antibodies due to complexity of the target molecules. These complex target molecules include G-protein-coupled receptors and ion channels which represent a large potential target class for therapeutic intervention with monoclonal antibodies. Although these targets have typically been addressed by small molecule approaches, the exquisite specificity of antibodies provides a significant opportunity to provide selective modulation of these target proteins. Given this opportunity, substantial effort has been applied to address the technical challenges of targeting these complex membrane proteins with monoclonal antibodies. In this review recent progress made in the strategies for discovery of functional monoclonal antibodies for these challenging membrane protein targets is addressed. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

PubMed

Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

2012-02-01

Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority <15.4%) of the individual target inhibitors of the same target pair and 0.58-7.1% of the other 6 targets outside the target pair. COMBI-SVMs showed low dual inhibitor false hit rates (0.006-0.056%, 0.042-0.21%, 0.2-4%) in screening 17 million PubChem compounds, 168,000 MDDR compounds, and 7-8181 MDDR compounds similar to the dual inhibitors. Compared with similarity searching, k-NN and PNN methods, COMBI-SVM produced comparable dual inhibitor yields, similar target selectivity, and lower false hit rate in screening 168,000 MDDR compounds. The annotated classes of many COMBI-SVMs identified MDDR virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents. Copyright © 2011 Elsevier Inc. All rights reserved.

Advances in cancer stem cell targeting: How to strike the evil at its root.

PubMed

Pützer, Brigitte M; Solanki, Manish; Herchenröder, Ottmar

2017-10-01

Cancer progression to metastatic stages is still unmanageable and the promise of effective anti-metastatic therapy remains largely unmet, emphasizing the need to develop novel therapeutics. The special focus here is on cancer stem cells (CSC) as the seed of tumor initiation, epithelial-mesenchymal transition, chemoresistance and, as a consequence, drivers of metastatic dissemination. We report on targeted therapies gearing towards the CSC's internal and membrane-anchored markers using agents such as antibody derivatives, nucleic therapeutics, small molecules and genetic payloads. Another emphasis lies on novel proceedings envisaged to deliver current and prospective therapies to the target sites using newest viral and non-viral vector technologies. In this review, we summarize recent progress and remaining challenges in therapeutic strategies to combat CSC. Copyright © 2017 Elsevier B.V. All rights reserved.

MRMPROBS: a data assessment and metabolite identification tool for large-scale multiple reaction monitoring based widely targeted metabolomics.

PubMed

Tsugawa, Hiroshi; Arita, Masanori; Kanazawa, Mitsuhiro; Ogiwara, Atsushi; Bamba, Takeshi; Fukusaki, Eiichiro

2013-05-21

We developed a new software program, MRMPROBS, for widely targeted metabolomics by using the large-scale multiple reaction monitoring (MRM) mode. The strategy became increasingly popular for the simultaneous analysis of up to several hundred metabolites at high sensitivity, selectivity, and quantitative capability. However, the traditional method of assessing measured metabolomics data without probabilistic criteria is not only time-consuming but is often subjective and makeshift work. Our program overcomes these problems by detecting and identifying metabolites automatically, by separating isomeric metabolites, and by removing background noise using a probabilistic score defined as the odds ratio from an optimized multivariate logistic regression model. Our software program also provides a user-friendly graphical interface to curate and organize data matrices and to apply principal component analyses and statistical tests. For a demonstration, we conducted a widely targeted metabolome analysis (152 metabolites) of propagating Saccharomyces cerevisiae measured at 15 time points by gas and liquid chromatography coupled to triple quadrupole mass spectrometry. MRMPROBS is a useful and practical tool for the assessment of large-scale MRM data available to any instrument or any experimental condition.

First shock tuning and backscatter measurements for large case-to-capsule ratio beryllium targets

NASA Astrophysics Data System (ADS)

Loomis, Eric; Yi, Austin; Kline, John; Kyrala, George; Simakov, Andrei; Wilson, Doug; Ralph, Joe; Dewald, Eduard; Strozzi, David; Celliers, Peter; Millot, Marius; Tommasini, Riccardo

2016-10-01

The current under performance of target implosions on the National Ignition Facility (NIF) has necessitated scaling back from high convergence ratio to access regimes of reduced physics uncertainties. These regimes, we expect, are more predictable by existing radiation hydrodynamics codes giving us a better starting point for isolating key physics questions. One key question is the lack of predictable in-flight and hot spot shape due to a complex hohlraum radiation environment. To achieve more predictable, shape tunable implosions we have designed and fielded a large 4.2 case-to-capsule ratio (CCR) target at the NIF using 6.72 mm diameter Au hohlraums and 1.6 mm diameter Cu-doped Be capsules. Simulations show that at these dimensions during a 10 ns 3-shock laser pulse reaching 270 eV hohlraum temperatures, the interaction between hohlraum and capsule plasma, which at lower CCR lead to beam propagation impedance by artificial plasma stagnation, are reduced. In this talk we will present measurements of early time drive symmetry using two-axis line-imaging velocimetry (VISAR) and streaked radiography measuring velocity of the imploding shell and their comparisons to post-shot calculations using the code HYDRA (Lawrence Livermore National Laboratory).

Beyond Monoamines-Novel Targets for Treatment-Resistant Depression: A Comprehensive Review

PubMed Central

Rosenblat, Christian; McIntyre, Roger S.; Alves, Gilberto S.; Fountoulakis, Konstantinos N.; Carvalho, André F.

2015-01-01

Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown. PMID:26467412

Differential Sensitivity of Target Genes to Translational Repression by miR-17~92

PubMed Central

Jin, Hyun Yong; Oda, Hiroyo; Chen, Pengda; Kang, Seung Goo; Valentine, Elizabeth; Liao, Lujian; Zhang, Yaoyang; Gonzalez-Martin, Alicia; Shepherd, Jovan; Head, Steven R.; Kim, Pyeung-Hyeun; Fu, Guo; Liu, Wen-Hsien; Han, Jiahuai

2017-01-01

MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes. PMID:28241004

The Expanding Diversity of Mycobacterium tuberculosis Drug Targets.

PubMed

Wellington, Samantha; Hung, Deborah T

2018-05-11

After decades of relative inactivity, a large increase in efforts to discover antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, nonreplicating Mtb with the hope of shortening the duration of required therapy. New knowledge about Mtb, along with new methods and technologies, has driven exploration into novel target areas, such as energy production and central metabolism, that diverge from the classical targets in macromolecular synthesis. Here, we review new small molecule drug candidates that act on these novel targets to highlight the methods and perspectives advancing the field. These new targets bring with them the aspiration of shortening treatment duration as well as a pipeline of effective regimens against XDR-TB, positioning Mtb drug discovery to become a model for anti-infective discovery.

A Survey of Recent Advances in Particle Filters and Remaining Challenges for Multitarget Tracking

PubMed Central

Wang, Xuedong; Sun, Shudong; Corchado, Juan M.

2017-01-01

We review some advances of the particle filtering (PF) algorithm that have been achieved in the last decade in the context of target tracking, with regard to either a single target or multiple targets in the presence of false or missing data. The first part of our review is on remarkable achievements that have been made for the single-target PF from several aspects including importance proposal, computing efficiency, particle degeneracy/impoverishment and constrained/multi-modal systems. The second part of our review is on analyzing the intractable challenges raised within the general multitarget (multi-sensor) tracking due to random target birth and termination, false alarm, misdetection, measurement-to-track (M2T) uncertainty and track uncertainty. The mainstream multitarget PF approaches consist of two main classes, one based on M2T association approaches and the other not such as the finite set statistics-based PF. In either case, significant challenges remain due to unknown tracking scenarios and integrated tracking management. PMID:29168772

Proteomic analysis of Chlorella vulgaris: Potential targets for enhanced lipid accumulation

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

Guarnieri, Michael T.; Nag, Ambarish; Yang, Shihui

2013-11-01

Oleaginous microalgae are capable of producing large quantities of fatty acids and triacylglycerides. As such, they are promising feedstocks for the production of biofuels and bioproducts. Genetic strain-engineering strategies offer a means to accelerate the commercialization of algal biofuels by improving the rate and total accumulation of microalgal lipids. However, the industrial potential of these organisms remains to be met, largely due to the incomplete knowledgebase surrounding the mechanisms governing the induction of algal lipid biosynthesis. Such strategies require further elucidation of genes and gene products controlling algal lipid accumulation. In this study, we have set out to examine thesemore » mechanisms and identify novel strain-engineering targets in the oleaginous microalga, Chlorella vulgaris. Comparative shotgun proteomic analyses have identified a number of novel targets, including previously unidentified transcription factors and proteins involved in cell signaling and cell cycle regulation. These results lay the foundation for strain-improvement strategies and demonstrate the power of translational proteomic analysis.« less

Regulatory perspective on remaining challenges for utilization of pharmacogenomics-guided drug developments.

PubMed

Otsubo, Yasuto; Ishiguro, Akihiro; Uyama, Yoshiaki

2013-01-01

Pharmacogenomics-guided drug development has been implemented in practice in the last decade, resulting in increased labeling of drugs with pharmacogenomic information. However, there are still many challenges remaining in utilizing this process. Here, we describe such remaining challenges from the regulatory perspective, specifically focusing on sample collection, biomarker qualification, ethnic factors, codevelopment of companion diagnostics and means to provide drugs for off-target patients. To improve the situation, it is important to strengthen international harmonization and collaboration among academia, industries and regulatory agencies, followed by the establishment of an international guideline on this topic. Communication with a regulatory agency from an early stage of drug development is also a key to success.

Target Search & Selection for the DI/EPOXI Spacecraft

NASA Technical Reports Server (NTRS)

Grebow, Daniel J.; Bhaskaran, Shyam; Chesley, Steven R.

2012-01-01

Upon completion of the Hartley 2 flyby in November 2010, the Deep Impact (DI) spacecraft resided in a solar orbit without possibility for gravity assist with any large body. Conservative estimates of remaining fuel were enough to provide only an 18 m/s impulse on the spacecraft. We present our method and results of our systematic scan of potential small body encounters for DI, and our criteria to narrow the selection to the asteroid 2002 GT as the target flyby body. The mission profile has two deterministic maneuvers to achieve the encounter, the first of which executed on November 25, 2011.

Tracking a convoy of multiple targets using acoustic sensor data

NASA Astrophysics Data System (ADS)

Damarla, T. R.

2003-08-01

In this paper we present an algorithm to track a convoy of several targets in a scene using acoustic sensor array data. The tracking algorithm is based on template of the direction of arrival (DOA) angles for the leading target. Often the first target is the closest target to the sensor array and hence the loudest with good signal to noise ratio. Several steps were used to generate a template of the DOA angle for the leading target, namely, (a) the angle at the present instant should be close to the angle at the previous instant and (b) the angle at the present instant should be within error bounds of the predicted value based on the previous values. Once the template of the DOA angles of the leading target is developed, it is used to predict the DOA angle tracks of the remaining targets. In order to generate the tracks for the remaining targets, a track is established if the angles correspond to the initial track values of the first target. Second the time delay between the first track and the remaining tracks are estimated at the highest correlation points between the first track and the remaining tracks. As the vehicles move at different speeds the tracks either compress or expand depending on whether a target is moving fast or slow compared to the first target. The expansion and compression ratios are estimated and used to estimate the predicted DOA angle values of the remaining targets. Based on these predicted DOA angles of the remaining targets the DOA angles obtained from the MVDR or Incoherent MUSIC will be appropriately assigned to proper tracks. Several other rules were developed to avoid mixing the tracks. The algorithm is tested on data collected at Aberdeen Proving Ground with a convoy of 3, 4 and 5 vehicles. Some of the vehicles are tracked and some are wheeled vehicles. The tracking algorithm results are found to be good. The results will be presented at the conference and in the paper.

Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

PubMed

Fu, Rong-Geng; Sun, Yuan; Sheng, Wen-Bing; Liao, Duan-Fang

2017-08-18

The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

A universal entropy-driven mechanism for thioredoxin–target recognition

PubMed Central

Palde, Prakash B.; Carroll, Kate S.

2015-01-01

Cysteine residues in cytosolic proteins are maintained in their reduced state, but can undergo oxidation owing to posttranslational modification during redox signaling or under conditions of oxidative stress. In large part, the reduction of oxidized protein cysteines is mediated by a small 12-kDa thiol oxidoreductase, thioredoxin (Trx). Trx provides reducing equivalents for central metabolic enzymes and is implicated in redox regulation of a wide number of target proteins, including transcription factors. Despite its importance in cellular redox homeostasis, the precise mechanism by which Trx recognizes target proteins, especially in the absence of any apparent signature binding sequence or motif, remains unknown. Knowledge of the forces associated with the molecular recognition that governs Trx–protein interactions is fundamental to our understanding of target specificity. To gain insight into Trx–target recognition, we have thermodynamically characterized the noncovalent interactions between Trx and target proteins before S-S reduction using isothermal titration calorimetry (ITC). Our findings indicate that Trx recognizes the oxidized form of its target proteins with exquisite selectivity, compared with their reduced counterparts. Furthermore, we show that recognition is dependent on the conformational restriction inherent to oxidized targets. Significantly, the thermodynamic signatures for multiple Trx targets reveal favorable entropic contributions as the major recognition force dictating these protein–protein interactions. Taken together, our data afford significant new insight into the molecular forces responsible for Trx–target recognition and should aid the design of new strategies for thiol oxidoreductase inhibition. PMID:26080424

Presidents' Pay Remains a Potent Political Target

ERIC Educational Resources Information Center

Stripling, Jack; Fuller, Andrea

2012-01-01

In a long-simmering national fight over compensation for public-college presidents, the State of California emerged this year as the primary battleground. More than any other institution in recent memory, California State University has publicly and sometimes bitterly wrestled with a vexing question for higher education: How much does a public…

Rapid assessment of target species: Byssate bivalves in a large tropical port.

PubMed

Minchin, Dan; Olenin, Sergej; Liu, Ta-Kang; Cheng, Muhan; Huang, Sheng-Chih

2016-11-15

Rapid assessment sampling for target species is a fast cost-effective method aimed at determining the presence, abundance and distribution of alien and native harmful aquatic organisms and pathogens that may have been introduced by shipping. In this study, the method was applied within a large tropical port expected to have a high species diversity. The port of Kaohsiung was sampled for bivalve molluscan species that attach using a byssus. Such species, due to their biological traits, are spread by ships to ports worldwide. We estimated the abundance and distribution range of one dreissenid (Mytilopsis sallei) and four mytilids (Brachidontes variabilis, Arcuatula senhousa, Mytilus galloprovincialis, Perna viridis) known to be successful invaders and identified as potential pests, or high-risk harmful native or non-native species. We conclude that a rapid assessment of their abundance and distribution within a port, and its vicinity, is efficient and can provide sufficient information for decision making by port managers where IMO port exemptions may be sought. Copyright © 2016. Published by Elsevier Ltd.

GLRS-R 2-colour retroreflector target design and predicted performance

NASA Astrophysics Data System (ADS)

Lund, Glenn

The retroreflector ground target design for the GLRS-R spaceborne dual wavelength laser ranging system is described. The passive design flows down from the requirements of high station autonomy, high global field of view, little or no multiple pulse returns, and adequate optical cross section for most ranging geometries. The solution makes use of five hollow cube corner retroreflectors of which one points to the zenith and the remaining four are inclined from the vertical at uniform azimuthal spacings. The need for large retroreflectors is expected to generate narrow diffraction lobes. A good compromise solution is found by spoiling just one of the retroereflector dihedral angles from 90 deg, thus generating two symmetrically oriented diffraction lobes in the return beam. The required spoil angles are found to have little dependance on ground target latitude. Various link budget analyses are presented. They show the influence of such factors as point ahead optimization, turbulence, ranging angle, atmospheric visibility, and ground target thermal deformations.

Impact of 7-TeV/c large hadron collider proton beam on a copper target

NASA Astrophysics Data System (ADS)

Tahir, N. A.; Goddard, B.; Kain, V.; Schmidt, R.; Shutov, A.; Lomonosov, I. V.; Piriz, A. R.; Temporal, M.; Hoffmann, D. H. H.; Fortov, V. E.

2005-04-01

The large hadron collider (LHC) will allow for collision between two 7TeV/c proton beams, each comprising 2808 bunches with 1.1×1011 protons per bunch, traveling in opposite direction. The bunch length is 0.5ns and two neighboring bunches are separated by 25ns so that the duration of the entire beam is about 89μs. The beam power profile in the transverse direction is a Gaussian with a standard deviation of 0.2mm. The energy stored in each beam is about 350MJ that is sufficient to melt 500kg of copper. In case of a failure in the machine protection systems, the entire beam could impact directly onto an accelerator equipment. A first estimate of the scale of damage resulting from such a failure has been assessed for a solid copper target hit by the beam by carrying out three-dimensional energy deposition calculations and two-dimensional numerical simulations of the hydrodynamic and thermodynamic response of the target. This work has shown that the penetration depth of the LHC protons will be between 10 and 40m in solid copper. These calculations show that material conditions obtained in the target are similar to those planned for beam impact at dedicated accelerators designed to study the physics of high-energy-density states of matter, for example, the Facility for Antiprotons and Ion Research at the Gesellschaft für Schwerionenforschung, Darmstadt [W. F. Henning, Nucl. Instrum Methods Phys. Res. B 214, 211 (2004)].

Modeling Retention at a Large Public University: Can At-Risk Students Be Identified Early Enough to Treat?

ERIC Educational Resources Information Center

Singell, Larry D.; Waddell, Glen R.

2010-01-01

We examine the extent to which readily available data at a large public university can be used to a priori identify at-risk students who may benefit from targeted retention efforts. Although it is possible to identify such students, there remains an inevitable tradeoff in any resource allocation between not treating the students who are likely to…

Unsteady penetration of a target by a liquid jet

PubMed Central

Uth, Tobias; Deshpande, Vikram S.

2013-01-01

It is widely acknowledged that ceramic armor experiences an unsteady penetration response: an impacting projectile may erode on the surface of a ceramic target without substantial penetration for a significant amount of time and then suddenly start to penetrate the target. Although known for more than four decades, this phenomenon, commonly referred to as dwell, remains largely unexplained. Here, we use scaled analog experiments with a low-speed water jet and a soft, translucent target material to investigate dwell. The transient target response, in terms of depth of penetration and impact force, is captured using a high-speed camera in combination with a piezoelectric force sensor. We observe the phenomenon of dwell using a soft (noncracking) target material. The results show that the penetration rate increases when the flow of the impacting water jet is reversed due to the deformation of the jet–target interface––this reversal is also associated with an increase in the force exerted by the jet on the target. Creep penetration experiments with a constant indentation force did not show an increase in the penetration rate, confirming that flow reversal is the cause of the unsteady penetration rate. Our results suggest that dwell can occur in a ductile noncracking target due to flow reversal. This phenomenon of flow reversal is rather widespread and present in a wide range of impact situations, including water-jet cutting, needleless injection, and deposit removal via a fluid jet. PMID:24277818

OVERVIEW OF CYANIDE PLANT REMAINS, TAILINGS PILES, PARKING LOT, AND ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

OVERVIEW OF CYANIDE PLANT REMAINS, TAILINGS PILES, PARKING LOT, AND MINE MANAGER'S HOME, LOOKING SOUTH SOUTHEAST. RIGHT, TAILINGS PILES ARE AT CENTER WITH CYANIDE PLANT FOUNDATIONS TO THE LEFT OF THE PILES. PARKING LOT IS AT UPPER LEFT. THE AREA BETWEEN THE COLLAPSED TANK AT CENTER LEFT AND THE REMAINS OF THE MANAGER'S HOUSE AT LOWER RIGHT IS A TAILINGS HOLDING AREA. TAILINGS FROM THE MILL WERE HELD HERE. THE LARGE SETTLING TANKS WERE CHARGED FROM THIS HOLDING AREA BY A TRAM ON RAILS AND BY A SLUICEWAY SEEN AS THE DARK SPOT ON THE CENTER LEFT EDGE OF THE FRAME. AFTER THE TAILINGS WERE LEACHED, THEY WERE DEPOSITED ON THE LARGE WASTE PILE AT CENTER RIGHT. THE TANK AT CENTER RIGHT EDGE IS WHERE THE WATER PIPELINE ENTERED THE WORKS. A STRAIGHT LINE OF POSTS IN THE GROUND GO ACROSS THE CENTER FROM LEFT TO RIGHT, WHICH ORIGINALLY SUSPENDED THE WATER PIPELINE GOING FROM THE WATER HOLDING TANK AT RIGHT UP TO THE SECONDARY WATER TANKS ABOVE THE MILL. - Keane Wonder Mine, Park Route 4 (Daylight Pass Cutoff), Death Valley Junction, Inyo County, CA

Large-D gravity and low-D strings.

PubMed

Emparan, Roberto; Grumiller, Daniel; Tanabe, Kentaro

2013-06-21

We show that in the limit of a large number of dimensions a wide class of nonextremal neutral black holes has a universal near-horizon limit. The limiting geometry is the two-dimensional black hole of string theory with a two-dimensional target space. Its conformal symmetry explains the properties of massless scalars found recently in the large-D limit. For black branes with string charges, the near-horizon geometry is that of the three-dimensional black strings of Horne and Horowitz. The analogies between the α' expansion in string theory and the large-D expansion in gravity suggest a possible effective string description of the large-D limit of black holes. We comment on applications to several subjects, in particular to the problem of critical collapse.

Instabilities in large economies: aggregate volatility without idiosyncratic shocks

NASA Astrophysics Data System (ADS)

Bonart, Julius; Bouchaud, Jean-Philippe; Landier, Augustin; Thesmar, David

2014-10-01

We study a dynamical model of interconnected firms which allows for certain market imperfections and frictions, restricted here to be myopic price forecasts and slow adjustment of production. Whereas the standard rational equilibrium is still formally a stationary solution of the dynamics, we show that this equilibrium becomes linearly unstable in a whole region of parameter space. When agents attempt to reach the optimal production target too quickly, coordination breaks down and the dynamics becomes chaotic. In the unstable, ‘turbulent’ phase, the aggregate volatility of the total output remains substantial even when the amplitude of idiosyncratic shocks goes to zero or when the size of the economy becomes large. In other words, crises become endogenous. This suggests an interesting resolution of the ‘small shocks, large business cycles’ puzzle.

Target Search and Selection for the DI/EPOXI Spacecraft

NASA Technical Reports Server (NTRS)

Grebow, Daniel J.; Bhaskaran, Shyam; Chesley, Steven R.

2012-01-01

Upon completion of the Hartley 2 flyby in November 2010, the Deep Impact (DI) spacecraft resided in a solar orbit without possibility for gravity assist with any large body. Conservative estimates of remaining fuel were enough to provide only an 18 m/s impulse on the spacecraft. We present our method and results of our systematic scan of potential small body encounters for DI, and our criteria to narrow the selection to the asteroid 2002 GT as the target flyby body. The mission profile has two deterministic maneuvers to achieve the encounter, the first of which executed on November 25, 2011.

Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation.

PubMed

Leisegang, Matthias; Engels, Boris; Schreiber, Karin; Yew, Poh Yin; Kiyotani, Kazuma; Idel, Christian; Arina, Ainhoa; Duraiswamy, Jaikumar; Weichselbaum, Ralph R; Uckert, Wolfgang; Nakamura, Yusuke; Schreiber, Hans

2016-06-01

Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic nonsynonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T-cell receptor (TCR) that is specific for a single AAS. By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy. When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intratumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T-cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar. Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer, but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape. Clin Cancer Res; 22(11); 2734-43. ©2015 AACRSee related commentary by Liu, p. 2602. ©2015 American Association for Cancer Research.

Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma.

PubMed

Hardy, Katharine M; Strizzi, Luigi; Margaryan, Naira V; Gupta, Kanika; Murphy, George F; Scolyer, Richard A; Hendrix, Mary J C

2015-04-01

Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently, FDA-approved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improving melanoma therapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain whether targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre- and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy. Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma. ©2015 American Association for Cancer Research.

Fossil human remains from Bolomor Cave (Valencia, Spain).

PubMed

Arsuaga, Juan Luis; Fernández Peris, Josep; Gracia-Téllez, Ana; Quam, Rolf; Carretero, José Miguel; Barciela González, Virginia; Blasco, Ruth; Cuartero, Felipe; Sañudo, Pablo

2012-05-01

Systematic excavations carried out since 1989 at Bolomor Cave have led to the recovery of four Pleistocene human fossil remains, consisting of a fibular fragment, two isolated teeth, and a nearly complete adult parietal bone. All of these specimens date to the late Middle and early Late Pleistocene (MIS 7-5e). The fibular fragment shows thick cortical bone, an archaic feature found in non-modern (i.e. non-Homo sapiens) members of the genus Homo. Among the dental remains, the lack of a midtrigonid crest in the M(1) represents a departure from the morphology reported for the majority of Neandertal specimens, while the large dimensions and pronounced shoveling of the marginal ridges in the C(1) are similar to other European Middle and late Pleistocene fossils. The parietal bone is very thick, with dimensions that generally fall above Neandertal fossils and resemble more closely the Middle Pleistocene Atapuerca (SH) adult specimens. Based on the presence of archaic features, all the fossils from Bolomor are attributed to the Neandertal evolutionary lineage. Copyright © 2012 Elsevier Ltd. All rights reserved.

SU-E-T-480: Radiobiological Dose Comparison of Single Fraction SRS, Multi-Fraction SRT and Multi-Stage SRS of Large Target Volumes Using the Linear-Quadratic Formula

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

Ding, C; Hrycushko, B; Jiang, S

2014-06-01

Purpose: To compare the radiobiological effect on large tumors and surrounding normal tissues from single fraction SRS, multi-fractionated SRT, and multi-staged SRS treatment. Methods: An anthropomorphic head phantom with a centrally located large volume target (18.2 cm{sup 3}) was scanned using a 16 slice large bore CT simulator. Scans were imported to the Multiplan treatment planning system where a total prescription dose of 20Gy was used for a single, three staged and three fractionated treatment. Cyber Knife treatment plans were inversely optimized for the target volume to achieve at least 95% coverage of the prescription dose. For the multistage plan,more » the target was segmented into three subtargets having similar volume and shape. Staged plans for individual subtargets were generated based on a planning technique where the beam MUs of the original plan on the total target volume are changed by weighting the MUs based on projected beam lengths within each subtarget. Dose matrices for each plan were export in DICOM format and used to calculate equivalent dose distributions in 2Gy fractions using an alpha beta ratio of 10 for the target and 3 for normal tissue. Results: Singe fraction SRS, multi-stage plan and multi-fractionated SRT plans had an average 2Gy dose equivalent to the target of 62.89Gy, 37.91Gy and 33.68Gy, respectively. The normal tissue within 12Gy physical dose region had an average 2Gy dose equivalent of 29.55Gy, 16.08Gy and 13.93Gy, respectively. Conclusion: The single fraction SRS plan had the largest predicted biological effect for the target and the surrounding normal tissue. The multi-stage treatment provided for a more potent biologically effect on target compared to the multi-fraction SRT treatments with less biological normal tissue than single-fraction SRS treatment.« less

A Target Coverage Scheduling Scheme Based on Genetic Algorithms in Directional Sensor Networks

PubMed Central

Gil, Joon-Min; Han, Youn-Hee

2011-01-01

As a promising tool for monitoring the physical world, directional sensor networks (DSNs) consisting of a large number of directional sensors are attracting increasing attention. As directional sensors in DSNs have limited battery power and restricted angles of sensing range, maximizing the network lifetime while monitoring all the targets in a given area remains a challenge. A major technique to conserve the energy of directional sensors is to use a node wake-up scheduling protocol by which some sensors remain active to provide sensing services, while the others are inactive to conserve their energy. In this paper, we first address a Maximum Set Covers for DSNs (MSCD) problem, which is known to be NP-complete, and present a greedy algorithm-based target coverage scheduling scheme that can solve this problem by heuristics. This scheme is used as a baseline for comparison. We then propose a target coverage scheduling scheme based on a genetic algorithm that can find the optimal cover sets to extend the network lifetime while monitoring all targets by the evolutionary global search technique. To verify and evaluate these schemes, we conducted simulations and showed that the schemes can contribute to extending the network lifetime. Simulation results indicated that the genetic algorithm-based scheduling scheme had better performance than the greedy algorithm-based scheme in terms of maximizing network lifetime. PMID:22319387

Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma.

PubMed

Matthews, Julie Marie; Bhatt, Shruti; Patricelli, Matthew P; Nomanbhoy, Tyzoon K; Jiang, Xiaoyu; Natkunam, Yasodha; Gentles, Andrew J; Martinez, Ezequiel; Zhu, Daxing; Chapman, Jennifer Rose; Cortizas, Elena; Shyam, Ragini; Chinichian, Shideh; Advani, Ranjana; Tan, Li; Zhang, Jianming; Choi, Hwan Geun; Tibshirani, Robert; Buhrlage, Sara J; Gratzinger, Dita; Verdun, Ramiro; Gray, Nathanael S; Lossos, Izidore S

2016-07-14

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, yet 40% to 50% of patients will eventually succumb to their disease, demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that germinal center kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell-cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Because the majority of DLBCL tumors (∼80%) exhibit activation of GCK, this therapy may be applicable to most patients. © 2016 by The American Society of Hematology.

Superdiffusive motion of membrane-targeting C2 domains

NASA Astrophysics Data System (ADS)

Campagnola, Grace; Nepal, Kanti; Schroder, Bryce W.; Peersen, Olve B.; Krapf, Diego

2015-12-01

Membrane-targeting domains play crucial roles in the recruitment of signalling molecules to the plasma membrane. For most peripheral proteins, the protein-to-membrane interaction is transient. After proteins dissociate from the membrane they have been observed to rebind following brief excursions in the bulk solution. Such membrane hops can have broad implications for the efficiency of reactions on membranes. We study the diffusion of membrane-targeting C2 domains using single-molecule tracking in supported lipid bilayers. The ensemble-averaged mean square displacement (MSD) exhibits superdiffusive behaviour. However, traditional time-averaged MSD analysis of individual trajectories remains linear and does not reveal superdiffusion. Our observations are explained in terms of bulk excursions that introduce jumps with a heavy-tail distribution. These hopping events allow proteins to explore large areas in a short time. The experimental results are shown to be consistent with analytical models of bulk-mediated diffusion and numerical simulations.

Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function.

PubMed

Storm, Elaine E; Durinck, Steffen; de Sousa e Melo, Felipe; Tremayne, Jarrod; Kljavin, Noelyn; Tan, Christine; Ye, Xiaofen; Chiu, Cecilia; Pham, Thinh; Hongo, Jo-Anne; Bainbridge, Travis; Firestein, Ron; Blackwood, Elizabeth; Metcalfe, Ciara; Stawiski, Eric W; Yauch, Robert L; Wu, Yan; de Sauvage, Frederic J

2016-01-07

Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.

Therapeutic Innovations for Targeting Childhood Neuroblastoma: Implications of the Neurokinin-1 Receptor System.

PubMed

Berger, Michael; VON Schweinitz, Dietrich

2017-11-01

Neuroblastoma is the most common solid extracranial malignant tumor in children. Despite recent advances in the treatment of this heterogenous tumor with surgery and chemotherapy, the prognosis in advanced stages remains poor. Interestingly, neuroblastoma is one of the few solid tumors, to date, in which an effect for targeted immunotherapy has been proven in controlled clinical trials, giving hope for further advances in the treatment of this and other tumors by targeted therapy. A large array of novel therapeutic options for targeted therapy of neuroblastoma is on the horizon. To this repεrtoirε, the neurokinin-1 receptor (NK1R) system was recently added. The present article explores the most recent developments in targeting neuroblastoma cells via the NK1R and how this new knowledge could be helpful to create new anticancer therapies agains neuroblastoma and other cancers. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Targeting Matrix Metalloproteinases in Cancer: Bringing New Life to Old Ideas.

PubMed

Cathcart, Jillian; Pulkoski-Gross, Ashleigh; Cao, Jian

2015-03-01

Since the identification of matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, as being a driving factor for cancer progression and patient prognosis, MMPs have been studied extensively. Although early programs targeting MMPs were largely unsuccessful in clinical trials, they remain a viable and highly desirable therapeutic target based on preclinical studies and their role in disease progression. As information regarding the structure and function of these proteinases is compiled and biotechnology evolves, tools to develop better inhibitors is within our grasp. Improved methods for high throughput screening and in silico drug design programs have identified compounds which are highly potent, have high binding affinities, and exhibit favorable pharmacokinetic profiles. More recently, advances in drug delivery methods or compounds which bind outside the active site have brought new light to the field. In this review, we highlight the role of MMPs in cancer, clinical trials for MMP inhibitors, and novel approaches to targeting MMPs in cancer.

Large-scale identification of target proteins of a glycosyltransferase isozyme by Lectin-IGOT-LC/MS, an LC/MS-based glycoproteomic approach

PubMed Central

Sugahara, Daisuke; Kaji, Hiroyuki; Sugihara, Kazushi; Asano, Masahide; Narimatsu, Hisashi

2012-01-01

Model organisms containing deletion or mutation in a glycosyltransferase-gene exhibit various physiological abnormalities, suggesting that specific glycan motifs on certain proteins play important roles in vivo. Identification of the target proteins of glycosyltransferase isozymes is the key to understand the roles of glycans. Here, we demonstrated the proteome-scale identification of the target proteins specific for a glycosyltransferase isozyme, β1,4-galactosyltransferase-I (β4GalT-I). Although β4GalT-I is the most characterized glycosyltransferase, its distinctive contribution to β1,4-galactosylation has been hardly described so far. We identified a large number of candidates for the target proteins specific to β4GalT-I by comparative analysis of β4GalT-I-deleted and wild-type mice using the LC/MS-based technique with the isotope-coded glycosylation site-specific tagging (IGOT) of lectin-captured N-glycopeptides. Our approach to identify the target proteins in a proteome-scale offers common features and trends in the target proteins, which facilitate understanding of the mechanism that controls assembly of a particular glycan motif on specific proteins. PMID:23002422

Video-rate volumetric neuronal imaging using 3D targeted illumination.

PubMed

Xiao, Sheng; Tseng, Hua-An; Gritton, Howard; Han, Xue; Mertz, Jerome

2018-05-21

Fast volumetric microscopy is required to monitor large-scale neural ensembles with high spatio-temporal resolution. Widefield fluorescence microscopy can image large 2D fields of view at high resolution and speed while remaining simple and costeffective. A focal sweep add-on can further extend the capacity of widefield microscopy by enabling extended-depth-of-field (EDOF) imaging, but suffers from an inability to reject out-of-focus fluorescence background. Here, by using a digital micromirror device to target only in-focus sample features, we perform EDOF imaging with greatly enhanced contrast and signal-to-noise ratio, while reducing the light dosage delivered to the sample. Image quality is further improved by the application of a robust deconvolution algorithm. We demonstrate the advantages of our technique for in vivo calcium imaging in the mouse brain.

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

PubMed Central

Barrett, Doug J. K.; Zobay, Oliver

2014-01-01

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

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

PubMed

Lam, Max; Trampush, Joey W; Yu, Jin; Knowles, Emma; Davies, Gail; Liewald, David C; Starr, John M; Djurovic, Srdjan; Melle, Ingrid; Sundet, Kjetil; Christoforou, Andrea; Reinvang, Ivar; DeRosse, Pamela; Lundervold, Astri J; Steen, Vidar M; Espeseth, Thomas; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G; Giegling, Ina; Konte, Bettina; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E; Payton, Antony; Ollier, William; Chiba-Falek, Ornit; Attix, Deborah K; Need, Anna C; Cirulli, Elizabeth T; Voineskos, Aristotle N; Stefanis, Nikos C; Avramopoulos, Dimitrios; Hatzimanolis, Alex; Arking, Dan E; Smyrnis, Nikolaos; Bilder, Robert M; Freimer, Nelson A; Cannon, Tyrone D; London, Edythe; Poldrack, Russell A; Sabb, Fred W; Congdon, Eliza; Conley, Emily Drabant; Scult, Matthew A; Dickinson, Dwight; Straub, Richard E; Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael; Hariri, Ahmad R; Weinberger, Daniel R; Pendleton, Neil; Bitsios, Panos; Rujescu, Dan; Lahti, Jari; Le Hellard, Stephanie; Keller, Matthew C; Andreassen, Ole A; Deary, Ian J; Glahn, David C; Malhotra, Anil K; Lencz, Todd

2017-11-28

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Targeting the tumor microenvironment

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

Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

2006-11-07

Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and reviewmore » the approaches being taken to disrupt these interactions.« less

Targeting Nodal in Conjunction with Dacarbazine Induces Synergistic Anti-cancer Effects in Metastatic Melanoma

PubMed Central

Hardy, Katharine M.; Strizzi, Luigi; Margaryan, Naira V.; Gupta, Kanika; Murphy, George F.; Scolyer, Richard A.; Hendrix, Mary J.C.

2015-01-01

Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent Dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently FDA approved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improving melanoma therapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain if targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre- and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy. Implications Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma. PMID:25767211

Targeted disruption of deep-lying neocortical microvessels in rat using ultrashort laser pulses

NASA Astrophysics Data System (ADS)

Nishimura, Nozomi; Schaffer, Christopher B.; Friedman, Beth; Tsai, Philbert S.; Lyden, Patrick D.; Kleinfeld, David

2004-06-01

The study of neurovascular diseases such as vascular dementia and stroke require novel models of targeted vascular disruption in the brain. We describe a model of microvascular disruption in rat neocortex that uses ultrashort laser pulses to induce localized injury to specific targeted microvessels and uses two-photon microscopy to monitor and guide the photodisruption process. In our method, a train of high-intensity, 100-fs laser pulses is tightly focused into the lumen of a blood vessel within the upper 500 μm of cortex. Photodisruption induced by these laser pulses creates injury to a single vessel located at the focus of the laser, leaving the surrounding tissue intact. This photodisruption results in three modalities of localized vascular injury. At low power, blood plasma extravasation can be induced. The vessel itself remains intact, while serum is extravasated into the intercellular space. Localized ischemia caused by an intravascular clot results when the photodisruption leads to a brief disturbance of the vascular walls that initiates an endogenous clotting cascade. The formation of a localized thrombus stops the blood flow at the location of the photodisruption. A hemorrhage, defined as a large extravasation of blood including plasma and red blood cells, results when higher laser power is used. The targeted vessel does not remain intact.

Targeted Social Mobilization in a Global Manhunt

PubMed Central

Dsouza, Sohan; McInerney, James; Naroditskiy, Victor; Venanzi, Matteo; Jennings, Nicholas R.; deLara, J. R.; Wahlstedt, Eero; Miller, Steven U.

2013-01-01

Social mobilization, the ability to mobilize large numbers of people via social networks to achieve highly distributed tasks, has received significant attention in recent times. This growing capability, facilitated by modern communication technology, is highly relevant to endeavors which require the search for individuals that possess rare information or skills, such as finding medical doctors during disasters, or searching for missing people. An open question remains, as to whether in time-critical situations, people are able to recruit in a targeted manner, or whether they resort to so-called blind search, recruiting as many acquaintances as possible via broadcast communication. To explore this question, we examine data from our recent success in the U.S. State Department's Tag Challenge, which required locating and photographing 5 target persons in 5 different cities in the United States and Europe – in under 12 hours – based only on a single mug-shot. We find that people are able to consistently route information in a targeted fashion even under increasing time pressure. We derive an analytical model for social-media fueled global mobilization and use it to quantify the extent to which people were targeting their peers during recruitment. Our model estimates that approximately 1 in 3 messages were of targeted fashion during the most time-sensitive period of the challenge. This is a novel observation at such short temporal scales, and calls for opportunities for devising viral incentive schemes that provide distance or time-sensitive rewards to approach the target geography more rapidly. This observation of ′12 hours of separation' between individuals has applications in multiple areas from emergency preparedness, to political mobilization. PMID:24098660

Targeted social mobilization in a global manhunt.

PubMed

Rutherford, Alex; Cebrian, Manuel; Rahwan, Iyad; Dsouza, Sohan; McInerney, James; Naroditskiy, Victor; Venanzi, Matteo; Jennings, Nicholas R; deLara, J R; Wahlstedt, Eero; Miller, Steven U

2013-01-01

Social mobilization, the ability to mobilize large numbers of people via social networks to achieve highly distributed tasks, has received significant attention in recent times. This growing capability, facilitated by modern communication technology, is highly relevant to endeavors which require the search for individuals that possess rare information or skills, such as finding medical doctors during disasters, or searching for missing people. An open question remains, as to whether in time-critical situations, people are able to recruit in a targeted manner, or whether they resort to so-called blind search, recruiting as many acquaintances as possible via broadcast communication. To explore this question, we examine data from our recent success in the U.S. State Department's Tag Challenge, which required locating and photographing 5 target persons in 5 different cities in the United States and Europe - in under 12 hours - based only on a single mug-shot. We find that people are able to consistently route information in a targeted fashion even under increasing time pressure. We derive an analytical model for social-media fueled global mobilization and use it to quantify the extent to which people were targeting their peers during recruitment. Our model estimates that approximately 1 in 3 messages were of targeted fashion during the most time-sensitive period of the challenge. This is a novel observation at such short temporal scales, and calls for opportunities for devising viral incentive schemes that provide distance or time-sensitive rewards to approach the target geography more rapidly. This observation of '12 hours of separation' between individuals has applications in multiple areas from emergency preparedness, to political mobilization.

Large longitudinal spin alignment generated in inelastic nuclear reactions

NASA Astrophysics Data System (ADS)

Hoff, D. E. M.; Potel, G.; Brown, K. W.; Charity, R. J.; Pruitt, C. D.; Sobotka, L. G.; Webb, T. B.; Roeder, B.; Saastamoinen, A.

2018-05-01

Large longitudinal spin alignment of E /A =24 MeV 7Li projectiles inelastically excited by Be, C, and Al targets was observed when the latter remain in their ground state. This alignment is a consequence of an angular-momentum-excitation-energy mismatch, which is well described by a DWBA cluster-model (α +t ). The longitudinal alignment of several other systems is also well described by DWBA calculations, including one where a cluster model is inappropriate, demonstrating that the alignment mechanism is a more general phenomenon. Predictions are made for inelastic excitation of 12C for beam energies above and below the mismatch threshold.

Current siRNA Targets in Atherosclerosis and Aortic Aneurysm

PubMed Central

Pradhan-Nabzdyk, Leena; Huang, Chenyu; Logerfo, Frank W.; Nabzdyk, Christoph S.

2014-01-01

Atherosclerosis (ATH) and aortic aneurysms (AA) remain challenging chronic diseases that confer high morbidity and mortality despite advances in medical, interventional, and surgical care. RNA interference represents a promising technology that may be utilized to silence genes contributing to ATH and AA. Despite positive results in preclinical and some clinical feasibility studies, challenges such as target/sequence validation, tissue specificity, transfection efficiency, and mitigation of unwanted off-target effects remain to be addressed. In this review the most current targets and some novel approaches in siRNA delivery are being discussed. Due to the plethora of investigated targets, only studies published between 2010 and 2014 were included. PMID:24882715

Large discrepancies observed in theoretical studies of ion-impact ionization of the atomic targets at large momentum transfer

NASA Astrophysics Data System (ADS)

Ghorbani, Omid; Ghanbari-Adivi, Ebrahim

2017-12-01

A full quantum mechanical version of the three-body distorted wave-eikonal initial state (3DW-EIS) theory is developed to study of the single ionization of the atomic targets by ion impact at different momentum transfers. The calculations are performed both with and without including the internuclear interaction in the transition amplitude. For 16 \\text{Mev} \\text{O}7+ \\text{-He}~(1s2 ) and 24 \\text{Mev} \\text{O}8+\\text{-Li}~(2s ) collisions, the emission of the active electron into the scattering plane is considered and the fully differential cross-sections (FDCSs) are calculated for a fixed value of the ejected electron energy and a variety of momentum transfers. For both the specified collision systems, the obtained results are compared with the experimental data and with the cross-sections obtained using the semi-classical continuum distorted wave-eikonal initial state (CDW-EIS) approach. For 16 \\text{Mev} \\text{O}7+ \\text{-He}~(1s^2) , we also compared the results with those of a four-body three-Coulomb-wave (3CW) model. In general, we find some large discrepancies between the results obtained by different theories. These discrepancies are much more significant at larger momentum transfers. Also, for some ranges of the electron emission angles the results are much more sensitive to the internuclear interaction to be either turned on or off.

Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets

PubMed Central

Arango, Daniel; Morohashi, Kengo; Yilmaz, Alper; Kuramochi, Kouji; Parihar, Arti; Brahimaj, Bledi; Grotewold, Erich; Doseff, Andrea I.

2013-01-01

Flavonoids constitute the largest class of dietary phytochemicals, adding essential health value to our diet, and are emerging as key nutraceuticals. Cellular targets for dietary phytochemicals remain largely unknown, posing significant challenges for the regulation of dietary supplements and the understanding of how nutraceuticals provide health value. Here, we describe the identification of human cellular targets of apigenin, a flavonoid abundantly present in fruits and vegetables, using an innovative high-throughput approach that combines phage display with second generation sequencing. The 160 identified high-confidence candidate apigenin targets are significantly enriched in three main functional categories: GTPase activation, membrane transport, and mRNA metabolism/alternative splicing. This last category includes the heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2), a factor involved in splicing regulation, mRNA stability, and mRNA transport. Apigenin binds to the C-terminal glycine-rich domain of hnRNPA2, preventing hnRNPA2 from forming homodimers, and therefore, it perturbs the alternative splicing of several human hnRNPA2 targets. Our results provide a framework to understand how dietary phytochemicals exert their actions by binding to many functionally diverse cellular targets. In turn, some of them may modulate the activity of a large number of downstream genes, which is exemplified here by the effects of apigenin on the alternative splicing activity of hnRNPA2. Hence, in contrast to small-molecule pharmaceuticals designed for defined target specificity, dietary phytochemicals affect a large number of cellular targets with varied affinities that, combined, result in their recognized health benefits. PMID:23697369

Work-related factors influencing home care nurse intent to remain employed.

PubMed

Tourangeau, Ann E; Patterson, Erin; Saari, Margaret; Thomson, Heather; Cranley, Lisa

Health care is shifting out of hospitals into community settings. In Ontario, Canada, home care organizations continue to experience challenges recruiting and retaining nurses. However, factors influencing home care nurse retention that can be modified remain largely unexplored. Several groups of factors have been identified as influencing home care nurse intent to remain employed including job characteristics, work structures, relationships and communication, work environment, responses to work, and conditions of employment. The aim of this study was to test and refine a model that identifies which factors are related to home care nurse intentions to remain employed for the next 5 years with their current home care employer organization. A cross-sectional survey design was implemented to test and refine a hypothesized model of home care nurse intent to remain employed. Logistic regression was used to determine which factors influence home care nurse intent to remain employed. Home care nurse intent to remain employed for the next 5 years was associated with increasing age, higher nurse-evaluated quality of care, having greater variety of patients, experiencing greater meaningfulness of work, having greater income stability, having greater continuity of client care, experiencing more positive relationships with supervisors, experiencing higher work-life balance, and being more satisfied with salary and benefits. Home care organizations can promote home care nurse intent to remain employed by (a) ensuring nurses have adequate training and resources to provide quality client care, (b) improving employment conditions to increase income stability and satisfaction with pay and benefits, (c) ensuring manageable workloads to facilitate improved work-life balance, and (d) ensuring leaders are accessible and competent.

Where do those remains come from?

PubMed

Nociarová, Dominika; Adserias, M Jose; Malgosa, Assumpció; Galtés, Ignasi

2014-12-01

Part of the study of skeletal remains or corpses in advance decay located in the field involves determining their origin. They may be the result of criminal activity, accident, unearthed because of erosion, or they may also have originated from a cemetery. The discovery site, condition of the remains, and the associated artifacts, are factors that could be helpful for the forensic anthropologist to identify the origin of the remains. In order to contribute to this recognition, an analysis was made of the exhumations of 168 unclaimed human remains from the cemetery of Terrassa (Catalonia, Spain). This investigation presents a description of artifacts and conditions of remains that could indicate that the human remains may have originated from a cemetery. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma.

PubMed

Yang, Yibin; Kelly, Priscilla; Shaffer, Arthur L; Schmitz, Roland; Yoo, Hee Min; Liu, Xinyue; Huang, Da Wei; Webster, Daniel; Young, Ryan M; Nakagawa, Masao; Ceribelli, Michele; Wright, George W; Yang, Yandan; Zhao, Hong; Yu, Xin; Xu, Weihong; Chan, Wing C; Jaffe, Elaine S; Gascoyne, Randy D; Campo, Elias; Rosenwald, Andreas; Ott, German; Delabie, Jan; Rimsza, Lisa; Staudt, Louis M

2016-04-11

Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetics target cIAP1/2 for destruction, and consequently suppress NF-κB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL. Copyright © 2016 Elsevier Inc. All rights reserved.

Scout-MRM: Multiplexed Targeted Mass Spectrometry-Based Assay without Retention Time Scheduling Exemplified by Dickeya dadantii Proteomic Analysis during Plant Infection.

PubMed

Rougemont, Blandine; Bontemps Gallo, Sébastien; Ayciriex, Sophie; Carrière, Romain; Hondermarck, Hubert; Lacroix, Jean Marie; Le Blanc, J C Yves; Lemoine, Jérôme

2017-02-07

Targeted mass spectrometry of a surrogate peptide panel is a powerful method to study the dynamics of protein networks, but chromatographic time scheduling remains a major limitation for dissemination and implementation of robust and large multiplexed assays. We unveil a Multiple Reaction Monitoring method (Scout-MRM) where the use of spiked scout peptides triggers complex transition lists, regardless of the retention time of targeted surrogate peptides. The interest of Scout-MRM method regarding the retention time independency, multiplexing capability, reproducibility, and putative interest in facilitating method transfer was illustrated by a 782-peptide-plex relative assay targeting 445 proteins of the phytopathogen Dickeya dadantii during plant infection.

Controversies in targeted therapy of adult T cell leukemia/lymphoma: ON target or OFF target effects?

PubMed

Nasr, Rihab; El Hajj, Hiba; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-06-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL.

GWASeq: targeted re-sequencing follow up to GWAS.

PubMed

Salomon, Matthew P; Li, Wai Lok Sibon; Edlund, Christopher K; Morrison, John; Fortini, Barbara K; Win, Aung Ko; Conti, David V; Thomas, Duncan C; Duggan, David; Buchanan, Daniel D; Jenkins, Mark A; Hopper, John L; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A; Casey, Graham; Marjoram, Paul

2016-03-03

For the last decade the conceptual framework of the Genome-Wide Association Study (GWAS) has dominated the investigation of human disease and other complex traits. While GWAS have been successful in identifying a large number of variants associated with various phenotypes, the overall amount of heritability explained by these variants remains small. This raises the question of how best to follow up on a GWAS, localize causal variants accounting for GWAS hits, and as a consequence explain more of the so-called "missing" heritability. Advances in high throughput sequencing technologies now allow for the efficient and cost-effective collection of vast amounts of fine-scale genomic data to complement GWAS. We investigate these issues using a colon cancer dataset. After QC, our data consisted of 1993 cases, 899 controls. Using marginal tests of associations, we identify 10 variants distributed among six targeted regions that are significantly associated with colorectal cancer, with eight of the variants being novel to this study. Additionally, we perform so-called 'SNP-set' tests of association and identify two sets of variants that implicate both common and rare variants in the etiology of colorectal cancer. Here we present a large-scale targeted re-sequencing resource focusing on genomic regions implicated in colorectal cancer susceptibility previously identified in several GWAS, which aims to 1) provide fine-scale targeted sequencing data for fine-mapping and 2) provide data resources to address methodological questions regarding the design of sequencing-based follow-up studies to GWAS. Additionally, we show that this strategy successfully identifies novel variants associated with colorectal cancer susceptibility and can implicate both common and rare variants.

Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification.

PubMed

Deans, Richard M; Morgens, David W; Ökesli, Ayşe; Pillay, Sirika; Horlbeck, Max A; Kampmann, Martin; Gilbert, Luke A; Li, Amy; Mateo, Roberto; Smith, Mark; Glenn, Jeffrey S; Carette, Jan E; Khosla, Chaitan; Bassik, Michael C

2016-05-01

Broad-spectrum antiviral drugs targeting host processes could potentially treat a wide range of viruses while reducing the likelihood of emergent resistance. Despite great promise as therapeutics, such drugs remain largely elusive. Here we used parallel genome-wide high-coverage short hairpin RNA (shRNA) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens to identify the cellular target and mechanism of action of GSK983, a potent broad-spectrum antiviral with unexplained cytotoxicity. We found that GSK983 blocked cell proliferation and dengue virus replication by inhibiting the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). Guided by mechanistic insights from both genomic screens, we found that exogenous deoxycytidine markedly reduced GSK983 cytotoxicity but not antiviral activity, providing an attractive new approach to improve the therapeutic window of DHODH inhibitors against RNA viruses. Our results highlight the distinct advantages and limitations of each screening method for identifying drug targets, and demonstrate the utility of parallel knockdown and knockout screens for comprehensive probing of drug activity.

Mechanisms of action of brief alcohol interventions remain largely unknown - a narrative review.

PubMed

Gaume, Jacques; McCambridge, Jim; Bertholet, Nicolas; Daeppen, Jean-Bernard

2014-01-01

A growing body of evidence has shown the efficacy of brief intervention (BI) for hazardous and harmful alcohol use in primary health care settings. Evidence for efficacy in other settings and effectiveness when implemented at larger scale are disappointing. Indeed, BI comprises varying content; exploring BI content and mechanisms of action may be a promising way to enhance efficacy and effectiveness. Medline and PsychInfo, as well as references of retrieved publications were searched for original research or review on active ingredients (components or mechanisms) of face-to-face BIs [and its subtypes, including brief advice and brief motivational interviewing (BMI)] for alcohol. Overall, BI active ingredients have been scarcely investigated, almost only within BMI, and mostly among patients in the emergency room, young adults, and US college students. This body of research has shown that personalized feedback may be an effective component; specific MI techniques showed mixed findings; decisional balance findings tended to suggest a potential detrimental effect; while change plan exercises, advice to reduce or stop drinking, presenting alternative change options, and moderation strategies are promising but need further study. Client change talk is a potential mediator of BMI effects; change in norm perceptions and enhanced discrepancy between current behavior and broader life goals and values have received preliminary support; readiness to change was only partially supported as a mediator; while enhanced awareness of drinking, perceived risks/benefits of alcohol use, alcohol treatment seeking, and self-efficacy were seldom studied and have as yet found no significant support as such. Research is obviously limited and has provided no clear and consistent evidence on the mechanisms of alcohol BI. How BI achieves the effects seen in randomized trials remains mostly unknown and should be investigated to inform the development of more effective interventions.

New fossil remains of Homo naledi from the Lesedi Chamber, South Africa

PubMed Central

Hawks, John; Elliott, Marina; Schmid, Peter; Churchill, Steven E; de Ruiter, Darryl J; Roberts, Eric M; Hilbert-Wolf, Hannah; Garvin, Heather M; Williams, Scott A; Delezene, Lucas K; Feuerriegel, Elen M; Randolph-Quinney, Patrick; Kivell, Tracy L; Laird, Myra F; Tawane, Gaokgatlhe; DeSilva, Jeremy M; Bailey, Shara E; Brophy, Juliet K; Meyer, Marc R; Skinner, Matthew M; Tocheri, Matthew W; VanSickle, Caroline; Walker, Christopher S; Campbell, Timothy L; Kuhn, Brian; Kruger, Ashley; Tucker, Steven; Gurtov, Alia; Hlophe, Nompumelelo; Hunter, Rick; Morris, Hannah; Peixotto, Becca; Ramalepa, Maropeng; van Rooyen, Dirk; Tsikoane, Mathabela; Boshoff, Pedro; Dirks, Paul HGM; Berger, Lee R

2017-01-01

The Rising Star cave system has produced abundant fossil hominin remains within the Dinaledi Chamber, representing a minimum of 15 individuals attributed to Homo naledi. Further exploration led to the discovery of hominin material, now comprising 131 hominin specimens, within a second chamber, the Lesedi Chamber. The Lesedi Chamber is far separated from the Dinaledi Chamber within the Rising Star cave system, and represents a second depositional context for hominin remains. In each of three collection areas within the Lesedi Chamber, diagnostic skeletal material allows a clear attribution to H. naledi. Both adult and immature material is present. The hominin remains represent at least three individuals based upon duplication of elements, but more individuals are likely present based upon the spatial context. The most significant specimen is the near-complete cranium of a large individual, designated LES1, with an endocranial volume of approximately 610 ml and associated postcranial remains. The Lesedi Chamber skeletal sample extends our knowledge of the morphology and variation of H. naledi, and evidence of H. naledi from both recovery localities shows a consistent pattern of differentiation from other hominin species. DOI: http://dx.doi.org/10.7554/eLife.24232.001 PMID:28483039

New fossil remains of Homo naledi from the Lesedi Chamber, South Africa.

PubMed

Hawks, John; Elliott, Marina; Schmid, Peter; Churchill, Steven E; Ruiter, Darryl J de; Roberts, Eric M; Hilbert-Wolf, Hannah; Garvin, Heather M; Williams, Scott A; Delezene, Lucas K; Feuerriegel, Elen M; Randolph-Quinney, Patrick; Kivell, Tracy L; Laird, Myra F; Tawane, Gaokgatlhe; DeSilva, Jeremy M; Bailey, Shara E; Brophy, Juliet K; Meyer, Marc R; Skinner, Matthew M; Tocheri, Matthew W; VanSickle, Caroline; Walker, Christopher S; Campbell, Timothy L; Kuhn, Brian; Kruger, Ashley; Tucker, Steven; Gurtov, Alia; Hlophe, Nompumelelo; Hunter, Rick; Morris, Hannah; Peixotto, Becca; Ramalepa, Maropeng; Rooyen, Dirk van; Tsikoane, Mathabela; Boshoff, Pedro; Dirks, Paul Hgm; Berger, Lee R

2017-05-09

The Rising Star cave system has produced abundant fossil hominin remains within the Dinaledi Chamber, representing a minimum of 15 individuals attributed to Homo naledi . Further exploration led to the discovery of hominin material, now comprising 131 hominin specimens, within a second chamber, the Lesedi Chamber. The Lesedi Chamber is far separated from the Dinaledi Chamber within the Rising Star cave system, and represents a second depositional context for hominin remains. In each of three collection areas within the Lesedi Chamber, diagnostic skeletal material allows a clear attribution to H. naledi . Both adult and immature material is present. The hominin remains represent at least three individuals based upon duplication of elements, but more individuals are likely present based upon the spatial context. The most significant specimen is the near-complete cranium of a large individual, designated LES1, with an endocranial volume of approximately 610 ml and associated postcranial remains. The Lesedi Chamber skeletal sample extends our knowledge of the morphology and variation of H. naledi , and evidence of H. naledi from both recovery localities shows a consistent pattern of differentiation from other hominin species.

Emerging immunotherapy and strategies directly targeting B cells for the treatment of diffuse large B-cell lymphoma.

PubMed

Witkowska, Magdalena; Smolewski, Piotr

2015-01-01

During the last decade, significant prolonged survival in diffusive large B-cell lymphoma (DLBCL) has been observed. The efficacy of initial treatment improved mostly due to addition of a chimeric anti-CD20 monoclonal antibody (rituximab) to standard chemotherapeutic regimens. Moreover, accurate understanding of DLBCL pathogenesis and remarkable progress in gene expression profiling have led to the development of a variety of tumor-specific regimens. Novel agents target directly the pathways involved in signal transduction, lead to apoptosis and cancer cells differentiation. In this article, we mainly focus on new treatment options, such as monoclonal antibodies, tyrosine kinase inhibitors and immunomodulatory drugs, currently investigated in aggressive B-cell lymphoma with particular attention to DLBCL type.

Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

PubMed Central

Nasr, Rihab; Hajj, Hiba El; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-01-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL. PMID:21994752

Targeted therapeutic delivery using engineered exosomes and its applications in cardiovascular diseases.

PubMed

Xitong, Dang; Xiaorong, Zeng

2016-01-10

Exosomes are 30-120 nm membrane bound vesicles secreted naturally by almost all cells and exist in all body fluids. Accumulating evidence has shown that exosomes contain proteins, lipids, DNA, mRNA, miRNA, and lncRNA that can be transferred from producer cells to recipient cells, facilitating cell-cell communication. As the natural carrier of these signal molecules, exosomes possess many other properties such as stability, biocompatibility, biological barrier permeability, low toxicity, and low immunogenicity, which make them an attractive vehicle for therapeutic delivery. How exosomes target recipient cells in vivo remains largely unknown, however, exosomes are selectively enriched in some transmembrane proteins that can be genetically engineered to display ligands/homing peptides on their surface, which confers exosome targeting capability to cells bearing cognate receptors. With the discovery of many peptides homing to diseased tissues or organs through phage display and in vivo biopanning technologies, there is ample opportunity to explore the potential use of exosome for targeted gene therapy. Here, we briefly review exosome biogenesis, mechanisms of exosome-mediated cell–cell communication, and exosome isolation and purification methods, and specifically focus on the emerging exosome targeting technologies.

GLRS-R 2-colour retroreflector target design and predicted performance

NASA Technical Reports Server (NTRS)

Lund, Glenn

1993-01-01

This paper reports on the retroreflector ground-target design for the GLRS-R spaceborne dual-wavelength laser ranging system. The described passive design flows down from the requirements of high station autonomy, high global FOV (up to 60 degrees zenith angle), little or no multiple pulse returns, and adequate optical cross section for most ranging geometries. The proposed solution makes use of 5 hollow cube-corner retroreflectors of which one points to the zenith and the remaining four are inclined from the vertical at uniform azimuthal spacings. The need for fairly large (is approximately 10 cm) retroreflectors is expected (within turbulence limitations) to generate quite narrow diffraction lobes, thus placing non-trivial requirements on the vectorial accuracy of velocity aberration corrections. A good compromise solution is found by appropriately spoiling just one of the retroreflector dihedral angles from 90 degrees, thus generating two symmetrically oriented diffraction lobes in the return beam. The required spoil angles are found to have little dependence on ground target latitude. Various link budget analyses are presented, showing the influence of such factors as point-ahead optimization, turbulence, ranging angle, atmospheric visibility and ground target thermal deformations.

GLRS-R 2-colour retroreflector target design and predicted performance

NASA Astrophysics Data System (ADS)

Lund, Glenn

1993-06-01

This paper reports on the retroreflector ground-target design for the GLRS-R spaceborne dual-wavelength laser ranging system. The described passive design flows down from the requirements of high station autonomy, high global FOV (up to 60 degrees zenith angle), little or no multiple pulse returns, and adequate optical cross section for most ranging geometries. The proposed solution makes use of 5 hollow cube-corner retroreflectors of which one points to the zenith and the remaining four are inclined from the vertical at uniform azimuthal spacings. The need for fairly large (is approximately 10 cm) retroreflectors is expected (within turbulence limitations) to generate quite narrow diffraction lobes, thus placing non-trivial requirements on the vectorial accuracy of velocity aberration corrections. A good compromise solution is found by appropriately spoiling just one of the retroreflector dihedral angles from 90 degrees, thus generating two symmetrically oriented diffraction lobes in the return beam. The required spoil angles are found to have little dependence on ground target latitude. Various link budget analyses are presented, showing the influence of such factors as point-ahead optimization, turbulence, ranging angle, atmospheric visibility and ground target thermal deformations.

Generation-specific incentives and disincentives for nurse faculty to remain employed.

PubMed

Tourangeau, Ann E; Wong, Matthew; Saari, Margaret; Patterson, Erin

2015-05-01

The aims of this paper are to: (1) describe work characteristics that nurse faculty report encourage them to remain in or leave their academic positions; and (2) determine if there are generational differences in work characteristics selected. Nurse faculty play key roles in preparing new nurses and graduate nurses. However, educational institutions are challenged to maintain full employment in faculty positions. A cross-sectional, descriptive survey design was employed. Ontario nurse faculty were asked to select, from a list, work characteristics that entice them to remain in or leave their faculty positions. Respondent data (n = 650) were collected using mailed surveys over four months in 2011. While preferred work characteristics differed across generations, the most frequently selected incentives enticing nurse faculty to stay were having: a supportive director/dean, reasonable workloads, supportive colleagues, adequate resources, manageable class sizes and work/life balance. The most frequently selected disincentives included: unmanageable workloads, unsupportive organizations, poor work environments, exposure to bullying, belittling and other types of incivility in the workplace and having an unsupportive director/dean. This research yields new and important knowledge about work characteristics that nurse faculty report shape their decisions to remain in or leave their current employment. Certain work characteristics were rated as important among all generations. Where similarities exist, broad strategies addressing work characteristics may effectively promote nurse faculty retention. However, where generational differences exist, retention-promoting strategies should target generation-specific preferences. © 2014 John Wiley & Sons Ltd.

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

PubMed Central

Bosseboeuf, Adrien; Feron, Delphine; Tallet, Anne; Rossi, Cédric; Charlier, Cathy; Garderet, Laurent; Caillot, Denis; Moreau, Philippe; Cardó-Vila, Marina; Pasqualini, Renata; Nelson, Alfreda Destea; Wilson, Bridget S.; Perreault, Hélène; Piver, Eric; Weigel, Pierre; Harb, Jean; Bigot-Corbel, Edith; Hermouet, Sylvie

2017-01-01

Subsets of mature B cell neoplasms are linked to infection with intracellular pathogens such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), or Helicobacter pylori. However, the association between infection and the immunoglobulin-secreting (Ig-secreting) B proliferative disorders remains largely unresolved. We investigated whether the monoclonal IgG (mc IgG) produced by patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) targets infectious pathogens. Antigen specificity of purified mc IgG from a large patient cohort (n = 244) was determined using a multiplex infectious-antigen array (MIAA), which screens for reactivity to purified antigens or lysates from 9 pathogens. Purified mc IgG from 23.4% of patients (57 of 244) specifically recognized 1 pathogen in the MIAA. EBV was the most frequent target (15.6%), with 36 of 38 mc IgGs recognizing EBV nuclear antigen-1 (EBNA-1). MM patients with EBNA-1–specific mc IgG (14.0%) showed substantially greater bone marrow plasma cell infiltration and higher β2-microglobulin and inflammation/infection–linked cytokine levels compared with other smoldering myeloma/MM patients. Five other pathogens were the targets of mc IgG: herpes virus simplex-1 (2.9%), varicella zoster virus (1.6%), cytomegalovirus (0.8%), hepatitis C virus (1.2%), and H. pylori (1.2%). We conclude that a dysregulated immune response to infection may underlie disease onset and/or progression of MGUS and MM for subsets of patients. PMID:28978808

Simultaneous Drug Targeting of the Promoter MYC G-Quadruplex and BCL2 i-Motif in Diffuse Large B-Cell Lymphoma Delays Tumor Growth.

PubMed

Kendrick, Samantha; Muranyi, Andrea; Gokhale, Vijay; Hurley, Laurence H; Rimsza, Lisa M

2017-08-10

Secondary DNA structures are uniquely poised as therapeutic targets due to their molecular switch function in turning gene expression on or off and scaffold-like properties for protein and small molecule interaction. Strategies to alter gene transcription through these structures thus far involve targeting single DNA conformations. Here we investigate the feasibility of simultaneously targeting different secondary DNA structures to modulate two key oncogenes, cellular-myelocytomatosis (MYC) and B-cell lymphoma gene-2 (BCL2), in diffuse large B-cell lymphoma (DLBCL). Cotreatment with previously identified ellipticine and pregnanol derivatives that recognize the MYC G-quadruplex and BCL2 i-motif promoter DNA structures lowered mRNA levels and subsequently enhanced sensitivity to a standard chemotherapy drug, cyclophosphamide, in DLBCL cell lines. In vivo repression of MYC and BCL2 in combination with cyclophosphamide also significantly slowed tumor growth in DLBCL xenograft mice. Our findings demonstrate concurrent targeting of different DNA secondary structures offers an effective, precise, medicine-based approach to directly impede transcription and overcome aberrant pathways in aggressive malignancies.

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

Targeted Proteomic Quantification on Quadrupole-Orbitrap Mass Spectrometer*

PubMed Central

Gallien, Sebastien; Duriez, Elodie; Crone, Catharina; Kellmann, Markus; Moehring, Thomas; Domon, Bruno

2012-01-01

There is an immediate need for improved methods to systematically and precisely quantify large sets of peptides in complex biological samples. To date protein quantification in biological samples has been routinely performed on triple quadrupole instruments operated in selected reaction monitoring mode (SRM), and two major challenges remain. Firstly, the number of peptides to be included in one survey experiment needs to be increased to routinely reach several hundreds, and secondly, the degree of selectivity should be improved so as to reliably discriminate the targeted analytes from background interferences. High resolution and accurate mass (HR/AM) analysis on the recently developed Q-Exactive mass spectrometer can potentially address these issues. This instrument presents a unique configuration: it is constituted of an orbitrap mass analyzer equipped with a quadrupole mass filter as the front-end for precursor ion mass selection. This configuration enables new quantitative methods based on HR/AM measurements, including targeted analysis in MS mode (single ion monitoring) and in MS/MS mode (parallel reaction monitoring). The ability of the quadrupole to select a restricted m/z range allows one to overcome the dynamic range limitations associated with trapping devices, and the MS/MS mode provides an additional stage of selectivity. When applied to targeted protein quantification in urine samples and benchmarked with the reference SRM technique, the quadrupole-orbitrap instrument exhibits similar or better performance in terms of selectivity, dynamic range, and sensitivity. This high performance is further enhanced by leveraging the multiplexing capability of the instrument to design novel acquisition methods and apply them to large targeted proteomic studies for the first time, as demonstrated on 770 tryptic yeast peptides analyzed in one 60-min experiment. The increased quality of quadrupole-orbitrap data has the potential to improve existing protein

New perspectives on targeted therapy in ovarian cancer

PubMed Central

Coward, Jermaine IG; Middleton, Kathryn; Murphy, Felicity

2015-01-01

Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose) inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer. PMID:25678824

{13C }/{12C } ratios of pleistocene mummified remains from beringia

NASA Astrophysics Data System (ADS)

Bombin, Miguel; Muehlenbachs, Karlis

1985-01-01

During the Quaternary glacial episodes, when sea level was considerably lower, Asia and North America were linked by large extensions of circumarctic land (Beringia), which remained unglaciated. This land mass served not only as a biogeographical bridge for plants, animals, and humans, but also supported a biome very different from present tundra or boreal coniferous forests, which was dominated by steppes and a rich mammalian megafauna. Carbon stable isotope ratios of Beringian late Pleistocene mummified remains of bison, equids, mammoth, caribou, musk-ox, moose, woolly rhino, and other undetermined species, found preserved in permafrost, indicate that these megaherbivores fed exclusively on C 3 plants, and that C 4 grasses were not differentially ingested by bison, as previously suggested. Paleoclimatic constraints probably prevented the formation of a warm-season (C 4) guild during the later part of the growing season in the steppes of Beringia during the last glaciation.

Rab7-a novel redox target that modulates inflammatory pain processing.

PubMed

Kallenborn-Gerhardt, Wiebke; Möser, Christine V; Lorenz, Jana E; Steger, Mirco; Heidler, Juliana; Scheving, Reynir; Petersen, Jonas; Kennel, Lea; Flauaus, Cathrin; Lu, Ruirui; Edinger, Aimee L; Tegeder, Irmgard; Geisslinger, Gerd; Heide, Heinrich; Wittig, Ilka; Schmidtko, Achim

2017-07-01

Chronic pain is accompanied by production of reactive oxygen species (ROS) in various cells that are important for nociceptive processing. Recent data indicate that ROS can trigger specific redox-dependent signaling processes, but the molecular targets of ROS signaling in the nociceptive system remain largely elusive. Here, we performed a proteome screen for pain-dependent redox regulation using an OxICAT approach, thereby identifying the small GTPase Rab7 as a redox-modified target during inflammatory pain in mice. Prevention of Rab7 oxidation by replacement of the redox-sensing thiols modulates its GTPase activity. Immunofluorescence studies revealed Rab7 expression to be enriched in central terminals of sensory neurons. Knockout mice lacking Rab7 in sensory neurons showed normal responses to noxious thermal and mechanical stimuli; however, their pain behavior during inflammatory pain and in response to ROS donors was reduced. The data suggest that redox-dependent changes in Rab7 activity modulate inflammatory pain sensitivity.

Bioinformatic Identification of Potential MicroRNAs and Their Targets in the Lingzhi or Reishi Medicinal Mushroom Ganoderma lucidum (Higher Basidiomycetes).

PubMed

Mu, Da-Shuai; Li, Chenyang; Shi, Liang; Zhang, Xuchen; Ren, Ang; Zhao, Ming-Wen

2015-01-01

MicroRNAs (miRNAs) are a class of small, endogenous, noncoding RNA molecules that negatively regulate gene expression at the transcriptional or the post-transcriptional level. Although a large number of miRNAs have been identified in many species, especially model plants and animals, miRNAs in fungi remain largely unknown. In this study, based on a database of expressed sequence tags in Ganoderma lucidum, 89 potential miRNAs were identified using computational methods. Real-time polymerase chain reaction analysis of miRNA-like samples prepared from G. lucidum at different development stages revealed that miRNA-like RNAs were differentially expressed in different stages. Furthermore, a total of 28 potential targets were found based on near-perfect or perfect complementarity between the randomly selected 9 miRNA-like RNAs and the target sequences, and potential targets for G. lucidum miRNA-like RNAs were predicted. Finally, we studied the expression pattern of 4 target genes in 3 different development stages of G. lucidum to further understand the mechanism of interaction between miRNA-like RNAs and their target genes. Our analysis paves the way toward identifying fungal miRNA-like RNAs that might be involved in various physiological and cellular differentiation processes.

Pavement Remaining Service Interval [Tech Brief

DOT National Transportation Integrated Search

2013-05-01

This document is a technical summary of the Federal Highway Administration reports, "Reformulated Pavement Remaining Service Life Framework" (FHWA-HRT-13-038) and "Pavement Remaining Service Interval Implementation Guidelines" (FHWA-HRT-13-050). At t...

TARGET Publication Guidelines | Office of Cancer Genomics

Cancer.gov

Like other NCI large-scale genomics initiatives, TARGET is a community resource project and data are made available rapidly after validation for use by other researchers. To act in accord with the Fort Lauderdale principles and support the continued prompt public release of large-scale genomic data prior to publication, researchers who plan to prepare manuscripts containing descriptions of TARGET pediatric cancer data that would be of comparable scope to an initial TARGET disease-specific comprehensive, global analysis publication, and journal editors who receive such manuscripts, are

Harnessing extracellular vesicles to direct endochondral repair of large bone defects

PubMed Central

Ferreira, E.

2018-01-01

Large bone defects remain a tremendous clinical challenge. There is growing evidence in support of treatment strategies that direct defect repair through an endochondral route, involving a cartilage intermediate. While culture-expanded stem/progenitor cells are being evaluated for this purpose, these cells would compete with endogenous repair cells for limited oxygen and nutrients within ischaemic defects. Alternatively, it may be possible to employ extracellular vesicles (EVs) secreted by culture-expanded cells for overcoming key bottlenecks to endochondral repair, such as defect vascularization, chondrogenesis, and osseous remodelling. While mesenchymal stromal/stem cells are a promising source of therapeutic EVs, other donor cells should also be considered. The efficacy of an EV-based therapeutic will likely depend on the design of companion scaffolds for controlled delivery to specific target cells. Ultimately, the knowledge gained from studies of EVs could one day inform the long-term development of synthetic, engineered nanovesicles. In the meantime, EVs harnessed from in vitro cell culture have near-term promise for use in bone regenerative medicine. This narrative review presents a rationale for using EVs to improve the repair of large bone defects, highlights promising cell sources and likely therapeutic targets for directing repair through an endochondral pathway, and discusses current barriers to clinical translation. Cite this article: E. Ferreira, R. M. Porter. Harnessing extracellular vesicles to direct endochondral repair of large bone defects. Bone Joint Res 2018;7:263–273. DOI: 10.1302/2046-3758.74.BJR-2018-0006. PMID:29922444

Testing light dark matter coannihilation with fixed-target experiments

DOE PAGES

Izaguirre, Eder; Kahn, Yonatan; Krnjaic, Gordan; ...

2017-09-01

In this paper, we introduce a novel program of fixed-target searches for thermal-origin Dark Matter (DM), which couples inelastically to the Standard Model. Since the DM only interacts by transitioning to a heavier state, freeze-out proceeds via coannihilation and the unstable heavier state is depleted at later times. For sufficiently large mass splittings, direct detection is kinematically forbidden and indirect detection is impossible, so this scenario can only be tested with accelerators. Here we propose new searches at proton and electron beam fixed-target experiments to probe sub-GeV coannihilation, exploiting the distinctive signals of up- and downscattering as well as decaymore » of the excited state inside the detector volume. We focus on a representative model in which DM is a pseudo-Dirac fermion coupled to a hidden gauge field (dark photon), which kinetically mixes with the visible photon. We define theoretical targets in this framework and determine the existing bounds by reanalyzing results from previous experiments. We find that LSND, E137, and BaBar data already place strong constraints on the parameter space consistent with a thermal freeze-out origin, and that future searches at Belle II and MiniBooNE, as well as recently-proposed fixed-target experiments such as LDMX and BDX, can cover nearly all remaining gaps. We also briefly comment on the discovery potential for proposed beam dump and neutrino experiments which operate at much higher beam energies.« less

Testing light dark matter coannihilation with fixed-target experiments

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

Izaguirre, Eder; Kahn, Yonatan; Krnjaic, Gordan

In this paper, we introduce a novel program of fixed-target searches for thermal-origin Dark Matter (DM), which couples inelastically to the Standard Model. Since the DM only interacts by transitioning to a heavier state, freeze-out proceeds via coannihilation and the unstable heavier state is depleted at later times. For sufficiently large mass splittings, direct detection is kinematically forbidden and indirect detection is impossible, so this scenario can only be tested with accelerators. Here we propose new searches at proton and electron beam fixed-target experiments to probe sub-GeV coannihilation, exploiting the distinctive signals of up- and downscattering as well as decaymore » of the excited state inside the detector volume. We focus on a representative model in which DM is a pseudo-Dirac fermion coupled to a hidden gauge field (dark photon), which kinetically mixes with the visible photon. We define theoretical targets in this framework and determine the existing bounds by reanalyzing results from previous experiments. We find that LSND, E137, and BaBar data already place strong constraints on the parameter space consistent with a thermal freeze-out origin, and that future searches at Belle II and MiniBooNE, as well as recently-proposed fixed-target experiments such as LDMX and BDX, can cover nearly all remaining gaps. We also briefly comment on the discovery potential for proposed beam dump and neutrino experiments which operate at much higher beam energies.« less

Testing light dark matter coannihilation with fixed-target experiments

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

Izaguirre, Eder; Kahn, Yonatan; Krnjaic, Gordan

In this paper, we introduce a novel program of fixed-target searches for thermal-origin Dark Matter (DM), which couples inelastically to the Standard Model. Since the DM only interacts by transitioning to a heavier state, freeze-out proceeds via coannihilation and the unstable heavier state is depleted at later times. For sufficiently large mass splittings, direct detection is kinematically forbidden and indirect detection is impossible, so this scenario can only be tested with accelerators. Here we propose new searches at proton and electron beam fixed-target experiments to probe sub-GeV coannihilation, exploiting the distinctive signals of up- and down-scattering as well as decaymore » of the excited state inside the detector volume. We focus on a representative model in which DM is a pseudo-Dirac fermion coupled to a hidden gauge field (dark photon), which kinetically mixes with the visible photon. We define theoretical targets in this framework and determine the existing bounds by reanalyzing results from previous experiments. We find that LSND, E137, and BaBar data already place strong constraints on the parameter space consistent with a thermal freeze-out origin, and that future searches at Belle II and MiniBooNE, as well as recently-proposed fixed-target experiments such as LDMX and BDX, can cover nearly all remaining gaps. We also briefly comment on the discovery potential for proposed beam dump and neutrino experiments which operate at much higher beam energies.« less

Quantification of proteins in urine samples using targeted mass spectrometry methods.

PubMed

Khristenko, Nina; Domon, Bruno

2015-01-01

Numerous clinical proteomics studies are focused on the development of biomarkers to improve either diagnostics for early disease detection or the monitoring of the response to the treatment. Although, a wealth of biomarker candidates are available, their evaluation and validation in a true clinical setup remains challenging. In biomarkers evaluation studies, a panel of proteins of interest are systematically analyzed in a large cohort of samples. However, in spite of the latest progresses in mass spectrometry, the consistent detection of pertinent proteins in high complex biological samples is still a challenging task. Thus, targeted LC-MS/MS methods are better suited for the systematic analysis of biomarkers rather than shotgun approaches. This chapter describes the workflow used to perform targeted quantitative analyses of proteins in urinary samples. The peptides, as surrogates of the protein of interest, are commonly measured using a triple quadrupole mass spectrometers operated in selected reaction monitoring (SRM) mode. More recently, the advances in targeted LC-MS/MS analysis based on parallel reaction monitoring (PRM) performed on a quadrupole-orbitrap instrument have allowed to increase the specificity and selectivity of the measurements.

[PALEOPATHOLOGY OF HUMAN REMAINS].

PubMed

Minozzi, Simona; Fornaciari, Gino

2015-01-01

Many diseases induce alterations in the human skeleton, leaving traces of their presence in ancient remains. Paleopathological examination of human remains not only allows the study of the history and evolution of the disease, but also the reconstruction of health conditions in the past populations. This paper describes the most interesting diseases observed in skeletal samples from the Roman Imperial Age necropoles found in urban and suburban areas of Rome during archaeological excavations in the last decades. The diseases observed were grouped into the following categories: articular diseases, traumas, infections, metabolic or nutritional diseases, congenital diseases and tumours, and some examples are reported for each group. Although extensive epidemiological investigation in ancient skeletal records is impossible, the palaeopathological study allowed to highlight the spread of numerous illnesses, many of which can be related to the life and health conditions of the Roman population.

Study Identifies New Lymphoma Treatment Target

Cancer.gov

NCI researchers have identified new therapeutic targets for diffuse large B-cell lymphoma. Drugs that hit these targets are under clinical development and the researchers hope to begin testing them in clinical trials of patients with DLBCL.

Vocal reporting of echolocation targets: dolphins often report before click trains end.

PubMed

Ridgway, S H; Elsberry, W R; Blackwood, D J; Kamolnick, T; Todd, M; Carder, D A; Chaplin, Monica; Cranford, T W

2012-01-01

Bottlenose dolphins (Tursiops truncatus) wore opaque suction cups over their eyes while stationing behind an acoustically opaque door. This put the dolphins in a known position and orientation. When the door opened, the dolphin clicked to detect targets. Trainers specified that Dolphin S emit a whistle if the target was a 7.5 cm water filled sphere, or a pulse burst if the target was a rock. S remained quiet if there was no target. Dolphin B whistled for the sphere. She remained quiet for rock and for no target. Thus, S had to choose between three different responses, whistle, pulse burst, or remain quiet. B had to choose between two different responses, whistle or remain quiet. S gave correct vocal responses averaging 114 ms after her last echolocation click (range 182 ms before and 219 ms after the last click). Average response for B was 21 ms before her last echolocation click (range 250 ms before and 95 ms after the last click in the train). More often than not, B began her whistle response before her echolocation train ended. The findings suggest separate neural pathways for generation of response vocalizations as opposed to echolocation clicks. © 2012 Acoustical Society of America.

Tes, a potential Mena-related cancer therapy target.

PubMed

Li, X

2008-02-01

Cancer remains one of the world's most prominent causes of human morbidity and mortality, particularly in developing countries. According to 2005 statistics from the WHO, approximately 7.6 million people died of cancer out of 58 million deaths worldwide, with 9 million people estimated to die from cancer in 2015 and 11.4 million to die in 2030 (http://www.who.int/mediacentre/factsheets/fs297/en/index.html). The principal and internationally recognized methods of cancer treatment are surgery, radiotherapy, chemotherapy, or multimodality therapy. With the recent development of cancer biology, more and more tumor-related targets have been identified, ushering in a new era for target therapy. Every possible step that causes cellular cancer, such as signal transduction pathways, oncogenes and anti-oncogenes, cytokines and receptors, antiangiogenesis, suicide genes, and telomerase (Shay JW, Keith WN. Br J Cancer 2008), that is biologically relevant, reproducibly measurable, and definably correlated with clinical benefit represents a target for target therapies like targeting gene-virotherapy and monoclonal antibody-directed therapy. These therapies can specifically inhibit the growth of tumor cells at the molecular level and even kill them. Generally speaking, cancer-related targets should be crucial to the tumor's malignant phenotype, easily measurable in readily obtained clinical samples, and yield a significant clinical response. Since tumorigenesis is a very complex process involving the interaction of multiple factors and pathways, target treatment offers hopes to maximize efficacy while minimizing toxicity and specificity. More importantly, treatment should have little or no toxicity on normal cells, thus representing the most promising aspect of cancer research (Friday BB, Adjei AA. Clin Cancer Res 2008; 14:342-346). A recent cancer study has provided exciting information. According to Xinhua News from London, Michael Way and fellow researchers from Cancer

Comparison of decomposition rates between autopsied and non-autopsied human remains.

PubMed

Bates, Lennon N; Wescott, Daniel J

2016-04-01

Penetrating trauma has been cited as a significant factor in the rate of decomposition. Therefore, penetrating trauma may have an effect on estimations of time-since-death in medicolegal investigations and on research examining decomposition rates and processes when autopsied human bodies are used. The goal of this study was to determine if there are differences in the rate of decomposition between autopsied and non-autopsied human remains in the same environment. The purpose is to shed light on how large incisions, such as those from a thorocoabdominal autopsy, effect time-since-death estimations and research on the rate of decomposition that use both autopsied and non-autopsied human remains. In this study, 59 non-autopsied and 24 autopsied bodies were studied. The number of accumulated degree days required to reach each decomposition stage was then compared between autopsied and non-autopsied remains. Additionally, both types of bodies were examined for seasonal differences in decomposition rates. As temperature affects the rate of decomposition, this study also compared the internal body temperatures of autopsied and non-autopsied remains to see if differences between the two may be leading to differential decomposition. For this portion of this study, eight non-autopsied and five autopsied bodies were investigated. Internal temperature was collected once a day for two weeks. The results showed that differences in the decomposition rate between autopsied and non-autopsied remains was not statistically significant, though the average ADD needed to reach each stage of decomposition was slightly lower for autopsied bodies than non-autopsied bodies. There was also no significant difference between autopsied and non-autopsied bodies in the rate of decomposition by season or in internal temperature. Therefore, this study suggests that it is unnecessary to separate autopsied and non-autopsied remains when studying gross stages of human decomposition in Central Texas

The CRISPR/Cas9 system produces specific and homozygous targeted gene editing in rice in one generation.

PubMed

Zhang, Hui; Zhang, Jinshan; Wei, Pengliang; Zhang, Botao; Gou, Feng; Feng, Zhengyan; Mao, Yanfei; Yang, Lan; Zhang, Heng; Xu, Nanfei; Zhu, Jian-Kang

2014-08-01

The CRISPR/Cas9 system has been demonstrated to efficiently induce targeted gene editing in a variety of organisms including plants. Recent work showed that CRISPR/Cas9-induced gene mutations in Arabidopsis were mostly somatic mutations in the early generation, although some mutations could be stably inherited in later generations. However, it remains unclear whether this system will work similarly in crops such as rice. In this study, we tested in two rice subspecies 11 target genes for their amenability to CRISPR/Cas9-induced editing and determined the patterns, specificity and heritability of the gene modifications. Analysis of the genotypes and frequency of edited genes in the first generation of transformed plants (T0) showed that the CRISPR/Cas9 system was highly efficient in rice, with target genes edited in nearly half of the transformed embryogenic cells before their first cell division. Homozygotes of edited target genes were readily found in T0 plants. The gene mutations were passed to the next generation (T1) following classic Mendelian law, without any detectable new mutation or reversion. Even with extensive searches including whole genome resequencing, we could not find any evidence of large-scale off-targeting in rice for any of the many targets tested in this study. By specifically sequencing the putative off-target sites of a large number of T0 plants, low-frequency mutations were found in only one off-target site where the sequence had 1-bp difference from the intended target. Overall, the data in this study point to the CRISPR/Cas9 system being a powerful tool in crop genome engineering. © 2014 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

A Novel Method for Proximity Detection of Moving Targets Using a Large-Scale Planar Capacitive Sensor System

PubMed Central

Ye, Yong; Deng, Jiahao; Shen, Sanmin; Hou, Zhuo; Liu, Yuting

2016-01-01

A novel method for proximity detection of moving targets (with high dielectric constants) using a large-scale (the size of each sensor is 31 cm × 19 cm) planar capacitive sensor system (PCSS) is proposed. The capacitive variation with distance is derived, and a pair of electrodes in a planar capacitive sensor unit (PCSU) with a spiral shape is found to have better performance on sensitivity distribution homogeneity and dynamic range than three other shapes (comb shape, rectangular shape, and circular shape). A driving excitation circuit with a Clapp oscillator is proposed, and a capacitance measuring circuit with sensitivity of 0.21 Vp−p/pF is designed. The results of static experiments and dynamic experiments demonstrate that the voltage curves of static experiments are similar to those of dynamic experiments; therefore, the static data can be used to simulate the dynamic curves. The dynamic range of proximity detection for three projectiles is up to 60 cm, and the results of the following static experiments show that the PCSU with four neighboring units has the highest sensitivity (the sensitivities of other units are at least 4% lower); when the attack angle decreases, the intensity of sensor signal increases. This proposed method leads to the design of a feasible moving target detector with simple structure and low cost, which can be applied in the interception system. PMID:27196905

Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases.

PubMed

Punetha, Jaya; Kesari, Akanchha; Uapinyoying, Prech; Giri, Mamta; Clarke, Nigel F; Waddell, Leigh B; North, Kathryn N; Ghaoui, Roula; O'Grady, Gina L; Oates, Emily C; Sandaradura, Sarah A; Bönnemann, Carsten G; Donkervoort, Sandra; Plotz, Paul H; Smith, Edward C; Tesi-Rocha, Carolina; Bertorini, Tulio E; Tarnopolsky, Mark A; Reitter, Bernd; Hausmanowa-Petrusewicz, Irena; Hoffman, Eric P

2016-05-27

Molecular diagnostics in the genetic myopathies often requires testing of the largest and most complex transcript units in the human genome (DMD, TTN, NEB). Iteratively targeting single genes for sequencing has traditionally entailed high costs and long turnaround times. Exome sequencing has begun to supplant single targeted genes, but there are concerns regarding coverage and needed depth of the very large and complex genes that frequently cause myopathies. To evaluate efficiency of next-generation sequencing technologies to provide molecular diagnostics for patients with previously undiagnosed myopathies. We tested a targeted re-sequencing approach, using a 45 gene emulsion PCR myopathy panel, with subsequent sequencing on the Illumina platform in 94 undiagnosed patients. We compared the targeted re-sequencing approach to exome sequencing for 10 of these patients studied. We detected likely pathogenic mutations in 33 out of 94 patients with a molecular diagnostic rate of approximately 35%. The remaining patients showed variants of unknown significance (35/94 patients) or no mutations detected in the 45 genes tested (26/94 patients). Mutation detection rates for targeted re-sequencing vs. whole exome were similar in both methods; however exome sequencing showed better distribution of reads and fewer exon dropouts. Given that costs of highly parallel re-sequencing and whole exome sequencing are similar, and that exome sequencing now takes considerably less laboratory processing time than targeted re-sequencing, we recommend exome sequencing as the standard approach for molecular diagnostics of myopathies.

Genetically targeted 3D visualisation of Drosophila neurons under Electron Microscopy and X-Ray Microscopy using miniSOG

PubMed Central

Ng, Julian; Browning, Alyssa; Lechner, Lorenz; Terada, Masako; Howard, Gillian; Jefferis, Gregory S. X. E.

2016-01-01

Large dimension, high-resolution imaging is important for neural circuit visualisation as neurons have both long- and short-range patterns: from axons and dendrites to the numerous synapses at terminal endings. Electron Microscopy (EM) is the favoured approach for synaptic resolution imaging but how such structures can be segmented from high-density images within large volume datasets remains challenging. Fluorescent probes are widely used to localise synapses, identify cell-types and in tracing studies. The equivalent EM approach would benefit visualising such labelled structures from within sub-cellular, cellular, tissue and neuroanatomical contexts. Here we developed genetically-encoded, electron-dense markers using miniSOG. We demonstrate their ability in 1) labelling cellular sub-compartments of genetically-targeted neurons, 2) generating contrast under different EM modalities, and 3) segmenting labelled structures from EM volumes using computer-assisted strategies. We also tested non-destructive X-ray imaging on whole Drosophila brains to evaluate contrast staining. This enabled us to target specific regions for EM volume acquisition. PMID:27958322

Spatial Targeting for Bovine Tuberculosis Control: Can the Locations of Infected Cattle Be Used to Find Infected Badgers?

PubMed

Smith, Catherine M; Downs, Sara H; Mitchell, Andy; Hayward, Andrew C; Fry, Hannah; Le Comber, Steven C

2015-01-01

Bovine tuberculosis is a disease of historical importance to human health in the UK that remains a major animal health and economic issue. Control of the disease in cattle is complicated by the presence of a reservoir species, the Eurasian badger. In spite of uncertainty in the degree to which cattle disease results from transmission from badgers, and opposition from environmental groups, culling of badgers has been licenced in two large areas in England. Methods to limit culls to smaller areas that target badgers infected with TB whilst minimising the number of uninfected badgers culled is therefore of considerable interest. Here, we use historical data from a large-scale field trial of badger culling to assess two alternative hypothetical methods of targeting TB-infected badgers based on the distribution of cattle TB incidents: (i) a simple circular 'ring cull'; and (ii) geographic profiling, a novel technique for spatial targeting of infectious disease control that predicts the locations of sources of infection based on the distribution of linked cases. Our results showed that both methods required coverage of very large areas to ensure a substantial proportion of infected badgers were removed, and would result in many uninfected badgers being culled. Geographic profiling, which accounts for clustering of infections in badger and cattle populations, produced a small but non-significant increase in the proportion of setts with TB-infected compared to uninfected badgers included in a cull. It also provided no overall improvement at targeting setts with infected badgers compared to the ring cull. Cattle TB incidents in this study were therefore insufficiently clustered around TB-infected badger setts to design an efficient spatially targeted cull; and this analysis provided no evidence to support a move towards spatially targeted badger culling policies for bovine TB control.

Transsynaptic Teneurin Signaling in Neuromuscular Synapse Organization and Target Choice

PubMed Central

Mosca, Timothy J.; Hong, Weizhe; Dani, Vardhan S.; Favaloro, Vincenzo; Luo, Liqun

2012-01-01

Synapse assembly requires transsynaptic signals between the pre- and postsynapse1, but the understanding of essential organizational molecules remains incomplete2. Teneurins are conserved, EGF-repeat containing transmembrane proteins with large extracellular domains3. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic while Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization transsynaptically and cell-autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with α-spectrin. Genetic analyses of teneurin and neuroligin reveal their differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates specific motoneuron-muscle target selection. Our study identifies the Teneurins as a key bi-directional transsynaptic signal in general synapse organization, and demonstrates that such a molecule can also regulate target selection. PMID:22426000

Experimental Simulations of Large-Scale Collisions

NASA Technical Reports Server (NTRS)

Housen, Kevin R.

2002-01-01

This report summarizes research on the effects of target porosity on the mechanics of impact cratering. Impact experiments conducted on a centrifuge provide direct simulations of large-scale cratering on porous asteroids. The experiments show that large craters in porous materials form mostly by compaction, with essentially no deposition of material into the ejecta blanket that is a signature of cratering in less-porous materials. The ratio of ejecta mass to crater mass is shown to decrease with increasing crater size or target porosity. These results are consistent with the observation that large closely-packed craters on asteroid Mathilde appear to have formed without degradation to earlier craters.

TAPIR, a web server for the prediction of plant microRNA targets, including target mimics.

PubMed

Bonnet, Eric; He, Ying; Billiau, Kenny; Van de Peer, Yves

2010-06-15

We present a new web server called TAPIR, designed for the prediction of plant microRNA targets. The server offers the possibility to search for plant miRNA targets using a fast and a precise algorithm. The precise option is much slower but guarantees to find less perfectly paired miRNA-target duplexes. Furthermore, the precise option allows the prediction of target mimics, which are characterized by a miRNA-target duplex having a large loop, making them undetectable by traditional tools. The TAPIR web server can be accessed at: http://bioinformatics.psb.ugent.be/webtools/tapir. Supplementary data are available at Bioinformatics online.

Taphonomic Patterning of Cemetery Remains Received at the Office of the Chief Medical Examiner, Boston, Massachusetts.

PubMed

Pokines, James T; Zinni, Debra Prince; Crowley, Kate

2016-01-01

A sample of 49 cases of cemetery remains received at the Office of the Chief Medical Examiner, Massachusetts (OCME-MA), in Boston was compared with published taphonomic profiles of cemetery remains. The present sample is composed of a cross section of typical cases in this region that ultimately are derived from modern to historical coffin burials and get turned over to or seized by law enforcement. The present sample was composed of a large portion of isolated remains, and most were completely skeletonized. The most prevalent taphonomic characteristics included uniform staining (77.6%), coffin wear (46.9%), and cortical Exfoliation (49.0%). Other taphonomic changes occurring due to later surface exposure of cemetery remains included subaerial weathering, animal gnawing, algae formation, and excavation marks. A case of one set of skeletal remains associated with coffin artifacts and cemetery offerings that was recovered from transported cemetery fill is also presented. © 2015 American Academy of Forensic Sciences.

A murine model of targeted infusion for intracranial tumors.

PubMed

Kim, Minhyung; Barone, Tara A; Fedtsova, Natalia; Gleiberman, Anatoli; Wilfong, Chandler D; Alosi, Julie A; Plunkett, Robert J; Gudkov, Andrei; Skitzki, Joseph J

2016-01-01

Historically, intra-arterial (IA) drug administration for malignant brain tumors including glioblastoma multiforme (GBM) was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous (IV) or oral administrations. Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience. The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors.

Optimization of interneuron function by direct coupling of cell migration and axonal targeting.

PubMed

Lim, Lynette; Pakan, Janelle M P; Selten, Martijn M; Marques-Smith, André; Llorca, Alfredo; Bae, Sung Eun; Rochefort, Nathalie L; Marín, Oscar

2018-06-18

Neural circuit assembly relies on the precise synchronization of developmental processes, such as cell migration and axon targeting, but the cell-autonomous mechanisms coordinating these events remain largely unknown. Here we found that different classes of interneurons use distinct routes of migration to reach the embryonic cerebral cortex. Somatostatin-expressing interneurons that migrate through the marginal zone develop into Martinotti cells, one of the most distinctive classes of cortical interneurons. For these cells, migration through the marginal zone is linked to the development of their characteristic layer 1 axonal arborization. Altering the normal migratory route of Martinotti cells by conditional deletion of Mafb-a gene that is preferentially expressed by these cells-cell-autonomously disrupts axonal development and impairs the function of these cells in vivo. Our results suggest that migration and axon targeting programs are coupled to optimize the assembly of inhibitory circuits in the cerebral cortex.

Drug discovery in tuberculosis. New drug targets and antimycobacterial agents.

PubMed

Campaniço, André; Moreira, Rui; Lopes, Francisca

2018-04-25

Tuberculosis (TB) remains a major health problem worldwide. The infectious agent, Mycobacterium tuberculosis, has a unique ability to survive within the host, alternating between active and latent disease states, and escaping the immune system defences. The extended duration of anti-TB regimens and the increasing prevalence of multidrug- (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains have created an urgent need for new antibiotics active against drug-resistant organisms and that can shorten standard therapy. However, despite success in identifying active compounds through phenotypic screens, the conversion of hits into novel chemical series and ultimately into clinical candidates is hampered by the poor efficacy in eliminating M. tuberculosis within different host compartments, including macrophages, as well as a lack of knowledge about the specific target(s) inhibited and/or upregulated. The current status of anti-TB lead generation has much improved over the last decade, as exemplified by the recent approval of bedaquiline and delamanid to treat MDR-TB and XDR-TB. This review provides a critical analysis on the strategies used to progress hit compounds into viable lead candidates, and how emerging targets may play a role in TB drug discovery in the near future. Four new relevant targets are addressed: the enoyl-acyl carrier protein reductase, InhA; the transmembrane transport protein large, MmpL3; the decaprenylphospho-beta-d-ribofuranose 2-oxidase, DprE1; and the ubiquinol-cytochrome C reductase, QcrB. Validated hit compounds for each target are presented and explored, and the medicinal chemistry strategies to expand SAR around novel chemotypes analyzed. In addition, very recent emerging targets are also discussed. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Targeted carbon conservation at national scales with high-resolution monitoring

PubMed Central

Asner, Gregory P.; Knapp, David E.; Martin, Roberta E.; Tupayachi, Raul; Anderson, Christopher B.; Mascaro, Joseph; Sinca, Felipe; Chadwick, K. Dana; Higgins, Mark; Farfan, William; Llactayo, William; Silman, Miles R.

2014-01-01

Terrestrial carbon conservation can provide critical environmental, social, and climate benefits. Yet, the geographically complex mosaic of threats to, and opportunities for, conserving carbon in landscapes remain largely unresolved at national scales. Using a new high-resolution carbon mapping approach applied to Perú, a megadiverse country undergoing rapid land use change, we found that at least 0.8 Pg of aboveground carbon stocks are at imminent risk of emission from land use activities. Map-based information on the natural controls over carbon density, as well as current ecosystem threats and protections, revealed three biogeographically explicit strategies that fully offset forthcoming land-use emissions. High-resolution carbon mapping affords targeted interventions to reduce greenhouse gas emissions in rapidly developing tropical nations. PMID:25385593

Targeted carbon conservation at national scales with high-resolution monitoring.

PubMed

Asner, Gregory P; Knapp, David E; Martin, Roberta E; Tupayachi, Raul; Anderson, Christopher B; Mascaro, Joseph; Sinca, Felipe; Chadwick, K Dana; Higgins, Mark; Farfan, William; Llactayo, William; Silman, Miles R

2014-11-25

Terrestrial carbon conservation can provide critical environmental, social, and climate benefits. Yet, the geographically complex mosaic of threats to, and opportunities for, conserving carbon in landscapes remain largely unresolved at national scales. Using a new high-resolution carbon mapping approach applied to Perú, a megadiverse country undergoing rapid land use change, we found that at least 0.8 Pg of aboveground carbon stocks are at imminent risk of emission from land use activities. Map-based information on the natural controls over carbon density, as well as current ecosystem threats and protections, revealed three biogeographically explicit strategies that fully offset forthcoming land-use emissions. High-resolution carbon mapping affords targeted interventions to reduce greenhouse gas emissions in rapidly developing tropical nations.

The sweet trap in tumors: aerobic glycolysis and potential targets for therapy.

PubMed

Yu, Li; Chen, Xun; Wang, Liantang; Chen, Shangwu

2016-06-21

Metabolic change is one of the hallmarks of tumor, which has recently attracted a great of attention. One of main metabolic characteristics of tumor cells is the high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in glycolysis pathway than that in tricarboxylic acid cycle. The molecular mechanism of a high glycolytic flux in tumor cells remains unclear. A large amount of intermediates derived from glycolytic pathway could meet the biosynthetic requirements of the proliferating cells. Hypoxia-induced HIF-1α, PI3K-Akt-mTOR signaling pathway, and many other factors, such as oncogene activation and tumor suppressor inactivation, drive cancer cells to favor glycolysis over mitochondrial oxidation. Several small molecules targeting glycolytic pathway exhibit promising anticancer activity both in vitro and in vivo. In this review, we will focus on the latest progress in the regulation of aerobic glycolysis and discuss the potential targets for the tumor therapy.

Real-time imaging of Huntingtin aggregates diverting target search and gene transcription

PubMed Central

Li, Li; Liu, Hui; Dong, Peng; Li, Dong; Legant, Wesley R; Grimm, Jonathan B; Lavis, Luke D; Betzig, Eric; Tjian, Robert; Liu, Zhe

2016-01-01

The presumptive altered dynamics of transient molecular interactions in vivo contributing to neurodegenerative diseases have remained elusive. Here, using single-molecule localization microscopy, we show that disease-inducing Huntingtin (mHtt) protein fragments display three distinct dynamic states in living cells – 1) fast diffusion, 2) dynamic clustering and 3) stable aggregation. Large, stable aggregates of mHtt exclude chromatin and form 'sticky' decoy traps that impede target search processes of key regulators involved in neurological disorders. Functional domain mapping based on super-resolution imaging reveals an unexpected role of aromatic amino acids in promoting protein-mHtt aggregate interactions. Genome-wide expression analysis and numerical simulation experiments suggest mHtt aggregates reduce transcription factor target site sampling frequency and impair critical gene expression programs in striatal neurons. Together, our results provide insights into how mHtt dynamically forms aggregates and disrupts the finely-balanced gene control mechanisms in neuronal cells. DOI: http://dx.doi.org/10.7554/eLife.17056.001 PMID:27484239

Therapeutic strategy with artificially-designed i-lncRNA targeting multiple oncogenic microRNAs exhibits effective antitumor activity in diffuse large B-cell lymphoma.

PubMed

Su, Yinghan; Sun, Bin; Lin, Xuejing; Zhao, Xinying; Ji, Weidan; He, Miaoxia; Qian, Haihua; Song, Xianmin; Yang, Jianmin; Wang, Jianmin; Chen, Jie

2016-08-02

In diffuse large B-cell lymphoma (DLBCL), many oncogenic microRNAs (OncomiRs) are highly expressed to promote disease development and progression by inhibiting the expression and function of certain tumor suppressor genes, and these OncomiRs comprise a promising new class of molecular targets for the treatment of DLBCL. However, most current therapeutic studies have focused on a single miRNA, with limited treatment outcomes. In this study, we generated tandem sequences of 10 copies of the complementary binding sequences to 13 OncomiRs and synthesized an interfering long non-coding RNA (i-lncRNA). The highly-expressed i-lncRNA in DLBCL cells would compete with the corresponding mRNAs of OncomiR target genes for binding OncomiRs, thereby effectively consuming a large amount of OncomiRs and protecting many tumor suppressor genes. The in vitro experiments confirmed that the i-lncRNA expression significantly inhibited cell proliferation, induced cell cycle arrest and apoptosis in DLBCL cell lines, mainly through upregulating the expression of PTEN, p27kip1, TIMP3, RECK and downregulating the expression of p38/MAPK, survivin, CDK4, c-myc. In the established SUDHL-4 xenografts in nude mice, the treatment strategy involving adenovirus-mediated i-lncRNA expression significantly inhibited the growth of DLBCL xenografts. Therefore, this treatment would specifically target the carcinogenic effects of many OncomiRs that are usually expressed in DLBCL and not in normal cells, such a strategy could improve anti-tumor efficacy and safety and may be a good prospect for clinical applications.

Large scale analysis of signal reachability.

PubMed

Todor, Andrei; Gabr, Haitham; Dobra, Alin; Kahveci, Tamer

2014-06-15

Major disorders, such as leukemia, have been shown to alter the transcription of genes. Understanding how gene regulation is affected by such aberrations is of utmost importance. One promising strategy toward this objective is to compute whether signals can reach to the transcription factors through the transcription regulatory network (TRN). Due to the uncertainty of the regulatory interactions, this is a #P-complete problem and thus solving it for very large TRNs remains to be a challenge. We develop a novel and scalable method to compute the probability that a signal originating at any given set of source genes can arrive at any given set of target genes (i.e., transcription factors) when the topology of the underlying signaling network is uncertain. Our method tackles this problem for large networks while providing a provably accurate result. Our method follows a divide-and-conquer strategy. We break down the given network into a sequence of non-overlapping subnetworks such that reachability can be computed autonomously and sequentially on each subnetwork. We represent each interaction using a small polynomial. The product of these polynomials express different scenarios when a signal can or cannot reach to target genes from the source genes. We introduce polynomial collapsing operators for each subnetwork. These operators reduce the size of the resulting polynomial and thus the computational complexity dramatically. We show that our method scales to entire human regulatory networks in only seconds, while the existing methods fail beyond a few tens of genes and interactions. We demonstrate that our method can successfully characterize key reachability characteristics of the entire transcriptions regulatory networks of patients affected by eight different subtypes of leukemia, as well as those from healthy control samples. All the datasets and code used in this article are available at bioinformatics.cise.ufl.edu/PReach/scalable.htm. © The Author 2014

Tools for in silico target fishing.

PubMed

Cereto-Massagué, Adrià; Ojeda, María José; Valls, Cristina; Mulero, Miquel; Pujadas, Gerard; Garcia-Vallve, Santiago

2015-01-01

Computational target fishing methods are designed to identify the most probable target of a query molecule. This process may allow the prediction of the bioactivity of a compound, the identification of the mode of action of known drugs, the detection of drug polypharmacology, drug repositioning or the prediction of the adverse effects of a compound. The large amount of information regarding the bioactivity of thousands of small molecules now allows the development of these types of methods. In recent years, we have witnessed the emergence of many methods for in silico target fishing. Most of these methods are based on the similarity principle, i.e., that similar molecules might bind to the same targets and have similar bioactivities. However, the difficult validation of target fishing methods hinders comparisons of the performance of each method. In this review, we describe the different methods developed for target prediction, the bioactivity databases most frequently used by these methods, and the publicly available programs and servers that enable non-specialist users to obtain these types of predictions. It is expected that target prediction will have a large impact on drug development and on the functional food industry. Copyright © 2014 Elsevier Inc. All rights reserved.

The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus.

PubMed

Martin, E Anne; Muralidhar, Shruti; Wang, Zhirong; Cervantes, Diégo Cordero; Basu, Raunak; Taylor, Matthew R; Hunter, Jennifer; Cutforth, Tyler; Wilke, Scott A; Ghosh, Anirvan; Williams, Megan E

2015-11-17

Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons. Consequently, loss of Kirrel3 robustly increases CA3 neuron activity in developing mice. Alterations in the Kirrel3 gene are repeatedly associated with intellectual disabilities, but the role of Kirrel3 at synapses remained largely unknown. Our findings demonstrate that subtle synaptic changes during development impact circuit function and provide the first insight toward understanding the cellular basis of Kirrel3-dependent neurodevelopmental disorders.

Prediction of miRNA targets.

PubMed

Oulas, Anastasis; Karathanasis, Nestoras; Louloupi, Annita; Pavlopoulos, Georgios A; Poirazi, Panayiota; Kalantidis, Kriton; Iliopoulos, Ioannis

2015-01-01

Computational methods for miRNA target prediction are currently undergoing extensive review and evaluation. There is still a great need for improvement of these tools and bioinformatics approaches are looking towards high-throughput experiments in order to validate predictions. The combination of large-scale techniques with computational tools will not only provide greater credence to computational predictions but also lead to the better understanding of specific biological questions. Current miRNA target prediction tools utilize probabilistic learning algorithms, machine learning methods and even empirical biologically defined rules in order to build models based on experimentally verified miRNA targets. Large-scale protein downregulation assays and next-generation sequencing (NGS) are now being used to validate methodologies and compare the performance of existing tools. Tools that exhibit greater correlation between computational predictions and protein downregulation or RNA downregulation are considered the state of the art. Moreover, efficiency in prediction of miRNA targets that are concurrently verified experimentally provides additional validity to computational predictions and further highlights the competitive advantage of specific tools and their efficacy in extracting biologically significant results. In this review paper, we discuss the computational methods for miRNA target prediction and provide a detailed comparison of methodologies and features utilized by each specific tool. Moreover, we provide an overview of current state-of-the-art high-throughput methods used in miRNA target prediction.

Biased normalized cuts for target detection in hyperspectral imagery

NASA Astrophysics Data System (ADS)

Zhang, Xuewen; Dorado-Munoz, Leidy P.; Messinger, David W.; Cahill, Nathan D.

2016-05-01

The Biased Normalized Cuts (BNC) algorithm is a useful technique for detecting targets or objects in RGB imagery. In this paper, we propose modifying BNC for the purpose of target detection in hyperspectral imagery. As opposed to other target detection algorithms that typically encode target information prior to dimensionality reduction, our proposed algorithm encodes target information after dimensionality reduction, enabling a user to detect different targets in interactive mode. To assess the proposed BNC algorithm, we utilize hyperspectral imagery (HSI) from the SHARE 2012 data campaign, and we explore the relationship between the number and the position of expert-provided target labels and the precision/recall of the remaining targets in the scene.

Chemical Structural Novelty: On-Targets and Off-Targets

PubMed Central

Yera, Emmanuel R.; Cleves, Ann. E.; Jain, Ajay N.

2011-01-01

Drug structures may be quantitatively compared based on 2D topological structural considerations and based on 3D characteristics directly related to binding. A framework for combining multiple similarity computations is presented along with its systematic application to 358 drugs with overlapping pharmacology. Given a new molecule along with a set of molecules sharing some biological effect, a single score based on comparison to the known set is produced, reflecting either 2D similarity, 3D similarity, or their combination. For prediction of primary targets, the benefit of 3D over 2D was relatively small, but for prediction of off-targets, the added benefit was large. In addition to assessing prediction, the relationship between chemical similarity and pharmacological novelty was studied. Drug pairs that shared high 3D similarity but low 2D similarity (i.e. a novel scaffold) were shown to be much more likely to exhibit pharmacologically relevant differences in terms of specific protein target modulation. PMID:21916467

New strategy for drug discovery by large-scale association analysis of molecular networks of different species.

PubMed

Zhang, Bo; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Wu, Ziyin; Zhang, Wenjuan; Yang, Xiaoyan; Gong, Fukai; Li, Yuerong; Chen, Xiaoyu; Gao, Shuo; Chen, Xuetong; Li, Yan; Lu, Aiping; Wang, Yonghua

2016-02-25

The development of modern omics technology has not significantly improved the efficiency of drug development. Rather precise and targeted drug discovery remains unsolved. Here a large-scale cross-species molecular network association (CSMNA) approach for targeted drug screening from natural sources is presented. The algorithm integrates molecular network omics data from humans and 267 plants and microbes, establishing the biological relationships between them and extracting evolutionarily convergent chemicals. This technique allows the researcher to assess targeted drugs for specific human diseases based on specific plant or microbe pathways. In a perspective validation, connections between the plant Halliwell-Asada (HA) cycle and the human Nrf2-ARE pathway were verified and the manner by which the HA cycle molecules act on the human Nrf2-ARE pathway as antioxidants was determined. This shows the potential applicability of this approach in drug discovery. The current method integrates disparate evolutionary species into chemico-biologically coherent circuits, suggesting a new cross-species omics analysis strategy for rational drug development.

Development of Bone Targeting Drugs.

PubMed

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J; Mackenzie, William G; Mason, Robert W; Orii, Tadao; Tomatsu, Shunji

2017-06-23

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca 2+ . The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments.

Development of Bone Targeting Drugs

PubMed Central

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J.; Mackenzie, William G.; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

2017-01-01

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments. PMID:28644392

Survival signals and targets for therapy in breast implant-associated ALK--anaplastic large cell lymphoma.

PubMed

Lechner, Melissa G; Megiel, Carolina; Church, Connor H; Angell, Trevor E; Russell, Sarah M; Sevell, Rikki B; Jang, Julie K; Brody, Garry S; Epstein, Alan L

2012-09-01

Anaplastic lymphoma kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphoma (T-ALCL) in patients with textured saline and silicone breast implants is a recently recognized clinical entity for which the etiology and optimal treatment remain unknown. Using three newly established model cell lines from patient biopsy specimens, designated T-cell breast lymphoma (TLBR)-1 to -3, we characterized the phenotype and function of these tumors to identify mechanisms of cell survival and potential therapeutic targets. Cytogenetics revealed chromosomal atypia with partial or complete trisomy and absence of the NPM-ALK (2;5) translocation. Phenotypic characterization showed strong positivity for CD30, CD71, T-cell CD2/5/7, and antigen presentation (HLA-DR, CD80, CD86) markers, and interleukin (IL)-2 (CD25, CD122) and IL-6 receptors. Studies of these model cell lines showed strong activation of STAT3 signaling, likely related to autocrine production of IL-6 and decreased SHP-1. STAT3 inhibition, directly or by recovery of SHP-1, and cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) chemotherapy reagents, effectively kill cells of all three TLBR models in vitro and may be pursued as therapies for patients with breast implant-associated T-ALCLs. The TLBR cell lines closely resemble the primary breast implant-associated lymphomas from which they were derived and as such provide valuable preclinical models to study their unique biology. ©2012 AACR.

Targeting vector construction through recombineering.

PubMed

Malureanu, Liviu A

2011-01-01

Gene targeting in mouse embryonic stem cells is an essential, yet still very expensive and highly time-consuming, tool and method to study gene function at the organismal level or to create mouse models of human diseases. Conventional cloning-based methods have been largely used for generating targeting vectors, but are hampered by a number of limiting factors, including the variety and location of restriction enzymes in the gene locus of interest, the specific PCR amplification of repetitive DNA sequences, and cloning of large DNA fragments. Recombineering is a technique that exploits the highly efficient homologous recombination function encoded by λ phage in Escherichia coli. Bacteriophage-based recombination can recombine homologous sequences as short as 30-50 bases, allowing manipulations such as insertion, deletion, or mutation of virtually any genomic region. The large availability of mouse genomic bacterial artificial chromosome (BAC) libraries covering most of the genome facilitates the retrieval of genomic DNA sequences from the bacterial chromosomes through recombineering. This chapter describes a successfully applied protocol and aims to be a detailed guide through the steps of generation of targeting vectors through recombineering.

Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER.

PubMed

Smart, Oliver S; Womack, Thomas O; Flensburg, Claus; Keller, Peter; Paciorek, Włodek; Sharff, Andrew; Vonrhein, Clemens; Bricogne, Gérard

2012-04-01

Maximum-likelihood X-ray macromolecular structure refinement in BUSTER has been extended with restraints facilitating the exploitation of structural similarity. The similarity can be between two or more chains within the structure being refined, thus favouring NCS, or to a distinct 'target' structure that remains fixed during refinement. The local structural similarity restraints (LSSR) approach considers all distances less than 5.5 Å between pairs of atoms in the chain to be restrained. For each, the difference from the distance between the corresponding atoms in the related chain is found. LSSR applies a restraint penalty on each difference. A functional form that reaches a plateau for large differences is used to avoid the restraints distorting parts of the structure that are not similar. Because LSSR are local, there is no need to separate out domains. Some restraint pruning is still necessary, but this has been automated. LSSR have been available to academic users of BUSTER since 2009 with the easy-to-use -autoncs and -target target.pdb options. The use of LSSR is illustrated in the re-refinement of PDB entries 5rnt, where -target enables the correct ligand-binding structure to be found, and 1osg, where -autoncs contributes to the location of an additional copy of the cyclic peptide ligand.

Large Diffractive Optics for GEo-Based Earth Surveillance

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

Hyde, R A

2003-09-11

The natural vantage point for performing Earth-centric operations from space is geosynchronous orbit (GEO); a platform there moves at the same rate as the Earth's surface, so appears to continually ''hover'' over a fixed site on the Earth. Unlike spacecraft in other orbits, which rapidly fly-over targets, a GEO-based platform remains in-position all the time. In order to insure continual access to sites using low earth orbit (LEO) platforms, one needs a large enough constellation ({approx} 50) of spacecraft so that one is always overhead; in contrast, a single GEO platform provides continuous coverage over sites throughout Euro-Asia. This permanentmore » coverage comes, unfortunately, with a stiff price-tag; geosynchronous orbit is 36,000 km high, so space platforms there must operate at ranges roughly 100 times greater than ones located in LEO. For optical-based applications, this extreme range is difficult to deal with; for surveillance the price is a 100-fold loss of resolution, for laser weapons it is a 10,000-fold loss in flux-on-target. These huge performance penalties are almost always unacceptable, preventing us from successfully using GEO-based platforms. In practice, we are forced to either settle for brief, infrequent access to targets, or, if we demand continuous coverage, to invest in large, many-satellite, constellations. There is, fortunately, a way to use GEO-based optical platforms without incurring the huge, range-dependent, performance penalties; one must simply use bigger optics. As long as the aperture of a platform's optics increases as much as its operating range, then its performance (resolution and/or flux) does not suffer; the price for operating from GEO is simply 100-fold larger optics. This is, of course, a very stiff price; while meter-class optics may suffice for many low-earth-orbit applications, 100 meter apertures are needed in order to achieve similar performance from GEO. Since even the largest Earth-based telescope is only 10

The Cell Cycle Regulator CCDC6 Is a Key Target of RNA-Binding Protein EWS

PubMed Central

Duggimpudi, Sujitha; Larsson, Erik; Nabhani, Schafiq; Borkhardt, Arndt; Hoell, Jessica I

2015-01-01

Genetic translocation of EWSR1 to ETS transcription factor coding region is considered as primary cause for Ewing sarcoma. Previous studies focused on the biology of chimeric transcription factors formed due to this translocation. However, the physiological consequences of heterozygous EWSR1 loss in these tumors have largely remained elusive. Previously, we have identified various mRNAs bound to EWS using PAR-CLIP. In this study, we demonstrate CCDC6, a known cell cycle regulator protein, as a novel target regulated by EWS. siRNA mediated down regulation of EWS caused an elevated apoptosis in cells in a CCDC6-dependant manner. This effect was rescued upon re-expression of CCDC6. This study provides evidence for a novel functional link through which wild-type EWS operates in a target-dependant manner in Ewing sarcoma. PMID:25751255

Novel pharmacological targets for the rhythm control management of atrial fibrillation.

PubMed

Burashnikov, Alexander; Antzelevitch, Charles

2011-12-01

Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Development of safe and effective pharmacological treatments for AF is one of the greatest unmet medical needs facing our society. In spite of significant progress in non-pharmacological AF treatments (largely due to the use of catheter ablation techniques), anti-arrhythmic agents (AADs) remain first line therapy for rhythm control management of AF for most AF patients. When considering efficacy, safety and tolerability, currently available AADs for rhythm control of AF are less than optimal. Ion channel inhibition remains the principal strategy for termination of AF and prevention of its recurrence. Practical clinical experience indicates that multi-ion channel blockers are generally more optimal for rhythm control of AF compared to ion channel-selective blockers. Recent studies suggest that atrial-selective sodium channel block can lead to safe and effective suppression of AF and that concurrent inhibition of potassium ion channels may potentiate this effect. An important limitation of the ion channel block approach for AF treatment is that non-electrical factors (largely structural remodeling) may importantly determine the generation of AF, so that "upstream therapy", aimed at preventing or reversing structural remodeling, may be required for effective rhythm control management. This review focuses on novel pharmacological targets for the rhythm control management of AF. Copyright © 2011 Elsevier Inc. All rights reserved.

Bodily matters above and below ground: the treatment of American remains from the Korean War.

PubMed

Keene, Judith

2010-02-01

Throughout most of the twentieth century, depending on the capabilities of the military mortuary services and the time limits set by government, the bodies of the American fallen in foreign wars have been repatriated home to their families. In the Korean War the conditions of combat posed large challenges to the recovery and returns of bodily remains. Almost half a century after that conflict, the American missing in Korea have become significant players within the government's expanding efforts that were prompted in answer to demands to locate American soldiers who remain unaccounted for from the Vietnam War. The essay traces the background to U.S. military mortuary services and the operation in the Korean War and in the subsequent joint expeditions in North Korea. The analysis concludes that in most of these ventures the outlay of resources has produced few remains.

Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.

PubMed

Mishra, Manoj K; Beaty, Claude A; Lesniak, Wojciech G; Kambhampati, Siva P; Zhang, Fan; Wilson, Mary A; Blue, Mary E; Troncoso, Juan C; Kannan, Sujatha; Johnston, Michael V; Baumgartner, William A; Kannan, Rangaramanujam M

2014-03-25

Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer-drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.

Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest

PubMed Central

2015-01-01

Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer–drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems. PMID:24499315

Cancer metabolism: strategic diversion from targeting cancer drivers to targeting cancer suppliers.

PubMed

Kim, Soo-Youl

2015-03-01

Drug development groups are close to discovering another pot of gold-a therapeutic target-similar to the success of imatinib (Gleevec) in the field of cancer biology. Modern molecular biology has improved cancer therapy through the identification of more pharmaceutically viable targets, and yet major problems and risks associated with late-phase cancer therapy remain. Presently, a growing number of reports have initiated a discussion about the benefits of metabolic regulation in cancers. The Warburg effect, a great discovery approximately 70 years ago, addresses the "universality" of cancer characteristics. For instance, most cancer cells prefer aerobic glycolysis instead of mitochondrial respiration. Recently, cancer metabolism has been explained not only by metabolites but also through modern molecular and chemical biological techniques. Scientists are seeking context-dependent universality among cancer types according to metabolic and enzymatic pathway signatures. This review presents current cancer metabolism studies and discusses future directions in cancer therapy targeting bio-energetics, bio-anabolism, and autophagy, emphasizing the important contribution of cancer metabolism in cancer therapy.

Quantitative accuracy of the closed-form least-squares solution for targeted SPECT.

PubMed

Shcherbinin, S; Celler, A

2010-10-07

The aim of this study is to investigate the quantitative accuracy of the closed-form least-squares solution (LSS) for single photon emission computed tomography (SPECT). The main limitation for employing this method in actual clinical reconstructions is the computational cost related to operations with a large-sized system matrix. However, in some clinical situations, the size of the system matrix can be decreased using targeted reconstruction. For example, some oncology SPECT studies are characterized by intense tracer uptakes that are localized in relatively small areas, while the remaining parts of the patient body have only a low activity background. Conventional procedures reconstruct the activity distribution in the whole object, which leads to relatively poor image accuracy/resolution for tumors while computer resources are wasted, trying to rebuild diagnostically useless background. In this study, we apply a concept of targeted reconstruction to SPECT phantom experiments imitating such oncology scans. Our approach includes two major components: (i) disconnection of the entire imaging system of equations and extraction of only those parts that correspond to the targets, i.e., regions of interest (ROI) encompassing active containers/tumors and (ii) generation of the closed-form LSS for each target ROI. We compared these ROI-based LSS with those reconstructed by the conventional MLEM approach. The analysis of the five processed cases from two phantom experiments demonstrated that the LSS approach outperformed MLEM in terms of the noise level inside ROI. On the other hand, MLEM better recovered total activity if the number of iterations was large enough. For the experiment without background activity, the ROI-based LSS led to noticeably better spatial activity distribution inside ROI. However, the distributions pertaining to both approaches were practically identical for the experiment with the concentration ratio 7:1 between the containers and the background.

Molecular targeted therapy for advanced gastric cancer.

PubMed

Kim, Jong Gwang

2013-03-01

Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

A systematic investigation into b values prior to coming large earthquakes

NASA Astrophysics Data System (ADS)

Nanjo, K.; Yoshida, A.

2017-12-01

The Gutenberg-Richter law for frequency-magnitude distribution of earthquakes is now well established in seismology. The b value, the slope of the distribution, is supposed to reflect heterogeneity of seismogenic region (e.g. Mogi 1962) and development of interplate coupling in subduction zone (e.g. Nanjo et al., 2012; Tormann et al. 2015). In the laboratory as well as in the Earth's crust, the b value is known to be inversely dependent on differential stresses (Scholz 1968, 2015). In this context, the b value could serve as a stress meter to help locate asperities, the highly-stressed patches, in fault planes where large rupture energy is released (e.g. Schorlemmer & Wiemer 2005). However, it still remains uncertain whether the b values of events prior to coming large earthquakes are always low significantly. To clarify this issue, we conducted a systematic investigation into b values prior to large earthquakes in the Japanese Mainland. Since no physical definition of mainshock, foreshock, and aftershock is known, we simply investigated b values of the events with magnitudes larger than the lower-cutoff magnitude, Mc, prior to earthquakes equal to or larger than a threshold magnitude, Mth, where Mth>Mc. Schorlemmer et al. (2005) showed that the b value for different fault types differs significantly, which is supposed to reflect the feature that the fracture stress depends on fault types. Therefore, we classified fault motions into normal, strike-slip, and thrust types based on the mechanism solution of earthquakes, and computed b values of events associated with each fault motion separately. We found that the target events (M≥Mth) and the events that occurred prior to the target events both show a common systematic change in b: normal faulting events have the highest b values, thrust events the lowest and strike-slip events intermediate values. Moreover, we found that the b values for the prior events (M≥Mc) are significantly lower than the b values for the

Development of a targeted transgenesis strategy in highly differentiated cells: a powerful tool for functional genomic analysis.

PubMed

Puttini, Stefania; Ouvrard-Pascaud, Antoine; Palais, Gael; Beggah, Ahmed T; Gascard, Philippe; Cohen-Tannoudji, Michel; Babinet, Charles; Blot-Chabaud, Marcel; Jaisser, Frederic

2005-03-16

Functional genomic analysis is a challenging step in the so-called post-genomic field. Identification of potential targets using large-scale gene expression analysis requires functional validation to identify those that are physiologically relevant. Genetically modified cell models are often used for this purpose allowing up- or down-expression of selected targets in a well-defined and if possible highly differentiated cell type. However, the generation of such models remains time-consuming and expensive. In order to alleviate this step, we developed a strategy aimed at the rapid and efficient generation of genetically modified cell lines with conditional, inducible expression of various target genes. Efficient knock-in of various constructs, called targeted transgenesis, in a locus selected for its permissibility to the tet inducible system, was obtained through the stimulation of site-specific homologous recombination by the meganuclease I-SceI. Our results demonstrate that targeted transgenesis in a reference inducible locus greatly facilitated the functional analysis of the selected recombinant cells. The efficient screening strategy we have designed makes possible automation of the transfection and selection steps. Furthermore, this strategy could be applied to a variety of highly differentiated cells.

Mechanistic Comparison of "Nearly Missed" Versus "On-Target" Rotor Ablation.

PubMed

Yamazaki, Masatoshi; Avula, Uma Mahesh R; Berenfeld, Omer; Kalifa, Jérôme

2015-08-01

This study used advanced optical mapping techniques to examine atrial fibrillation (AF) dynamics before and after 2 distinct electrogram-based ablation strategies: complex fractionated atrial electrograms (CFAEs) and DFmax/rotor ablation. Among the electrogram analytical features proposed to unravel the atrial regions that perpetuate AF, CFAEs, highest dominant frequency sites (DFmax), and, more recently, phase analysis-enabled rotor mapping have received the largest attention. Still, the mechanisms by which these approaches modulate AF dynamics and lead to AF termination are unknown. In Langendorff-perfused sheep hearts, AF was maintained by the continuous perfusion of acetylcholine and high-resolution endocardial-epicardial optical videos were recorded from the left atrial free wall and the posterior left atrium. Then, DFmax/rotor regions (n = 7), or CFAE regions harboring the highest wavebreak density (HWD) (n = 5), were targeted with a 4F ablation catheter (5 to 15 W, 30 to 60 s/point). Thereafter, we examined the changes in AF dynamics and whether AF terminated. DFmax/rotor point ablation resulted in a significant decrease in DFmax values. In 2 animals AF terminated, whereas in the remaining 5 animals the post-ablation DFmax domain remained in the vicinity of its pre-ablation location. However, after HWD/CFAEs density ablation, DFmax values did not change, AF did not terminate, and post-ablation DFmax domains relocated from the left atrial free wall to the pulmonary vein-posterior left atrium region. In another group of hearts (n = 12), we observed that upon a progressive increase in acetylcholine concentration-mimicking the acute electrophysiological changes occurring after ablation-3-dimensional rotors drifted from one atrial region to another along large gradients of myocardial thickness. "On-target" DFmax/rotor ablation leads to the annihilation of the fibrillation-driving rotor. This translates into large decreases in AF frequency or AF termination. In

USGS aerial resolution targets.

USGS Publications Warehouse

Salamonowicz, P.H.

1982-01-01

It is necessary to measure the achievable resolution of any airborne sensor that is to be used for metric purposes. Laboratory calibration facilities may be inadequate or inappropriate for determining the resolution of non-photographic sensors such as optical-mechanical scanners, television imaging tubes, and linear arrays. However, large target arrays imaged in the field can be used in testing such systems. The USGS has constructed an array of resolution targets in order to permit field testing of a variety of airborne sensing systems. The target array permits any interested organization with an airborne sensing system to accurately determine the operational resolution of its system. -from Author

Reduced OSM for Long Duration Targets: Individuation or Items Loaded into VSTM?

ERIC Educational Resources Information Center

Guest, Duncan; Gellatly, Angus; Pilling, Michael

2012-01-01

Typical studies of object substitution masking (OSM) employ a briefly presented search array. The target item is indicated by a cue/mask that surrounds but does not overlap the target and, compared to a common offset control condition, report of the target is reduced when the mask remains present after target offset. Given how little observers are…

Target charging in short-pulse-laser-plasma experiments.

PubMed

Dubois, J-L; Lubrano-Lavaderci, F; Raffestin, D; Ribolzi, J; Gazave, J; Compant La Fontaine, A; d'Humières, E; Hulin, S; Nicolaï, Ph; Poyé, A; Tikhonchuk, V T

2014-01-01

Interaction of high-intensity laser pulses with solid targets results in generation of large quantities of energetic electrons that are the origin of various effects such as intense x-ray emission, ion acceleration, and so on. Some of these electrons are escaping the target, leaving behind a significant positive electric charge and creating a strong electromagnetic pulse long after the end of the laser pulse. We propose here a detailed model of the target electric polarization induced by a short and intense laser pulse and an escaping electron bunch. A specially designed experiment provides direct measurements of the target polarization and the discharge current in the function of the laser energy, pulse duration, and target size. Large-scale numerical simulations describe the energetic electron generation and their emission from the target. The model, experiment, and numerical simulations demonstrate that the hot-electron ejection may continue long after the laser pulse ends, enhancing significantly the polarization charge.

Water limited agriculture in Africa: Climate change sensitivity of large scale land investments

NASA Astrophysics Data System (ADS)

Rulli, M. C.; D'Odorico, P.; Chiarelli, D. D.; Davis, K. F.

2015-12-01

The past few decades have seen unprecedented changes in the global agricultural system with a dramatic increase in the rates of food production fueled by an escalating demand for food calories, as a result of demographic growth, dietary changes, and - more recently - new bioenergy policies. Food prices have become consistently higher and increasingly volatile with dramatic spikes in 2007-08 and 2010-11. The confluence of these factors has heightened demand for land and brought a wave of land investment to the developing world: some of the more affluent countries are trying to secure land rights in areas suitable for agriculture. According to some estimates, to date, roughly 38 million hectares have been acquired worldwide by large scale investors, 16 million of which in Africa. More than 85% of large scale land acquisitions in Africa are by foreign investors. Many land deals are motivated not only by the need for fertile land but for the water resources required for crop production. Despite some recent assessments of the water appropriation associated with large scale land investments, their impact on the water resources of the target countries under present conditions and climate change scenarios remains poorly understood. Here we investigate irrigation water requirements by various crops planted in the acquired land as an indicator of the pressure likely placed by land investors on ("blue") water resources of target regions in Africa and evaluate the sensitivity to climate changes scenarios.

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

NASA Astrophysics Data System (ADS)

Jayant, Krishna; Hirtz, Jan J.; Plante, Ilan Jen-La; Tsai, David M.; de Boer, Wieteke D. A. M.; Semonche, Alexa; Peterka, Darcy S.; Owen, Jonathan S.; Sahin, Ozgur; Shepard, Kenneth L.; Yuste, Rafael

2017-05-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ∼15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

PubMed Central

Jayant, Krishna; Hirtz, Jan J.; Plante, Ilan Jen-La; Tsai, David M.; De Boer, Wieteke D. A. M.; Semonche, Alexa; Peterka, Darcy S.; Owen, Jonathan S.; Sahin, Ozgur; Shepard, Kenneth L.; Yuste, Rafael

2017-01-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ~15–30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5–1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures. PMID:27941898

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes.

PubMed

Jayant, Krishna; Hirtz, Jan J; Plante, Ilan Jen-La; Tsai, David M; De Boer, Wieteke D A M; Semonche, Alexa; Peterka, Darcy S; Owen, Jonathan S; Sahin, Ozgur; Shepard, Kenneth L; Yuste, Rafael

2017-05-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ∼15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

Large aperture diffractive space telescope

DOEpatents

Hyde, Roderick A.

2001-01-01

A large (10's of meters) aperture space telescope including two separate spacecraft--an optical primary objective lens functioning as a magnifying glass and an optical secondary functioning as an eyepiece. The spacecraft are spaced up to several kilometers apart with the eyepiece directly behind the magnifying glass "aiming" at an intended target with their relative orientation determining the optical axis of the telescope and hence the targets being observed. The objective lens includes a very large-aperture, very-thin-membrane, diffractive lens, e.g., a Fresnel lens, which intercepts incoming light over its full aperture and focuses it towards the eyepiece. The eyepiece has a much smaller, meter-scale aperture and is designed to move along the focal surface of the objective lens, gathering up the incoming light and converting it to high quality images. The positions of the two space craft are controlled both to maintain a good optical focus and to point at desired targets which may be either earth bound or celestial.

Increasing on-target cleavage efficiency for CRISPR/Cas9-induced large fragment deletion in Myxococcus xanthus.

PubMed

Yang, Ying-Jie; Wang, Ye; Li, Zhi-Feng; Gong, Ya; Zhang, Peng; Hu, Wen-Chao; Sheng, Duo-Hong; Li, Yue-Zhong

2017-08-16

The CRISPR/Cas9 system is a powerful tool for genome editing, in which the sgRNA binds and guides the Cas9 protein for the sequence-specific cleavage. The protocol is employable in different organisms, but is often limited by cell damage due to the endonuclease activity of the introduced Cas9 and the potential off-target DNA cleavage from incorrect guide by the 20 nt spacer. In this study, after resolving some critical limits, we have established an efficient CRISPR/Cas9 system for the deletion of large genome fragments related to the biosynthesis of secondary metabolites in Myxococcus xanthus cells. We revealed that the high expression of a codon-optimized cas9 gene in M. xanthus was cytotoxic, and developed a temporally high expression strategy to reduce the cell damage from high expressions of Cas9. We optimized the deletion protocol by using the tRNA-sgRNA-tRNA chimeric structure to ensure correct sgRNA sequence. We found that, in addition to the position-dependent nucleotide preference, the free energy of a 20 nt spacer was a key factor for the deletion efficiency. By using the developed protocol, we achieved the CRISPR/Cas9-induced deletion of large biosynthetic gene clusters for secondary metabolites in M. xanthus DK1622 and its epothilone-producing mutant. The findings and the proposals described in this paper were suggested to be workable in other organisms, for example, other Gram negative bacteria with high GC content.

The OncoPPi Portal: an integrative resource to explore and prioritize protein-protein interactions for cancer target discovery. | Office of Cancer Genomics

Cancer.gov

Motivation: As cancer genomics initiatives move toward comprehensive identification of genetic alterations in cancer, attention is now turning to understanding how interactions among these genes lead to the acquisition of tumor hallmarks. Emerging pharmacological and clinical data suggest a highly promising role of cancer-specific protein-protein interactions (PPIs) as druggable cancer targets. However, large-scale experimental identification of cancer-related PPIs remains challenging, and currently available resources to explore oncogenic PPI networks are limited.

Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project | Office of Cancer Genomics

Cancer.gov

TARGET researchers sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with activated kinase signaling, including Ph-like ALL, to establish the incidence of tyrosine kinase mutations in this cohort. The study confirmed previously identified somatic mutations in JAK and FLT3, but did not find novel alterations in any additional tyrosine kinases or downstream genes. The mechanism of kinase signaling activation in this high-risk subgroup of pediatric ALL remains largely unknown.

A robust close-range photogrammetric target extraction algorithm for size and type variant targets

NASA Astrophysics Data System (ADS)

Nyarko, Kofi; Thomas, Clayton; Torres, Gilbert

2016-05-01

The Photo-G program conducted by Naval Air Systems Command at the Atlantic Test Range in Patuxent River, Maryland, uses photogrammetric analysis of large amounts of real-world imagery to characterize the motion of objects in a 3-D scene. Current approaches involve several independent processes including target acquisition, target identification, 2-D tracking of image features, and 3-D kinematic state estimation. Each process has its own inherent complications and corresponding degrees of both human intervention and computational complexity. One approach being explored for automated target acquisition relies on exploiting the pixel intensity distributions of photogrammetric targets, which tend to be patterns with bimodal intensity distributions. The bimodal distribution partitioning algorithm utilizes this distribution to automatically deconstruct a video frame into regions of interest (ROI) that are merged and expanded to target boundaries, from which ROI centroids are extracted to mark target acquisition points. This process has proved to be scale, position and orientation invariant, as well as fairly insensitive to global uniform intensity disparities.

An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people

PubMed Central

Nelson, Matthew R.; Wegmann, Daniel; Ehm, Margaret G.; Kessner, Darren; St. Jean, Pamela; Verzilli, Claudio; Shen, Judong; Tang, Zhengzheng; Bacanu, Silviu-Alin; Fraser, Dana; Warren, Liling; Aponte, Jennifer; Zawistowski, Matthew; Liu, Xiao; Zhang, Hao; Zhang, Yong; Li, Jun; Li, Yun; Li, Li; Woollard, Peter; Topp, Simon; Hall, Matthew D.; Nangle, Keith; Wang, Jun; Abecasis, Gonçalo; Cardon, Lon R.; Zöllner, Sebastian; Whittaker, John C.; Chissoe, Stephanie L.; Novembre, John; Mooser, Vincent

2015-01-01

Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (one every 17 bases) and geographically localized, such that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. Overall we conclude that, due to rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk. PMID:22604722

Revisiting inconsistency in large pharmacogenomic studies

PubMed Central

Safikhani, Zhaleh; Smirnov, Petr; Freeman, Mark; El-Hachem, Nehme; She, Adrian; Rene, Quevedo; Goldenberg, Anna; Birkbak, Nicolai J.; Hatzis, Christos; Shi, Leming; Beck, Andrew H.; Aerts, Hugo J.W.L.; Quackenbush, John; Haibe-Kains, Benjamin

2017-01-01

In 2013, we published a comparative analysis of mutation and gene expression profiles and drug sensitivity measurements for 15 drugs characterized in the 471 cancer cell lines screened in the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE). While we found good concordance in gene expression profiles, there was substantial inconsistency in the drug responses reported by the GDSC and CCLE projects. We received extensive feedback on the comparisons that we performed. This feedback, along with the release of new data, prompted us to revisit our initial analysis. We present a new analysis using these expanded data, where we address the most significant suggestions for improvements on our published analysis — that targeted therapies and broad cytotoxic drugs should have been treated differently in assessing consistency, that consistency of both molecular profiles and drug sensitivity measurements should be compared across cell lines, and that the software analysis tools provided should have been easier to run, particularly as the GDSC and CCLE released additional data. Our re-analysis supports our previous finding that gene expression data are significantly more consistent than drug sensitivity measurements. Using new statistics to assess data consistency allowed identification of two broad effect drugs and three targeted drugs with moderate to good consistency in drug sensitivity data between GDSC and CCLE. For three other targeted drugs, there were not enough sensitive cell lines to assess the consistency of the pharmacological profiles. We found evidence of inconsistencies in pharmacological phenotypes for the remaining eight drugs. Overall, our findings suggest that the drug sensitivity data in GDSC and CCLE continue to present challenges for robust biomarker discovery. This re-analysis provides additional support for the argument that experimental standardization and validation of pharmacogenomic response will be necessary to

Targeted Cellular Drug Delivery using Tailored Dendritic Nanostructures

NASA Astrophysics Data System (ADS)

Kannan, Rangaramanujam; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

2002-03-01

Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorble, ‘peripheral’ functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug and gene delivery. The large number of end groups can also be tailored to create special affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, in-vitro drug loading, in-vitro drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Polyamidoamine and Polyol dendrimers, with different generations and end-groups are studied, with drugs such as Ibuprofen and Methotrexate. Our results indicate that a large number of drug molecules can be encapsulated/attached to the dendrimers, depending on the end groups. The drug-encapsulated dendrimer is able to enter the cells rapidly and deliver the drug. Targeting strategies being explored

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.

Automated Target Planning for FUSE Using the SOVA Algorithm

NASA Technical Reports Server (NTRS)

Heatwole, Scott; Lanzi, R. James; Civeit, Thomas; Calvani, Humberto; Kruk, Jeffrey W.; Suchkov, Anatoly

2007-01-01

IRUs and four reaction wheels. Over time through various failures, the satellite has been left with one reaction wheel on the vehicle skew axis and two gyros. To remain operational, a control scheme has been implemented using the magnetic torque rods and the remaining momentum wheel.[2] As a consequence, there are attitude regions where there is insufficient torque authority to overcome environmental disturbances (e.g. gravity gradient torques). The situation is further complicated by the fact that these attitude regions shift inertially with time as the spacecraft moves through earth s magnetic field during the course of its orbit. Under these conditions, the burden of planning targets and target-to-target slew maneuvers has increased significantly since the beginning of the mission.[3] Individual targets must be selected so that the magnetic field remains roughly aligned with the skew wheel axis to provide enough control authority to the other two orthogonal axes. If the field moves too far away from the skew axis, the lack of control authority allows environmental torques to pull the satellite away from the target and can potentially cause it to tumble. Slew maneuver planning must factor the stability of targets at the beginning and end, and the torque authority at all points along the slew. Due to the time varying magnetic field geometry relative to any two inertial targets, small modifications in slew maneuver timing can make large differences in the achievability of a maneuver.

Benchmark data sets for structure-based computational target prediction.

PubMed

Schomburg, Karen T; Rarey, Matthias

2014-08-25

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

Controlled and in situ target strengths of the jumbo squid Dosidicus gigas and identification of potential acoustic scattering sources.

PubMed

Benoit-Bird, Kelly J; Gilly, William F; Au, Whitlow W L; Mate, Bruce

2008-03-01

This study presents the first target strength measurements of Dosidicus gigas, a large squid that is a key predator, a significant prey, and the target of an important fishery. Target strength of live, tethered squid was related to mantle length with values standardized to the length squared of -62.0, -67.4, -67.9, and -67.6 dB at 38, 70, 120, and 200 kHz, respectively. There were relatively small differences in target strength between dorsal and anterior aspects and none between live and freshly dead squid. Potential scattering mechanisms in squid have been long debated. Here, the reproductive organs had little effect on squid target strength. These data support the hypothesis that the pen may be an important source of squid acoustic scattering. The beak, eyes, and arms, probably via the sucker rings, also play a role in acoustic scattering though their effects were small and frequency specific. An unexpected source of scattering was the cranium of the squid which provided a target strength nearly as high as that of the entire squid though the mechanism remains unclear. Our in situ measurements of the target strength of free-swimming squid support the use of the values presented here in D. gigas assessment studies.

Development of a large peptoid-DOTA combinatorial library.

PubMed

Singh, Jaspal; Lopes, Daniel; Gomika Udugamasooriya, D

2016-09-01

Conventional one-bead one-compound (OBOC) library synthesis is typically used to identify molecules with therapeutic value. The design and synthesis of OBOC libraries that contain molecules with imaging or even potentially therapeutic and diagnostic capacities (e.g. theranostic agents) has been overlooked. The development of a therapeutically active molecule with a built-in imaging component for a certain target is a daunting task, and structure-based rational design might not be the best approach. We hypothesize to develop a combinatorial library with potentially therapeutic and imaging components fused together in each molecule. Such molecules in the library can be used to screen, identify, and validate as direct theranostic candidates against targets of interest. As the first step in achieving that aim, we developed an on-bead library of 153,600 Peptoid-DOTA compounds in which the peptoids are the target-recognizing and potentially therapeutic components and the DOTA is the imaging component. We attached the DOTA scaffold to TentaGel beads using one of the four arms of DOTA, and we built a diversified 6-mer peptoid library on the remaining three arms. We evaluated both the synthesis and the mass spectrometric sequencing capacities of the test compounds and of the final library. The compounds displayed unique ionization patterns including direct breakages of the DOTA scaffold into two units, allowing clear decoding of the sequences. Our approach provides a facile synthesis method for the complete on-bead development of large peptidomimetic-DOTA libraries for screening against biological targets for the identification of potential theranostic agents in the future. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 673-684, 2016. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc.

Cultivating Uncultured Bacteria from Northern Wetlands: Knowledge Gained and Remaining Gaps

PubMed Central

Dedysh, Svetlana N.

2011-01-01

Northern wetlands play a key role in the global carbon budget, particularly in the budgets of the greenhouse gas methane. These ecosystems also determine the hydrology of northern rivers and represent one of the largest reservoirs of fresh water in the Northern Hemisphere. Sphagnum-dominated peat bogs and fens are the most extensive types of northern wetlands. In comparison to many other terrestrial ecosystems, the bacterial diversity in Sphagnum-dominated wetlands remains largely unexplored. As demonstrated by cultivation-independent studies, a large proportion of the indigenous microbial communities in these acidic, cold, nutrient-poor, and water-saturated environments is composed of as-yet-uncultivated bacteria with unknown physiologies. Most of them are slow-growing, oligotrophic microorganisms that are difficult to isolate and to manipulate in the laboratory. Yet, significant breakthroughs in cultivation of these elusive organisms have been made during the last decade. This article describes the major prerequisites for successful cultivation of peat-inhabiting microbes, gives an overview of the currently captured bacterial diversity from northern wetlands and discusses the unique characteristics of the newly discovered organisms. PMID:21954394

The Impact of Nursing Leader's Behavioral Integrity and Intragroup Relationship Conflict on Staff Nurses' Intention to Remain.

PubMed

Kang, Seung-Wan; Lee, Soojin; Choi, Suk Bong

2017-05-01

This study tested a multilevel model examining the effect of nursing leader's behavioral integrity and intragroup relationship conflict on staff nurses' intent to remain. In the challenging situation of nursing shortage, nurse executives are required to focus on the retention of nurses. No previous studies have examined the impact of nursing leader's behavioral integrity and intragroup relationship conflict on nurses' intention to remain. A cross-sectional survey of 480 RNs in 34 nursing units of a large public hospital in South Korea was conducted to test the hypothesized multilevel model. Nursing leader's behavioral integrity was positively related to nurses' intention to remain (b = 0.34, P < .001). This relationship was enhanced when the level of intragroup relationship conflict was high (b = 0.21, P < .05). Nursing leaders assigned to units with a high level of intragroup relationship conflict should endeavor to maintain their behavioral integrity to promote nurses' intention to remain.

The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

PubMed Central

Wang, Liantang; Chen, Shangwu

2016-01-01

Metabolic change is one of the hallmarks of tumor, which has recently attracted a great of attention. One of main metabolic characteristics of tumor cells is the high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in glycolysis pathway than that in tricarboxylic acid cycle. The molecular mechanism of a high glycolytic flux in tumor cells remains unclear. A large amount of intermediates derived from glycolytic pathway could meet the biosynthetic requirements of the proliferating cells. Hypoxia-induced HIF-1α, PI3K-Akt-mTOR signaling pathway, and many other factors, such as oncogene activation and tumor suppressor inactivation, drive cancer cells to favor glycolysis over mitochondrial oxidation. Several small molecules targeting glycolytic pathway exhibit promising anticancer activity both in vitro and in vivo. In this review, we will focus on the latest progress in the regulation of aerobic glycolysis and discuss the potential targets for the tumor therapy. PMID:26918353

Action Potential Dynamics in Fine Axons Probed with an Axonally Targeted Optical Voltage Sensor.

PubMed

Ma, Yihe; Bayguinov, Peter O; Jackson, Meyer B

2017-01-01

The complex and malleable conduction properties of axons determine how action potentials propagate through extensive axonal arbors to reach synaptic terminals. The excitability of axonal membranes plays a major role in neural circuit function, but because most axons are too thin for conventional electrical recording, their properties remain largely unexplored. To overcome this obstacle, we used a genetically encoded hybrid voltage sensor (hVOS) harboring an axonal targeting motif. Expressing this probe in transgenic mice enabled us to monitor voltage changes optically in two populations of axons in hippocampal slices, the large axons of dentate granule cells (mossy fibers) in the stratum lucidum of the CA3 region and the much finer axons of hilar mossy cells in the inner molecular layer of the dentate gyrus. Action potentials propagated with distinct velocities in each type of axon. Repetitive firing broadened action potentials in both populations, but at an intermediate frequency the degree of broadening differed. Repetitive firing also attenuated action potential amplitudes in both mossy cell and granule cell axons. These results indicate that the features of use-dependent action potential broadening, and possible failure, observed previously in large nerve terminals also appear in much finer unmyelinated axons. Subtle differences in the frequency dependences could influence the propagation of activity through different pathways to excite different populations of neurons. The axonally targeted hVOS probe used here opens up the diverse repertoire of neuronal processes to detailed biophysical study.

New advances in targeted gastric cancer treatment.

PubMed

Lazăr, Daniela Cornelia; Tăban, Sorina; Cornianu, Marioara; Faur, Alexandra; Goldiş, Adrian

2016-08-14

Despite a decrease in incidence over past decades, gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours.

New advances in targeted gastric cancer treatment

PubMed Central

Lazăr, Daniela Cornelia; Tăban, Sorina; Cornianu, Marioara; Faur, Alexandra; Goldiş, Adrian

2016-01-01

Despite a decrease in incidence over past decades, gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours. PMID:27570417

Camouflage target reconnaissance based on hyperspectral imaging technology

NASA Astrophysics Data System (ADS)

Hua, Wenshen; Guo, Tong; Liu, Xun

2015-08-01

Efficient camouflaged target reconnaissance technology makes great influence on modern warfare. Hyperspectral images can provide large spectral range and high spectral resolution, which are invaluable in discriminating between camouflaged targets and backgrounds. Hyperspectral target detection and classification technology are utilized to achieve single class and multi-class camouflaged targets reconnaissance respectively. Constrained energy minimization (CEM), a widely used algorithm in hyperspectral target detection, is employed to achieve one class camouflage target reconnaissance. Then, support vector machine (SVM), a classification method, is proposed to achieve multi-class camouflage target reconnaissance. Experiments have been conducted to demonstrate the efficiency of the proposed method.

Trends in the Cost and Use of Targeted Cancer Therapies for the Privately Insured Nonelderly: 2001 to 2011

PubMed Central

Shih, Ya-Chen Tina; Smieliauskas, Fabrice; Geynisman, Daniel M.; Kelly, Ronan J.; Smith, Thomas J.

2015-01-01

Purpose This study sought to define and identify drivers of trends in cost and use of targeted therapeutics among privately insured nonelderly patients with cancer receiving chemotherapy between 2001 and 2011. Methods We classified oncology drugs as targeted oral anticancer medications, targeted intravenous anticancer medications, and all others. Using the LifeLink Health Plan Claims Database, we studied and disaggregated trends in use and in insurance and out-of-pocket payments per patient per month and during the first year of chemotherapy. Results We found a large increase in the use of targeted intravenous anticancer medications and a gradual increase in targeted oral anticancer medications; targeted therapies accounted for 63% of all chemotherapy expenditures in 2011. Insurance payments per patient per month and in the first year of chemotherapy for targeted oral anticancer medications more than doubled in 10 years, surpassing payments for targeted intravenous anticancer medications, which remained fairly constant throughout. Substitution toward targeted therapies and growth in drug prices both at launch and postlaunch contributed to payer spending growth. Out-of-pocket spending for targeted oral anticancer medications was ≤ half of the amount for targeted intravenous anticancer medications. Conclusion Targeted therapies now dominate anticancer drug spending. More aggressive management of pharmacy benefits for targeted oral anticancer medications and payment reform for injectable drugs hold promise. Restraining the rapid rise in spending will require more than current oral drug parity laws, such as value-based insurance that makes the benefits and costs transparent and involves the patient directly in the choice of treatment. PMID:25987701

miR-133 involves in lung adenocarcinoma cell metastasis by targeting FLOT2.

PubMed

Wei, Guangxia; Xu, Yahuan; Peng, Tao; Yan, Jie

2018-03-01

Dysregulated microRNAs (miRNAs) reported to involve into the oncogenesis and progression in various human cancers. However, the roles and mechanism of miR-133 in lung adenocarcinoma remain largely unclear. In this study, qPCR assay and western blot were used to detect the expression levels of miR-133, Akt and FLOT2. Luciferase reporter assay was used to identify the target role of miR-133 on FLOT2. The cell invasion and the migration capability were performed using the transwell invasion assay and wound healing assay. We found that miR-133 expression levels were downregulated in human lung adenocarcinoma specimens and cell lines compared with the adjacent normal tissues and normal human bronchial epithelial cell. miR-133 significantly suppressed metastasis of lung adenocarcinoma cells in vitro. Furthermore, FLOT2 (flotillin-2) identified as a direct target of miR-133, and FLOT2 expression levels were inversely correlated with miR-133 expression levels in human lung adenocarcinoma specimens. And the restoration studies suggested FGF2 as a downstream effector of miR-133 which acted through Akt signalling pathway. Our study revealed the mechanism that miR-133 suppresses lung adenocarcinoma metastasis by targeting FLOT2 via Akt signalling pathway, implicating a potential prognostic biomarker and therapeutic target for lung adenocarcinoma treatment.

Target Context Specification Can Reduce Costs in Nonfocal Prospective Memory

ERIC Educational Resources Information Center

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

2013-01-01

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

TargetCOPD: a pragmatic randomised controlled trial of targeted case finding for COPD versus routine practice in primary care: protocol.

PubMed

Jordan, Rachel E; Adab, Peymané; Jowett, Sue; Marsh, Jen L; Riley, Richard D; Enocson, Alexandra; Miller, Martin R; Cooper, Brendan G; Turner, Alice M; Ayres, Jon G; Cheng, Kar Keung; Jolly, Kate; Stockley, Robert A; Greenfield, Sheila; Siebert, Stanley; Daley, Amanda; Fitzmaurice, David A

2014-10-04

Many people with clinically significant chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide. There are a number of small studies which have examined possible methods of case finding through primary care, but no large RCTs that have adequately assessed the most cost-effective approach. In this study, using a cluster randomised controlled trial (RCT) in 56 general practices in the West Midlands, we plan to investigate the effectiveness and cost-effectiveness of a Targeted approach to case finding for COPD compared with routine practice. Using an individual patient RCT nested in the Targeted arm, we plan also to compare the effectiveness and cost-effectiveness of Active case finding using a postal questionnaire (with supplementary opportunistic questionnaires), and Opportunistic-only case finding during routine surgery consultations.All ever-smoking patients aged 40-79 years, without a current diagnosis of COPD and registered with participating practices will be eligible. Patients in the Targeted arm who report positive respiratory symptoms (chronic cough or phlegm, wheeze or dyspnoea) using a brief questionnaire will be invited for further spirometric assessment to ascertain whether they have COPD or not. Post-bronchodilator spirometry will be conducted to ATS standards using an Easy One spirometer by trained research assistants.The primary outcomes will be new cases of COPD and cost per new case identified, comparing targeted case finding with routine care, and two types of targeted case finding (active versus opportunistic). A multilevel logistic regression model will be used to model the probability of detecting a new case of COPD for each treatment arm, with clustering of patients (by practice and household) accounted for using a multi-level structure.A trial-based analysis will be undertaken using costs and outcomes collected during the trial. Secondary outcomes include the feasibility, efficiency, long-term cost-effectiveness, patient and

Anticancer Pyrroloquinazoline LBL1 Targets Nuclear Lamins.

PubMed

Li, Bingbing X; Chen, Jingjin; Chao, Bo; David, Larry L; Xiao, Xiangshu

2018-05-18

Target identification of bioactive compounds is critical for understanding their mechanism of action. We previously discovered a novel pyrroloquinazoline compound LBL1 with significant anticancer activity. However, its molecular targets remain to be established. Herein, we developed a clickable photoaffinity probe based on LBL1. Using extensive chemical, biochemical, and cellular studies with this probe and LBL1, we found that LBL1 targets nuclear lamins, which are type V intermediate filament (IF) proteins. Further studies showed that LBL1 binds to the coiled-coil domain of lamin A. These results revealed that IF proteins can also be targeted with appropriate small molecules besides two other cytoskeletal proteins actin filaments and microtubules, providing a novel avenue to investigate lamin biology and a novel strategy to develop distinct anticancer therapies.

Genomes2Drugs: Identifies Target Proteins and Lead Drugs from Proteome Data

PubMed Central

Toomey, David; Hoppe, Heinrich C.; Brennan, Marian P.; Nolan, Kevin B.; Chubb, Anthony J.

2009-01-01

Background Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. Methodology/Principal Findings To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. Conclusions/Significance Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under ‘change-of-application’ patents. PMID:19593435

Small, medium, large or supersize? The development and evaluation of interventions targeted at portion size.

PubMed

Vermeer, W M; Steenhuis, I H M; Poelman, M P

2014-07-01

In the past decades, portion sizes of high-caloric foods and drinks have increased and can be considered an important environmental obesogenic factor. This paper describes a research project in which the feasibility and effectiveness of environmental interventions targeted at portion size was evaluated. The studies that we conducted revealed that portion size labeling, offering a larger variety of portion sizes, and proportional pricing (that is, a comparable price per unit regardless of the size) were considered feasible to implement according to both consumers and point-of-purchase representatives. Studies into the effectiveness of these interventions demonstrated that the impact of portion size labeling on the (intended) consumption of soft drinks was, at most, modest. Furthermore, the introduction of smaller portion sizes of hot meals in worksite cafeterias in addition to the existing size stimulated a moderate number of consumers to replace their large meals by a small meal. Elaborating on these findings, we advocate further research into communication and marketing strategies related to portion size interventions; the development of environmental portion size interventions as well as educational interventions that improve people's ability to deal with a 'super-sized' environment; the implementation of regulation with respect to portion size labeling, and the use of nudges to stimulate consumers to select healthier portion sizes.

Design and testing of a controlled electromagnetic spinal cord impactor for use in large animal models of acute traumatic spinal cord injury.

PubMed

Petteys, Rory J; Spitz, Steven M; Syed, Hasan; Rice, R Andrew; Sarabia-Estrada, Rachel; Goodwin, C Rory; Sciubba, Daniel M; Freedman, Brett A

2017-09-01

Spinal cord injury (SCI) causes debilitating neurological dysfunction and has been observed in warfighters injured in IED blasts. Clinical benefit of SCI treatment remains elusive and better large animal models are needed to assess treatment options. Here, we describe a controlled electromagnetic spinal cord impactor for use in large animal models of SCI. A custom spinal cord impactor and platform were fabricated for large animals (e.g., pig, sheep, dog, etc.). Impacts were generated by a voice coil actuator; force and displacement were measured with a load cell and potentiometer respectively. Labview (National Instruments, Austin, TX) software was used to control the impact cycle and import force and displacement data. Software finite impulse response (FIR) filtering was employed for all input data. Silicon tubing was used a surrogate for spinal cord in order to test the device; repeated impacts were performed at 15, 25, and 40 Newtons. Repeated impacts demonstrated predictable results at each target force. The average duration of impact was 71.2 ±6.1ms. At a target force of 40N, the output force was 41.5 ±0.7N. With a target of 25N, the output force was 23.5 ±0.6N; a target of 15Newtons revealed an output force of 15.2 ±1.4N. The calculated acceleration range was 12.5-21.2m/s 2 . This custom spinal cord impactor reliably delivers precise impacts to the spinal cord and will be utilized in future research to study acute traumatic SCI in a large animal. Published by Elsevier Ltd.

Multiple shell fusion targets

DOEpatents

Lindl, J.D.; Bangerter, R.O.

1975-10-31

Multiple shell fusion targets for use with electron beam and ion beam implosion systems are described. The multiple shell targets are of the low-power type and use a separate relatively low Z, low density ablator at large radius for the outer shell, which reduces the focusing and power requirements of the implosion system while maintaining reasonable aspect ratios. The targets use a high Z, high density pusher shell placed at a much smaller radius in order to obtain an aspect ratio small enough to protect against fluid instability. Velocity multiplication between these shells further lowers the power requirements. Careful tuning of the power profile and intershell density results in a low entropy implosion which allows breakeven at low powers. For example, with ion beams as a power source, breakeven at 10-20 Terrawatts with 10 MeV alpha particles for imploding a multiple shell target can be accomplished.

Sexual Dimorphism Floral MicroRNA Profiling and Target Gene Expression in Andromonoecious Poplar (Populus tomentosa)

PubMed Central

Song, Yuepeng; Ma, Kaifeng; Ci, Dong; Zhang, Zhiyi; Zhang, Deqiang

2013-01-01

Although the molecular basis of poplar sex-specific flower development remains largely unknown, increasing evidence indicates an essential role for microRNAs (miRNAs). The specific miRNA types and precise miRNA expression patterns in dioecious plant flower development remain unclear. Here, we used andromonoecious poplar, an exceptional model system, to eliminate the confounding effects of genetic background of dioecious plants. This system, combined with high-throughput sequencing and computational analysis, allowed us to characterize sex-specific miRNAomes from female and male flowers. Comparative miRNAome analysis combined with quantitative real-time PCR revealed the expression patterns of 27 miRNAs in poplar flower and showed that the targets of these miRNAs are involved in flower organogenesis, Ca2+ transport, phytohormone synthesis and metabolism, and DNA methylation. This paper describes a complex regulatory network consisting of these miRNAs expressed in sex-specific flower development in a dioecious plant. The conserved and novel miRNA locations were annotated in the Populus trichocarpa genome. Among these, miRNA Pto-F70 and 4 targets are located in the sex-determination regions of chromosome XIX. Furthermore, two novel miRNAs, Pto-F47 and Pto-F68, were shown for the first time to be regulatory factors in phytohormone interactions. To our knowledge, this report is the first systematic investigation of sex-specific flower-related miRNAs and their targets in poplar, and it deepens our understanding of the important regulatory functions of miRNAs in female and male flower development in this dioecious plant. PMID:23667507

Activated GTPase movement on an RNA scaffold drives cotranslational protein targeting

PubMed Central

Shen, Kuang; Arslan, Sinan; Akopian, David; Ha, Taekjip; Shan, Shu-ou

2012-01-01

Roughly one third of the proteome is initially destined for the eukaryotic endoplasmic reticulum or the bacterial plasma membrane1. The proper localization of these proteins is mediated by a universally conserved protein targeting machinery, the signal recognition particle (SRP), which recognizes ribosomes carrying signal sequences2–4 and, via interactions with the SRP receptor5,6, delivers them to the protein translocation machinery on the target membrane7. The SRP is an ancient ribonucleoprotein particle containing an essential, elongated SRP RNA whose precise functions have remained elusive. Here, we used single molecule fluorescence microscopy to demonstrate that the SRP-receptor GTPase complex, after initial assembly at the tetraloop end of SRP RNA, travels over 100 Å to the distal end of this RNA where rapid GTP hydrolysis occurs. This movement is negatively regulated by the translating ribosome and, at a later stage, positively regulated by the SecYEG translocon, providing an attractive mechanism to ensure the productive exchange of the targeting and translocation machineries at the ribosome exit site with exquisite spatial and temporal accuracy. Our results show that large RNAs can act as molecular scaffolds that enable the facile exchange of distinct factors and precise timing of molecular events in a complex cellular process; this concept may be extended to similar phenomena in other ribonucleoprotein complexes. PMID:23235881

Slp-76 is a critical determinant of NK-cell mediated recognition of missing-self targets.

PubMed

Lampe, Kristin; Endale, Mehari; Cashman, Siobhan; Fang, Hao; Mattner, Jochen; Hildeman, David; Hoebe, Kasper

2015-07-01

Absence of MHC class I expression is an important mechanism by which NK cells recognize a variety of target cells, yet the pathways underlying "missing-self" recognition, including the involvement of activating receptors, remain poorly understood. Using ethyl-N-nitrosourea mutagenesis in mice, we identified a germline mutant, designated Ace, with a marked defect in NK cell mediated recognition and elimination of "missing-self" targets. The causative mutation was linked to chromosome 11 and identified as a missense mutation (Thr428Ile) in the SH2 domain of Slp-76-a critical adapter molecule downstream of ITAM-containing surface receptors. The Slp-76 Ace mutation behaved as a hypomorphic allele-while no major defects were observed in conventional T-cell development/function, a marked defect in NK cell mediated elimination of β2-microglobulin (β2M) deficient target cells was observed. Further studies revealed Slp-76 to control NK-cell receptor expression and maturation; however, activation of Slp-76(ace/ace) NK cells through ITAM-containing NK-cell receptors or allogeneic/tumor target cells appeared largely unaffected. Imagestream analysis of the NK-β2M(-/-) target cell synapse revealed a specific defect in actin recruitment to the conjugate synapse in Slp-76(ace/ace) NK cells. Overall these studies establish Slp-76 as a critical determinant of NK-cell development and NK cell mediated elimination of missing-self target cells in mice. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Slp-76 is a critical determinant of NK cell-mediated recognition of missing-self targets

PubMed Central

Lampe, Kristin; Endale, Mehari; Cashman, Siobhan; Fang, Hao; Mattner, Jochen; Hildeman, David; Hoebe, Kasper

2015-01-01

Absence of MHC class I expression is an important mechanism by which NK cells recognize a variety of target cells, yet the pathways underlying “missing-self” recognition, including the involvement of activating receptors, remain poorly understood. Using ENU mutagenesis in mice, we identified a germline mutant, designated Ace, with a marked defect in NK cell-mediated recognition and elimination of “missing-self” targets. The causative mutation was linked to chromosome 11 and identified as a missense mutation [Thr428Ile] in the SH2 domain of Slp-76—a critical adapter molecule downstream of ITAM-containing surface receptors. The Slp-76 Ace mutation behaved as a hypomorphic allele—while no major defects were observed in conventional T cell development/function, a marked defect in NK cell-mediated elimination of β2-Microglobulin (β2M)-deficient target cells was observed. Further studies revealed Slp-76 to control NK cell receptor expression and maturation, however, activation of Slp-76ace/ace NK cells through ITAM-containing NK cell receptors or allogeneic/tumor target cells appeared largely unaffected. Imagestream analysis of the NK-β2M−/− target cell synapse, revealed a specific defect in actin recruitment to the conjugate synapse in Slp-76ace/ace NK cells. Overall these studies establish Slp-76 as a critical determinant of NK cell development and NK cell-mediated elimination of missing-self target cells. PMID:25929249

DNA and RNA profiling of excavated human remains with varying postmortem intervals.

PubMed

van den Berge, M; Wiskerke, D; Gerretsen, R R R; Tabak, J; Sijen, T

2016-11-01

When postmortem intervals (PMIs) increase such as with longer burial times, human remains suffer increasingly from the taphonomic effects of decomposition processes such as autolysis and putrefaction. In this study, various DNA analysis techniques and a messenger RNA (mRNA) profiling method were applied to examine for trends in nucleic acid degradation and the postmortem interval. The DNA analysis techniques include highly sensitive DNA quantitation (with and without degradation index), standard and low template STR profiling, insertion and null alleles (INNUL) of retrotransposable elements typing and mitochondrial DNA profiling. The used mRNA profiling system targets genes with tissue specific expression for seven human organs as reported by Lindenbergh et al. (Int J Legal Med 127:891-900, 27) and has been applied to forensic evidentiary traces but not to excavated tissues. The techniques were applied to a total of 81 brain, lung, liver, skeletal muscle, heart, kidney and skin samples obtained from 19 excavated graves with burial times ranging from 4 to 42 years. Results show that brain and heart are the organs in which both DNA and RNA remain remarkably stable, notwithstanding long PMIs. The other organ tissues either show poor overall profiling results or vary for DNA and RNA profiling success, with sometimes DNA and other times RNA profiling being more successful. No straightforward relations were observed between nucleic acid profiling results and the PMI. This study shows that not only DNA but also RNA molecules can be remarkably stable and used for profiling of long-buried human remains, which corroborate forensic applications. The insight that the brain and heart tissues tend to provide the best profiling results may change sampling policies in identification cases of degrading cadavers.

The role of large—scale BECCS in the pursuit of the 1.5°C target: an Earth system model perspective

NASA Astrophysics Data System (ADS)

Muri, Helene

2018-04-01

The increasing awareness of the many damaging aspects of climate change has prompted research into ways of reducing and reversing the anthropogenic increase in carbon concentrations in the atmosphere. Most emission scenarios stabilizing climate at low levels, such as the 1.5 °C target as outlined by the Paris Agreement, require large-scale deployment of Bio-Energy with Carbon Capture and Storage (BECCS). Here, the potential of large-scale BECCS deployment in contributing towards the 1.5 °C global warming target is evaluated using an Earth system model, as well as associated climate responses and carbon cycle feedbacks. The geographical location of the bioenergy feedstock is shown to be key to the success of such measures in the context of temperature targets. Although net negative emissions were reached sooner, by ∼6 years, and scaled up, land use change emissions and reductions in forest carbon sinks outweigh these effects in one scenario. Re-cultivating mid-latitudes was found to be beneficial, on the other hand, contributing in the right direction towards the 1.5 °C target, only by ‑0.1 °C and ‑54 Gt C in avoided emissions, however. Obstacles remain related to competition for land from nature preservation and food security, as well as the technological availability of CCS.

Tritium target manufacturing for use in accelerators

NASA Astrophysics Data System (ADS)

Bach, P.; Monnin, C.; Van Rompay, M.; Ballanger, A.

2001-07-01

As a neutron tube manufacturer, SODERN is now in charge of manufacturing tritium targets for accelerators, in cooperation with CEA/DAM/DTMN in Valduc. Specific deuterium and tritium targets are manufactured on request, according to the requirements of the users, starting from titanium target on copper substrate, and going to more sophisticated devices. A wide range of possible uses is covered, including thin targets for neutron calibration, thick targets with controlled loading of deuterium and tritium, rotating targets for higher lifetimes, or large size rotating targets for accelerators used in boron neutron therapy. Activity of targets lies in the 1 to 1000 Curie, diameter of targets being up to 30 cm. Special targets are also considered, including surface layer targets for lowering tritium desorption under irradiation, or those made from different kinds of occluders such as titanium, zirconium, erbium, scandium, with different substrates. It is then possible to optimize either neutron output, or lifetime and stability, or thermal behavior.

Cancer-targeted therapies and radiopharmaceuticals

PubMed Central

Rachner, Tilman D; Jakob, Franz; Hofbauer, Lorenz C

2015-01-01

The treatment of bone metastases remains a clinical challenge. Although a number of well-established agents, namely bisphosphonates and denosumab, are available to reduce the occurrence of skeletal-related events, additional cancer-targeted therapies are required to improve patients' prognosis and quality of life. This review focuses on novel targets and agents that are under clinical evaluation for the treatment of malignant bone diseases such as activin A, src and endothelin-1 inhibition or agents that are clinically approved and may positively influence bone, such as the mTOR inhibitor everolimus. In addition, the potential of alpharadin, a novel radiopharmaceutical approved for the treatment of prostatic bone disease, is discussed. PMID:26131359

Identification of the remains of King Richard III.

PubMed

King, Turi E; Fortes, Gloria Gonzalez; Balaresque, Patricia; Thomas, Mark G; Balding, David; Maisano Delser, Pierpaolo; Neumann, Rita; Parson, Walther; Knapp, Michael; Walsh, Susan; Tonasso, Laure; Holt, John; Kayser, Manfred; Appleby, Jo; Forster, Peter; Ekserdjian, David; Hofreiter, Michael; Schürer, Kevin

2014-12-02

In 2012, a skeleton was excavated at the presumed site of the Grey Friars friary in Leicester, the last-known resting place of King Richard III. Archaeological, osteological and radiocarbon dating data were consistent with these being his remains. Here we report DNA analyses of both the skeletal remains and living relatives of Richard III. We find a perfect mitochondrial DNA match between the sequence obtained from the remains and one living relative, and a single-base substitution when compared with a second relative. Y-chromosome haplotypes from male-line relatives and the remains do not match, which could be attributed to a false-paternity event occurring in any of the intervening generations. DNA-predicted hair and eye colour are consistent with Richard's appearance in an early portrait. We calculate likelihood ratios for the non-genetic and genetic data separately, and combined, and conclude that the evidence for the remains being those of Richard III is overwhelming.

Identification of the remains of King Richard III

PubMed Central

King, Turi E.; Fortes, Gloria Gonzalez; Balaresque, Patricia; Thomas, Mark G.; Balding, David; Delser, Pierpaolo Maisano; Neumann, Rita; Parson, Walther; Knapp, Michael; Walsh, Susan; Tonasso, Laure; Holt, John; Kayser, Manfred; Appleby, Jo; Forster, Peter; Ekserdjian, David; Hofreiter, Michael; Schürer, Kevin

2014-01-01

In 2012, a skeleton was excavated at the presumed site of the Grey Friars friary in Leicester, the last-known resting place of King Richard III. Archaeological, osteological and radiocarbon dating data were consistent with these being his remains. Here we report DNA analyses of both the skeletal remains and living relatives of Richard III. We find a perfect mitochondrial DNA match between the sequence obtained from the remains and one living relative, and a single-base substitution when compared with a second relative. Y-chromosome haplotypes from male-line relatives and the remains do not match, which could be attributed to a false-paternity event occurring in any of the intervening generations. DNA-predicted hair and eye colour are consistent with Richard’s appearance in an early portrait. We calculate likelihood ratios for the non-genetic and genetic data separately, and combined, and conclude that the evidence for the remains being those of Richard III is overwhelming. PMID:25463651

A non-destructive method for dating human remains

USGS Publications Warehouse

Lail, Warren K.; Sammeth, David; Mahan, Shannon; Nevins, Jason

2013-01-01

The skeletal remains of several Native Americans were recovered in an eroded state from a creek bank in northeastern New Mexico. Subsequently stored in a nearby museum, the remains became lost for almost 36 years. In a recent effort to repatriate the remains, it was necessary to fit them into a cultural chronology in order to determine the appropriate tribe(s) for consultation pursuant to the Native American Grave Protection and Repatriation Act (NAGPRA). Because the remains were found in an eroded context with no artifacts or funerary objects, their age was unknown. Having been asked to avoid destructive dating methods such as radiocarbon dating, the authors used Optically Stimulated Luminescence (OSL) to date the sediments embedded in the cranium. The OSL analyses yielded reliable dates between A.D. 1415 and A.D. 1495. Accordingly, we conclude that the remains were interred somewhat earlier than A.D. 1415, but no later than A.D. 1495. We believe the remains are from individuals ancestral to the Ute Mouache Band, which is now being contacted for repatriation efforts. Not only do our methods contribute to the immediate repatriation efforts, they provide archaeologists with a versatile, non-destructive, numerical dating method that can be used in many burial contexts.

Targeting of a Nicotiana plumbaginifolia H+ -ATPase to the plasma membrane is not by default and requires cytosolic structural determinants.

PubMed

Lefebvre, Benoit; Batoko, Henri; Duby, Geoffrey; Boutry, Marc

2004-07-01

The structural determinants involved in the targeting of multitransmembrane-span proteins to the plasma membrane (PM) remain poorly understood. The plasma membrane H+ -ATPase (PMA) from Nicotiana plumbaginifolia, a well-characterized 10 transmembrane-span enzyme, was used as a model to identify structural elements essential for targeting to the PM. When PMA2 and PMA4, representatives of the two main PMA subfamilies, were fused to green fluorescent protein (GFP), the chimeras were shown to be still functional and to be correctly and rapidly targeted to the PM in transgenic tobacco. By contrast, chimeric proteins containing various combinations of PMA transmembrane spanning domains accumulated in the Golgi apparatus and not in the PM and displayed slow traffic properties through the secretory pathway. Individual deletion of three of the four cytosolic domains did not prevent PM targeting, but deletion of the large loop or of its nucleotide binding domain resulted in GFP fluorescence accumulating exclusively in the endoplasmic reticulum. The results show that, at least for this polytopic protein, the PM is not the default pathway and that, in contrast with single-pass membrane proteins, cytosolic structural determinants are required for correct targeting.

Targeting of a Nicotiana plumbaginifolia H+-ATPase to the Plasma Membrane Is Not by Default and Requires Cytosolic Structural Determinants

PubMed Central

Lefebvre, Benoit; Batoko, Henri; Duby, Geoffrey; Boutry, Marc

2004-01-01

The structural determinants involved in the targeting of multitransmembrane-span proteins to the plasma membrane (PM) remain poorly understood. The plasma membrane H+-ATPase (PMA) from Nicotiana plumbaginifolia, a well-characterized 10 transmembrane–span enzyme, was used as a model to identify structural elements essential for targeting to the PM. When PMA2 and PMA4, representatives of the two main PMA subfamilies, were fused to green fluorescent protein (GFP), the chimeras were shown to be still functional and to be correctly and rapidly targeted to the PM in transgenic tobacco. By contrast, chimeric proteins containing various combinations of PMA transmembrane spanning domains accumulated in the Golgi apparatus and not in the PM and displayed slow traffic properties through the secretory pathway. Individual deletion of three of the four cytosolic domains did not prevent PM targeting, but deletion of the large loop or of its nucleotide binding domain resulted in GFP fluorescence accumulating exclusively in the endoplasmic reticulum. The results show that, at least for this polytopic protein, the PM is not the default pathway and that, in contrast with single-pass membrane proteins, cytosolic structural determinants are required for correct targeting. PMID:15208389

Odor analysis of decomposing buried human remains

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

Vass, Arpad Alexander; Smith, Rob R; Thompson, Cyril V

2008-01-01

This study, conducted at the University of Tennessee's Anthropological Research Facility (ARF), lists and ranks the primary chemical constituents which define the odor of decomposition of human remains as detected at the soil surface of shallow burial sites. Triple sorbent traps were used to collect air samples in the field and revealed eight major classes of chemicals which now contain 478 specific volatile compounds associated with burial decomposition. Samples were analyzed using gas chromatography-mass spectrometry (GC-MS) and were collected below and above the body, and at the soil surface of 1.5-3.5 ft. (0.46-1.07 m) deep burial sites of four individualsmore » over a 4-year time span. New data were incorporated into the previously established Decompositional Odor Analysis (DOA) Database providing identification, chemical trends, and semi-quantitation of chemicals for evaluation. This research identifies the 'odor signatures' unique to the decomposition of buried human remains with projected ramifications on human remains detection canine training procedures and in the development of field portable analytical instruments which can be used to locate human remains in shallow burial sites.« less

Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin.

PubMed

Rink, Jonathan S; Yang, Shuo; Cen, Osman; Taxter, Tim; McMahon, Kaylin M; Misener, Sol; Behdad, Amir; Longnecker, Richard; Gordon, Leo I; Thaxton, C Shad

2017-11-06

Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy, while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL drastically reduces the ability of HDL NPs to reduce cellular cholesterol and induce cell death. Therefore, we combined HDL NP with the BCR signaling inhibitor ibrutinib and the SYK inhibitor R406. By targeting both cellular cholesterol uptake and BCR-associated de novo cholesterol synthesis, we achieved cellular cholesterol reduction and induced apoptosis in otherwise resistant ABC DLBCL cell lines. These results in lymphoma demonstrate that reduction of cellular cholesterol is a powerful mechanism to induce apoptosis. Cells rich in cholesterol require HDL NP therapy to reduce uptake and molecularly targeted agents that inhibit upstream pathways that stimulate de novo cholesterol synthesis, thus, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer.

Small maritime target detection through false color fusion

NASA Astrophysics Data System (ADS)

Toet, Alexander; Wu, Tirui

2008-04-01

We present an algorithm that produces a fused false color representation of a combined multiband IR and visual imaging system for maritime applications. Multispectral IR imaging techniques are increasingly deployed in maritime operations, to detect floating mines or to find small dinghies and swimmers during search and rescue operations. However, maritime backgrounds usually contain a large amount of clutter that severely hampers the detection of small targets. Our new algorithm deploys the correlation between the target signatures in two different IR frequency bands (3-5 and 8-12 μm) to construct a fused IR image with a reduced amount of clutter. The fused IR image is then combined with a visual image in a false color RGB representation for display to a human operator. The algorithm works as follows. First, both individual IR bands are filtered with a morphological opening top-hat transform to extract small details. Second, a common image is extracted from the two filtered IR bands, and assigned to the red channel of an RGB image. Regions of interest that appear in both IR bands remain in this common image, while most uncorrelated noise details are filtered out. Third, the visual band is assigned to the green channel and, after multiplication with a constant (typically 1.6) also to the blue channel. Fourth, the brightness and colors of this intermediate false color image are renormalized by adjusting its first order statistics to those of a representative reference scene. The result of these four steps is a fused color image, with naturalistic colors (bluish sky and grayish water), in which small targets are clearly visible.

The SpaceInn-SISMA Database: Characterization of a Large Sample of Variable and Active Stars by Means of Harps Spectra

NASA Astrophysics Data System (ADS)

Rainer, M.; Poretti, E.; Mistò, A.; Panzera, M. R.; Molinaro, M.; Cepparo, F.; Roth, M.; Michel, E.; Monteiro, M. J. P. F. G.

2016-12-01

We created a large database of physical parameters and variability indicators by fully reducing and analyzing the large number of spectra taken to complement the asteroseismic observations of the COnvection, ROtation and planetary Transits (CoRoT) satellite. 7103 spectra of 261 stars obtained with the ESO echelle spectrograph HARPS have been stored in the VO-compliant database Spectroscopic Indicators in a SeisMic Archive (SISMA), along with the CoRoT photometric data of the 72 CoRoT asteroseismic targets. The remaining stars belong to the same variable classes of the CoRoT targets and were observed to better characterize the properties of such classes. Several useful variability indicators (mean line profiles, indices of differential rotation, activity and emission lines) together with v\\sin I and radial-velocity measurements have been extracted from the spectra. The atmospheric parameters {T}{eff},{log}g, and [Fe/H] have been computed following a homogeneous procedure. As a result, we fully characterize a sample of new and known variable stars by computing several spectroscopic indicators, also providing some cases of simultaneous photometry and spectroscopy.

Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model.

PubMed

Arvanitis, Costas D; Vykhodtseva, Natalia; Jolesz, Ferenc; Livingstone, Margaret; McDannold, Nathan

2016-05-01

OBJECT Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an emerging noninvasive alternative to surgery and radiosurgery that is undergoing testing for tumor ablation and functional neurosurgery. The method is currently limited to central brain targets due to skull heating and other factors. An alternative ablative approach combines very low intensity ultrasound bursts and an intravenously administered microbubble agent to locally destroy the vasculature. The objective of this work was to investigate whether it is feasible to use this approach at deep brain targets near the skull base in nonhuman primates. METHODS In 4 rhesus macaques, targets near the skull base were ablated using a clinical TcMRgFUS system operating at 220 kHz. Low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes in conjunction with the ultrasound contrast agent Definity, which was administered as a bolus injection or continuous infusion. The acoustic power level was set to be near the inertial cavitation threshold, which was measured using passive monitoring of the acoustic emissions. The resulting tissue effects were investigated with MRI and with histological analysis performed 3 hours to 1 week after sonication. RESULTS Thirteen targets were sonicated in regions next to the optic tract in the 4 animals. Inertial cavitation, indicated by broadband acoustic emissions, occurred at acoustic pressure amplitudes ranging from 340 to 540 kPa. MRI analysis suggested that the lesions had a central region containing red blood cell extravasations that was surrounded by edema. Blood-brain barrier disruption was observed on contrast-enhanced MRI in the lesions and in a surrounding region corresponding to the prefocal area of the FUS system. In histology, lesions consisting of tissue undergoing ischemic necrosis were found in all regions that were sonicated above the inertial cavitation threshold. Tissue damage in prefocal areas was found in several cases, suggesting that in

Integrated Targeting and Guidance for Powered Planetary Descent

NASA Astrophysics Data System (ADS)

Azimov, Dilmurat M.; Bishop, Robert H.

2018-02-01

This paper presents an on-board guidance and targeting design that enables explicit state and thrust vector control and on-board targeting for planetary descent and landing. These capabilities are developed utilizing a new closed-form solution for the constant thrust arc of the braking phase of the powered descent trajectory. The key elements of proven targeting and guidance architectures, including braking and approach phase quartics, are employed. It is demonstrated that implementation of the proposed solution avoids numerical simulation iterations, thereby facilitating on-board execution of targeting procedures during the descent. It is shown that the shape of the braking phase constant thrust arc is highly dependent on initial mass and propulsion system parameters. The analytic solution process is explicit in terms of targeting and guidance parameters, while remaining generic with respect to planetary body and descent trajectory design. These features increase the feasibility of extending the proposed integrated targeting and guidance design to future cargo and robotic landing missions.

Integrated Targeting and Guidance for Powered Planetary Descent

NASA Astrophysics Data System (ADS)

Azimov, Dilmurat M.; Bishop, Robert H.

2018-06-01

This paper presents an on-board guidance and targeting design that enables explicit state and thrust vector control and on-board targeting for planetary descent and landing. These capabilities are developed utilizing a new closed-form solution for the constant thrust arc of the braking phase of the powered descent trajectory. The key elements of proven targeting and guidance architectures, including braking and approach phase quartics, are employed. It is demonstrated that implementation of the proposed solution avoids numerical simulation iterations, thereby facilitating on-board execution of targeting procedures during the descent. It is shown that the shape of the braking phase constant thrust arc is highly dependent on initial mass and propulsion system parameters. The analytic solution process is explicit in terms of targeting and guidance parameters, while remaining generic with respect to planetary body and descent trajectory design. These features increase the feasibility of extending the proposed integrated targeting and guidance design to future cargo and robotic landing missions.

Hierarchical effects on target detection and conflict monitoring

PubMed Central

Cao, Bihua; Gao, Feng; Ren, Maofang; Li, Fuhong

2016-01-01

Previous neuroimaging studies have demonstrated a hierarchical functional structure of the frontal cortices of the human brain, but the temporal course and the electrophysiological signature of the hierarchical representation remains unaddressed. In the present study, twenty-one volunteers were asked to perform a nested cue-target task, while their scalp potentials were recorded. The results showed that: (1) in comparison with the lower-level hierarchical targets, the higher-level targets elicited a larger N2 component (220–350 ms) at the frontal sites, and a smaller P3 component (350–500 ms) across the frontal and parietal sites; (2) conflict-related negativity (non-target minus target) was greater for the lower-level hierarchy than the higher-level, reflecting a more intensive process of conflict monitoring at the final step of target detection. These results imply that decision making, context updating, and conflict monitoring differ among different hierarchical levels of abstraction. PMID:27561989

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

PubMed

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

2017-01-01

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

A Track Initiation Method for the Underwater Target Tracking Environment

NASA Astrophysics Data System (ADS)

Li, Dong-dong; Lin, Yang; Zhang, Yao

2018-04-01

A novel efficient track initiation method is proposed for the harsh underwater target tracking environment (heavy clutter and large measurement errors): track splitting, evaluating, pruning and merging method (TSEPM). Track initiation demands that the method should determine the existence and initial state of a target quickly and correctly. Heavy clutter and large measurement errors certainly pose additional difficulties and challenges, which deteriorate and complicate the track initiation in the harsh underwater target tracking environment. There are three primary shortcomings for the current track initiation methods to initialize a target: (a) they cannot eliminate the turbulences of clutter effectively; (b) there may be a high false alarm probability and low detection probability of a track; (c) they cannot estimate the initial state for a new confirmed track correctly. Based on the multiple hypotheses tracking principle and modified logic-based track initiation method, in order to increase the detection probability of a track, track splitting creates a large number of tracks which include the true track originated from the target. And in order to decrease the false alarm probability, based on the evaluation mechanism, track pruning and track merging are proposed to reduce the false tracks. TSEPM method can deal with the track initiation problems derived from heavy clutter and large measurement errors, determine the target's existence and estimate its initial state with the least squares method. What's more, our method is fully automatic and does not require any kind manual input for initializing and tuning any parameter. Simulation results indicate that our new method improves significantly the performance of the track initiation in the harsh underwater target tracking environment.

The Effects of Soil Texture on the Ability of Human Remains Detection Dogs to Detect Buried Human Remains.

PubMed

Alexander, Michael B; Hodges, Theresa K; Wescott, Daniel J; Aitkenhead-Peterson, Jacqueline A

2016-05-01

Despite technological advances, human remains detection (HRD) dogs still remain one of the best tools for locating clandestine graves. However, soil texture may affect the escape of decomposition gases and therefore the effectiveness of HDR dogs. Six nationally credentialed HRD dogs (three HRD only and three cross-trained) were evaluated on novel buried human remains in contrasting soils, a clayey and a sandy soil. Search time and accuracy were compared for the clayey soil and sandy soil to assess odor location difficulty. Sandy soil (p < 0.001) yielded significantly faster trained response times, but no significant differences were found in performance accuracy between soil textures or training method. Results indicate soil texture may be significant factor in odor detection difficulty. Prior knowledge of soil texture and moisture may be useful for search management and planning. Appropriate adjustments to search segment sizes, sweep widths and search time allotment depending on soil texture may optimize successful detection. © 2016 American Academy of Forensic Sciences.

Small, medium, large or supersize? The development and evaluation of interventions targeted at portion size

PubMed Central

Vermeer, W M; Steenhuis, I H M; Poelman, M P

2014-01-01

In the past decades, portion sizes of high-caloric foods and drinks have increased and can be considered an important environmental obesogenic factor. This paper describes a research project in which the feasibility and effectiveness of environmental interventions targeted at portion size was evaluated. The studies that we conducted revealed that portion size labeling, offering a larger variety of portion sizes, and proportional pricing (that is, a comparable price per unit regardless of the size) were considered feasible to implement according to both consumers and point-of-purchase representatives. Studies into the effectiveness of these interventions demonstrated that the impact of portion size labeling on the (intended) consumption of soft drinks was, at most, modest. Furthermore, the introduction of smaller portion sizes of hot meals in worksite cafeterias in addition to the existing size stimulated a moderate number of consumers to replace their large meals by a small meal. Elaborating on these findings, we advocate further research into communication and marketing strategies related to portion size interventions; the development of environmental portion size interventions as well as educational interventions that improve people's ability to deal with a ‘super-sized' environment; the implementation of regulation with respect to portion size labeling, and the use of nudges to stimulate consumers to select healthier portion sizes. PMID:25033959

Humans and seasonal climate variability threaten large-bodied coral reef fish with small ranges.

PubMed

Mellin, C; Mouillot, D; Kulbicki, M; McClanahan, T R; Vigliola, L; Bradshaw, C J A; Brainard, R E; Chabanet, P; Edgar, G J; Fordham, D A; Friedlander, A M; Parravicini, V; Sequeira, A M M; Stuart-Smith, R D; Wantiez, L; Caley, M J

2016-02-03

Coral reefs are among the most species-rich and threatened ecosystems on Earth, yet the extent to which human stressors determine species occurrences, compared with biogeography or environmental conditions, remains largely unknown. With ever-increasing human-mediated disturbances on these ecosystems, an important question is not only how many species can inhabit local communities, but also which biological traits determine species that can persist (or not) above particular disturbance thresholds. Here we show that human pressure and seasonal climate variability are disproportionately and negatively associated with the occurrence of large-bodied and geographically small-ranging fishes within local coral reef communities. These species are 67% less likely to occur where human impact and temperature seasonality exceed critical thresholds, such as in the marine biodiversity hotspot: the Coral Triangle. Our results identify the most sensitive species and critical thresholds of human and climatic stressors, providing opportunity for targeted conservation intervention to prevent local extinctions.

Humans and seasonal climate variability threaten large-bodied coral reef fish with small ranges

PubMed Central

Mellin, C.; Mouillot, D.; Kulbicki, M.; McClanahan, T. R.; Vigliola, L.; Bradshaw, C. J. A.; Brainard, R. E.; Chabanet, P.; Edgar, G. J.; Fordham, D. A.; Friedlander, A. M.; Parravicini, V.; Sequeira, A. M. M.; Stuart-Smith, R. D.; Wantiez, L.; Caley, M. J.

2016-01-01

Coral reefs are among the most species-rich and threatened ecosystems on Earth, yet the extent to which human stressors determine species occurrences, compared with biogeography or environmental conditions, remains largely unknown. With ever-increasing human-mediated disturbances on these ecosystems, an important question is not only how many species can inhabit local communities, but also which biological traits determine species that can persist (or not) above particular disturbance thresholds. Here we show that human pressure and seasonal climate variability are disproportionately and negatively associated with the occurrence of large-bodied and geographically small-ranging fishes within local coral reef communities. These species are 67% less likely to occur where human impact and temperature seasonality exceed critical thresholds, such as in the marine biodiversity hotspot: the Coral Triangle. Our results identify the most sensitive species and critical thresholds of human and climatic stressors, providing opportunity for targeted conservation intervention to prevent local extinctions. PMID:26839155

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

PubMed

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

2017-02-01

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

Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies.

PubMed

Seelig, Davis M; Ito, Daisuke; Forster, Colleen L; Yoon, Una A; Breen, Matthew; Burns, Linda J; Bachanova, Veronika; Lindblad-Toh, Kerstin; O'Brien, Timothy D; Schmechel, Stephen C; Rizzardi, Anthony E; Modiano, Jaime F; Linden, Michael A

2017-07-01

Activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a common molecular event observed in both human and canine diffuse large B-cell lymphoma (DLBCL). Although the oncogenic potential of the alternative NFκB pathway (ANFκBP) has also been recently identified in DLBCL, its precise role in tumor pathogenesis and potential as a treatment target is understudied. We hypothesized that up-regulation of the ANFκBP plays an important role in the proliferation and survival of canine DLBCL cells, and we demonstrate that the ANFκBP is constitutively active in primary canine DLBCL samples and a cell line (CLBL1). We further demonstrate that a small interfering RNA inhibits the activation of the NFκB pathway and induces apoptosis in canine DLBCL cells. In conclusion, the ANFκBP facilitates survival of canine DLBCL cells, and thus, dogs with spontaneous DLBCL can provide a useful large animal model to study therapies targeting the ANFκBP.

“Why We Stay”: Immigrants’ motivations for remaining in communities impacted by anti-immigration policy

PubMed Central

Valdez, Carmen R.; Valentine, Jessa L.; Padilla, Brian

2013-01-01

Although restrictive immigration policy reduces incentives for unauthorized immigrants to remain in the United States, many immigrants remain in their U.S. community in spite of the anti-immigration climate surrounding them. This study explores motivations shaping immigrants’ intentions to stay in Arizona after passage of Senate Bill 1070 in 2010, one of the most restrictive immigration policies in recent decades. We conducted three focus groups in a large metropolitan city in Arizona with Mexican immigrant parents (N = 25). Themes emerging from the focus groups described multiple and interlocking personal, family and community, and contemporary sociopolitical motivations to stay in their community, and suggest that some important motivating factors have evolved as a result of immigrants’ changing environment. Implications for research and social policy reform are discussed. PMID:23875853

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

PubMed Central

Mruk, Dolores D.; Silvestrini, Bruno; Cheng, C. Yan

2010-01-01

In multicellular organisms, cell-cell interactions are mediated in part by cell junctions, which underlie tissue architecture. Throughout spermatogenesis, for instance, preleptotene leptotene spermatocytes residing in the basal compartment of the seminiferous epithelium must traverse the blood-testis barrier to enter the adluminal compartment for continued development. At the same time, germ cells must also remain attached to Sertoli cells, and numerous studies have reported extensive restructuring at the Sertoli-Sertoli and Sertoli-germ cell interface during germ cell movement across the seminiferous epithelium. Furthermore, the proteins and signaling cascades that regulate adhesion between testicular cells have been largely delineated. These findings have unveiled a number of potential “druggable” targets that can be used to induce premature release of germ cells from the seminiferous epithelium, resulting in transient infertility. Herein, we discuss a novel approach with the aim of developing a nonhormonal male contraceptive for future human use, one that involves perturbing adhesion between Sertoli and germ cells in the testis. PMID:18483144

Eradication of Yaws: Historical Efforts and Achieving WHO's 2020 Target

PubMed Central

Asiedu, Kingsley; Fitzpatrick, Christopher; Jannin, Jean

2014-01-01

Background Yaws, one of the 17 neglected tropical diseases (NTDs), is targeted for eradication by 2020 in resolution WHA66.12 of the World Health Assembly (2013) and the WHO roadmap on NTDs (2012). The disease frequently affects children who live in poor socioeconomic conditions. Between 1952 and 1964, WHO and the United Nations Children's Fund (UNICEF) led a global eradication campaign using injectable benzathine penicillin. Recent developments using a single dose of oral azithromycin have renewed optimism that eradication can be achieved through a comprehensive large-scale treatment strategy. We review historical efforts to eradicate yaws and argue that this goal is now technically feasible using new tools and with the favorable environment for control of NTDs. We also summarize the work of WHO's Department of Control of Neglected Tropical Diseases in leading the renewed eradication initiative and call on the international community to support efforts to achieve the 2020 eradication goal. The critical factor remains access to azithromycin. Excluding medicines, the financial cost of yaws eradication could be as little as US$ 100 million. Conclusions The development of new tools has renewed interest in eradication of yaws; with modest support, the WHO eradication target of 2020 can be achieved. PMID:25254372

Ancient class of translocated oomycete effectors targets the host nucleus.

PubMed

Schornack, Sebastian; van Damme, Mireille; Bozkurt, Tolga O; Cano, Liliana M; Smoker, Matthew; Thines, Marco; Gaulin, Elodie; Kamoun, Sophien; Huitema, Edgar

2010-10-05

Pathogens use specialized secretion systems and targeting signals to translocate effector proteins inside host cells, a process that is essential for promoting disease and parasitism. However, the amino acid sequences that determine host delivery of eukaryotic pathogen effectors remain mostly unknown. The Crinkler (CRN) proteins of oomycete plant pathogens, such as the Irish potato famine organism Phytophthora infestans, are modular proteins with predicted secretion signals and conserved N-terminal sequence motifs. Here, we provide direct evidence that CRN N termini mediate protein transport into plant cells. CRN host translocation requires a conserved motif that is present in all examined plant pathogenic oomycetes, including the phylogenetically divergent species Aphanomyces euteiches that does not form haustoria, specialized infection structures that have been implicated previously in delivery of effectors. Several distinct CRN C termini localized to plant nuclei and, in the case of CRN8, required nuclear accumulation to induce plant cell death. These results reveal a large family of ubiquitous oomycete effector proteins that target the host nucleus. Oomycetes appear to have acquired the ability to translocate effector proteins inside plant cells relatively early in their evolution and before the emergence of haustoria. Finally, this work further implicates the host nucleus as an important cellular compartment where the fate of plant-microbe interactions is determined.

One shot, one kill: the forces delivered by archer fish shots to distant targets.

PubMed

Burnette, Morgan F; Ashley-Ross, Miriam A

2015-10-01

Archer fishes are skillful hunters of terrestrial prey, firing jets of water that dislodge insects perched on overhead vegetation. In the current investigation, we sought an answer to the question: are distant targets impractical foraging choices? Targets far from the shooter might not be hit with sufficient force to cause them to fall. However, observations from other investigators show that archer fish fire streams of water that travel in a non-ballistic fashion, which is thought to keep on-target forces high, even to targets that are several body lengths distant from the fish. We presented targets at different distances and investigated three aspects of foraging behavior: (i) on-target forces, (ii) shot velocity, (iii) a two-target choice assay to determine if fish would show any preference for downing closer targets or more distant targets. In general, shots from our fish (Toxotes chatareus) showed a mild decrease (less than 15% on average) in on-target forces at our most distant target offered (5.8 body lengths) with respect to the closest target offered (2.3 body lengths). One individual in our investigation showed slightly, but significantly, greater on-target forces as target distance increased. Forces on the furthest targets offered were found to double that of attachment forces for 200mg insects, even for individuals whose on-target forces showed mild decreases with increases in target distance. High-speed video analysis of jet impact with the target revealed that the shot was traveling in a non-ballistic manner, even to our most distant target offered, corroborating previous suppositions that on-target forces should remain high. Fish were able to accomplish this without large changes to shot velocity, but we did find evidence that the water jets appeared to differ in the timing of their acceleration as target distance increased. Our two-target choice experiment revealed that fish show preference for downing the closer target first, even though impact

Probability based remaining capacity estimation using data-driven and neural network model

NASA Astrophysics Data System (ADS)

Wang, Yujie; Yang, Duo; Zhang, Xu; Chen, Zonghai

2016-05-01

Since large numbers of lithium-ion batteries are composed in pack and the batteries are complex electrochemical devices, their monitoring and safety concerns are key issues for the applications of battery technology. An accurate estimation of battery remaining capacity is crucial for optimization of the vehicle control, preventing battery from over-charging and over-discharging and ensuring the safety during its service life. The remaining capacity estimation of a battery includes the estimation of state-of-charge (SOC) and state-of-energy (SOE). In this work, a probability based adaptive estimator is presented to obtain accurate and reliable estimation results for both SOC and SOE. For the SOC estimation, an n ordered RC equivalent circuit model is employed by combining an electrochemical model to obtain more accurate voltage prediction results. For the SOE estimation, a sliding window neural network model is proposed to investigate the relationship between the terminal voltage and the model inputs. To verify the accuracy and robustness of the proposed model and estimation algorithm, experiments under different dynamic operation current profiles are performed on the commercial 1665130-type lithium-ion batteries. The results illustrate that accurate and robust estimation can be obtained by the proposed method.

A BRDF-BPDF database for the analysis of Earth target reflectances

NASA Astrophysics Data System (ADS)

Breon, Francois-Marie; Maignan, Fabienne

2017-01-01

Land surface reflectance is not isotropic. It varies with the observation geometry that is defined by the sun, view zenith angles, and the relative azimuth. In addition, the reflectance is linearly polarized. The reflectance anisotropy is quantified by the bidirectional reflectance distribution function (BRDF), while its polarization properties are defined by the bidirectional polarization distribution function (BPDF). The POLDER radiometer that flew onboard the PARASOL microsatellite remains the only space instrument that measured numerous samples of the BRDF and BPDF of Earth targets. Here, we describe a database of representative BRDFs and BPDFs derived from the POLDER measurements. From the huge number of data acquired by the spaceborne instrument over a period of 7 years, we selected a set of targets with high-quality observations. The selection aimed for a large number of observations, free of significant cloud or aerosol contamination, acquired in diverse observation geometries with a focus on the backscatter direction that shows the specific hot spot signature. The targets are sorted according to the 16-class International Geosphere-Biosphere Programme (IGBP) land cover classification system, and the target selection aims at a spatial representativeness within the class. The database thus provides a set of high-quality BRDF and BPDF samples that can be used to assess the typical variability of natural surface reflectances or to evaluate models. It is available freely from the PANGAEA website (target="_blank">doi:10.1594/PANGAEA.864090). In addition to the database, we provide a visualization and analysis tool based on the Interactive Data Language (IDL). It allows an interactive analysis of the measurements and a comparison against various BRDF and BPDF analytical models. The present paper describes the input data, the selection principles, the database format, and the analysis tool

"Recent" macrofossil remains from the Lomonosov Ridge, central Arctic Ocean

NASA Astrophysics Data System (ADS)

Le Duc, Cynthia; de Vernal, Anne; Archambault, Philippe; Brice, Camille; Roberge, Philippe

2016-04-01

The examination of surface sediment samples collected from 17 sites along the Lomonosov Ridge at water depths ranging from 737 to 3339 meters during Polarstern Expedition PS87 in 2014 (Stein, 2015), indicates a rich biogenic content almost exclusively dominated by calcareous remains. Amongst biogenic remains, microfossils (planktic and benthic foraminifers, pteropods, ostracods, etc.) dominate but millimetric to centrimetric macrofossils occurred frequently at the surface of the sediment. The macrofossil remains consist of a large variety of taxa, including gastropods, bivalvia, polychaete tubes, scaphopods, echinoderm plates and spines, and fish otoliths. Among the Bivalvia, the most abundant taxa are Portlandia arctica, Hyalopecten frigidus, Cuspidaria glacilis, Policordia densicostata, Bathyarca spp., and Yoldiella spp. Whereas a few specimens are well preserved and apparently pristine, most mollusk shells displayed extensive alteration features. Moreover, most shells were covered by millimeter scale tubes of the serpulid polychaete Spirorbis sp. suggesting transport from low intertidal or subtidal zone. Both the ecological affinity and known geographic distribution of identified bivalvia as named above support the hypothesis of transportation rather than local development. In addition to mollusk shells, more than a hundred fish otoliths were recovered in surface sediments. The otoliths mostly belong to the Gadidae family. Most of them are well preserved and without serpulid tubes attached to their surface, suggesting a local/regional origin, unlike the shell remains. Although recovered at the surface, the macrofaunal assemblages of the Lomonosov Ridge do not necessarily represent the "modern" environments as they may result from reworking and because their occurrence at the surface of the sediment may also be due to winnowing of finer particles. Although the shells were not dated, we suspect that their actual ages may range from modern to several thousands of

Breaking bad habits: Targeting MDSCs to alleviate immunosuppression in prostate cancer.

PubMed

Pal, Sumanta K; Kortylewski, Marcin

2016-02-01

The myeloid-derived suppressor cells (MDSCs) contribute to tumor immune evasion and still remain an elusive therapeutic target. Our study identified granulocytic MDSCs accumulating in prostate cancer patients during disease progression. We demonstrate the feasibility of using STAT3siRNA-based strategy for targeting MDSCs to alleviate arginase-dependent suppression of T cell activity.

Small molecules targeting viral RNA.

PubMed

Hermann, Thomas

2016-11-01

Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug-like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug-like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA-binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect-borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg). WIREs RNA 2016, 7:726-743. doi: 10.1002/wrna.1373 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

Targeted Capture Sequencing in Whitebark Pine Reveals Range-Wide Demographic and Adaptive Patterns Despite Challenges of a Large, Repetitive Genome.

PubMed

Syring, John V; Tennessen, Jacob A; Jennings, Tara N; Wegrzyn, Jill; Scelfo-Dalbey, Camille; Cronn, Richard

2016-01-01

Whitebark pine (Pinus albicaulis) inhabits an expansive range in western North America, and it is a keystone species of subalpine environments. Whitebark is susceptible to multiple threats - climate change, white pine blister rust, mountain pine beetle, and fire exclusion - and it is suffering significant mortality range-wide, prompting the tree to be listed as 'globally endangered' by the International Union for Conservation of Nature and 'endangered' by the Canadian government. Conservation collections (in situ and ex situ) are being initiated to preserve the genetic legacy of the species. Reliable, transferrable, and highly variable genetic markers are essential for quantifying the genetic profiles of seed collections relative to natural stands, and ensuring the completeness of conservation collections. We evaluated the use of hybridization-based target capture to enrich specific genomic regions from the 27 GB genome of whitebark pine, and to evaluate genetic variation across loci, trees, and geography. Probes were designed to capture 7,849 distinct genes, and screening was performed on 48 trees. Despite the inclusion of repetitive elements in the probe pool, the resulting dataset provided information on 4,452 genes and 32% of targeted positions (528,873 bp), and we were able to identify 12,390 segregating sites from 47 trees. Variations reveal strong geographic trends in heterozygosity and allelic richness, with trees from the southern Cascade and Sierra Range showing the greatest distinctiveness and differentiation. Our results show that even under non-optimal conditions (low enrichment efficiency; inclusion of repetitive elements in baits), targeted enrichment produces high quality, codominant genotypes from large genomes. The resulting data can be readily integrated into management and gene conservation activities for whitebark pine, and have the potential to be applied to other members of 5-needle pine group (Pinus subsect. Quinquefolia) due to their

Identification of differentially expressed small RNAs and prediction of target genes in Italian Large White pigs with divergent backfat deposition.

PubMed

Davoli, R; Gaffo, E; Zappaterra, M; Bortoluzzi, S; Zambonelli, P

2018-06-01

The identification of the molecular mechanisms regulating pathways associated with the potential for fat deposition in pigs can lead to the detection of key genes and markers for the genetic improvement of fat traits. Interactions of microRNAs (miRNAs) with target RNAs regulate gene expression and modulate pathway activation in cells and tissues. In pigs, miRNA discovery is far from saturation, and the knowledge of miRNA expression in backfat tissue and particularly of the impact of miRNA variations is still fragmentary. Using RNA-seq, we characterized the small RNA (sRNA) expression profiles in Italian Large White pig backfat tissue. Comparing two groups of pigs divergent for backfat deposition, we detected 31 significant differentially expressed (DE) sRNAs: 14 up-regulated (including ssc-miR-132, ssc-miR-146b, ssc-miR-221-5p, ssc-miR-365-5p and the moRNA ssc-moR-21-5p) and 17 down-regulated (including ssc-miR-136, ssc-miR-195, ssc-miR-199a-5p and ssc-miR-335). To understand the biological impact of the observed miRNA expression variations, we used the expression correlation of DE miRNA target transcripts expressed in the same samples to define a regulatory network of 193 interactions between DE miRNAs and 40 DE target transcripts showing opposite expression profiles and being involved in specific pathways. Several miRNAs and mRNAs in the network were found to be expressed from backfat-related pig QTL. These results are informative for the complex mechanisms influencing fat traits, shed light on a new aspect of the genetic regulation of fat deposition in pigs and facilitate the prospective implementation of innovative strategies of pig genetic improvement based on genomic markers. © 2018 Stichting International Foundation for Animal Genetics.

PIE preparation of the MEGAPIE target

NASA Astrophysics Data System (ADS)

Wohlmuther, Michael; Wagner, Werner

2012-12-01

The MEGAPIE target, after successfully operating for 4 months at a beam power of 0.77 MW, is now being prepared for post irradiation examination PIE. The lead-bismuth eutectic (LBE) target was irradiated from August until December 2006, and in this period received a beam charge of 2.8 A h of 575 MeV protons. After that, the target was stored in the target storage facility of PSI, waiting for its post irradiation examination. In the meantime several campaigns of tests have been conducted by PSI and ZWILAG, the interim storage facility of Swiss nuclear power plants. In these tests the feasibility of the conditioning of the target and the extraction of sample material for the PIE has been proven. After transport to the hot cell facility at ZWILAG in June 2009, the dismantling of the MEGAPIE target started. It finally was cut into 21 pieces. Ten of these pieces will be shipped to the Hot Laboratory of PSI ('PSI hotlab') to extract samples from the structural materials as well as from the LBE. Currently it is foreseen that the sample extraction will start in the first half of 2011. The remaining parts of the MEGAPIE target were conditioned as radioactive waste. The present paper will mainly focus on the dismantling and first visual inspection of the MEGAPIE target. In addition an outlook on the PIE phase of MEGAPIE is given.

Recovery of uranium from an irradiated solid target after removal of molybdenum-99 produced from the irradiated target

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

Reilly, Sean Douglas; May, Iain; Copping, Roy

A process for minimizing waste and maximizing utilization of uranium involves recovering uranium from an irradiated solid target after separating the medical isotope product, molybdenum-99, produced from the irradiated target. The process includes irradiating a solid target comprising uranium to produce fission products comprising molybdenum-99, and thereafter dissolving the target and conditioning the solution to prepare an aqueous nitric acid solution containing irradiated uranium. The acidic solution is then contacted with a solid sorbent whereby molybdenum-99 remains adsorbed to the sorbent for subsequent recovery. The uranium passes through the sorbent. The concentrations of acid and uranium are then adjusted tomore » concentrations suitable for crystallization of uranyl nitrate hydrates. After inducing the crystallization, the uranyl nitrate hydrates are separated from a supernatant. The process results in the purification of uranyl nitrate hydrates from fission products and other contaminants. The uranium is therefore available for reuse, storage, or disposal.« less

A dual-targeting liposome conjugated with transferrin and arginine-glycine-aspartic acid peptide for glioma-targeting therapy.

PubMed

Qin, Li; Wang, Cheng-Zheng; Fan, Hui-Jie; Zhang, Chong-Jian; Zhang, Heng-Wei; Lv, Min-Hao; Cui, Shu-DE

2014-11-01

The treatment of a brain glioma remains one of the most difficult challenges in oncology. In the present study a delivery system was developed for targeted drug delivery across the blood-brain barrier (BBB) to the brain cancer cells. A cyclic arginine-glycine-aspartic acid (RGD) peptide and transferrin (TF) were utilized as targeting ligands. Cyclic RGD peptides are specific targeting ligands of cancer cells and TFs are ligands that specifically target the BBB and cancer cells. Liposome (LP) was used to conjugate the cyclic RGD and TFs to establish the brain glioma cascade delivery system (RGD/TF-LP). The LPs were prepared by the thin film hydration method and physicochemical characterization was conducted. In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could target endothelial and tumor cells, as well as penetrate the tumor cells to reach the core of the tumor spheroids. The results of the in vivo imaging further demonstrated that the RGD/TF-LP provided the highest brain distribution. As a result, the paclitaxel-loaded RGD/TF-LP presents the best antiproliferative activity against C6 cells and tumor spheroids. In conclusion, the RGD/TF-LP may precisely target brain glioma, which may be valuable for glioma imaging and therapy.

Protecting Important Sites for Biodiversity Contributes to Meeting Global Conservation Targets

PubMed Central

Butchart, Stuart H. M.; Scharlemann, Jörn P. W.; Evans, Mike I.; Quader, Suhel; Aricò, Salvatore; Arinaitwe, Julius; Balman, Mark; Bennun, Leon A.; Bertzky, Bastian; Besançon, Charles; Boucher, Timothy M.; Brooks, Thomas M.; Burfield, Ian J.; Burgess, Neil D.; Chan, Simba; Clay, Rob P.; Crosby, Mike J.; Davidson, Nicholas C.; De Silva, Naamal; Devenish, Christian; Dutson, Guy C. L.; Fernández, David F. Día z; Fishpool, Lincoln D. C.; Fitzgerald, Claire; Foster, Matt; Heath, Melanie F.; Hockings, Marc; Hoffmann, Michael; Knox, David; Larsen, Frank W.; Lamoreux, John F.; Loucks, Colby; May, Ian; Millett, James; Molloy, Dominic; Morling, Paul; Parr, Mike; Ricketts, Taylor H.; Seddon, Nathalie; Skolnik, Benjamin; Stuart, Simon N.; Upgren, Amy; Woodley, Stephen

2012-01-01

Protected areas (PAs) are a cornerstone of conservation efforts and now cover nearly 13% of the world's land surface, with the world's governments committed to expand this to 17%. However, as biodiversity continues to decline, the effectiveness of PAs in reducing the extinction risk of species remains largely untested. We analyzed PA coverage and trends in species' extinction risk at globally significant sites for conserving birds (10,993 Important Bird Areas, IBAs) and highly threatened vertebrates and conifers (588 Alliance for Zero Extinction sites, AZEs) (referred to collectively hereafter as ‘important sites’). Species occurring in important sites with greater PA coverage experienced smaller increases in extinction risk over recent decades: the increase was half as large for bird species with>50% of the IBAs at which they occur completely covered by PAs, and a third lower for birds, mammals and amphibians restricted to protected AZEs (compared with unprotected or partially protected sites). Globally, half of the important sites for biodiversity conservation remain unprotected (49% of IBAs, 51% of AZEs). While PA coverage of important sites has increased over time, the proportion of PA area covering important sites, as opposed to less important land, has declined (by 0.45–1.14% annually since 1950 for IBAs and 0.79–1.49% annually for AZEs). Thus, while appropriately located PAs may slow the rate at which species are driven towards extinction, recent PA network expansion has under-represented important sites. We conclude that better targeted expansion of PA networks would help to improve biodiversity trends. PMID:22457717

LDL-C goal attainment in patients who remain on atorvastatin or switch to equivalent or non-equivalent doses of simvastatin: a retrospective matched cohort study in clinical practice.

PubMed

Rublee, Dale A; Burke, James P

2010-03-01

As clinical trials have shown the benefits of more intensive cholesterol control, treatment targets for low-density lipoprotein cholesterol (LDL-C) have decreased progressively. At the same time, physicians have been encouraged to contain costs by prescribing cheaper, generic statins for cholesterol management. To determine how these possibly conflicting goals are managed in clinical practice, we examined LDL-C control in patients switched from a potent, branded statin (atorvastatin) to a less potent, generic statin (simvastatin). Patients who switched from atorvastatin to simvastatin between July 2006 and January 2008 were retrospectively identified from a US medical and pharmacy claims database, and matched with controls remaining on atorvastatin. Outcomes measured were the number of switched patients receiving a simvastatin milligram dose>or=2 times their previous atorvastatin dose, changes in LDL-C levels, and percentage of patients achieving recommended LDL-C targets. All study variables were analyzed descriptively. After applying exclusion and inclusion criteria, 1048 patients who switched from atorvastatin to simvastatin and 1048 matched controls who remained on atorvastatin were included. Among the switchers, 379 (36%) received an inappropriately low dose of simvastatin (<2 times atorvastatin dose). In patients remaining on atorvastatin, mean LDL-C decreased from 105.7 mg/dL to 102.3 mg/dL after 44 weeks, whereas in switched patients, LDL-C remained similar, at 105.9 mg/dL on atorvastatin and 105.8 mg/dL on simvastatin. Before switching, when all patients were receiving atorvastatin, 67.4% of switchers and 69.9% of controls achieved recommended LDL-C targets. After switching, significantly fewer switchers than controls met LDL-C targets (69.1% vs 74.6%; P=0.005). However, among patients who switched to an equivalent dose of simvastatin (>or=2 times prior atorvastatin dose), similar proportions met LDL-C targets (72.8% vs 74.6% of controls; P=0.402), whereas

Allowable carbon emissions lowered by multiple climate targets.

PubMed

Steinacher, Marco; Joos, Fortunat; Stocker, Thomas F

2013-07-11

Climate targets are designed to inform policies that would limit the magnitude and impacts of climate change caused by anthropogenic emissions of greenhouse gases and other substances. The target that is currently recognized by most world governments places a limit of two degrees Celsius on the global mean warming since preindustrial times. This would require large sustained reductions in carbon dioxide emissions during the twenty-first century and beyond. Such a global temperature target, however, is not sufficient to control many other quantities, such as transient sea level rise, ocean acidification and net primary production on land. Here, using an Earth system model of intermediate complexity (EMIC) in an observation-informed Bayesian approach, we show that allowable carbon emissions are substantially reduced when multiple climate targets are set. We take into account uncertainties in physical and carbon cycle model parameters, radiative efficiencies, climate sensitivity and carbon cycle feedbacks along with a large set of observational constraints. Within this framework, we explore a broad range of economically feasible greenhouse gas scenarios from the integrated assessment community to determine the likelihood of meeting a combination of specific global and regional targets under various assumptions. For any given likelihood of meeting a set of such targets, the allowable cumulative emissions are greatly reduced from those inferred from the temperature target alone. Therefore, temperature targets alone are unable to comprehensively limit the risks from anthropogenic emissions.

Large benefits to marine fisheries of meeting the 1.5°C global warming target.

PubMed

Cheung, William W L; Reygondeau, Gabriel; Frölicher, Thomas L

2016-12-23

Translating the Paris Agreement to limit global warming to 1.5°C above preindustrial level into impact-related targets facilitates communication of the benefits of mitigating climate change to policy-makers and stakeholders. Developing ecologically relevant impact-related targets for marine ecosystem services, such as fisheries, is an important step. Here, we use maximum catch potential and species turnover as climate-risk indicators for fisheries. We project that potential catches will decrease by more than 3 million metric tons per degree Celsius of warming. Species turnover is more than halved when warming is lowered from 3.5° to 1.5°C above the preindustrial level. Regionally, changes in maximum catch potential and species turnover vary across ecosystems, with the biggest risk reduction in the Indo-Pacific and Arctic regions when the Paris Agreement target is achieved. Copyright © 2016, American Association for the Advancement of Science.

Genome-wide STAT3 binding analysis after histone deacetylase inhibition reveals novel target genes in dendritic cells

PubMed Central

Sun, Yaping; Iyer, Matthew; McEachin, Richard; Zhao, Meng; Wu, Yi-Mi; Cao, Xuhong; Oravecz-Wilson, Katherine; Zajac, Cynthia; Mathewson, Nathan; Wu, Shin-Rong Julia; Rossi, Corinne; Toubai, Tomomi; Qin, Zhaohui S.; Chinnaiya, Arul M.; Reddy, Pavan

2016-01-01

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP-seq coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of non-canonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of pro-inflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition. PMID:27866206

Enhanced cellular transport and drug targeting using dendritic nanostructures

NASA Astrophysics Data System (ADS)

Kannan, R. M.; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

2003-03-01

Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. The large density of end groups can also be tailored to create enhanced affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, drug/ligand conjugation, in vitro cellular and in vivo drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Results on PAMAM dendrimers and polyol hyperbranched polymers suggest that: (1) These materials complex/encapsulate a large number of drug molecules and release them at tailorable rates; (2) The drug-dendrimer complex is transported very rapidly through a A549 lung epithelial cancel cell line, compared to free drug, perhaps by endocytosis. The ability of the drug-dendrimer-ligand complexes to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

Hyperfiltration-mediated injury in the remaining kidney of a transplant donor.

PubMed

Srivastava, Tarak; Hariharan, Sundaram; Alon, Uri S; McCarthy, Ellen T; Sharma, Ram; El-Meanawy, Ashraf; Savin, Virginia J; Sharma, Mukut

2018-05-29

Kidney donors face a small but definite risk of end-stage renal disease 15-30 years postdonation. The development of proteinuria, hypertension with gradual decrease in kidney function in the donor after surgical resection of 1 kidney has been attributed to hyperfiltration. Genetic variations, physiological adaptations, and co-morbidities exacerbate the hyperfiltration-induced loss of kidney function in the years following donation. A focus on glomerular hemodynamics and capillary pressure has led to the development of drugs that target the renin-angiotensin-aldosterone system (RAAS), but these agents yield mixed results in transplant recipients and donors. Recent work on glomerular biomechanical forces highlights the differential effects of tensile stress and fluid flow shear stress (FFSS) from hyperfiltration. Capillary wall stretch due to glomerular capillary pressure increases tensile stress on podocyte foot processes that cover the capillary. In parallel, increased flow of the ultrafiltrate due to single nephron glomerular filtration rate elevates FFSS on the podocyte cell body. While tensile stress invokes the RAAS, FFSS predominantly activates the COX2-PGE2-EP2 axis. Distinguishing these 2 mechanisms is critical, as current therapeutic approaches focus on the RAAS system. A better understanding of the biomechanical forces can lead to novel therapeutic agents to target FFSS through the COX2-PGE2-EP2 axis in hyperfiltration-mediated injury. We present an overview of several aspects of the risk to transplant donors and discuss the relevance of FFSS in podocyte injury, loss of glomerular barrier function leading to albuminuria and gradual loss of renal function, and potential therapeutic strategies to mitigate hyperfiltration-mediated injury to the remaining kidney.

Genome-Wide Identification of CBX2 Targets: Insights in the Human Sex Development Network

PubMed Central

Eid, Wassim; Opitz, Lennart

2015-01-01

Chromobox homolog 2 (CBX2) is a chromatin modifier that plays an important role in sexual development and its disorders (disorders of sex development [DSD]), yet the exact rank and function of human CBX2 in this pathway remains unclear. Here, we performed large-scale mapping and analysis of in vivo target loci of the protein CBX2 in Sertoli-like NT-2D1 cells, using the DNA adenine methyltransferase identification technique. We identified close to 1600 direct targets for CBX2. Intriguingly, validation of selected candidate genes using qRT-PCR in cells overexpressing CBX2 or in which CBX2 has been knocked down indicated that several CBX2-responsive genes encode proteins that are involved in DSD. We further validated these effects on the candidate genes using a mutated CBX2 causing DSD in human patient. Overall, our findings suggest that CBX2 role in the sex development cascade is to stimulate the male pathway and concurrently inhibit the female pathway. These data provide fundamental insights into potential etiology of DSD. PMID:25569159

Examining practical nursing experiences to discover ways in which to retain and invigorate the remaining functions of the elderly with a demented and complex disability in nursing homes.

PubMed

Park, Min-Sun; Lim, Sun-Young; Kim, Eun-Young; Lee, Su-Jung; Chang, Sung-Ok

2018-01-01

The bedridden elderly with moderate-to-severe dementia account for a large proportion of the residents in nursing homes and form a specialized group requiring customized care in order to encourage their remaining functions, which determine the quality of their residual life. The purpose of this study was to search for ways to invigorate and foster the remaining functions of this complex-disability group, based on practical nursing strategies in nursing homes. The qualitative thematic analysis was done by conducting in-depth interviews with 29 nurses working at 11 different nursing homes in South Korea. This study proposed four main themes and 19 sub themes as keys for providing specialized nursing care to the elderly with physical and cognitive disabilities. The main themes encourage the residents' remaining functions: (i) accurate identification of an elderly resident's physical, cognitive, and behavioral baseline is necessary in order to determine their functional levels; (ii) nurses provide meticulous management to support the remaining functions in order to prevent further deterioration; (iii) optimized know-how, based on accumulated experience and knowledge, is reflected in nursing strategies that maximize the effects of nursing interventions; and (iv) steady compliance with nursing guidelines and standards in nursing homes creates the best therapeutic environment and brings unexpected positive changes in the elderly's status. A practical nursing strategy to target the group with a demented and complex disability in nursing homes was developed through thematic analysis of the empirical knowledge of nurses. The findings provide new insights for developing specialized nursing interventions and practical nursing models in long-term care facilities. © 2017 Japan Academy of Nursing Science.

Upper Palaeolithic ritualistic cannibalism at Gough's Cave (Somerset, UK): The human remains from head to toe.

PubMed

Bello, Silvia M; Saladié, Palmira; Cáceres, Isabel; Rodríguez-Hidalgo, Antonio; Parfitt, Simon A

2015-05-01

A recurring theme of late Upper Palaeolithic Magdalenian human bone assemblages is the remarkable rarity of primary burials and the common occurrence of highly-fragmentary human remains mixed with occupation waste at many sites. One of the most extensive Magdalenian human bone assemblages comes from Gough's Cave, a sizeable limestone cave set in Cheddar Gorge (Somerset), UK. After its discovery in the 1880s, the site was developed as a show cave and largely emptied of sediment, at times with minimal archaeological supervision. Some of the last surviving remnants of sediment within the cave were excavated between 1986 and 1992. The excavations uncovered intensively-processed human bones intermingled with abundant butchered large mammal remains and a diverse range of flint, bone, antler, and ivory artefacts. New ultrafiltrated radiocarbon determinations demonstrate that the Upper Palaeolithic human remains were deposited over a very short period of time, possibly during a series of seasonal occupations, about 14,700 years BP (before present). The human remains have been the subject of several taphonomic studies, culminating in a detailed reanalysis of the cranial remains that showed they had been carefully modified to make skull-cups. Our present analysis of the postcrania has identified a far greater degree of human modification than recorded in earlier studies. We identify extensive evidence for defleshing, disarticulation, chewing, crushing of spongy bone, and the cracking of bones to extract marrow. The presence of human tooth marks on many of the postcranial bones provides incontrovertible evidence for cannibalism. In a wider context, the treatment of the human corpses and the manufacture and use of skull-cups at Gough Cave have parallels with other Magdalenian sites in central and western Europe. This suggests that cannibalism during the Magdalenian was part of a customary mortuary practice that combined intensive processing and consumption of the bodies with

Transcriptome-wide Analysis of Exosome Targets

PubMed Central

Schneider, Claudia; Kudla, Grzegorz; Wlotzka, Wiebke; Tuck, Alex; Tollervey, David

2012-01-01

Summary The exosome plays major roles in RNA processing and surveillance but the in vivo target range and substrate acquisition mechanisms remain unclear. Here we apply in vivo RNA crosslinking (CRAC) to the nucleases (Rrp44, Rrp6), two structural subunits (Rrp41, Csl4) and a cofactor (Trf4) of the yeast exosome. Analysis of wild-type Rrp44 and catalytic mutants showed that both the CUT and SUT classes of non-coding RNA, snoRNAs and, most prominently, pre-tRNAs and other Pol III transcripts are targeted for oligoadenylation and exosome degradation. Unspliced pre-mRNAs were also identified as targets for Rrp44 and Rrp6. CRAC performed using cleavable proteins (split-CRAC) revealed that Rrp44 endonuclease and exonuclease activities cooperate on most substrates. Mapping oligoadenylated reads suggests that the endonuclease activity may release stalled exosome substrates. Rrp6 was preferentially associated with structured targets, which frequently did not associate with the core exosome indicating that substrates follow multiple pathways to the nucleases. PMID:23000172

Molecular Targets of Cannabidiol in Neurological Disorders.

PubMed

Ibeas Bih, Clementino; Chen, Tong; Nunn, Alistair V W; Bazelot, Michaël; Dallas, Mark; Whalley, Benjamin J

2015-10-01

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases

Tumor target amplification: Implications for nano drug delivery systems.

PubMed

Seidi, Khaled; Neubauer, Heidi A; Moriggl, Richard; Jahanban-Esfahlan, Rana; Javaheri, Tahereh

2018-04-10

Tumor cells overexpress surface markers which are absent from normal cells. These tumor-restricted antigenic signatures are a fundamental basis for distinguishing on-target from off-target cells for ligand-directed targeting of cancer cells. Unfortunately, tumor heterogeneity impedes the establishment of a solid expression pattern for a given target marker, leading to drastic changes in quality (availability) and quantity (number) of the target. Consequently, a subset of cancer cells remains untargeted during the course of treatment, which subsequently promotes drug-resistance and cancer relapse. Since target inefficiency is only problematic for cancer treatment and not for treatment of other pathological conditions such as viral/bacterial infections, target amplification or the generation of novel targets is key to providing eligible antigenic markers for effective targeted therapy. This review summarizes the limitations of current ligand-directed targeting strategies and provides a comprehensive overview of tumor target amplification strategies, including self-amplifying systems, dual targeting, artificial markers and peptide modification. We also discuss the therapeutic and diagnostic potential of these approaches, the underlying mechanism(s) and established methodologies, mostly in the context of different nanodelivery systems, to facilitate more effective ligand-directed cancer cell monitoring and targeting. Copyright © 2018 Elsevier B.V. All rights reserved.

Activity of Nanobins Targeted to the Urokinase Plasminogen Activator System

NASA Astrophysics Data System (ADS)

Hankins, Patrick Leon

While innovations in nanotechnology have resulted in numerous medical advancements for the treatment of cancer, there remains an urgent unmet need for safe and efficient molecular platforms that facilitate the delivery of potent therapeutics to solid tumors. Nanoscale formulations help to overcome the poor bioavailability and systemic organ toxicity associated with many small molecule drugs. Of these nanoparticle drug delivery systems, the greatest clinical successes to date have employed simple nanoscale lipid bilayer assemblies which encase large payloads of chemotherapeutic. While the nanobin platform we have developed has seen initial success through the passive accumulation into tumors, actively targeting nanobins to tumor specific antigens has the potential to increase the therapeutic index of these nanoparticle drugs. We have identified the urokinase plasminogen activator (uPA) and its cell surface bound receptor (uPAR) as ideal targets for drug delivery due to their selective overexpression in metastatic cancers and their important role in tumor progression. From a panel of monoclonal antibodies targeted to uPA and uPAR, we have selected ATN291 and ATN658 as lead candidates for nanobin targeting based on their tumor cell binding and ability to be internalized by cells. A novel method of conjugating antibodies to liposomes was developed for our nanobin platform that preserves the high binding affinity and specificity of these antibodies. We evaluated these uPA- and uPAR-targeted nanobins in several xenograft tumor models and found that they were well-tolerated over a wide range of doses and demonstrated significantly increased antitumor efficacy over untargeted nanobins in multiple tumor types. Preliminary studies suggest that uPA-targeted nanobins are readily internalized by tumor cells, and we believe this is the mechanism for their increased antitumor effect. A method for radiolabeling nanobins with gallium-67 was developed, and preliminary SPECT

Target and beam-target spin asymmetries in exclusive pion electroproduction for Q2>1 GeV2 . I. e p →e π+n

NASA Astrophysics Data System (ADS)

Bosted, P. E.; Amaryan, M. J.; Anefalos Pereira, S.; Avakian, H.; Badui, R. A.; Ball, J.; Baltzell, N. A.; Battaglieri, M.; Batourine, V.; Bedlinskiy, I.; Biselli, A. S.; Briscoe, W. J.; Bültmann, S.; Burkert, V. D.; Carman, D. S.; Celentano, A.; Chandavar, S.; Charles, G.; Ciullo, G.; Clark, L.; Colaneri, L.; Cole, P. L.; Contalbrigo, M.; Crede, V.; D'Angelo, A.; De Vita, R.; Deur, A.; De Sanctis, E.; Djalali, C.; Dupre, R.; Egiyan, H.; El Alaoui, A.; El Fassi, L.; Elouadrhiri, L.; Eugenio, P.; Fanchini, E.; Fedotov, G.; Filippi, A.; Fleming, J. A.; Forest, T.; Fradi, A.; Gevorgyan, N.; Ghandilyan, Y.; Gilfoyle, G. P.; Girod, F. X.; Gleason, C.; Gohn, W.; Golovatch, E.; Gothe, R. W.; Griffioen, K. A.; Guidal, M.; Hakobyan, H.; Hattawy, M.; Hicks, K.; Holtrop, M.; Hughes, S. M.; Ilieva, Y.; Ireland, D. G.; Ishkhanov, B. S.; Isupov, E. L.; Jiang, H.; Jo, H. S.; Joo, K.; Joosten, S.; Khachatryan, G.; Khandaker, M.; Kim, A.; Kim, W.; Klein, F. J.; Koirala, S.; Kubarovsky, V.; Kuhn, S. E.; Lanza, L.; Net, L. A.; Lenisa, P.; Livingston, K.; MacGregor, I. J. D.; McCracken, M. E.; McKinnon, B.; Meyer, C. A.; Mirazita, M.; Mokeev, V. I.; Montgomery, R. A.; Munevar, E.; Munoz Camacho, C.; Murdoch, G.; Nadel-Turonski, P.; Niccolai, S.; Osipenko, M.; Ostrovidov, A. I.; Park, K.; Pasyuk, E.; Peng, P.; Phelps, W.; Pisano, S.; Pogorelko, O.; Price, J. W.; Prok, Y.; Protopopescu, D.; Puckett, A. J. R.; Raue, B. A.; Ripani, M.; Rosner, G.; Rossi, P.; Schumacher, R. A.; Seder, E.; Skorodumina, Iu.; Smith, G. D.; Sokhan, D.; Sparveris, N.; Stankovic, I.; Stepanyan, S.; Strakovsky, I. I.; Strauch, S.; Taiuti, M.; Tian, Ye; Torayev, B.; Ungaro, M.; Voskanyan, H.; Voutier, E.; Walford, N. K.; Wei, X.; Weinstein, L. B.; Zachariou, N.; Zhang, J.; Zhao, Z. W.; Zonta, I.; CLAS Collaboration

2017-03-01

Beam-target double-spin asymmetries and target single-spin asymmetries were measured for the exclusive π+ electroproduction reaction γ*p →n π+ . The results were obtained from scattering of 6-GeV longitudinally polarized electrons off longitudinally polarized protons using the CEBAF Large Acceptance Spectrometer at Jefferson Laboratory. The kinematic range covered is 1.1 large target-spin asymmetries are observed over the entire W region. Reasonable agreement is found with phenomenological fits to previous data for W <1.6 GeV, but very large differences are seen at higher values of W . A generalized parton distributions (GPD)-based model is in poor agreement with the data. When combined with cross-sectional measurements, the present results provide powerful constraints on nucleon resonance amplitudes at moderate and large values of Q2, for resonances with masses as high as 2.4 GeV.

Target and beam-target spin asymmetries in exclusive pion electroproduction for Q 2 > 1 GeV 2 . I. e p → e π + n

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

Bosted, P. E.; Amaryan, M. J.; Anefalos Pereira, S.

2017-03-20

Beam-target double-spin asymmetries and target single-spin asymmetries were measured for the exclusive π+ electroproduction reaction γ*p → nπ +. The results were obtained from scattering of 6-GeV longitudinally polarized electrons off longitudinally polarized protons using the CEBAF Large Acceptance Spectrometer at Jefferson Laboratory. The kinematic range covered is 1.1 < W < 3 GeV and 1 < Q 2 < 6GeV 2. Results were obtained for about 6000 bins in W, Q 2, cos(θ*), and Φ*. Except at forward angles, very large target-spin asymmetries are observed over the entire W region. Reasonable agreement is found with phenomenological fits to previousmore » data for W < 1.6 GeV, but very large differences are seen at higher values of W. Finally, a generalized parton distributions (GPD)-based model is in poor agreement with the data. When combined with cross-sectional measurements, the present results provide powerful constraints on nucleon resonance amplitudes at moderate and large values of Q 2, for resonances with masses as high as 2.4 GeV.« less

All That Remains of Exploded Star

NASA Image and Video Library

2011-10-24

Infrared images from NASA Spitzer Space Telescope and Wide-field Infrared Survey Explorer are combined in this image of RCW 86, the dusty remains of the oldest documented example of an exploding star, or supernova.

Targeted therapy in advanced gastric carcinoma: the future is beginning.

PubMed

Schinzari, G; Cassano, A; Orlandi, A; Basso, M; Barone, C

2014-01-01

Gastric cancer represents one of the most common cancer worldwide. Unfortunately, the majority of patients present in advanced stage and outcome still remains poor with high mortality rate despite decreasing incidence and new diagnostic and therapeutic strategies. Although utility of classical chemotherapy agents has been widely explored, advances have been slow and the efficacy of these agents has reached a plateau of median overall survival not higher than 12 months. Therefore, researchers focused their attention on better understanding molecular biology of carcinogenesis and deeper knowledge of the cancer cell phenotype, as well on development of rationally designed drugs that would target specific molecular aberrancies in signal transduction pathways. These targets include cell surface receptors, circulating growth and angiogenic factors and other molecules involved in downstream intracellular signaling pathways, including receptor tyrosine kinases. However, therapeutic advances in gastric cancer are not so encouraging when compared to other solid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted agents in gastric cancer as single-agent therapy or in combination regimens, including their rational and emerging mechanism of action, current and emerging data. We focused our attention mainly on published phase III studies, therefore cornerstone clinical trials with trastuzumab and bevacizumab have been largely discussed. Phase III studies presented in important international meetings are also reviewed as well phase II published studies and promising new therapies investigated in preclinical or phase I studies. Today, in first-line treatment only trastuzumab has shown significantly increased survival in combination with chemotherapy, whereas ramucirumab as single agent resulted effective in progressing patients, but - despite several disappointing results - these are the proof of principle that targeting the proper

Changing strategies for target therapy in gastric cancer.

PubMed

Lee, Suk-Young; Oh, Sang Cheul

2016-01-21

In spite of a worldwide decrease in the incidence of gastric cancer, this malignancy still remains one of the leading causes of cancer mortality. Great efforts have been made to improve treatment outcomes in patients with metastatic gastric cancer, and the introduction of trastuzumab has greatly improved the overall survival. The trastuzumab treatment took its first step in opening the era of molecular targeted therapy, however several issues still need to be resolved to increase the efficacy of targeted therapy. Firstly, many patients with metastatic gastric cancer who receive trastuzumab in combination with chemotherapeutic agents develop resistance to the targeted therapy. Secondly, many clinical trials testing novel molecular targeted agents with demonstrated efficacy in other malignancies have failed to show benefit in patients with metastatic gastric cancer, suggesting the importance of the selection of appropriate indications according to molecular characteristics in application of targeted agents. Herein, we review the molecular targeted agents currently approved and in use, and clinical trials in patients with metastatic gastric cancer, and demonstrate the limitations and future direction in treatment of advanced gastric cancer.

3T MRI evaluation of large nerve perineural spread of head and neck cancers.

PubMed

Baulch, Justin; Gandhi, Mitesh; Sommerville, Jennifer; Panizza, Ben

2015-10-01

Accurate definition of the presence and extent of large nerve perineural spread (PNS) is a vital component in planning appropriate surgery and radiotherapy for head and neck cancers. Our research aimed to define the sensitivity and specificity of 3T MRI in detecting the presence and extent of large nerve PNS, compared with histologic evaluation. Retrospective review of surgically proven cases of large nerve PNS in patients with preoperative 3T MRI performed as high resolution neurogram. 3T MRI had a sensitivity of 95% and a specificity of 84%, detecting PNS in 36 of 38 nerves and correctly identifying uninvolved nerves in 16 of 19 cases. It correctly identified the zonal extent of spread in 32 of 36 cases (89%), underestimating the extent in three cases and overestimating the extent in one case. Targeted 3T MRI is highly accurate in defining the presence and extent of large nerve PNS in head and neck cancers. However, there is still a tendency to undercall the zonal extent due to microscopic, radiologically occult involvement. Superficial large nerve involvement also remains a difficult area of detection for radiologists and should be included as a 'check area' for review. Further research is required to define the role radiation-induced neuritis plays in the presence of false-positive PNS on MRI. © 2015 The Royal Australian and New Zealand College of Radiologists.

New Zealand's emergency department target - did it reduce ED length of stay, and if so, how and when?

PubMed

Tenbensel, Tim; Chalmers, Linda; Jones, Peter; Appleton-Dyer, Sarah; Walton, Lisa; Ameratunga, Shanthi

2017-09-26

In 2009, the New Zealand government introduced a hospital emergency department (ED) target - 95% of patients seen, treated or discharged within 6 h - in order to alleviate crowding in public hospital EDs. While these targets were largely met by 2012, research suggests that such targets can be met without corresponding overall reductions in ED length-of-stay (LOS). Our research explores whether the NZ ED time target actually reduced ED LOS, and if so, how and when. We adopted a mixed-methods approach with integration of data sources. After selecting four hospitals as case study sites, we collected all ED utilisation data for the period 2006 to 2012. ED LOS data was derived in two forms-reported ED LOS, and total ED LOS - which included time spent in short-stay units. This data was used to identify changes in the length of ED stay, and describe the timing of these changes to these indicators. Sixty-eight semi-structured interviews and two surveys of hospital clinicians and managers were conducted between 2011 and 2013. This data was then explored to identify factors that could account for ED LOS changes and their timing. Reported ED LOS reduced in all sites after the introduction of the target, and continued to reduce in 2011 and 2012. However, total ED LOS only decreased from 2008 to 2010, and did not reduce further in any hospital. Increased use of short-stay units largely accounted for these differences. Interview and survey data showed changes to improve patient flow were introduced in the early implementation period, whereas increased ED resources, better information systems to monitor target performance, and leadership and social marketing strategies mainly took throughout 2011 and 2012 when total ED LOS was not reducing. While the ED target clearly stimulated improvements in patient flow, our analysis also questions the value of ED targets as a long term approach. Increased use of short-stay units suggests that the target became less effective in 'standing

Predicting the remaining service life of concrete

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

Clifton, J.F.

1991-11-01

Nuclear power plants are providing, currently, about 17 percent of the U.S. electricity and many of these plants are approaching their licensed life of 40 years. The U.S. Nuclear Regulatory Commission and the Department of Energy`s Oak Ridge National Laboratory are carrying out a program to develop a methodology for assessing the remaining safe-life of the concrete components and structures in nuclear power plants. This program has the overall objective of identifying potential structural safety issues, as well as acceptance criteria, for use in evaluations of nuclear power plants for continued service. The National Institute of Standards and Technology (NIST)more » is contributing to this program by identifying and analyzing methods for predicting the remaining life of in-service concrete materials. This report examines the basis for predicting the remaining service lives of concrete materials of nuclear power facilities. Methods for predicting the service life of new and in-service concrete materials are analyzed. These methods include (1) estimates based on experience, (2) comparison of performance, (3) accelerated testing, (4) stochastic methods, and (5) mathematical modeling. New approaches for predicting the remaining service lives of concrete materials are proposed and recommendations for their further development given. Degradation processes are discussed based on considerations of their mechanisms, likelihood of occurrence, manifestations, and detection. They include corrosion, sulfate attack, alkali-aggregate reactions, frost attack, leaching, radiation, salt crystallization, and microbiological attack.« less

Food appropriation through large scale land acquisitions

NASA Astrophysics Data System (ADS)

Rulli, Maria Cristina; D'Odorico, Paolo

2014-05-01

The increasing demand for agricultural products and the uncertainty of international food markets has recently drawn the attention of governments and agribusiness firms toward investments in productive agricultural land, mostly in the developing world. The targeted countries are typically located in regions that have remained only marginally utilized because of lack of modern technology. It is expected that in the long run large scale land acquisitions (LSLAs) for commercial farming will bring the technology required to close the existing crops yield gaps. While the extent of the acquired land and the associated appropriation of freshwater resources have been investigated in detail, the amount of food this land can produce and the number of people it could feed still need to be quantified. Here we use a unique dataset of land deals to provide a global quantitative assessment of the rates of crop and food appropriation potentially associated with LSLAs. We show how up to 300-550 million people could be fed by crops grown in the acquired land, should these investments in agriculture improve crop production and close the yield gap. In contrast, about 190-370 million people could be supported by this land without closing of the yield gap. These numbers raise some concern because the food produced in the acquired land is typically exported to other regions, while the target countries exhibit high levels of malnourishment. Conversely, if used for domestic consumption, the crops harvested in the acquired land could ensure food security to the local populations.

Malaria parasites target the hepatocyte receptor EphA2 for successful host infection.

PubMed

Kaushansky, Alexis; Douglass, Alyse N; Arang, Nadia; Vigdorovich, Vladimir; Dambrauskas, Nicholas; Kain, Heather S; Austin, Laura S; Sather, D Noah; Kappe, Stefan H I

2015-11-27

The invasion of a suitable host hepatocyte by mosquito-transmitted Plasmodium sporozoites is an essential early step in successful malaria parasite infection. Yet precisely how sporozoites target their host cell and facilitate productive infection remains largely unknown. We found that the hepatocyte EphA2 receptor was critical for establishing a permissive intracellular replication compartment, the parasitophorous vacuole. Sporozoites productively infected hepatocytes with high EphA2 expression, and the deletion of EphA2 protected mice from liver infection. Lack of host EphA2 phenocopied the lack of the sporozoite proteins P52 and P36. Our data suggest that P36 engages EphA2, which is likely to be a key step in establishing the permissive replication compartment. Copyright © 2015, American Association for the Advancement of Science.

Roles and potential therapeutic targets of the ubiquitin proteasome system in muscle wasting

PubMed Central

Nury, David; Doucet, Christine; Coux, Olivier

2007-01-01

Muscle wasting, characterized by the loss of protein mass in myofibers, is in most cases largely due to the activation of intracellular protein degradation by the ubiquitin proteasome system (UPS). During the last decade, mechanisms contributing to this activation have been unraveled and key mediators of this process identified. Even though much remains to be understood, the available information already suggests screens for new compounds inhibiting these mechanisms and highlights the potential for pharmaceutical drugs able to treat muscle wasting when it becomes deleterious. This review presents an overview of the main pathways contributing to UPS activation in muscle and describes the present state of efforts made to develop new strategies aimed at blocking or slowing muscle wasting. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; ). PMID:18047744

Skeletal Remains from Punic Carthage Do Not Support Systematic Sacrifice of Infants

PubMed Central

Schwartz, Jeffrey H.; Houghton, Frank; Macchiarelli, Roberto; Bondioli, Luca

2010-01-01

Two types of cemeteries occur at Punic Carthage and other Carthaginian settlements: one centrally situated housing the remains of older children through adults, and another at the periphery of the settlement (the “Tophet”) yielding small urns containing the cremated skeletal remains of very young animals and humans, sometimes comingled. Although the absence of the youngest humans at the primary cemeteries is unusual and worthy of discussion, debate has focused on the significance of Tophets, especially at Carthage, as burial grounds for the young. One interpretation, based on two supposed eye-witness reports of large-scale Carthaginian infant sacrifice [Kleitarchos (3rd c. BCE) and Diodorus Siculus (1st c. BCE)], a particular translation of inscriptions on some burial monuments, and the argument that if the animals had been sacrificed so too were the humans, is that Tophets represent burial grounds reserved for sacrificial victims. An alternative hypothesis acknowledges that while the Carthaginians may have occasionally sacrificed humans, as did their contemporaries, the extreme youth of Tophet individuals suggests these cemeteries were not only for the sacrificed, but also for the very young, however they died. Here we present the first rigorous analysis of the largest sample of cremated human skeletal remains (348 burial urns, N = 540 individuals) from the Carthaginian Tophet based on tooth formation, enamel histology, cranial and postcranial metrics, and the potential effects of heat-induced bone shrinkage. Most of the sample fell within the period prenatal to 5-to-6 postnatal months, with a significant presence of prenates. Rather than indicating sacrifice as the agent of death, this age distribution is consistent with modern-day data on perinatal mortality, which at Carthage would also have been exacerbated by numerous diseases common in other major cities, such as Rome and Pompeii. Our diverse approaches to analyzing the cremated human remains from

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

Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER

PubMed Central

Smart, Oliver S.; Womack, Thomas O.; Flensburg, Claus; Keller, Peter; Paciorek, Włodek; Sharff, Andrew; Vonrhein, Clemens; Bricogne, Gérard

2012-01-01

Maximum-likelihood X-ray macromolecular structure refinement in BUSTER has been extended with restraints facilitating the exploitation of structural similarity. The similarity can be between two or more chains within the structure being refined, thus favouring NCS, or to a distinct ‘target’ structure that remains fixed during refinement. The local structural similarity restraints (LSSR) approach considers all distances less than 5.5 Å between pairs of atoms in the chain to be restrained. For each, the difference from the distance between the corresponding atoms in the related chain is found. LSSR applies a restraint penalty on each difference. A functional form that reaches a plateau for large differences is used to avoid the restraints distorting parts of the structure that are not similar. Because LSSR are local, there is no need to separate out domains. Some restraint pruning is still necessary, but this has been automated. LSSR have been available to academic users of BUSTER since 2009 with the easy-to-use -autoncs and -­target target.pdb options. The use of LSSR is illustrated in the re-refinement of PDB entries 5rnt, where -target enables the correct ligand-binding structure to be found, and 1osg, where -autoncs contributes to the location of an additional copy of the cyclic peptide ligand. PMID:22505257

49 CFR 845.51 - Investigation to remain open.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Investigation to remain open. 845.51 Section 845... § 845.51 Investigation to remain open. Accident investigations are never officially closed but are kept open for the submission of new and pertinent evidence by any interested person. If the Board finds that...

49 CFR 845.51 - Investigation to remain open.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 7 2011-10-01 2011-10-01 false Investigation to remain open. 845.51 Section 845... § 845.51 Investigation to remain open. Accident investigations are never officially closed but are kept open for the submission of new and pertinent evidence by any interested person. If the Board finds that...

49 CFR 845.51 - Investigation to remain open.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 7 2013-10-01 2013-10-01 false Investigation to remain open. 845.51 Section 845... § 845.51 Investigation to remain open. Accident investigations are never officially closed but are kept open for the submission of new and pertinent evidence by any interested person. If the Board finds that...

49 CFR 845.51 - Investigation to remain open.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 7 2012-10-01 2012-10-01 false Investigation to remain open. 845.51 Section 845... § 845.51 Investigation to remain open. Accident investigations are never officially closed but are kept open for the submission of new and pertinent evidence by any interested person. If the Board finds that...

49 CFR 845.51 - Investigation to remain open.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 7 2014-10-01 2014-10-01 false Investigation to remain open. 845.51 Section 845... § 845.51 Investigation to remain open. Accident investigations are never officially closed but are kept open for the submission of new and pertinent evidence by any interested person. If the Board finds that...

Targeting tachykinin receptors in neuroblastoma.

PubMed

Henssen, Anton G; Odersky, Andrea; Szymansky, Annabell; Seiler, Marleen; Althoff, Kristina; Beckers, Anneleen; Speleman, Frank; Schäfers, Simon; De Preter, Katleen; Astrahanseff, Kathy; Struck, Joachim; Schramm, Alexander; Eggert, Angelika; Bergmann, Andreas; Schulte, Johannes H

2017-01-03

Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma.

Effectiveness of Drug-Eluting Stents versus Bare-Metal Stents in Large Coronary Arteries in Patients with Acute Myocardial Infarction

PubMed Central

Sim, Doo Sun; Ahn, Youngkeun; Kim, Young Jo; Chae, Shung Chull; Hong, Taek Jong; Seong, In Whan; Chae, Jei Keon; Kim, Chong Jin; Cho, Myeong Chan; Seung, Ki Bae; Park, Seung Jung

2011-01-01

This study compared clinical outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in large coronary arteries in patients with acute myocardial infarction (MI). A total of 985 patients who underwent single-vessel percutaneous coronary intervention (PCI) in large coronary arteries (≥ 3.5 mm) in lesions < 25 mm were divided into DES group (n = 841) and BMS group (n = 144). Clinical outcomes during 12 months were compared. In-hospital outcome was similar between the groups. At six months, death/MI rate was not different. However, DES group had significantly lower rates of target-lesion revascularization (TLR) (1.7% vs 5.6%, P = 0.021), target-vessel revascularization (TVR) (2.2% vs 5.6%, P = 0.032), and total major adverse cardiac events (MACE) (3.4% vs 11.9%, P = 0.025). At 12 months, the rates of TLR and TVR remained lower in the DES group (2.5% vs 5.9%, P = 0.032 and 5.9% vs 3.1%, P = 0.041), but the rates of death/MI and total MACE were not statistically different. The use of DES in large vessels in the setting of acute MI is associated with lower need for repeat revascularization compared to BMS without compromising the overall safety over the course of one-year follow-up. PMID:21468259

Next generation semiconductor based-sequencing of a nutrigenetics target gene (GPR120) and association with growth rate in Italian Large White pigs.

PubMed

Fontanesi, Luca; Bertolini, Francesca; Scotti, Emilio; Schiavo, Giuseppina; Colombo, Michela; Trevisi, Paolo; Ribani, Anisa; Buttazzoni, Luca; Russo, Vincenzo; Dall'Olio, Stefania

2015-01-01

The GPR120 gene (also known as FFAR4 or O3FAR1) encodes for a functional omega-3 fatty acid receptor/sensor that mediates potent insulin sensitizing effects by repressing macrophage-induced tissue inflammation. For its functional role, GPR120 could be considered a potential target gene in animal nutrigenetics. In this work we resequenced the porcine GPR120 gene by high throughput Ion Torrent semiconductor sequencing of amplified fragments obtained from 8 DNA pools derived, on the whole, from 153 pigs of different breeds/populations (two Italian Large White pools, Italian Duroc, Italian Landrace, Casertana, Pietrain, Meishan, and wild boars). Three single nucleotide polymorphisms (SNPs), two synonymous substitutions and one in the putative 3'-untranslated region (g.114765469C > T), were identified and their allele frequencies were estimated by sequencing reads count. The g.114765469C > T SNP was also genotyped by PCR-RFLP confirming estimated frequency in Italian Large White pools. Then, this SNP was analyzed in two Italian Large White cohorts using a selective genotyping approach based on extreme and divergent pigs for back fat thickness (BFT) estimated breeding value (EBV) and average daily gain (ADG) EBV. Significant differences of allele and genotype frequencies distribution was observed between the extreme ADG-EBV groups (P < 0.001) whereas this marker was not associated with BFT-EBV.

Sizzling Remains of a Dead Star

NASA Image and Video Library

2013-01-07

This new view of the historical supernova remnant Cassiopeia A, located 11,000 light-years away, was taken by NASA Nuclear Spectroscopic Telescope Array, or NuSTAR. While the star is long dead, its remains are still bursting with action.

TRIC: an automated alignment strategy for reproducible protein quantification in targeted proteomics

PubMed Central

Röst, Hannes L.; Liu, Yansheng; D’Agostino, Giuseppe; Zanella, Matteo; Navarro, Pedro; Rosenberger, George; Collins, Ben C.; Gillet, Ludovic; Testa, Giuseppe; Malmström, Lars; Aebersold, Ruedi

2016-01-01

Large scale, quantitative proteomic studies have become essential for the analysis of clinical cohorts, large perturbation experiments and systems biology studies. While next-generation mass spectrometric techniques such as SWATH-MS have substantially increased throughput and reproducibility, ensuring consistent quantification of thousands of peptide analytes across multiple LC-MS/MS runs remains a challenging and laborious manual process. To produce highly consistent and quantitatively accurate proteomics data matrices in an automated fashion, we have developed the TRIC software which utilizes fragment ion data to perform cross-run alignment, consistent peak-picking and quantification for high throughput targeted proteomics. TRIC uses a graph-based alignment strategy based on non-linear retention time correction to integrate peak elution information from all LC-MS/MS runs acquired in a study. When compared to state-of-the-art SWATH-MS data analysis, the algorithm was able to reduce the identification error by more than 3-fold at constant recall, while correcting for highly non-linear chromatographic effects. On a pulsed-SILAC experiment performed on human induced pluripotent stem (iPS) cells, TRIC was able to automatically align and quantify thousands of light and heavy isotopic peak groups and substantially increased the quantitative completeness and biological information in the data, providing insights into protein dynamics of iPS cells. Overall, this study demonstrates the importance of consistent quantification in highly challenging experimental setups, and proposes an algorithm to automate this task, constituting the last missing piece in a pipeline for automated analysis of massively parallel targeted proteomics datasets. PMID:27479329

Using genetic methods to define the targets of compounds with antimalarial activity

PubMed Central

Flannery, Erika L.; Fidock, David A.; Winzeler, Elizabeth A.

2013-01-01

Although phenotypic cellular screening has been used to drive antimalarial drug discovery in recent years, in some cases target-based drug discovery remains more attractive. This is especially true when appropriate high-throughput cellular assays are lacking, as is the case for drug discovery efforts that aim to provide a replacement for primaquine (4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), the only drug that can block Plasmodium transmission to Anopheles mosquitoes and eliminate liver-stage hypnozoites. At present, however, there are no known chemically validated parasite protein targets that are important in all Plasmodium parasite developmental stages and that can be used in traditional biochemical compound screens. We propose that a plethora of novel, chemically validated, cross-stage antimalarial targets still remain to be discovered from the ~5,500 proteins encoded by the Plasmodium genomes. Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens. PMID:23927658

Target and beam-target spin asymmetries in exclusive pion electroproduction for Q 2 > 1 GeV 2 . II. e p → e π 0 p

DOE PAGES

Bosted, P. E.; Amaryan, M. J.; Anefalos Pereira, S.; ...

2017-03-20

Beam-target double-spin asymmetries and target single-spin asymmetries were measured for the exclusive π + electroproduction reaction γ*p→nπ +. The results were obtained from scattering of 6-GeV longitudinally polarized electrons off longitudinally polarized protons using the CEBAF Large Acceptance Spectrometer at Jefferson Laboratory. The kinematic range covered is 1.1 < W < 3 GeV and 1 < Q 2 < 6GeV 2. Results were obtained for about 6000 bins in W, Q 2, cos(θ*), and Φ*. Except at forward angles, very large target-spin asymmetries are observed over the entire W region. Reasonable agreement is found with phenomenological fits to previous datamore » for W < 1.6 GeV, but very large differences are seen at higher values of W. A generalized parton distributions (GPD)-based model is in poor agreement with the data. As a result, when combined with cross-sectional measurements, the present results provide powerful constraints on nucleon resonance amplitudes at moderate and large values of Q 2, for resonances with masses as high as 2.4 GeV.« less

THE EPITHELIUM AS A TARGET IN SEPSIS.

PubMed

Chawla, Lakhmir S; Fink, Mitchell; Goldstein, Stuart L; Opal, Steven; Gómez, Alonso; Murray, Patrick; Gómez, Hernando; Kellum, John A

2016-03-01

Organ dysfunction induced by sepsis has been consistently associated with worse outcome and death. Regardless of the organ compromised, epithelial dysfunction is present throughout the body, affecting those organs that contain epithelia like the skin, lungs, liver, gut, and kidneys. Despite their obvious differences, sepsis seems to alter common features of all epithelia, such as barrier function and vectorial ion transport. Such alterations in the lung, the gut, and the kidney have direct implications that may explain the profound organ functional impairments in the absence of overt cell death. Epithelial injury in this context is not only an explanatory real pathophysiologic event, but also represents a source of biomarkers that have been explored to identify organ compromise earlier, predict outcome, and even to test novel therapeutic interventions such as blood purification. However, this remains largely experimental, and despite promising results, work is still required to better understand the response of the epithelial cells to sepsis, to define their role in adaptation to insults, to comprehend the interorgan cross-talk that occurs in these circumstances, and to exploit these aspects in pursuit of targeted therapies like blood purification, which may improve outcome for these patients in the future.

Directional control of WAVE2 membrane targeting by EB1 and phosphatidylinositol 3,4,5-triphosphate.

PubMed

Takahashi, Kazuhide; Tanaka, Tacu; Suzuki, Katsuo

2010-03-01

Membrane targeting of WAVE2 along microtubules is mediated by a motor protein kinesin and requires Pak1, a downstream effector of Rac1. However, the mechanism by which WAVE2 targeting to the leading edge is directionally controlled remains largely unknown. Here we demonstrate that EB1, a microtubule plus-end-binding protein, constitutively associates with stathmin, a microtubule-destabilizing protein, in human breast cancer cells. Stimulation of the cells with insulin-like growth factor I (IGF-I) induced Pak1-dependent binding of the EB1-stathmin complex to microtubules that bear WAVE2 and colocalization of the complex with WAVE2 at the leading edge. Depletion of EB1 by small interfering RNA (siRNA) abrogated the IGF-I-induced WAVE2 targeting and stathmin binding to microtubules. On the other hand, chemotaxis chamber assays indicated that the IGF-I receptor (IGF-IR) was locally activated in the region facing toward IGF-I. In addition, IGF-I caused phosphatidylinositol 3-kinase (PI 3-kinase)-dependent production of phosphatidylinositol 3,4,5-triphosphate (PIP3) near activated IGF-IR and WAVE2 colocalization with it. Collectively, WAVE2-membrane targeting is directionally controlled by binding of the EB1-stathmin complex to WAVE2-bearing microtubules and by the interaction between WAVE2 and PIP3 produced near IGF-IR that is locally activated by IGF-I.

A National Perspective: An Analysis of Factors That Influence Special Educators to Remain in the Field of Education

ERIC Educational Resources Information Center

Nickson, Lautrice M.; Kritsonis, William Allan

2006-01-01

The purpose of this article is to analyze factors that influence special educators to remain in the field of education. School administrators are perplexed by the large number of teachers who decide to leave the field of education after three years. The retention rates of special educators' require school administrators to focus on developing a…

Repatriation of human remains following death in international travellers.

PubMed

Connolly, Ruairi; Prendiville, Richard; Cusack, Denis; Flaherty, Gerard

2017-03-01

Death during international travel and the repatriation of human remains to one's home country is a distressing and expensive process. Much organization is required involving close liaison between various agencies. A review of the literature was conducted using the PubMed database. Search terms included: 'repatriation of remains', 'death', 'abroad', 'tourism', 'travel', 'travellers', 'travelling' and 'repatriation'. Additional articles were obtained from grey literature sources and reference lists. The local national embassy, travel insurance broker and tour operator are important sources of information to facilitate the repatriation of the deceased traveller. Formal identification of the deceased's remains is required and a funeral director must be appointed. Following this, the coroner in the country or jurisdiction receiving the repatriated remains will require a number of documents prior to providing clearance for burial. Costs involved in repatriating remains must be borne by the family of the deceased although travel insurance may help defray some of the costs. If the death is secondary to an infectious disease, cremation at the site of death is preferred. No standardized procedure is in place to deal with the remains of a migrant's body at present and these remains are often not repatriated to their country of origin. Repatriation of human remains is a difficult task which is emotionally challenging for the bereaving family and friends. As a travel medicine practitioner, it is prudent to discuss all eventualities, including the risk of death, during the pre-travel consultation. Awareness of the procedures involved in this process may ease the burden on the grieving family at a difficult time. © International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Brain-inspired cheminformatics of drug-target brain interactome, synthesis, and assay of TVP1022 derivatives.

PubMed

Romero-Durán, Francisco J; Alonso, Nerea; Yañez, Matilde; Caamaño, Olga; García-Mera, Xerardo; González-Díaz, Humberto

2016-04-01

The use of Cheminformatics tools is gaining importance in the field of translational research from Medicinal Chemistry to Neuropharmacology. In particular, we need it for the analysis of chemical information on large datasets of bioactive compounds. These compounds form large multi-target complex networks (drug-target interactome network) resulting in a very challenging data analysis problem. Artificial Neural Network (ANN) algorithms may help us predict the interactions of drugs and targets in CNS interactome. In this work, we trained different ANN models able to predict a large number of drug-target interactions. These models predict a dataset of thousands of interactions of central nervous system (CNS) drugs characterized by > 30 different experimental measures in >400 different experimental protocols for >150 molecular and cellular targets present in 11 different organisms (including human). The model was able to classify cases of non-interacting vs. interacting drug-target pairs with satisfactory performance. A second aim focus on two main directions: the synthesis and assay of new derivatives of TVP1022 (S-analogues of rasagiline) and the comparison with other rasagiline derivatives recently reported. Finally, we used the best of our models to predict drug-target interactions for the best new synthesized compound against a large number of CNS protein targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells.

PubMed

Hesbacher, Sonja; Pfitzer, Lisa; Wiedorfer, Katharina; Angermeyer, Sabrina; Borst, Andreas; Haferkamp, Sebastian; Scholz, Claus-Jürgen; Wobser, Marion; Schrama, David; Houben, Roland

2016-05-31

The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties. Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors. Notably, several viral oncoproteins are capable of binding and inhibiting PPs. Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells. Therefore, we analyzed the interaction of MCPyV-LT with the PPs. Co-IP experiments indicate that MCPyV-LT binds potently only to RB1. Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown. Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression. Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent. Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells.

Authenticated DNA from Ancient Wood Remains

PubMed Central

LIEPELT, SASCHA; SPERISEN, CHRISTOPH; DEGUILLOUX, MARIE-FRANCE; PETIT, REMY J.; KISSLING, ROY; SPENCER, MATTHEW; DE BEAULIEU, JACQUES-LOUIS; TABERLET, PIERRE; GIELLY, LUDOVIC; ZIEGENHAGEN, BIRGIT

2006-01-01

• Background The reconstruction of biological processes and human activities during the last glacial cycle relies mainly on data from biological remains. Highly abundant tissues, such as wood, are candidates for a genetic analysis of past populations. While well-authenticated DNA has now been recovered from various fossil remains, the final ‘proof’ is still missing for wood, despite some promising studies. • Scope The goal of this study was to determine if ancient wood can be analysed routinely in studies of archaeology and palaeogenetics. An experiment was designed which included blind testing, independent replicates, extensive contamination controls and rigorous statistical tests. Ten samples of ancient wood from major European forest tree genera were analysed with plastid DNA markers. • Conclusions Authentic DNA was retrieved from wood samples up to 1000 years of age. A new tool for real-time vegetation history and archaeology is ready to use. PMID:16987920

Remaining questions about clinical variola major.

PubMed

Lane, J Michael

2011-04-01

After the recent summary of World Health Organization-authorized research on smallpox, several clinical issues remain. This policy review addresses whether early hemorrhagic smallpox is disseminated intravascular coagulation and speculates about the cause of the high mortality rate among pregnant women and whether ocular smallpox is partly the result of trachoma or vitamin A deficiency. The joint destruction common in children with smallpox might be prevented by antiviral drugs, but intraarticular infusion of antiviral drugs is unprecedented. Development of highly effective antiviral drugs against smallpox raises the issue of whether postexposure vaccination can be performed without interference by an antiviral drug. Clinicians should consider whether patients with smallpox should be admitted to general hospitals. Although an adequate supply of second-generation smallpox vaccine exists in the United States, its use is unclear. Finally, political and ethical forces suggest that destruction of the remaining stocks of live smallpox virus is now appropriate.

Why Japanese workers remain in the labor force so long: lessons for the United States?

PubMed

Williamson, John B; Higo, Masa

2009-12-01

As part of the search for ways to increase labor force participation rates among older workers in the United States, it makes sense to take a close look at evidence from Japan, one of the few industrial countries with a substantially higher labor force participation rate among older workers, particularly men, than the United States. Based mainly on prior studies and original interview data, we first discuss five potential factors which help explain why Japanese workers remain in the labor force as long as they do: (1) perceived economic necessity; (2) the large fraction of workers who are self-employed; (3) a culture that puts a high value on remaining in the labor force throughout the life course; (4) the long healthy life expectancy; and (5) the government's role in facilitating the labor force participation of older workers. We suggest that the Japanese national cultural value on remaining economically productive well into old age clearly underlies the development of the government's legislative initiatives aiming to extend the working lives of older workers. We then outline three policy suggestions for those seeking to increase labor force participation rates among older U.S. workers: (1) increase the financial incentive to workers who remain in the labor force; (2) improve public programs designed to foster efforts by older workers to become self-employed; and (3) increase the extent of government efforts to link older workers to prospective employers.

Motivation for entry, occupational commitment and intent to remain: a survey regarding Registered Nurse retention.

PubMed

Gambino, Kathleen M

2010-11-01

This paper is a report of a study of the relationships between Registered Nurses' motivation for entering the profession, occupational commitment and intent to remain with an employer until retirement. Identifying and supporting nurses who are strongly committed to their profession may be the single most influential intervention in combating the nursing shortage. An understanding of the characteristics these individuals possess could lead to a decline in the high attrition rates plaguing the profession. Using a survey design, Registered Nurses enrolled at the school of nursing and/or employed at the associated university medical centre of a large, not-for-profit state university were polled in 2008. Logistic regression analysis was used to determine how the variables of motivation for entry and occupational commitment could indicate intent to remain. The strongest indicators of intent to remain were normative commitment and age, with a 70% average rate of correctly estimating retention. Exp(B) values for normative commitment (1·09) and age (1·07) indicated that for each one-point increase on the normative commitment scale or one-point increase in age, the odds of remaining with an employer until retirement increased by 1·1%. Transformational changes in healthcare environments and nursing schools must be made to encourage loyalty and obligation, the hallmarks of normative commitment. Retention strategies should accommodate mature nurses as well as promote normative commitment in younger nurses. © 2010 Blackwell Publishing Ltd.

Remaining Useful Life Estimation in Prognosis: An Uncertainty Propagation Problem

NASA Technical Reports Server (NTRS)

Sankararaman, Shankar; Goebel, Kai

2013-01-01

The estimation of remaining useful life is significant in the context of prognostics and health monitoring, and the prediction of remaining useful life is essential for online operations and decision-making. However, it is challenging to accurately predict the remaining useful life in practical aerospace applications due to the presence of various uncertainties that affect prognostic calculations, and in turn, render the remaining useful life prediction uncertain. It is challenging to identify and characterize the various sources of uncertainty in prognosis, understand how each of these sources of uncertainty affect the uncertainty in the remaining useful life prediction, and thereby compute the overall uncertainty in the remaining useful life prediction. In order to achieve these goals, this paper proposes that the task of estimating the remaining useful life must be approached as an uncertainty propagation problem. In this context, uncertainty propagation methods which are available in the literature are reviewed, and their applicability to prognostics and health monitoring are discussed.

Ductility recovery in structural materials for spallation targets by post-irradiation annealing

NASA Astrophysics Data System (ADS)

Chen, J.; Jung, P.; Rödig, M.; Ullmaier, H.; Bauer, G. S.

2005-08-01

Low temperature irradiation embrittlement is one of the major criteria to determine the lifetime of spallation targets. Embrittlement is especially high at low service temperatures, e.g. 250 °C in liquid-mercury sources. It was the aim of the present study to investigate the effect of post-irradiation annealing on the mechanical properties of irradiated structural materials. The specimens used were obtained from spent target components of operating spallation facilities (Los Alamos Neutron Science Center, LANSCE, and the Spallation Neutron Source at Rutherford-Appleton Laboratory, ISIS). The investigated materials include a nickel-based alloy (IN718), an austenitic stainless steel (AISI 304L), a martensitic stainless steel (DIN 1.4926) and a refractory metal (Ta) which experienced 800 MeV proton irradiation to fluences of several 10 25 p/m 2. The specimens were annealed from 300 °C to 700 °C for 1 to 10 h, respectively, and their mechanical property changes were subsequently investigated at room temperature and 250 °C by tensile testing and fracture surface analysis conducted by scanning electron microscopy (SEM). The results showed that the ductility recovered to a large degree in 304L and DIN 1.4926 materials while their strength remained almost unchanged. Especially for DIN 1.4926, the ductility recovery is remarkable already at 400 °C. Together with its favorable thermo-mechanical properties, this makes martensitic steel a candidate for structural materials of spallation targets.

Targeted gene flow and rapid adaptation in an endangered marsupial.

PubMed

Kelly, Ella; Phillips, Ben L

2018-06-13

Targeted gene flow is an emerging conservation strategy. It involves translocating individuals with favorable genes to areas where they will have a conservation benefit. The applications for targeted gene flow are wide-ranging, but include pre-adapting natives to the arrival of invasive species. The endangered carnivorous marsupial, the northern quoll, has declined rapidly since the introduction of the cane toad, which fatally poisons quolls that attack them. There are, however, a few remaining toad-invaded quoll populations in which the quolls survive because they know not to eat cane toads. It is this "toad-smart" behavior that we hope to promote through targeted gene flow. For targeted gene flow to be feasible, however, toad-smarts must have a genetic basis. To assess this, we used a common garden experiment and found offspring from toad-exposed populations were substantially less likely to eat toads than those with toad-naïve parents. Hybrid offspring showed similar responses to quolls with two toad-exposed parents, indicating the trait may be dominant. Together, these results suggest a heritable trait and rapid adaptive response in small number of toad-impacted populations. Although questions remain about outbreeding depression, our results are encouraging for targeted gene flow: suggesting it should be possible to introduce toad-smart behavior into soon to be impacted quoll populations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Impact of high energy high intensity proton beams on targets: Case studies for Super Proton Synchrotron and Large Hadron Collider

NASA Astrophysics Data System (ADS)

Tahir, N. A.; Sancho, J. Blanco; Shutov, A.; Schmidt, R.; Piriz, A. R.

2012-05-01

The Large Hadron Collider (LHC) is designed to collide two proton beams with unprecedented particle energy of 7 TeV. Each beam comprises 2808 bunches and the separation between two neighboring bunches is 25 ns. The energy stored in each beam is 362 MJ, sufficient to melt 500 kg copper. Safety of operation is very important when working with such powerful beams. An accidental release of even a very small fraction of the beam energy can result in severe damage to the equipment. The machine protection system is essential to handle all types of possible accidental hazards; however, it is important to know about possible consequences of failures. One of the critical failure scenarios is when the entire beam is lost at a single point. In this paper we present detailed numerical simulations of the full impact of one LHC beam on a cylindrical solid carbon target. First, the energy deposition by the protons is calculated with the FLUKA code and this energy deposition is used in the BIG2 code to study the corresponding thermodynamic and the hydrodynamic response of the target that leads to a reduction in the density. The modified density distribution is used in FLUKA to calculate new energy loss distribution and the two codes are thus run iteratively. A suitable iteration step is considered to be the time interval during which the target density along the axis decreases by 15%-20%. Our simulations suggest that the full LHC proton beam penetrates up to 25 m in solid carbon whereas the range of the shower from a single proton in solid carbon is just about 3 m (hydrodynamic tunneling effect). It is planned to perform experiments at the experimental facility HiRadMat (High Radiation Materials) at CERN using the proton beam from the Super Proton Synchrotron (SPS), to compare experimental results with the theoretical predictions. Therefore simulations of the response of a solid copper cylindrical target hit by the SPS beam were performed. The particle energy in the SPS beam is 440

Sustaining Community Participation: What Remains After the Money Ends?

NASA Astrophysics Data System (ADS)

Nkansa, Grace Akukwe; Chapman, David W.

2006-12-01

SUSTAINING COMMUNITY PARTICIPATION: WHAT REMAINS AFTER THE MONEY ENDS? - A major concern confronting development specialists in the education sector is the sustainability of project activities and outcomes, that is, their ability to persist once external funding ends. The increased attention of international development-assistance organizations to sustainability reflects the greater recent focus on outcome-based funding. The present study investigates differences between six communities in Ghana that varied in their ability to sustain externally initiated community-participation activities beyond the life of the external development-assistance project that promoted those activities. It was hypothesized that high- and low-sustaining communities differ in eight managerial and socio-cultural dimensions suggested by earlier research to be important for sustainability of community-level activities: planning, transparency, leadership, and participation, on one hand, and, on the other, social cohesion, resources, community skills, and valuing of education. Findings indicate that leadership and social cohesion are the two most vital elements in the sustainability of organizational structures intended to promote community participation in the oversight of local schools. Other factors suggested by the model are largely subsumed under leadership, so that the model can be simplified.

Molecular Targeted Intervention for Pancreatic Cancer

PubMed Central

Mohammed, Altaf; Janakiram, Naveena B.; Pant, Shubham; Rao, Chinthalapally V.

2015-01-01

Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. PMID:26266422

Target seedling strategies for intensively managed plantations in the Oregon Coast Range

Treesearch

Mark Wall

2011-01-01

The target Douglas-fir seedling for outplanting on Roseburg Resources Company timberlands is a least-cost, large [stem] caliper 1- to 2-year old bareroot (>8 mm) or container (>6 mm) seedling with good form, high root growth potential, and the ability to withstand browse without the use of browse deterrents. This target is achieved through the use of large cell...

A Thick Target for Synchrotrons and Betatrons

DOE R&D Accomplishments Database

McMillan, E. M.

1950-09-19

If a wide x-ray beam from an electron synchrotron or betatron is desired, in radiographic work with large objects for example, the usually very thin target may be replaced by a thick one, provided the resulting distortion of the x-ray spectrum due to multiple radiative processes is permissible. It is difficult to make the circulating electron beam traverse a thick target directly because of the small spacing between successive turns. Mounting a very thin beryllium, or other low-z material, fin on the edge of the thick target so that the fin projects into the beam will cause the beam to lose sufficient energy, and therefore radium, to strike the thick target the next time around. Sample design calculations are given.

Centrifuge impact cratering experiments: Scaling laws for non-porous targets

NASA Technical Reports Server (NTRS)

Schmidt, Robert M.

1987-01-01

A geotechnical centrifuge was used to investigate large body impacts onto planetary surfaces. At elevated gravity, it is possible to match various dimensionless similarity parameters which were shown to govern large scale impacts. Observations of crater growth and target flow fields have provided detailed and critical tests of a complete and unified scaling theory for impact cratering. Scaling estimates were determined for nonporous targets. Scaling estimates for large scale cratering in rock proposed previously by others have assumed that the crater radius is proportional to powers of the impactor energy and gravity, with no additional dependence on impact velocity. The size scaling laws determined from ongoing centrifuge experiments differ from earlier ones in three respects. First, a distinct dependence of impact velocity is recognized, even for constant impactor energy. Second, the present energy exponent for low porosity targets, like competent rock, is lower than earlier estimates. Third, the gravity exponent is recognized here as being related to both the energy and the velocity exponents.

Highly multiplexed targeted proteomics using precise control of peptide retention time.

PubMed

Gallien, Sebastien; Peterman, Scott; Kiyonami, Reiko; Souady, Jamal; Duriez, Elodie; Schoen, Alan; Domon, Bruno

2012-04-01

Large-scale proteomics applications using SRM analysis on triple quadrupole mass spectrometers present new challenges to LC-MS/MS experimental design. Despite the automation of building large-scale LC-SRM methods, the increased numbers of targeted peptides can compromise the balance between sensitivity and selectivity. To facilitate large target numbers, time-scheduled SRM transition acquisition is performed. Previously published results have demonstrated incorporation of a well-characterized set of synthetic peptides enabled chromatographic characterization of the elution profile for most endogenous peptides. We have extended this application of peptide trainer kits to not only build SRM methods but to facilitate real-time elution profile characterization that enables automated adjustment of the scheduled detection windows. Incorporation of dynamic retention time adjustments better facilitate targeted assays lasting several days without the need for constant supervision. This paper provides an overview of how the dynamic retention correction approach identifies and corrects for commonly observed LC variations. This adjustment dramatically improves robustness in targeted discovery experiments as well as routine quantification experiments. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Enabling large-scale forest restoration in Minas Gerais state, Brazil

NASA Astrophysics Data System (ADS)

Nunes, Felipe S. M.; Soares-Filho, Britaldo S.; Rajão, Raoni; Merry, Frank

2017-04-01

Large-scale forest restoration is a cornerstone of Brazil’s new Forest Code and a key element in its National Determined Contribution (NDC) to emissions reduction. But the path to this target remains unclear due to a lack of information on its economics and implementation challenges. Here, we begin to fill this gap by developing a spatially-explicit model for Minas Gerais state that estimates the costs and benefits of native vegetation regeneration under different restoration approaches. Our results show that 36% (0.7 million ha) of the Forest Code debt in Minas Gerais can be restored using only passive restoration, at a cost of US 175 ± 47 million. Adding low-cost assisted natural regeneration would increase that number to 75% (1.5 million ha) at a cost of US 776 ± 137 million over a 20 yr period. This would result in a potential sequestration of 284 MtCO2e. However, including the intensive planting methods needed to restore the remaining 25% of highly degraded areas—to fully solve the Forest Code debt and result in a potential sequestration of 345 MtCO2e—would more than double the costs to US 1.7 ± 0.3 billion. Our results emphasize the need to implement regional policies that take advantage of the natural regeneration potential as well as prioritize the restoration of areas key to ecosystem services.

Targeting Phosphatidylserince for Radioimmunotherapy of Breast Cancer Brain Metastasis

DTIC Science & Technology

2014-10-01

remained negative for exposed PS. 15. SUBJECT TERMS Nothing Listed 16. SECURITY CLASSIFICATION OF: unclassified 17. LIMITATION OF ABSTRACT 18...cells of brain metastases. • PS-targeting antibody, PGN635F(ab’)2 has been successfully conjugated with radioisotope , enabling in vivo PET imaging

Targeted Drug-Carrying Bacteriophages as Antibacterial Nanomedicines▿

PubMed Central

Yacoby, Iftach; Bar, Hagit; Benhar, Itai

2007-01-01

While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of ∼20,000 compared to the free drug. PMID:17404004

The search for new antigenic targets in myasthenia gravis.

PubMed

Cossins, Judith; Belaya, Katsiaryna; Zoltowska, Katarzyna; Koneczny, Inga; Maxwell, Susan; Jacobson, Leslie; Leite, Maria Isabel; Waters, Patrick; Vincent, Angela; Beeson, David

2012-12-01

Around 80% of myasthenia gravis patients have antibodies against the acetylcholine receptor, and 0-60% of the remaining patients have antibodies against the muscle-specific tyrosine kinase, MuSK. Another recently identified antigen is low-density lipoprotein receptor-related protein 4 (Lrp4). To improve the existing assays and widen the search for new antigenic targets, we have employed cell-based assays in which candidate target proteins are expressed on the cell surface of transfected cells and probed with patient sera. These assays, combined with use of myotube cultures to explore the effects of the antibodies, enable us to begin to identify new antigenic targets and test antibody pathogenicity in vitro. © 2012 New York Academy of Sciences.

Fluorescent imaging of cancerous tissues for targeted surgery

PubMed Central

Bu, Lihong; Shen, Baozhong; Cheng, Zhen

2014-01-01

To maximize tumor excision and minimize collateral damage is the primary goal of cancer surgery. Emerging molecular imaging techniques have to “image-guided surgery” developing into “molecular imaging-guided surgery”, which is termed “targeted surgery” in this review. Consequently, the precision of surgery can be advanced from tissue-scale to molecule-scale, enabling “targeted surgery” to be a component of “targeted therapy”. Evidence from numerous experimental and clinical studies has demonstrated significant benefits of fluorescent imaging in targeted surgery with preoperative molecular diagnostic screening. Fluorescent imaging can help to improve intraoperative staging and enable more radical cytoreduction, detect obscure tumor lesions in special organs, highlight tumor margins, better map lymph node metastases, and identify important normal structures intraoperatively. Though limited tissue penetration of fluorescent imaging and tumor heterogeneity are two major hurdles for current targeted surgery, multimodality imaging and multiplex imaging may provide potential solutions to overcome these issues, respectively. Moreover, though many fluorescent imaging techniques and probes have been investigated, targeted surgery remains at a proof-of-principle stage. The impact of fluorescent imaging on cancer surgery will likely be realized through persistent interdisciplinary amalgamation of research in diverse fields. PMID:25064553

MicroRNA-targeted therapeutics for lung cancer treatment.

PubMed

Xue, Jing; Yang, Jiali; Luo, Meihui; Cho, William C; Liu, Xiaoming

2017-02-01

Lung cancer is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that repress the expression of a broad array of target genes. Many efforts have been made to therapeutically target miRNAs in cancer treatments using miRNA mimics and miRNA antagonists. Areas covered: This article summarizes the recent findings with the role of miRNAs in lung cancer, and discusses the potential and challenges of developing miRNA-targeted therapeutics in this dreadful disease. Expert opinion: The development of miRNA-targeted therapeutics has become an important anti-cancer strategy. Results from both preclinical and clinical trials of microRNA replacement therapy have shown some promise in cancer treatment. However, some obstacles, including drug delivery, specificity, off-target effect, toxicity mediation, immunological activation and dosage determination should be addressed. Several delivery strategies have been employed, including naked oligonucleotides, liposomes, aptamer-conjugates, nanoparticles and viral vectors. However, delivery remains a main challenge in miRNA-targeting therapeutics. Furthermore, immune-related serious adverse events are also a concern, which indicates the complexity of miRNA-based therapy in clinical settings.

Yersinia pestis targets neutrophils via complement receptor 3

PubMed Central

Merritt, Peter M.; Nero, Thomas; Bohman, Lesley; Felek, Suleyman; Krukonis, Eric S.; Marketon, Melanie M.

2015-01-01

Yersinia species display a tropism for lymphoid tissues during infection, and the bacteria select innate immune cells for delivery of cytotoxic effectors by the type III secretion system. Yet the mechanism for target cell selection remains a mystery. Here we investigate the interaction of Yersinia pestis with murine splenocytes to identify factors that participate in the targeting process. We find that interactions with primary immune cells rely on multiple factors. First, the bacterial adhesin Ail is required for efficient targeting of neutrophils in vivo. However, Ail does not appear to directly mediate binding to a specific cell type. Instead, we find that host serum factors direct Y. pestis to specific innate immune cells, particularly neutrophils. Importantly, specificity towards neutrophils was increased in the absence of bacterial adhesins due to reduced targeting of other cell types, but this phenotype was only visible in the presence of mouse serum. Addition of antibodies against complement receptor 3 and CD14 blocked target cell selection, suggesting that a combination of host factors participate in steering bacteria toward neutrophils during plague infection. PMID:25359083

Juveniles' Motivations for Remaining in Prostitution

ERIC Educational Resources Information Center

Hwang, Shu-Ling; Bedford, Olwen

2004-01-01

Qualitative data from in-depth interviews were collected in 1990-1991, 1992, and 2000 with 49 prostituted juveniles remanded to two rehabilitation centers in Taiwan. These data are analyzed to explore Taiwanese prostituted juveniles' feelings about themselves and their work, their motivations for remaining in prostitution, and their difficulties…

Compensatory hypertrophy of the teres minor muscle after large rotator cuff tear model in adult male rat.

PubMed

Ichinose, Tsuyoshi; Yamamoto, Atsushi; Kobayashi, Tsutomu; Shitara, Hitoshi; Shimoyama, Daisuke; Iizuka, Haku; Koibuchi, Noriyuki; Takagishi, Kenji

2016-02-01

Rotator cuff tear (RCT) is a common musculoskeletal disorder in the elderly. The large RCT is often irreparable due to the retraction and degeneration of the rotator cuff muscle. The integrity of the teres minor (TM) muscle is thought to affect postoperative functional recovery in some surgical treatments. Hypertrophy of the TM is found in some patients with large RCTs; however, the process underlying this hypertrophy is still unclear. The objective of this study was to determine if compensatory hypertrophy of the TM muscle occurs in a large RCT rat model. Twelve Wistar rats underwent transection of the suprascapular nerve and the supraspinatus and infraspinatus tendons in the left shoulder. The rats were euthanized 4 weeks after the surgery, and the cuff muscles were collected and weighed. The cross-sectional area and the involvement of Akt/mammalian target of rapamycin (mTOR) signaling were examined in the remaining TM muscle. The weight and cross-sectional area of the TM muscle was higher in the operated-on side than in the control side. The phosphorylated Akt/Akt protein ratio was not significantly different between these sides. The phosphorylated-mTOR/mTOR protein ratio was significantly higher on the operated-on side. Transection of the suprascapular nerve and the supraspinatus and infraspinatus tendons activates mTOR signaling in the TM muscle, which results in muscle hypertrophy. The Akt-signaling pathway may not be involved in this process. Nevertheless, activation of mTOR signaling in the TM muscle after RCT may be an effective therapeutic target of a large RCT. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

MicroRNA-590-5p Inhibits Intestinal Inflammation by Targeting YAP.

PubMed

Yu, Minhao; Luo, Yang; Cong, Zhijie; Mu, Yifei; Qiu, Yier; Zhong, Ming

2018-04-18

Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, survival, apoptosis, and stem cell self-renewal. In addition, Hippo signaling is profoundly implicated in intestinal regeneration and cancer. However, its roles in the pathogenesis of Crohn's disease (CD) remain largely unexplored. Quantitative real-time PCR was performed to identify the deregulated molecules in Hippo signaling. Expression of the highly upregulated Yes Associated Protein 1 (YAP) was subsequently examined by qRT-PCR, western blotting and immunohistochemistry in the intestinal tissues of CD patients and the colons of 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis mice. The miRNAs predicted to target YAP were explored by transfection of miR-590-5p mimics or inhibitors and analyzed by luciferase reporter assay. The role of the miR-590-5p/YAP axis in CD and colorectal cancer were studied in experimental colitis mice and colorectal cancer cell lines. YAP mRNA was significantly upregulated in intestinal epithelial cells in CD patients and TNBS-induced colitis mice. MiR-590-5p suppressed YAP expression by directly targeting the YAP 3'-untranslated region in Caco-2 cells and SW620 cells. Upregulation of miR-590-5p in colon reduced YAP level and its downstream targets in IECs. Treatment of miR-590-5p or YAP inhibitor Verteporfin alleviated experimental colitis. Targeting the miR-590-5p/YAP axis inhibited cell proliferation and invasiveness of CRC cells in vitro. Our results suggest that miR-590-5p inhibits intestinal inflammation in mouse colon and tumorigenesis of colorectal cancer cells by inhibiting YAP. The miR-590-5p/YAP axis may be an important novel mechanism in the pathogenesis of CD and colorectal cancer.

How Many Ultra-Low Delta-v Near Earth Objects Remain Undiscovered? Implications for missions.

NASA Astrophysics Data System (ADS)

Elvis, Martin; Ranjan, Sukrit; Galache, Jose Luis; Murphy, Max

2015-08-01

The past decade has witnessed considerable growth of interest in missions to Near-Earth Objects (NEOs). NEOs are considered prime targets for manned and robotic missions, for both scientific objectives as well as in-situ resource utilization including harvesting of water for propellant and life support and mining of high-value elements for sale on Earth. Appropriate targets are crucial to such missions. Hence, ultra-low delta-v mission targets are strongly favored. Some mission architectures rely on the discovery of more ultra-low delta-v NEOs. In fact the approved and executed NEO missions have all targeted asteroids with ultra-low LEO to asteroid rendezvous delta-v <5.5 km/s.In this paper, we estimate the total NEO population as a function of delta-v, and how many remain to be discovered in various size ranges down to ~100m. We couple the NEOSSat-1 model (Greenstreet et al., 2012) to the NEO size distribution derived from the NEOWISE survey (Mainzer et al., 2011b) to compute an absolute NEO population model. We compare the Minor Planet Center (MPC) catalog of known NEOs to this NEO population model. We compute the delta-v from LEO to asteroid rendezvous orbits using a modified Shoemaker-Helin (S-H) formalism that empirically removes biases found comparing S-H with the results from NHATS. The median delta-v of the known NEOs is 7.3 km/s, the median delta-v predicted by our NEO model is 9.8 km/s, suggesting that undiscovered objects are biased to higher delta-v. The survey of delta-v <10.3 km/s NEOs is essentially complete for objects with diameter D >300 m. However, there are tens of thousands of objects with delta-v <10.3 km/s to be discovered in the D = 50 - 300 m size class (H = 20.4 - 24.3). Our work suggests that there are 100 yet-undiscovered NEOs with delta-v < 5:8 km/s, and 1000 undiscovered NEOs with v < 6.3 km/s. We conclude that, even with complete NEO surveys, the selection of good (i.e. ultra-low delta-v) mission targets is limited given current

PPI4DOCK: large scale assessment of the use of homology models in free docking over more than 1000 realistic targets.

PubMed

Yu, Jinchao; Guerois, Raphaël

2016-12-15

Protein-protein docking methods are of great importance for understanding interactomes at the structural level. It has become increasingly appealing to use not only experimental structures but also homology models of unbound subunits as input for docking simulations. So far we are missing a large scale assessment of the success of rigid-body free docking methods on homology models. We explored how we could benefit from comparative modelling of unbound subunits to expand docking benchmark datasets. Starting from a collection of 3157 non-redundant, high X-ray resolution heterodimers, we developed the PPI4DOCK benchmark containing 1417 docking targets based on unbound homology models. Rigid-body docking by Zdock showed that for 1208 cases (85.2%), at least one correct decoy was generated, emphasizing the efficiency of rigid-body docking in generating correct assemblies. Overall, the PPI4DOCK benchmark contains a large set of realistic cases and provides new ground for assessing docking and scoring methodologies. Benchmark sets can be downloaded from http://biodev.cea.fr/interevol/ppi4dock/ CONTACT: guerois@cea.frSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Targeting fibroblast growth factor pathways in endometrial cancer.

PubMed

Winterhoff, Boris; Konecny, Gottfried E

Novel treatments that improve outcomes for patients with recurrent or metastatic endometrial cancer (EC) remain an unmet need. Aberrant signaling by fibroblast growth factors (FGFs) and FGF receptors (FGFRs) has been implicated in several human cancers. Activating mutations in FGFR2 have been found in up to 16% of ECs, suggesting an opportunity for targeted therapy. This review summarizes the role of the FGF pathway in angiogenesis and EC, and provides an overview of FGFR-targeted therapies under clinical development for the treatment of EC. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Voyager 2 Neptune targeting strategy

NASA Technical Reports Server (NTRS)

Potts, C. L.; Francis, K.; Matousek, S. E.; Cesarone, R. J.; Gray, D. L.

1989-01-01

The success of the Voyager 2 flybys of Neptune and Triton depends upon the ability to correct the spacecraft's trajectory. Accurate spacecraft delivery to the desired encounter conditions will promote the maximum science return. However, Neptune's great distance causes large a priori uncertainties in Neptune and Triton ephemerides and planetary system parameters. Consequently, the 'ideal' trajectory is unknown beforehand. The targeting challenge is to utilize the gradually improving knowledge as the spacecraft approaches Neptune to meet the science objectives, but with an overriding concern for spacecraft safety and a desire to limit propellant expenditure. A unique targeting strategy has been developed in response to this challenge. Through the use of a Monte Carlo simulation, candidate strategies are evaluated by the degree to which they meet these objectives and are compared against each other in determining the targeting strategy to be adopted.

[Large vessel vasculitides].

PubMed

Morović-Vergles, Jadranka; Puksić, Silva; Gracanin, Ana Gudelj

2013-01-01

Large vessel vasculitis includes Giant cell arteritis and Takayasu arteritis. Giant cell arteritis is the most common form of vasculitis affect patients aged 50 years or over. The diagnosis should be considered in older patients who present with new onset of headache, visual disturbance, polymyalgia rheumatica and/or fever unknown cause. Glucocorticoides remain the cornerstone of therapy. Takayasu arteritis is a chronic panarteritis of the aorta ant its major branches presenting commonly in young ages. Although all large arteries can be affected, the aorta, subclavian and carotid arteries are most commonly involved. The most common symptoms included upper extremity claudication, hypertension, pain over the carotid arteries (carotidynia), dizziness and visual disturbances. Early diagnosis and treatment has improved the outcome in patients with TA.

Nanoparticles that Communicate In Vivo to Amplify Tumour Targeting

PubMed Central

von Maltzahn, Geoffrey; Park, Ji-Ho; Lin, Kevin Y.; Singh, Neetu; Schwöppe, Christian; Mesters, Rolf; Berdel, Wolfgang E.; Ruoslahti, Erkki; Sailor, Michael J.; Bhatia, Sangeeta N.

2012-01-01

Nanomedicines have enormous potential to improve the precision of cancer therapy, yet our ability to efficiently home these materials to regions of disease in vivo remains very limited. Inspired by the ability for communication to improve targeting in biological systems, such inflammatory cell recruitment to sites of disease, we construct systems where synthetic biological and nanotechnological components communicate to amplify disease targeting in vivo. These systems are composed of ‘Signalling’ modules (nanoparticles or engineered proteins) that target tumours and then locally active the coagulation cascade to broadcast tumour location to clot-targeted ‘Receiving’ nanoparticles in circulation that carry a diagnostic or therapeutic cargo, thereby amplifying their delivery. We show that communicating nanoparticle systems can be composed from multiple types of Signalling and Receiving modules, can transmit information via multiple molecular pathways in coagulation, can operate autonomously, and can target over 40-fold higher doses of chemotherapeutics to tumours than non-communicating controls. PMID:21685903

Strategies for targeting primate neural circuits with viral vectors

PubMed Central

El-Shamayleh, Yasmine; Ni, Amy M.

2016-01-01

Understanding how the brain works requires understanding how different types of neurons contribute to circuit function and organism behavior. Progress on this front has been accelerated by optogenetics and chemogenetics, which provide an unprecedented level of control over distinct neuronal types in small animals. In primates, however, targeting specific types of neurons with these tools remains challenging. In this review, we discuss existing and emerging strategies for directing genetic manipulations to targeted neurons in the adult primate central nervous system. We review the literature on viral vectors for gene delivery to neurons, focusing on adeno-associated viral vectors and lentiviral vectors, their tropism for different cell types, and prospects for new variants with improved efficacy and selectivity. We discuss two projection targeting approaches for probing neural circuits: anterograde projection targeting and retrograde transport of viral vectors. We conclude with an analysis of cell type-specific promoters and other nucleotide sequences that can be used in viral vectors to target neuronal types at the transcriptional level. PMID:27052579

Nanoparticles that communicate in vivo to amplify tumour targeting

NASA Astrophysics Data System (ADS)

von Maltzahn, Geoffrey; Park, Ji-Ho; Lin, Kevin Y.; Singh, Neetu; Schwöppe, Christian; Mesters, Rolf; Berdel, Wolfgang E.; Ruoslahti, Erkki; Sailor, Michael J.; Bhatia, Sangeeta N.

2011-07-01

Nanomedicines have enormous potential to improve the precision of cancer therapy, yet our ability to efficiently home these materials to regions of disease in vivo remains very limited. Inspired by the ability of communication to improve targeting in biological systems, such as inflammatory-cell recruitment to sites of disease, we construct systems where synthetic biological and nanotechnological components communicate to amplify disease targeting in vivo. These systems are composed of ‘signalling’ modules (nanoparticles or engineered proteins) that target tumours and then locally activate the coagulation cascade to broadcast tumour location to clot-targeted ‘receiving’ nanoparticles in circulation that carry a diagnostic or therapeutic cargo, thereby amplifying their delivery. We show that communicating nanoparticle systems can be composed of multiple types of signalling and receiving modules, can transmit information through multiple molecular pathways in coagulation, can operate autonomously and can target over 40 times higher doses of chemotherapeutics to tumours than non-communicating controls.

Drug-induced amplification of nanoparticle targeting to tumors

PubMed Central

Lin, Kevin Y.; Kwon, Ester J.; Lo, Justin H.; Bhatia, Sangeeta N.

2018-01-01

Summary Nanomedicines have the potential to significantly impact cancer therapy by improving drug efficacy and decreasing off-target effects, yet our ability to efficiently home nanoparticles to disease sites remains limited. One frequently overlooked constraint of current active targeting schemes is the relative dearth of targetable antigens within tumors, which restricts the amount of cargo that can be delivered in a tumor-specific manner. To address this limitation, we exploit tumor-specific responses to drugs to construct a cooperative targeting system where a small molecule therapeutic modulates the disease microenvironment to amplify nanoparticle recruitment in vivo. We first administer a vascular disrupting agent, ombrabulin, which selectively affects tumors and leads to locally elevated presentation of the stress-related protein, p32. This increase in p32 levels provides more binding sites for circulating p32-targeted nanoparticles, enhancing their delivery of diagnostic or therapeutic cargos to tumors. We show that this cooperative targeting system recruits over five times higher doses of nanoparticles to tumors and decreases tumor burden when compared with non-cooperative controls. These results suggest that using nanomedicine in conjunction with drugs that enhance the presentation of target antigens in the tumor environment may be an effective strategy for improving the diagnosis and treatment of cancer. PMID:29731806

A new three-dimensional conformal radiotherapy (3DCRT) technique for large breast and/or high body mass index patients: evaluation of a novel fields assessment aimed to reduce extra-target-tissue irradiation.

PubMed

Gerardina, Stimato; Edy, Ippolito; Sonia, Silipigni; Cristina, Di Venanzio; Carla Germana, Rinaldi; Diego, Gaudino; Michele, Fiore; Lucio, Trodella; Maria, D'Angelillo Rolando; Sara, Ramella

2016-09-01

To develop an alternative three-dimensional treatment plan with standardized fields class solution for whole-breast radiotherapy in patients with large/pendulous breast and/or high body mass index (BMI). Two treatment plans [tangential fields and standardized five-fields technique (S5F)] for a total dose of 50 Gy/25 fractions were generated for patients with large breasts [planning target volume (PTV) >1000 cm(3) and/or BMI >25 kg m(-2)], supine positioned. S5F plans consist of two wedged tangential beams, anteroposterior: 20° for the right breast and 340° for the left breast, and posteroanterior: 181° for the right breast and 179° for the left breast. A field in field in medial-lateral beam and additional fields were added to reduce hot spot areas and extra-target-tissue irradiation and to improve dose distribution. The percentage of PTV receiving 95% of the prescribed dose (PTV V95%), percentage of PTV receiving 105% of the prescribed dose (PTV V105%), maximal dose to PTV (PTV Dmax), homogeneity index (HI) and conformity index were recorded. V10%, V20%, V105% and V107% of a "proper" normal tissue structure (body-PTV healthy tissue) were recorded. Statistical analyses were performed using SYSTAT v.12.0 (SPSS, Chicago, IL). In 38 patients included, S5F improved HI (8.4 vs 10.1; p ≤ 0.001) and significantly reduced PTV Dmax and PTV V105%. The extra-target-tissue irradiation was significantly reduced using S5F for V105% (cm(3)) and V107% (cm(3)) with a very high difference in tissue irradiation (46.6 vs 3.0 cm(3), p ≤ 0.001 for V105% and 12.2 vs 0.0 cm(3), p ≤ 0.001 for V107% for tangential field and S5F plans, respectively). Only a slight increase in low-dose extra-target-tissue irradiation (V10%) was observed (2.2719 vs 1.8261 cm(3), p = 0.002). The S5F technique in patients with large breast or high BMI increases HI and decreases hot spots in extra-target-tissues and can therefore be easily implemented in breast cancer

Mitochondrial permeability transition in cardiac ischemia–reperfusion: whether cyclophilin D is a viable target for cardioprotection?

PubMed Central

Jang, Sehwan; Parodi-Rullan, Rebecca; Khuchua, Zaza; Kuznetsov, Andrey V.

2018-01-01

Growing number of studies provide strong evidence that the mitochondrial permeability transition pore (PTP), a non-selective channel in the inner mitochondrial membrane, is involved in the pathogenesis of cardiac ischemia–reperfusion and can be targeted to attenuate reperfusion-induced damage to the myocardium. The molecular identity of the PTP remains unknown and cyclophilin D is the only protein commonly accepted as a major regulator of the PTP opening. Therefore, cyclophilin D is an attractive target for pharmacological or genetic therapies to reduce ischemia–reperfusion injury in various animal models and humans. Most animal studies demonstrated cardioprotective effects of PTP inhibition; however, a recent large clinical trial conducted by international groups demonstrated that cyclosporine A, a cyclophilin D inhibitor, failed to protect the heart in patients with myocardial infarction. These studies, among others, raise the question of whether cyclophilin D, which plays an important physiological role in the regulation of cell metabolism and mitochondrial bioenergetics, is a viable target for cardioprotection. This review discusses previous studies to provide comprehensive information on the physiological role of cyclophilin D as well as PTP opening in the cell that can be taken into consideration for the development of new PTP inhibitors. PMID:28378042

Controversies in cancer stem cells: targeting embryonic signaling pathways.

PubMed

Takebe, Naoko; Ivy, S Percy

2010-06-15

Selectively targeting cancer stem cells (CSC) or tumor-initiating cells (TIC; from this point onward referred to as CSCs) with novel agents is a rapidly emerging field of oncology. Our knowledge of CSCs and their niche microenvironments remains a nascent field. CSC's critical dependence upon self-renewal makes these regulatory signaling pathways ripe for the development of experimental therapeutic agents. Investigational agents targeting the Notch, Hedgehog, and Wnt pathways are currently in late preclinical development stages, with some early phase 1-2 testing in human subjects. This series of articles will provide an overview and summary of the current state of knowledge of CSCs, their interactive microenvironment, and how they may serve as important targets for antitumor therapies. We also examine the scope and stage of development of early experimental agents that specifically target these highly conserved embryonic signaling pathways. (c) 2010 AACR.

Hypertensive emergencies remain a clinical problem and are associated with high mortality.

PubMed

Roubsanthisuk, Weranuj; Wongsurin, Unticha; Buranakitjaroen, Peera

2010-01-01

We suspect that hypertensive emergencies remain a clinical problem and data on their long-term prognosis are lacking. This study was conducted in order to determine the frequency, management, and outcome of hypertensive emergencies in this era, in which hypertension treatment is more effective than in the past. We reviewed the medical records of patients with hypertensive emergencies admitted to the medical wards of Siriraj Hospital in 2003 and collected data on their characteristic, management, investigations, and follow-ups through 31 December 2007. There were 184 patients included. Hypertension has been previously diagnosed in 89% of cases. Nearly half also had diabetes mellitus and around a quarter had chronic kidney failure. Mean +/- SD of blood pressure at presentation was 205.96 +/- 21.36/114.60 +/- 20.59 mmHg. Cardiac complications and stroke accounted for 71% and 23% of all target organ damage, respectively. Intravenous nitroglycerine and furosemide were most frequently prescribed. Additional investigations to search for the causes of hypertension were performed in only 55 cases. The average hospital stay was 9.8 days. The in-hospital mortality rate was 15%. Some 26% of patients were lost to follow-up and another 20% died later. Only 19% of patients had regular follow-ups until the end of 2007 and remained on an average of 2.4 antihypertensive drugs. Hypertensive emergencies are usually found in patients with a history of hypertension and diabetes mellitus or kidney failure. Recommended investigations usually failed to identify the cause of hypertension. The mortality rate of these patients was extremely high while their adherence to treatment was extremely poor.

Contextual remapping in visual search after predictable target-location changes.

PubMed

Conci, Markus; Sun, Luning; Müller, Hermann J

2011-07-01

Invariant spatial context can facilitate visual search. For instance, detection of a target is faster if it is presented within a repeatedly encountered, as compared to a novel, layout of nontargets, demonstrating a role of contextual learning for attentional guidance ('contextual cueing'). Here, we investigated how context-based learning adapts to target location (and identity) changes. Three experiments were performed in which, in an initial learning phase, observers learned to associate a given context with a given target location. A subsequent test phase then introduced identity and/or location changes to the target. The results showed that contextual cueing could not compensate for target changes that were not 'predictable' (i.e. learnable). However, for predictable changes, contextual cueing remained effective even immediately after the change. These findings demonstrate that contextual cueing is adaptive to predictable target location changes. Under these conditions, learned contextual associations can be effectively 'remapped' to accommodate new task requirements.

Characterization of the targeting signal in mitochondrial β-barrel proteins

PubMed Central

Jores, Tobias; Klinger, Anna; Groß, Lucia E.; Kawano, Shin; Flinner, Nadine; Duchardt-Ferner, Elke; Wöhnert, Jens; Kalbacher, Hubert; Endo, Toshiya; Schleiff, Enrico; Rapaport, Doron

2016-01-01

Mitochondrial β-barrel proteins are synthesized on cytosolic ribosomes and must be specifically targeted to the organelle before their integration into the mitochondrial outer membrane. The signal that assures such precise targeting and its recognition by the organelle remained obscure. In the present study we show that a specialized β-hairpin motif is this long searched for signal. We demonstrate that a synthetic β-hairpin peptide competes with the import of mitochondrial β-barrel proteins and that proteins harbouring a β-hairpin peptide fused to passenger domains are targeted to mitochondria. Furthermore, a β-hairpin motif from mitochondrial proteins targets chloroplast β-barrel proteins to mitochondria. The mitochondrial targeting depends on the hydrophobicity of the β-hairpin motif. Finally, this motif interacts with the mitochondrial import receptor Tom20. Collectively, we reveal that β-barrel proteins are targeted to mitochondria by a dedicated β-hairpin element, and this motif is recognized at the organelle surface by the outer membrane translocase. PMID:27345737

Interferon-targeted therapy in systemic lupus erythematosus: Is this an alternative to targeting B and T cells?

PubMed

Kalunian, K C

2016-09-01

Clinical trials of investigational agents in systemic lupus erythematosus (SLE) have focused on targeting dysregulated B and T cells; however, recent translational research findings of the importance of the dysregulation of the innate immune system in SLE have led to clinical trials that target interferon. Three biologics that target type I interferons have been tested for their efficacy and safety in active SLE patients; these phase II trials have tested the hypothesis that down-regulation of interferon-regulated gene expression (the interferon signature) lessen the clinical burden of SLE. Rontalizumab, an anti-interferon-α monoclonal antibody, was studied in patients who had discontinued immunosuppressants. This study failed to show efficacy as assessed by both two outcome assessments; however, in low interferon signature patients, response was higher and corticosteroid usage was less in rontalizumab-treated patients. Sifalimumab, another anti-interferon-α monoclonal antibody, was studied in patients who remained on standard of care therapy. This study showed significantly better efficacy in patients treated with two sifalimumab dosages; significant differences were seen in the high interferon signature group. In a similar design and in a similar population as the sifalimumab study, anifrolumab, a monoclonal antibody that binds to a type I interferon receptor, was studied in patients who remained on standard of care therapy. In this study, one dosage group demonstrated efficacy and statistically significant effects were achieved in both tested dosage groups with secondary end points. Oral corticosteroid reduction to ≤7.5 mg daily was achieved in one of the tested dosage groups and organ-specific outcomes were significantly improved in that same group. For all studies, no significant differences in serious adverse effects were seen; although, herpes zoster infections were increased in sifalimumab- and anifrolumab-treated patients and influenza rates were

Dynamic inversion enables external magnets to concentrate ferromagnetic rods to a central target.

PubMed

Nacev, A; Weinberg, I N; Stepanov, P Y; Kupfer, S; Mair, L O; Urdaneta, M G; Shimoji, M; Fricke, S T; Shapiro, B

2015-01-14

The ability to use magnets external to the body to focus therapy to deep tissue targets has remained an elusive goal in magnetic drug targeting. Researchers have hitherto been able to manipulate magnetic nanotherapeutics in vivo with nearby magnets but have remained unable to focus these therapies to targets deep within the body using magnets external to the body. One of the factors that has made focusing of therapy to central targets between magnets challenging is Samuel Earnshaw's theorem as applied to Maxwell's equations. These mathematical formulations imply that external static magnets cannot create a stable potential energy well between them. We posited that fast magnetic pulses could act on ferromagnetic rods before they could realign with the magnetic field. Mathematically, this is equivalent to reversing the sign of the potential energy term in Earnshaw's theorem, thus enabling a quasi-static stable trap between magnets. With in vitro experiments, we demonstrated that quick, shaped magnetic pulses can be successfully used to create inward pointing magnetic forces that, on average, enable external magnets to concentrate ferromagnetic rods to a central location.

Computational Simulation of Large Droplet Icing

DOT National Transportation Integrated Search

1996-01-01

Certification for flight into known icing remains one of the more challenging goals for aircraft manufacturers. This activity has been further complicated by the current interest in large droplet icing. Due to the lack of data available on the meteor...

43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

Code of Federal Regulations, 2013 CFR

2013-10-01

... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or... unidentifiable human remains. (a) General. This section implements section 8(c)(5) of the Act and applies to...

43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

Code of Federal Regulations, 2014 CFR

2014-10-01

... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or... unidentifiable human remains. (a) General. This section implements section 8(c)(5) of the Act and applies to...

43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

Code of Federal Regulations, 2012 CFR

2012-10-01

... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or... unidentifiable human remains. (a) General. This section implements section 8(c)(5) of the Act and applies to...

Leaf δ18O of remaining trees is affected by thinning intensity in a semiarid pine forest.

PubMed

Moreno-Gutiérrez, Cristina; Barberá, Gonzalo G; Nicolás, Emilio; DE Luis, Martín; Castillo, Víctor M; Martínez-Fernández, Faustino; Querejeta, José I

2011-06-01

Silvicultural thinning usually improves the water status of remaining trees in water-limited forests. We evaluated the usefulness of a dual stable isotope approach (δ¹³C, δ¹⁸O) for comparing the physiological performance of remaining trees between forest stands subjected to two different thinning intensities (moderate versus heavy) in a 60-year-old Pinus halepensis Mill. plantation in semiarid southeastern Spain. We measured bulk leaf δ¹³C and δ¹⁸O, foliar elemental concentrations, stem water content, stem water δ¹⁸O (δ¹⁸O(stem water)), tree ring widths and leaf gas exchange rates to assess the influence of forest stand density on tree performance. Remaining trees in low-density stands (heavily thinned) showed lower leaf δ¹⁸O, and higher stomatal conductance (g(s)), photosynthetic rate and radial growth than those in moderate-density stands (moderately thinned). By contrast, leaf δ¹³C, intrinsic water-use efficiency, foliar elemental concentrations and δ¹⁸O(stem water) were unaffected by stand density. Lower foliar δ¹⁸O in heavily thinned stands reflected higher g(s) of remaining trees due to decreased inter-tree competition for water, whereas higher photosynthetic rate was largely attributable to reduced stomatal limitation to CO₂ uptake. The dual isotope approach provided insight into the early (12 months) effects of stand density manipulation on the physiological performance of remaining trees. © 2011 Blackwell Publishing Ltd.

Genistein Ameliorates Non-alcoholic Fatty Liver Disease by Targeting the Thromboxane A2 Pathway.

PubMed

Wang, Wenzhe; Chen, Junliang; Mao, Jinyan; Li, Hongling; Wang, Mingfu; Zhang, Hao; Li, Haitao; Chen, Wei

2018-06-13

Non-alcoholic fatty liver disease (NAFLD) is now a public health issue worldwide, but no drug has yet received approval. Genistein, an isoflavonoid derived from soybean, ameliorates high-fat-diet-induced NAFLD in mice, but the molecular underpinnings remain largely elusive. Arachidonic acid (AA) is a major ingredient of animal fats, and the AA cascade has been implicated in chronic inflammation. In this study, we investigated whether genistein was against NAFLD by targeting the AA cascade. Using a mouse model, we showed that genistein supplementation improved high-fat-diet-induced NAFLD by normalizing hepatomegaly, liver steatosis, aminotransferase abnormalities, and glucose tolerance. The thromboxane A 2 (TXA 2 ) pathway was aberrantly active in NAFLD, evidenced by an elevation of circulating TXA 2 and hepatic thromboxane A 2 receptor expression. Mechanistically, we found that genistein directly targeted cyclooxygenase-1 activity as well as its downstream TXA 2 biosynthesis, while the TXA 2 pathway might mediate NAFLD progression by impairing insulin sensitivity. Taken together, our study revealed a crucial pathophysiological role of the TXA 2 pathway in NAFLD and provided an explanation as to how genistein was against NAFLD progression.

Characteristics and Treatments of Large Cystic Brain Metastasis: Radiosurgery and Stereotactic Aspiration

PubMed Central

Kim, Moinay; Cheok, Stephanie; Chung, Lawrance K.; Ung, Nolan; Thill, Kimberly; Voth, Brittany; Kwon, Do Hoon; Kim, Jeong Hoon; Kim, Chang Jin; Tenn, Stephen; Lee, Percy

2015-01-01

Brain metastasis represents one of the most common causes of intracranial tumors in adults, and the incidence of brain metastasis continues to rise due to the increasing survival of cancer patients. Yet, the development of cystic brain metastasis remains a relatively rare occurrence. In this review, we describe the characteristics of cystic brain metastasis and evaluate the combined use of stereotactic aspiration and radiosurgery in treating large cystic brain metastasis. The results of several studies show that stereotactic radiosurgery produces comparable local tumor control and survival rates as other surgery protocols. When the size of the tumor interferes with radiosurgery, stereotactic aspiration of the metastasis should be considered to reduce the target volume as well as decreasing the chance of radiation induced necrosis and providing symptomatic relief from mass effect. The combined use of stereotactic aspiration and radiosurgery has strong implications in improving patient outcomes. PMID:25977901

Why Do Some Cores Remain Starless?

NASA Astrophysics Data System (ADS)

Anathpindika, S.

2016-08-01

Prestellar cores, by definition, are gravitationally bound but starless pockets of dense gas. Physical conditions that could render a core starless (in the local Universe) is the subject of investigation in this work. To this end, we studied the evolution of four starless cores, B68, L694-2, L1517B, L1689, and L1521F, a VeLLO. We demonstrate: (i) cores contracted in quasistatic manner over a timescale on the order of ~ 105 yr. Those that remained starless briefly acquired a centrally concentrated density configuration that mimicked the profile of a unstable BonnorEbert sphere before rebounding, (ii) three cores viz. L694-2, L1689-SMM16, and L1521F remained starless despite becoming thermally super-critical. By contrast, B68 and L1517B remained sub-critical; L1521F collapsed to become a VeLLO only when gas-cooling was enhanced by increasing the size of dust-grains. This result is robust, for other starless cores viz. B68, L694-2, L1517B, and L1689 could also be similarly induced to collapse. The temperature-profile of starless cores and those that collapsed was found to be radically different. While in the former type, only very close to the centre of a core was there any evidence of decline in gas temperature, by contrast, a core of the latter type developed a more uniformly cold interior. Our principle conclusions are: (a) thermal super-criticality of a core is insufficient to ensure it will become protostellar, (b) potential star-forming cores (the VeLLO L1521F here), could be experiencing dust-coagulation that must enhance gasdust coupling and in turn lower gas temperature, thereby assisting collapse. This also suggests, mere gravitational/virial boundedness of a core is insufficient to ensure it will form stars.

More target features in visual working memory leads to poorer search guidance: Evidence from contralateral delay activity

PubMed Central

Schmidt, Joseph; MacNamara, Annmarie; Proudfit, Greg Hajcak; Zelinsky, Gregory J.

2014-01-01

The visual-search literature has assumed that the top-down target representation used to guide search resides in visual working memory (VWM). We directly tested this assumption using contralateral delay activity (CDA) to estimate the VWM load imposed by the target representation. In Experiment 1, observers previewed four photorealistic objects and were cued to remember the two objects appearing to the left or right of central fixation; Experiment 2 was identical except that observers previewed two photorealistic objects and were cued to remember one. CDA was measured during a delay following preview offset but before onset of a four-object search array. One of the targets was always present, and observers were asked to make an eye movement to it and press a button. We found lower magnitude CDA on trials when the initial search saccade was directed to the target (strong guidance) compared to when it was not (weak guidance). This difference also tended to be larger shortly before search-display onset and was largely unaffected by VWM item-capacity limits or number of previews. Moreover, the difference between mean strong- and weak-guidance CDA was proportional to the increase in search time between mean strong-and weak-guidance trials (as measured by time-to-target and reaction-time difference scores). Contrary to most search models, our data suggest that trials resulting in the maintenance of more target features results in poor search guidance to a target. We interpret these counterintuitive findings as evidence for strong search guidance using a small set of highly discriminative target features that remain after pruning from a larger set of features, with the load imposed on VWM varying with this feature-consolidation process. PMID:24599946

More target features in visual working memory leads to poorer search guidance: evidence from contralateral delay activity.

PubMed

Schmidt, Joseph; MacNamara, Annmarie; Proudfit, Greg Hajcak; Zelinsky, Gregory J

2014-03-05

The visual-search literature has assumed that the top-down target representation used to guide search resides in visual working memory (VWM). We directly tested this assumption using contralateral delay activity (CDA) to estimate the VWM load imposed by the target representation. In Experiment 1, observers previewed four photorealistic objects and were cued to remember the two objects appearing to the left or right of central fixation; Experiment 2 was identical except that observers previewed two photorealistic objects and were cued to remember one. CDA was measured during a delay following preview offset but before onset of a four-object search array. One of the targets was always present, and observers were asked to make an eye movement to it and press a button. We found lower magnitude CDA on trials when the initial search saccade was directed to the target (strong guidance) compared to when it was not (weak guidance). This difference also tended to be larger shortly before search-display onset and was largely unaffected by VWM item-capacity limits or number of previews. Moreover, the difference between mean strong- and weak-guidance CDA was proportional to the increase in search time between mean strong-and weak-guidance trials (as measured by time-to-target and reaction-time difference scores). Contrary to most search models, our data suggest that trials resulting in the maintenance of more target features results in poor search guidance to a target. We interpret these counterintuitive findings as evidence for strong search guidance using a small set of highly discriminative target features that remain after pruning from a larger set of features, with the load imposed on VWM varying with this feature-consolidation process.

New targeted therapies for relapsed pediatric acute lymphoblastic leukemia.

PubMed

Pierro, Joanna; Hogan, Laura E; Bhatla, Teena; Carroll, William L

2017-08-01

The improvement in outcomes for children with acute lymphoblastic leukemia (ALL) is one of the greatest success stories of modern oncology however the prognosis for patients who relapse remains dismal. Recent discoveries by high resolution genomic technologies have characterized the biology of relapsed leukemia, most notably pathways leading to the drug resistant phenotype. These observations open the possibility of targeting such pathways to prevent and/or treat relapse. Likewise, early experiences with new immunotherapeutic approaches have shown great promise. Areas covered: We performed a literature search on PubMed and recent meeting abstracts using the keywords below. We focused on the biology and clonal evolution of relapsed disease highlighting potential new targets of therapy. We further summarized the results of early trials of the three most prominent immunotherapy agents currently under investigation. Expert commentary: Discovery of targetable pathways that lead to drug resistance and recent breakthroughs in immunotherapy show great promise towards treating this aggressive disease. The best way to treat relapse, however, is to prevent it which makes incorporation of these new approaches into frontline therapy the best approach. Challenges remain to balance efficacy with toxicity and to prevent the emergence of resistant subclones which is why combining these newer agents with conventional chemotherapy will likely become standard of care.

Targeted protein degradation by PROTACs.

PubMed

Neklesa, Taavi K; Winkler, James D; Crews, Craig M

2017-06-01

Targeted protein degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases driven by the aberrant expression of a disease-causing protein. PROTAC molecules are bifunctional small molecules that simultaneously bind a target protein and an E3-ubiquitin ligase, thus causing ubiquitination and degradation of the target protein by the proteasome. Like small molecules, PROTAC molecules possess good tissue distribution and the ability to target intracellular proteins. Herein, we highlight the advantages of protein degradation using PROTACs, and provide specific examples where degradation offers therapeutic benefit over classical enzyme inhibition. Foremost, PROTACs can degrade proteins regardless of their function. This includes the currently "undruggable" proteome, which comprises approximately 85% of all human proteins. Other beneficial aspects of protein degradation include the ability to target overexpressed and mutated proteins, as well as the potential to demonstrate prolonged pharmacodynamics effect beyond drug exposure. Lastly, due to their catalytic nature and the pre-requisite ubiquitination step, an exquisitely potent molecules with a high degree of degradation selectivity can be designed. Impressive preclinical in vitro and in vivo PROTAC data have been published, and these data have propelled the development of clinically viable PROTACs. With the molecular weight falling in the 700-1000Da range, the delivery and bioavailability of PROTACs remain the largest hurdles on the way to the clinic. Solving these issues and demonstrating proof of concept clinical data will be the focus of many labs over the next few years. Copyright © 2017 Elsevier Inc. All rights reserved.

De-Trending K2 Exoplanet Targets for High Spacecraft Motion

NASA Astrophysics Data System (ADS)

Saunders, Nicholas; Luger, Rodrigo; Barnes, Rory

2018-01-01

After the failure of two reaction wheels, the Kepler space telescope lost its fine pointing ability and entered a new phase of observation, K2. Targets observed by K2 have high motion relative to the detector and K2 light curves have higher noise than Kepler observations. Despite the increased noise, systematics removal pipelines such as K2SFF and EVEREST have enabled continued high-precision transiting planet science with the telescope, resulting in the detection of hundreds of new exoplanets. However, as the spacecraft begins to run out of fuel, sputtering will drive large and random variations in pointing that can prevent detection of exoplanets during the remaining 5 campaigns. In general, higher motion will spread the stellar point spread function (PSF) across more pixels during a campaign, which increases the number of degrees of freedom in the noise component and significantly reduces the de-trending power of traditional systematics removal methods. We use a model of the Kepler CCD combined with pixel-level information of a large number of stars across the detector to improve the performance of the EVEREST pipeline at high motion. We also consider the problem of increased crowding for static apertures in the high-motion regime and develop pixel response function (PRF)-fitting techniques to mitigate contamination and maximize the de-trending power. We assess the performance of our code by simulating sputtering events and assessing exoplanet detection efficiency with transit injection/recovery tests. We find that targets with roll amplitudes of up to 8 pixels, approximately 15 times K2 roll, can be de-trended within 2 to 3 factors of current K2 photometric precision for stars up to 14th magnitude. Achieved recovery precision allows detection of small planets around 11th and 12th magnitude stars. These methods can be applied to the light curves of K2 targets for existing and future campaigns to ensure that precision exoplanet science can still be performed

The identification of submerged skeletonized remains.

PubMed

Byard, Roger W; Both, Katrin; Simpson, Ellie

2008-03-01

Examination was undertaken of skeletonized remains contained within 2 rubber boots dredged by a fishing boat from a depth of 145 m, approximately 185 km off the southern Australian coast in the Great Australian Bight. The boots had been manufactured in Australia in July 1993 and were of a type commonly used by local fishermen. Examination of the lower legs and feet revealed well-preserved bones with arthritic changes in keeping with an older male. DNA analyses using reference samples taken from relatives of fishermen who had disappeared in the area resulted in the identification of the victim as a 52-year-old prawn fisherman who had been swept off a boat over a decade earlier. DNA stability had been maintained by the low light, cold temperatures, and alkaline pH of the ocean floor. Integration of pathologic, anthropologic, and biologic analyses with police investigations enabled a positive identification to be made despite the unusual nature of the location of the remains and the time lapse since the disappearance of the victim.

Advances in silica based nanoparticles for targeted cancer therapy.

PubMed

Yang, Yannan; Yu, Chengzhong

2016-02-01

Targeted delivery of anticancer drug specifically to tumor site without damaging normal tissues has been the dream of all scientists fighting against cancer for decades. Recent breakthrough on nanotechnology based medicines has provided a possible tool to solve this puzzle. Among diverse nanomaterials that are under development and extensive study, silica based nanoparticles with vast advantages have attracted great attention. In this review, we concentrate on the recent progress using silica based nanoparticles, particularly mesoporous silica nanoparticles (MSNs), for targeted drug delivery applications. First, we discuss the passive targeting capability of silica based nanoparticles in relation to their physiochemical properties. Then, we focus on the recent advances of active targeting strategies involving tumor cell targeting, vascular targeting, nuclear targeting and multistage targeting, followed by an introduction to magnetic field directed targeting approach. We conclude with our personal perspectives on the remaining challenges and the possible future directions. Chemotherapy has been one of the mainstays of cancer treatment. The advances in nanotechnology has allowed the development of novel carrier systems for the delivery of anticancer drugs. Mesoporous silica has shown great promise in this respect. In this review article, the authors provided a comprehensive overview of the use of this nanoparticle in both passive, as well as active targeting in the field of oncology. The advantages of this particle were further discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

CRISPR/Cas9-mediated gene targeting in Arabidopsis using sequential transformation.

PubMed

Miki, Daisuke; Zhang, Wenxin; Zeng, Wenjie; Feng, Zhengyan; Zhu, Jian-Kang

2018-05-17

Homologous recombination-based gene targeting is a powerful tool for precise genome modification and has been widely used in organisms ranging from yeast to higher organisms such as Drosophila and mouse. However, gene targeting in higher plants, including the most widely used model plant Arabidopsis thaliana, remains challenging. Here we report a sequential transformation method for gene targeting in Arabidopsis. We find that parental lines expressing the bacterial endonuclease Cas9 from the egg cell- and early embryo-specific DD45 gene promoter can improve the frequency of single-guide RNA-targeted gene knock-ins and sequence replacements via homologous recombination at several endogenous sites in the Arabidopsis genome. These heritable gene targeting can be identified by regular PCR. Our approach enables routine and fine manipulation of the Arabidopsis genome.

The roles of pathology in targeted therapy of women with gynecologic cancers.

PubMed

Murali, Rajmohan; Grisham, Rachel N; Soslow, Robert A

2018-01-01

The role of the pathologist in the multidisciplinary management of women with gynecologic cancer has evolved substantially over the past decade. Pathologists' evaluation of parameters such as pathologic stage, histologic subtype, grade and microsatellite instability, and their identification of patients at risk for Lynch syndrome have become essential components of diagnosis, prognostic assessment and determination of optimal treatment of affected women. Despite the use of multimodality treatment and combination cytotoxic chemotherapy, the prognosis of women with advanced-stage gynecologic cancer is often poor. Therefore, expanding the arsenal of available systemic therapies with targeted therapeutic agents is appealing. Anti-angiogenic therapies, immunotherapy and poly ADP ribose polymerase (PARP) inhibitors are now routinely used for the treatment of advanced gynecologic cancer, and many more are under investigation. Pathologists remain important in the clinical management of patients with targeted therapy, by identifying potentially targetable tumors on the basis of their pathologic phenotype, by assessing biomarkers that are predictive of response to targeted therapy (e.g. microsatellite instability, PD1/PDL1 expression), and by monitoring treatment response and resistance. Pathologists are also vital to research efforts exploring novel targeted therapies by identifying homogenous subsets of tumors for more reliable and meaningful analyses, and by confirming expression in tumor tissues of novel targets identified in genomic, epigenetic or other screening studies. In the era of precision gynecologic oncology, the roles of pathologists in the discovery, development and implementation of targeted therapeutic strategies remain as central as they are for traditional (surgery-chemotherapy-radiotherapy) management of women with gynecologic cancers. Copyright © 2017 Elsevier Inc. All rights reserved.

Optimized multi-electrode stimulation increases focality and intensity at target

NASA Astrophysics Data System (ADS)

Dmochowski, Jacek P.; Datta, Abhishek; Bikson, Marom; Su, Yuzhuo; Parra, Lucas C.

2011-08-01

Transcranial direct current stimulation (tDCS) provides a non-invasive tool to elicit neuromodulation by delivering current through electrodes placed on the scalp. The present clinical paradigm uses two relatively large electrodes to inject current through the head resulting in electric fields that are broadly distributed over large regions of the brain. In this paper, we present a method that uses multiple small electrodes (i.e. 1.2 cm diameter) and systematically optimize the applied currents to achieve effective and targeted stimulation while ensuring safety of stimulation. We found a fundamental trade-off between achievable intensity (at the target) and focality, and algorithms to optimize both measures are presented. When compared with large pad-electrodes (approximated here by a set of small electrodes covering 25cm2), the proposed approach achieves electric fields which exhibit simultaneously greater focality (80% improvement) and higher target intensity (98% improvement) at cortical targets using the same total current applied. These improvements illustrate the previously unrecognized and non-trivial dependence of the optimal electrode configuration on the desired electric field orientation and the maximum total current (due to safety). Similarly, by exploiting idiosyncratic details of brain anatomy, the optimization approach significantly improves upon prior un-optimized approaches using small electrodes. The analysis also reveals the optimal use of conventional bipolar montages: maximally intense tangential fields are attained with the two electrodes placed at a considerable distance from the target along the direction of the desired field; when radial fields are desired, the maximum-intensity configuration consists of an electrode placed directly over the target with a distant return electrode. To summarize, if a target location and stimulation orientation can be defined by the clinician, then the proposed technique is superior in terms of both focality

Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61.

PubMed

Huang, Kuan-Chun; Chen, Zhihong; Jiang, Yimin; Akare, Sandeep; Kolber-Simonds, Donna; Condon, Krista; Agoulnik, Sergei; Tendyke, Karen; Shen, Yongchun; Wu, Kuo-Ming; Mathieu, Steven; Choi, Hyeong-Wook; Zhu, Xiaojie; Shimizu, Hajime; Kotake, Yoshihiko; Gerwick, William H; Uenaka, Toshimitsu; Woodall-Jappe, Mary; Nomoto, Kenichi

2016-06-01

Apratoxin A is a natural product with potent antiproliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biologic activities of apratoxin A and its in vivo toxicity has remained largely unknown. A better understanding of this relationship is critically important for any further development of apratoxin A as an anticancer drug. Here, we describe a detailed pathologic analysis that revealed a specific pancreas-targeting activity of apratoxin A, such that severe pancreatic atrophy was observed in apratoxin A-treated animals. Follow-up tissue distribution studies further uncovered a unique drug distribution profile for apratoxin A, showing high drug exposure in pancreas and salivary gland. It has been shown previously that apratoxin A inhibits the protein secretory pathway by preventing cotranslational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well defined. By using a (3)H-labeled apratoxin A probe and specific Sec 61α/β antibodies, we identified that the Sec 61 complex is the molecular target of apratoxin A. We conclude that apratoxin A in vivo toxicity is likely caused by pancreas atrophy due to high apratoxin A exposure. Mol Cancer Ther; 15(6); 1208-16. ©2016 AACR. ©2016 American Association for Cancer Research.

Erlotinib induced target-like purpura.

PubMed

Rungtrakulchai, R; Rerknimitr, P

2014-02-18

Erlotinib is an epidermal growth factor receptor (EGFR) inhibitor, used as a treatment for advanced stage cancer. The most common side effect is cutaneous toxicity including the already known papulopustular reaction. We herein report a case of erlotinib induced target-like purpura, a peculiar cutaneous adverse event. A 57-year-old patient with advanced non-small cell lung cancer was treated by erolotinib 150 mg daily. After taking the drug for three days, an unusual target-like purpura developed on her lower legs. Skin biopsy specimen taken from the lesion revealed an extravasation of erythrocytes in the upper dermis without destruction of blood vessel walls. This skin eruption cleared after the drug was withdrawn and recurred after erlotinib was re-challenged. The mechanism underlying this cutaneous adverse event remains to be elucidated. Physicians should be aware of the rare side effect of this increasingly used drug.

Chloride channels as drug targets

PubMed Central

Verkman, Alan S.; Galietta, Luis J. V.

2013-01-01

Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets. Chloride channels are involved in a wide range of biological functions, including epithelial fluid secretion, cell-volume regulation, neuroexcitation, smooth-muscle contraction and acidification of intracellular organelles. Mutations in several chloride channels cause human diseases, including cystic fibrosis, macular degeneration, myotonia, kidney stones, renal salt wasting and hyperekplexia. Chloride-channel modulators have potential applications in the treatment of some of these disorders, as well as in secretory diarrhoeas, polycystic kidney disease, osteoporosis and hypertension. Modulators of GABAA (γ-aminobutyric acid A) receptor chloride channels are in clinical use and several small-molecule chloride-channel modulators are in preclinical development and clinical trials. Here, we discuss the broad opportunities that remain in chloride-channel-based drug discovery. PMID:19153558

Accuracy of software-assisted detection of tumour feeders in transcatheter hepatic chemoembolization using three target definition protocols.

PubMed

Iwazawa, J; Ohue, S; Hashimoto, N; Mitani, T

2014-02-01

To compare the accuracy of computer software analysis using three different target-definition protocols to detect tumour feeder vessels for transarterial chemoembolization of hepatocellular carcinoma. C-arm computed tomography (CT) data were analysed for 81 tumours from 57 patients who had undergone chemoembolization using software-assisted detection of tumour feeders. Small, medium, and large-sized targets were manually defined for each tumour. The tumour feeder was verified when the target tumour was enhanced on selective C-arm CT of the investigated vessel during chemoembolization. The sensitivity, specificity, and accuracy of the three protocols were evaluated and compared. One hundred and eight feeder vessels supplying 81 lesions were detected. The sensitivity of the small, medium, and large target protocols was 79.8%, 91.7%, and 96.3%, respectively; specificity was 95%, 88%, and 50%, respectively; and accuracy was 87.5%, 89.9%, and 74%, respectively. The sensitivity was significantly higher for the medium (p = 0.003) and large (p < 0.001) target protocols than for the small target protocol. The specificity and accuracy were higher for the small (p < 0.001 and p < 0.001, respectively) and medium (p < 0.001 and p < 0.001, respectively) target protocols than for the large target protocol. The overall accuracy of software-assisted automated feeder analysis in transarterial chemoembolization for hepatocellular carcinoma is affected by the target definition size. A large target definition increases sensitivity and decreases specificity in detecting tumour feeders. A target size equivalent to the tumour size most accurately predicts tumour feeders. Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Visual Target Tracking in the Presence of Unknown Observer Motion

NASA Technical Reports Server (NTRS)

Williams, Stephen; Lu, Thomas

2009-01-01

Much attention has been given to the visual tracking problem due to its obvious uses in military surveillance. However, visual tracking is complicated by the presence of motion of the observer in addition to the target motion, especially when the image changes caused by the observer motion are large compared to those caused by the target motion. Techniques for estimating the motion of the observer based on image registration techniques and Kalman filtering are presented and simulated. With the effects of the observer motion removed, an additional phase is implemented to track individual targets. This tracking method is demonstrated on an image stream from a buoy-mounted or periscope-mounted camera, where large inter-frame displacements are present due to the wave action on the camera. This system has been shown to be effective at tracking and predicting the global position of a planar vehicle (boat) being observed from a single, out-of-plane camera. Finally, the tracking system has been extended to a multi-target scenario.

Target and beam-target spin asymmetries in exclusive π+ and π- electroproduction with 1.6- to 5.7-GeV electrons

NASA Astrophysics Data System (ADS)

Bosted, P. E.; Biselli, A. S.; Careccia, S.; Dodge, G.; Fersch, R.; Guler, N.; Kuhn, S. E.; Pierce, J.; Prok, Y.; Zheng, X.; Adhikari, K. P.; Adikaram, D.; Akbar, Z.; Amaryan, M. J.; Anefalos Pereira, S.; Asryan, G.; Avakian, H.; Badui, R. A.; Ball, J.; Baltzell, N. A.; Battaglieri, M.; Batourine, V.; Bedlinskiy, I.; Boiarinov, S.; Briscoe, W. J.; Bültmann, S.; Burkert, V. D.; Cao, T.; Carman, D. S.; Celentano, A.; Chandavar, S.; Charles, G.; Chetry, T.; Ciullo, G.; Clark, L.; Colaneri, L.; Cole, P. L.; Contalbrigo, M.; Cortes, O.; Crede, V.; D'Angelo, A.; Dashyan, N.; De Vita, R.; Deur, A.; Djalali, C.; Dupre, R.; Egiyan, H.; El Alaoui, A.; El Fassi, L.; Eugenio, P.; Fanchini, E.; Fedotov, G.; Filippi, A.; Fleming, J. A.; Forest, T. A.; Fradi, A.; Garçon, M.; Gevorgyan, N.; Ghandilyan, Y.; Gilfoyle, G. P.; Giovanetti, K. L.; Girod, F. X.; Gleason, C.; Gohn, W.; Golovatch, E.; Gothe, R. W.; Griffioen, K. A.; Guo, L.; Hafidi, K.; Hanretty, C.; Harrison, N.; Hattawy, M.; Heddle, D.; Hicks, K.; Holtrop, M.; Hughes, S. M.; Ilieva, Y.; Ireland, D. G.; Ishkhanov, B. S.; Isupov, E. L.; Jenkins, D.; Jiang, H.; Jo, H. S.; Joo, K.; Joosten, S.; Keller, D.; Khandaker, M.; Kim, W.; Klein, A.; Klein, F. J.; Kubarovsky, V.; Kuleshov, S. V.; Lanza, L.; Lenisa, P.; Livingston, K.; Lu, H. Y.; MacGregor, I. J. D.; Markov, N.; McCracken, M. E.; McKinnon, B.; Meyer, C. A.; Minehart, R.; Mirazita, M.; Mokeev, V.; Movsisyan, A.; Munevar, E.; Munoz Camacho, C.; Nadel-Turonski, P.; Net, L. A.; Ni, A.; Niccolai, S.; Niculescu, G.; Niculescu, I.; Osipenko, M.; Ostrovidov, A. I.; Paremuzyan, R.; Park, K.; Pasyuk, E.; Peng, P.; Phelps, W.; Pisano, S.; Pogorelko, O.; Price, J. W.; Procureur, S.; Protopopescu, D.; Puckett, A. J. R.; Raue, B. A.; Ripani, M.; Rizzo, A.; Rosner, G.; Rossi, P.; Roy, P.; Sabatié, F.; Salgado, C.; Schumacher, R. A.; Seder, E.; Sharabian, Y. G.; Simonyan, A.; Skorodumina, Iu.; Smith, G. D.; Sparveris, N.; Stankovic, Ivana; Stepanyan, S.; Strakovsky, I. I.; Strauch, S.; Sytnik, V.; Taiuti, M.; Tian, Ye; Torayev, B.; Ungaro, M.; Voskanyan, H.; Voutier, E.; Walford, N. K.; Watts, D. P.; Wei, X.; Weinstein, L. B.; Wood, M. H.; Zachariou, N.; Zana, L.; Zhang, J.; Zhao, Z. W.; Zonta, I.; CLAS Collaboration

2016-11-01

Beam-target double-spin asymmetries and target single-spin asymmetries in exclusive π+ and quasiexclusive π- electroproduction were obtained from scattering of 1.6- to 5.7-GeV longitudinally polarized electrons from longitudinally polarized protons (for π+) and deuterons (for π-) using the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. The kinematic range covered is 1.1 1.5 GeV. Very large target-spin asymmetries are observed for W >1.6 GeV. When combined with cross-section measurements, the present results can provide powerful constraints on nucleon resonance amplitudes at moderate and large values of Q2, for resonances with masses as high as 2.3 GeV.

Target and beam-target spin asymmetries in exclusive π + and π - electroproduction with 1.6- to 5.7-GeV electrons

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

Bosted, P. E.; Biselli, A. S.; Careccia, S.

Beam-target double-spin asymmetries and target single-spin asymmetries in exclusive pi(+) and quasiexclusive pi(-) electroproduction were obtained from scattering of 1.6- to 5.7-GeV longitudinally polarized electrons from longitudinally polarized protons (for pi(+)) and deuterons (for pi(-)) using the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. The kinematic range covered is 1.1 < W < 2.6 GeV and 0.05 < Q(2) < 5 GeV2, with good angular coverage in the forward hemisphere. The asymmetry results were divided into approximately 40 000 kinematic bins for pi(+) from free protons and 15 000 bins for pi(-) production from bound nucleons in the deuteron.more » The present results are found to be in reasonable agreement with fits to previous world data for W < 1.7 GeV and Q(2) < 0.5 GeV2, with discrepancies increasing at higher values of Q(2), especially for W > 1.5 GeV. Very large target-spin asymmetries are observed for W > 1.6 GeV. When combined with cross-section measurements, the present results can provide powerful constraints on nucleon resonance amplitudes at moderate and large values of Q(2), for resonances with masses as high as 2.3 GeV.« less

Target engagement imaging of PARP inhibitors in small-cell lung cancer.

PubMed

Carney, Brandon; Kossatz, Susanne; Lok, Benjamin H; Schneeberger, Valentina; Gangangari, Kishore K; Pillarsetty, Naga Vara Kishore; Weber, Wolfgang A; Rudin, Charles M; Poirier, John T; Reiner, Thomas

2018-01-12

Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo. We measure PARP1/2 inhibition over time to calculate effective doses for individual drugs. Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens. This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through real-time monitoring of drug delivery.

Network-assisted target identification for haploinsufficiency and homozygous profiling screens

PubMed Central

Wang, Sheng

2017-01-01

Chemical genomic screens have recently emerged as a systematic approach to drug discovery on a genome-wide scale. Drug target identification and elucidation of the mechanism of action (MoA) of hits from these noisy high-throughput screens remain difficult. Here, we present GIT (Genetic Interaction Network-Assisted Target Identification), a network analysis method for drug target identification in haploinsufficiency profiling (HIP) and homozygous profiling (HOP) screens. With the drug-induced phenotypic fitness defect of the deletion of a gene, GIT also incorporates the fitness defects of the gene’s neighbors in the genetic interaction network. On three genome-scale yeast chemical genomic screens, GIT substantially outperforms previous scoring methods on target identification on HIP and HOP assays, respectively. Finally, we showed that by combining HIP and HOP assays, GIT further boosts target identification and reveals potential drug’s mechanism of action. PMID:28574983

Process and targets for production of no-carrier-added radiotin

DOEpatents

Srivastava, Suresh C; Zhuikov, Boris Leonidovich; Ermolaev, Stanislav Victorovich; Konyakhin, Nikolay Alexandrovich; Kokhanyuk, Vladimir Mikhailovich; Khamyanov, Stepan Vladimirovich; Togaeva, Natalya Roaldovna

2014-04-22

One embodiment of the present invention includes a process for production and recovery of no-carrier-added radioactive tin (NCA radiotin). An antimony target can be irradiated with a beam of accelerated particles forming NCA radiotin, followed by separation of the NCA radiotin from the irradiated target. The target is metallic Sb in a hermetically sealed shell. The shell can be graphite, molybdenum, or stainless steel. The irradiated target can be removed from the shell by chemical or mechanical means, and dissolved in an acidic solution. Sb can be removed from the dissolved irradiated target by extraction. NCA radiotin can be separated from the remaining Sb and other impurities using chromatography on silica gel sorbent. NCA tin-117m can be obtained from this process. NCA tin-117m can be used for labeling organic compounds and biological objects to be applied in medicine for imaging and therapy of various diseases.

Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4.

PubMed

Xiao, Junjie; Lv, Dongchao; Zhou, Jinzhe; Bei, Yihua; Chen, Ting; Hu, Muren; Zhou, Qiulian; Fu, Siyi; Huang, Qi

2017-01-01

Dysregulation of microRNAs (miRNAs, miRs) and their putative target genes have been increasingly reported to contribute to colorectal cancer. However, miRNAs that directly target the mutated in colorectal cancer (MCC) gene, a tumor suppressor which is downregulated or inactivated in colorectal cancer, remain largely unknown. By using an array-based miRNA analysis, we identified a group of miRNAs that were dysregulated in human metastatic versus non-metastatic colorectal cancer tissues. One of these miRNAs, miR-4260, was predicted to target MCC in the miRDB database. Results using human HCT116 and HT29 colorectal cancer cell lines showed that miR-4260 mimic enhanced cell proliferation and migration and reduced apoptosis induced by the chemotherapeutic agent 5-fluorouracil while miR-4260 inhibitor had inverse effects. Furthermore, miR-4260 negatively regulated MCC as well as SMAD4 by directly binding to the 3'untranslational region (3'UTR). Using siRNAs targeting MCC or SMAD4, we showed that upregulation of MCC and SMAD4 was essential to mediate the functional roles of miR-4260 inhibitor in colorectal cancer cells. Our in vivo experiments indicated that inhibition of miR-4260 reduced colorectal tumor growth in nude mice subcutaneously implanted with HCT116 cells. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4, strongly suggesting the clinical relevance of targeting miR-4260 in the treatment of colorectal cancer. In summary, we identified miR-4260 as a novel oncomiR for colorectal cancer that targets MCC and SMAD4. Inhibition of miR-4260 can, therefore, be a potential therapeutic strategy for colorectal cancer.

Targeting tumor highly-expressed LAT1 transporter with amino acid-modified nanoparticles: Toward a novel active targeting strategy in breast cancer therapy.

PubMed

Li, Lin; Di, Xingsheng; Wu, Mingrui; Sun, Zhisu; Zhong, Lu; Wang, Yongjun; Fu, Qiang; Kan, Qiming; Sun, Jin; He, Zhonggui

2017-04-01

Designing active targeting nanocarriers with increased cellular accumulation of chemotherapeutic agents is a promising strategy in cancer therapy. Herein, we report a novel active targeting strategy based on the large amino acid transporter 1 (LAT1) overexpressed in a variety of cancers. Glutamate was conjugated to polyoxyethylene stearate as a targeting ligand to achieve LAT1-targeting PLGA nanoparticles. The targeting efficiency of nanoparticles was investigated in HeLa and MCF-7 cells. Significant increase in cellular uptake and cytotoxicity was observed in LAT1-targeting nanoparticles compared to the unmodified ones. More interestingly, the internalized LAT1 together with targeting nanoparticles could recycle back to the cell membrane within 3 h, guaranteeing sufficient transporters on cell membrane for continuous cellular uptake. The LAT1 targeting nanoparticles exhibited better tumor accumulation and antitumor effects. These results suggested that the overexpressed LAT1 on cancer cells holds a great potential to be a high-efficiency target for the rational design of active-targeting nanosystems. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of large wood retention at check dams on sediment continuity

NASA Astrophysics Data System (ADS)

Schmocker, Lukas; Schalko, Isabella; Weitbrecht, Volker

2017-04-01

Large wood transport during flood events may seriously increase the damage potential due to accumulations at river infrastructures. The large wood is therefore mostly retained upstream of populated areas using retention structures that often combine a check dam with a debris rack. One disadvantages of this structures is, that the bed-load gets retained along with the wood. Especially if large wood blocks the rack early during a flood event, sediment continuity is completely interrupted. This may lead to severe bed erosion downstream of the check dam. So far, no common design to retain large wood but maintain sediment continuity is available. One attempt to separate the large wood from the bed-load was made with the large wood retention structure at River Sihl in Zürich, Switzerland. The retention of the large wood occurs in a bypass channel located along the main river. The bypass is located at an outer river bend, where a separation of bed-load and large wood results due to the secondary currents induced by the river curvature. Large wood floats towards the outer bend due to inertia and the secondary currents whereas bed-load remains at the inner bend. The bypass is separated by a side weir from the main river to ensure that the bed-load remains in the river during bed forming discharges and flood events. New model test are currently carried out at the Laboratory of Hydraulics, Hydrology, and Glaciology (VAW) of ETH Zurich, where sediment continuity should be achieved using an inclined rack. The rack is inclined in flow direction with a degree of 45° to 20°. First results show that the large wood deposits at the upper part of the rack whereas the lower part of the rack remains free for bed-load transport. Furthermore, the backwater rise for the inclined rack due to the accumulated wood is considerably reduced compared to a vertical rack, as a large part of the rack remains clear for the flow to pass. The findings of this studies help to understand the complex

miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1

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

Wan, Lu-Ying; Deng, Jun; Xiang, Xiao-Jun

2015-02-06

Highlights: • miR-320 plays a significant role in chemoresistance. • This role might be attribute to targeting FOXM1. • The Wnt/β-catenin pathway also involves in this chemotherapy sensitivity. - Abstract: miR-320 expression level is found to be down-regulated in human colon cancer. To date, however, its underlying mechanisms in the chemo-resistance remain largely unknown. In this study, we demonstrated that ectopic expression of miR-320 led to inhibit HCT-116 cell proliferation, invasion and hypersensitivity to 5-Fu and Oxaliplatin. Also, knockdown of miR-320 reversed these effects in HT-29 cells. Furthermore, we identified an oncogene, FOXM1, as a direct target of miR-320. Inmore » addition, miR-320 could inactive the activity of Wnt/β-catenin pathway. Finally, we found that miR-320 and FOXM1 protein had a negative correlation in colon cancer tissues and adjacent normal tissues. These findings implied that miR-320–FOXM1 axis may overcome chemo-resistance of colon cancer cells and provide a new therapeutic target for the treatment of colon cancer.« less

Cortical neurons of bats respond best to echoes from nearest targets when listening to natural biosonar multi-echo streams.

PubMed

Beetz, M Jerome; Hechavarría, Julio C; Kössl, Manfred

2016-10-27

Bats orientate in darkness by listening to echoes from their biosonar calls, a behaviour known as echolocation. Recent studies showed that cortical neurons respond in a highly selective manner when stimulated with natural echolocation sequences that contain echoes from single targets. However, it remains unknown how cortical neurons process echolocation sequences containing echo information from multiple objects. In the present study, we used echolocation sequences containing echoes from three, two or one object separated in the space depth as stimuli to study neuronal activity in the bat auditory cortex. Neuronal activity was recorded with multi-electrode arrays placed in the dorsal auditory cortex, where neurons tuned to target-distance are found. Our results show that target-distance encoding neurons are mostly selective to echoes coming from the closest object, and that the representation of echo information from distant objects is selectively suppressed. This suppression extends over a large part of the dorsal auditory cortex and may override possible parallel processing of multiple objects. The presented data suggest that global cortical suppression might establish a cortical "default mode" that allows selectively focusing on close obstacle even without active attention from the animals.

Cortical neurons of bats respond best to echoes from nearest targets when listening to natural biosonar multi-echo streams

PubMed Central

Beetz, M. Jerome; Hechavarría, Julio C.; Kössl, Manfred

2016-01-01

Bats orientate in darkness by listening to echoes from their biosonar calls, a behaviour known as echolocation. Recent studies showed that cortical neurons respond in a highly selective manner when stimulated with natural echolocation sequences that contain echoes from single targets. However, it remains unknown how cortical neurons process echolocation sequences containing echo information from multiple objects. In the present study, we used echolocation sequences containing echoes from three, two or one object separated in the space depth as stimuli to study neuronal activity in the bat auditory cortex. Neuronal activity was recorded with multi-electrode arrays placed in the dorsal auditory cortex, where neurons tuned to target-distance are found. Our results show that target-distance encoding neurons are mostly selective to echoes coming from the closest object, and that the representation of echo information from distant objects is selectively suppressed. This suppression extends over a large part of the dorsal auditory cortex and may override possible parallel processing of multiple objects. The presented data suggest that global cortical suppression might establish a cortical “default mode” that allows selectively focusing on close obstacle even without active attention from the animals. PMID:27786252

Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER

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

Smart, Oliver S., E-mail: osmart@globalphasing.com; Womack, Thomas O.; Flensburg, Claus

2012-04-01

Local structural similarity restraints (LSSR) provide a novel method for exploiting NCS or structural similarity to an external target structure. Two examples are given where BUSTER re-refinement of PDB entries with LSSR produces marked improvements, enabling further structural features to be modelled. Maximum-likelihood X-ray macromolecular structure refinement in BUSTER has been extended with restraints facilitating the exploitation of structural similarity. The similarity can be between two or more chains within the structure being refined, thus favouring NCS, or to a distinct ‘target’ structure that remains fixed during refinement. The local structural similarity restraints (LSSR) approach considers all distances less thanmore » 5.5 Å between pairs of atoms in the chain to be restrained. For each, the difference from the distance between the corresponding atoms in the related chain is found. LSSR applies a restraint penalty on each difference. A functional form that reaches a plateau for large differences is used to avoid the restraints distorting parts of the structure that are not similar. Because LSSR are local, there is no need to separate out domains. Some restraint pruning is still necessary, but this has been automated. LSSR have been available to academic users of BUSTER since 2009 with the easy-to-use -autoncs and @@target target.pdb options. The use of LSSR is illustrated in the re-refinement of PDB entries http://scripts.iucr.org/cgi-bin/cr.cgi?rm, where -target enables the correct ligand-binding structure to be found, and http://scripts.iucr.org/cgi-bin/cr.cgi?rm, where -autoncs contributes to the location of an additional copy of the cyclic peptide ligand.« less

Ghost Remains After Black Hole Eruption

NASA Astrophysics Data System (ADS)

2009-05-01

it has died," said co-author Scott Chapman, also of Cambridge University. "This means we don't have to catch the black holes in the act to witness the big impact they have." This is the first X-ray ghost ever seen after the demise of radio-bright jets. Astronomers have observed extensive X-ray emission with a similar origin, but only from galaxies with radio emission on large scales, signifying continued eruptions. In HDF 130, only a point source is detected in radio images, coinciding with the massive elliptical galaxy seen in its optical image. This radio source indicates the presence of a growing supermassive black hole. People Who Read This Also Read... Milky Way's Super-efficient Particle Accelerators Caught in The Act NASA Joins "Around the World in 80 Telescopes" Celebrate the International Year of Astronomy Galaxies Coming of Age in Cosmic Blobs "This result hints that the X-ray sky should be littered with such ghosts," said co-author Caitlin Casey, also of Cambridge, "especially if black hole eruptions are as common as we think they are in the early Universe." The power contained in the black hole eruption was likely to be considerable, equivalent to about a billion supernovas. The energy is dumped into the surroundings and transports and heats the gas. "Even after the ghost disappears, most of the energy from the black hole's eruption remains", said Fabian. "Because they're so powerful, these eruptions can have profound effects lasting for billions of years." The details of Chandra's data of HDF 130 helped secure its true nature. For example, in X-rays, HDF 130 has a cigar-like shape that extends for some 2.2 million light years. The linear shape of the X-ray source is consistent with the shape of radio jets and not with that of a galaxy cluster, which is expected to be circular. The energy distribution of the X-rays is also consistent with the interpretation of an X-ray ghost. NASA's Marshall Space Flight Center in Huntsville, Ala., manages the Chandra

Target and double spin asymmetries of deeply virtual π0 production with a longitudinally polarized proton target and CLAS

NASA Astrophysics Data System (ADS)

Kim, A.; Avakian, H.; Burkert, V.; Joo, K.; Kim, W.; Adhikari, K. P.; Akbar, Z.; Anefalos Pereira, S.; Badui, R. A.; Battaglieri, M.; Batourine, V.; Bedlinskiy, I.; Biselli, A. S.; Boiarinov, S.; Bosted, P.; Briscoe, W. J.; Brooks, W. K.; Bültmann, S.; Cao, T.; Carman, D. S.; Celentano, A.; Chandavar, S.; Charles, G.; Chetry, T.; Colaneri, L.; Cole, P. L.; Compton, N.; Contalbrigo, M.; Cortes, O.; Crede, V.; D'Angelo, A.; Dashyan, N.; De Vita, R.; De Sanctis, E.; Djalali, C.; Egiyan, H.; El Alaoui, A.; El Fassi, L.; Eugenio, P.; Fedotov, G.; Fersch, R.; Filippi, A.; Fleming, J. A.; Fradi, A.; Garc con, M.; Ghandilyan, Y.; Gilfoyle, G. P.; Giovanetti, K. L.; Girod, F. X.; Gohn, W.; Golovatch, E.; Gothe, R. W.; Griffioen, K. A.; Guo, L.; Hafidi, K.; Hanretty, C.; Hattawy, M.; Heddle, D.; Hicks, K.; Holtrop, M.; Ilieva, Y.; Ireland, D. G.; Ishkhanov, B. S.; Jenkins, D.; Jiang, H.; Jo, H. S.; Joosten, S.; Keller, D.; Khachatryan, G.; Khandaker, M.; Klein, A.; Klein, F. J.; Kubarovsky, V.; Kuhn, S. E.; Kuleshov, S. V.; Lanza, L.; Lenisa, P.; Lu, H. Y.; MacGregor, I. J. D.; Markov, N.; Mattione, P.; McCracken, M. E.; McKinnon, B.; Mokeev, V.; Movsisyan, A.; Munevar, E.; Nadel-Turonski, P.; Net, L. A.; Niccolai, S.; Osipenko, M.; Ostrovidov, A. I.; Paolone, M.; Park, K.; Pasyuk, E.; Phelps, W.; Pisano, S.; Pogorelko, O.; Price, J. W.; Prok, Y.; Ripani, M.; Rizzo, A.; Rosner, G.; Rossi, P.; Roy, P.; Salgado, C.; Schumacher, R. A.; Seder, E.; Sharabian, Y. G.; Skorodumina, Iu.; Smith, G. D.; Sokhan, D.; Sparveris, N.; Stepanyan, S.; Stoler, P.; Strakovsky, I. I.; Strauch, S.; Sytnik, V.; Taiuti, M.; Torayev, B.; Ungaro, M.; Voskanyan, H.; Voutier, E.; Watts, D. P.; Wei, X.; Weinstein, L. B.; Zachariou, N.; Zana, L.; Zhang, J.

2017-05-01

The target and double spin asymmetries of the exclusive pseudoscalar channel e → p → → epπ0 were measured for the first time in the deep-inelastic regime using a longitudinally polarized 5.9 GeV electron beam and a longitudinally polarized proton target at Jefferson Lab with the CEBAF Large Acceptance Spectrometer (CLAS). The data were collected over a large kinematic phase space and divided into 110 four-dimensional bins of Q2, xB, -t and ϕ. Large values of asymmetry moments clearly indicate a substantial contribution to the polarized structure functions from transverse virtual photon amplitudes. The interpretation of experimental data in terms of generalized parton distributions (GPDs) provides the first insight on the chiral-odd GPDs H˜T and ET, and complement previous measurements of unpolarized structure functions sensitive to the GPDs HT and EbarT. These data provide a crucial input for parametrizations of essentially unknown chiral-odd GPDs and will strongly influence existing theoretical calculations based on the handbag formalism.

Target and double spin asymmetries of deeply virtual π 0 production with a longitudinally polarized proton target and CLAS

DOE PAGES

Kim, A.; Avakian, H.; Burkert, V.; ...

2017-02-22

The target and double spin asymmetries of the exclusive pseudoscalar channelmore » $$\\vec e\\vec p\\to ep\\pi^0$$ were measured for the first time in the deep-inelastic regime using a longitudinally polarized 5.9 GeV electron beam and a longitudinally polarized proton target at Jefferson Lab with the CEBAF Large Acceptance Spectrometer (CLAS). The data were collected over a large kinematic phase space and divided into 110 four-dimensional bins of $Q^2$, $$x_B$$, $-t$ and $$\\phi$$. Large values of asymmetry moments clearly indicate a substantial contribution to the polarized structure functions from transverse virtual photon amplitudes. The interpretation of experimental data in terms of generalized parton distributions (GPDs) provides the first insight on the chiral-odd GPDs $$\\tilde{H}_T$$ and $$E_T$$, and complement previous measurements of unpolarized structure functions sensitive to the GPDs $$H_T$$ and $$\\bar E_T$$. Finally, these data provide necessary constraints for chiral-odd GPD parametrizations and will strongly influence existing theoretical handbag models.« less

Value-focused framework for defining landscape-scale conservation targets

USGS Publications Warehouse

Romañach, Stephanie; Benscoter, Allison M.; Brandt, Laura A.

2016-01-01

Conservation of natural resources can be challenging in a rapidly changing world and require collaborative efforts for success. Conservation planning is the process of deciding how to protect, conserve, and enhance or minimize loss of natural and cultural resources. Establishing conservation targets (also called indicators or endpoints), the measurable expressions of desired resource conditions, can help with site-specific up to landscape-scale conservation planning. Using conservation targets and tracking them through time can deliver benefits such as insight into ecosystem health and providing early warnings about undesirable trends. We describe an approach using value-focused thinking to develop statewide conservation targets for Florida. Using such an approach allowed us to first identify stakeholder objectives and then define conservation targets to meet those objectives. Stakeholders were able to see how their shared efforts fit into the broader conservation context, and also anticipate the benefits of multi-agency and -organization collaboration. We developed an iterative process for large-scale conservation planning that included defining a shared framework for the process, defining the conservation targets themselves, as well as developing management and monitoring strategies for evaluation of their effectiveness. The process we describe is applicable to other geographies where multiple parties are seeking to implement collaborative, large-scale biological planning.

Quantifying design trade-offs of beryllium targets on NIF

NASA Astrophysics Data System (ADS)

Yi, S. A.; Zylstra, A. B.; Kline, J. L.; Loomis, E. N.; Kyrala, G. A.; Shah, R. C.; Perry, T. S.; Kanzleiter, R. J.; Batha, S. H.; MacLaren, S. A.; Ralph, J. E.; Masse, L. P.; Salmonson, J. D.; Tipton, R. E.; Callahan, D. A.; Hurricane, O. A.

2017-10-01

An important determinant of target performance is implosion kinetic energy, which scales with the capsule size. The maximum achievable performance for a given laser is thus related to the largest capsule that can be imploded symmetrically, constrained by drive uniformity. A limiting factor for symmetric radiation drive is the ratio of hohlraum to capsule radii, or case-to-capsule ratio (CCR). For a fixed laser energy, a larger hohlraum allows for driving bigger capsules symmetrically at the cost of reduced peak radiation temperature (Tr). Beryllium ablators may thus allow for unique target design trade-offs due to their higher ablation efficiency at lower Tr. By utilizing larger hohlraum sizes than most modern NIF designs, beryllium capsules thus have the potential to operate in unique regions of the target design parameter space. We present design simulations of beryllium targets with a large CCR = 4.3 3.7 . These are scaled surrogates of large hohlraum low Tr beryllium targets, with the goal of quantifying symmetry tunability as a function of CCR. This work performed under the auspices of the U.S. DOE by LANL under contract DE-AC52- 06NA25396, and by LLNL under Contract DE-AC52-07NA27344.

N-acetylgalactosamine-functionalized dendrimers as hepatic cancer cell-targeted carriers.

PubMed

Medina, Scott H; Tekumalla, Venkatesh; Chevliakov, Maxim V; Shewach, Donna S; Ensminger, William D; El-Sayed, Mohamed E H

2011-06-01

There is an urgent need for novel polymeric carriers that can selectively deliver a large dose of chemotherapeutic agents into hepatic cancer cells to achieve high therapeutic activity with minimal systemic side effects. PAMAM dendrimers are characterized by a unique branching architecture and a large number of chemical surface groups suitable for coupling of chemotherapeutic agents. In this article, we report the coupling of N-acetylgalactosamine (NAcGal) to generation 5 (G5) of poly(amidoamine) (PAMAM-NH₂) dendrimers via peptide and thiourea linkages to prepare NAcGal-targeted carriers used for targeted delivery of chemotherapeutic agents into hepatic cancer cells. We describe the uptake of NAcGal-targeted and non-targeted G5 dendrimers into hepatic cancer cells (HepG2) as a function of G5 concentration and incubation time. We examine the contribution of the asialoglycoprotein receptor (ASGPR) to the internalization of NAcGal-targeted dendrimers into hepatic cancer cells through a competitive inhibition assay. Our results show that uptake of NAcGal-targeted G5 dendrimers into hepatic cancer cells occurs via ASGPR-mediated endocytosis. Internalization of these targeted carriers increased with the increase in G5 concentration and incubation time following Michaelis-Menten kinetics characteristic of receptor-mediated endocytosis. These results collectively indicate that G5-NAcGal conjugates function as targeted carriers for selective delivery of chemotherapeutic agents into hepatic cancer cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

Differentiation between decomposed remains of human origin and bigger mammals.

PubMed

Rosier, E; Loix, S; Develter, W; Van de Voorde, W; Cuypers, E; Tytgat, J

2017-08-01

This study is a follow-up study in the search for a human specific marker in the decomposition where the VOC-profile of decomposing human, pig, lamb and roe remains were analyzed using a thermal desorber combined with a gas chromatograph coupled to a mass spectrometer in a laboratory environment during 6 months. The combination of 8 previously identified human and pig specific compounds (ethyl propionate, propyl propionate, propyl butyrate, ethyl pentanoate, 3-methylthio-1-propanol, methyl(methylthio)ethyl disulfide, diethyl disulfide and pyridine) was also seen in these analyzed mammals. However, combined with 5 additional compounds (hexane, heptane, octane, N-(3-methylbutyl)- and N-(2-methylpropyl)acetamide) human remains could be separated from pig, lamb and roe remains. Based on a higher number of remains analyzed, as compared with the pilot study, it was no longer possible to rely on the 5 previously proposed esters to separate pig from human remains. From this follow-up study reported, it was found that pyridine is an interesting compound specific to human remains. Such a human specific marker can help in the training of cadaver dogs or in the development of devices to search for human remains. However, further investigations have to verify these results. Copyright © 2017 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Large scale tracking algorithms

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

Hansen, Ross L.; Love, Joshua Alan; Melgaard, David Kennett

2015-01-01

Low signal-to-noise data processing algorithms for improved detection, tracking, discrimination and situational threat assessment are a key research challenge. As sensor technologies progress, the number of pixels will increase signi cantly. This will result in increased resolution, which could improve object discrimination, but unfortunately, will also result in a significant increase in the number of potential targets to track. Many tracking techniques, like multi-hypothesis trackers, suffer from a combinatorial explosion as the number of potential targets increase. As the resolution increases, the phenomenology applied towards detection algorithms also changes. For low resolution sensors, "blob" tracking is the norm. For highermore » resolution data, additional information may be employed in the detection and classfication steps. The most challenging scenarios are those where the targets cannot be fully resolved, yet must be tracked and distinguished for neighboring closely spaced objects. Tracking vehicles in an urban environment is an example of such a challenging scenario. This report evaluates several potential tracking algorithms for large-scale tracking in an urban environment.« less

Healthcare stocks expected to remain strong.

PubMed

Pallarito, K

1991-05-27

While healthcare stocks are likely to remain at the top of Wall Street's list of favorites, healthcare analysts and money managers say they don't expect to see the same quality of healthcare companies issuing stock the rest of the year. They say that in the coming months, more companies of lesser quality will sell stock at inflated prices, compared with their earnings.

Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma.

PubMed

Gu, De-Leung; Chen, Yen-Hsieh; Shih, Jou-Ho; Lin, Chi-Hung; Jou, Yuh-Shan; Chen, Chian-Feng

2013-12-21

High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma (HCC) cohorts confirmed previously identified frequently mutated somatic genes, such as TP53, CTNNB1 and AXIN1, and identified several novel genes with moderate mutation frequencies, including ARID1A, ARID2, MLL, MLL2, MLL3, MLL4, IRF2, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3, JAK1, KEAP1, NFE2L2, C16orf62, LEPR, RAC2, and IL6ST. Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling, Wnt/β-catenin signaling, JAK/STAT signaling, and oxidative stress play critical roles in HCC tumorigenesis. Nevertheless, because there are few druggable genes used in HCC therapy, the identification of new therapeutic targets through integrated genomic approaches remains an important task. Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain, copy number alteration (CNA) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons, homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression. Moreover, integration of CNAs with other high-throughput genomic data, such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models, provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.

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

PubMed

Gibiansky, Leonid; Gibiansky, Ekaterina

2018-02-01

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

Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model.

PubMed

van Vliet, Danique; Bruinenberg, Vibeke M; Mazzola, Priscila N; van Faassen, Martijn Hjr; de Blaauw, Pim; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Kema, Ido P; Heiner-Fokkema, M Rebecca; van der Zee, Eddy A; van Spronsen, Francjan J

2016-11-01

Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established. In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria. Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine. The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus

Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.

PubMed

Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri

2010-05-14

Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

The role of contact system in septic shock: the next target? An overview of the current evidence.

PubMed

Nicola, Henrique

2017-01-01

Septic shock remains challenging to intensive care units worldwide, despite recent documented improvement in mortality over the years. Multiple new therapies have been attempted without success in large clinical trials. Evidence concerning the role of the contact system and bradykinin on septic shock physiological manifestations is shown by this article. The objective of the study is to review the current evidence linking contact system activation and septic shock, as well as efficacy of available therapies targeting this pathophysiological pathway and to evaluate the potential of further researching the matter. Multiple animal studies are already available and suggestive of a meaningful role of contact system activation on septic shock. However, human trials are still scarce, and the ones available are not enough to establish such a strong connection. Furthermore, attempted therapies have been successful across multiple species, but not as much in humans. Therefore, contact system and septic shock relationship remains plentiful in questions to be answered in the coming years or decades. Whether the contact system is not as relevant in humans as it is in animals or there is only lack of evidence remains to be explained. The subject is an attractive open field for further research aiming to aid in tackling such a burdensome condition.

Double-shell target fabrication workshop-2016 report

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

Wang, Y. Morris; Oertel, John; Farrell, Michael

On June 30, 2016, over 40 representatives from Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), General Atomics (GA), Laboratory for Laser Energetics (LLE), Schafer Corporation, and NNSA headquarter attended a double-shell (DS) target fabrication workshop at Livermore, California. Pushered-single-shell (PSS) and DS metalgas platforms potentially have a large impact on programmatic applications. The goal of this focused workshop is to bring together target fabrication scientists, physicists, and designers to brainstorm future PSS and DS target fabrication needs and strategies. This one-day workshop intends to give an overall view of historical information, recent approaches, and future research activitiesmore » at each participating organization. Five topical areas have been discussed that are vital to the success of future DS target fabrications, including inner metal shells, foam spheres, outer ablators, fill tube assembly, and metrology.« less

Targeted therapies in gastric cancer and future perspectives.

PubMed

Yazici, Ozan; Sendur, M Ali Nahit; Ozdemir, Nuriye; Aksoy, Sercan

2016-01-14

Advanced gastric cancer (AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after first-line platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase I-II trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER (2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.

Yersinia pestis Orientalis in Remains of Ancient Plague Patients

PubMed Central

Drancourt, Michel; Signoli, Michel; Dang, La Vu; Bizot, Bruno; Roux, Véronique; Tzortzis, Stéfan

2007-01-01

Yersinia pestis DNA was recently detected in human remains from 2 ancient plague pandemics in France and Germany. We have now sequenced Y. pestis glpD gene in such remains, showing a 93-bp deletion specific for biotype Orientalis. These data show that only Orientalis type caused the 3 plague pandemics. PMID:17479906

Target identification of small molecules based on chemical biology approaches.

PubMed

Futamura, Yushi; Muroi, Makoto; Osada, Hiroyuki

2013-05-01

Recently, a phenotypic approach-screens that assess the effects of compounds on cells, tissues, or whole organisms-has been reconsidered and reintroduced as a complementary strategy of a target-based approach for drug discovery. Although the finding of novel bioactive compounds from large chemical libraries has become routine, the identification of their molecular targets is still a time-consuming and difficult process, making this step rate-limiting in drug development. In the last decade, we and other researchers have amassed a large amount of phenotypic data through progress in omics research and advances in instrumentation. Accordingly, the profiling methodologies using these datasets expertly have emerged to identify and validate specific molecular targets of drug candidates, attaining some progress in current drug discovery (e.g., eribulin). In the case of a compound that shows an unprecedented phenotype likely by inhibiting a first-in-class target, however, such phenotypic profiling is invalid. Under the circumstances, a photo-crosslinking affinity approach should be beneficial. In this review, we describe and summarize recent progress in both affinity-based (direct) and phenotypic profiling (indirect) approaches for chemical biology target identification.

Foucault on targets.

PubMed

Lynch, John

2004-01-01

This paper seeks to gain an insight into the behavior of a large NHS trust, in its attempt to meet a 90 percent patient access target, in a week long national audit in March 2003. Why did individuals act in dramatically different ways to their norm over this period. The work of Michel Foucault is used to explore these issues. The discourses of power, knowledge, discipline and governmentality are identified as key foucaudian themes that offer an alternative interpretation of how individuals behave in their place of work. The importance of the historical context of discourse within the NHS cannot be underestimated in shaping the behavior of individuals and groups today. Power and knowledge permeate NHS organizations through disciplinary practices and dressage. Governmentality seeks to maintain the status quo through disciplinary processes such as national healthcare targets. The natural response of NHS organizations is therefore, to seek order and conformity rather than disorder and conflict.

Echo scintillation Index affected by cat-eye target's caliber with Cassegrain lens

NASA Astrophysics Data System (ADS)

Shan, Cong-miao; Sun, Hua-yan; Zhao, Yan-zhong; Zheng, Yong-hui

2015-10-01

The optical aperture of cat-eye target has the aperture averaging effect to the active detecting laser of active laser detection system, which can be used to identify optical targets. The echo scintillation characteristics of the transmission-type lens target have been studied in previous work. Discussing the differences of the echo scintillation characteristics between the transmission-type lens target and Cassegrain lens target can be helpful to targets classified. In this paper, the echo scintillation characteristics of Cat-eye target's caliber with Cassegrain lens has been discussed . By using the flashing theory of spherical wave in the weak atmospheric turbulence, the annular aperture filter function and the Kolmogorov power spectrum, the analytic expression of the scintillation index of the cat-eye target echo of the horizontal path two-way transmission was given when the light is normal incidence. Then the impact of turbulence inner and outer scale to the echo scintillation index and the analytic expression of the echo scintillation index at the receiving aperture were presented using the modified Hill spectrum and the modified Von Karman spectrum. Echo scintillation index shows the tendency of decreasing with the target aperture increases and different ratios of the inner and outer aperture diameter show the different echo scintillation index curves. This conclusion has a certain significance for target recognition in the active laser detection system that can largely determine the target type by largely determining the scope of the cat-eye target which depending on echo scintillation index.

The continuing role of chemotherapy for advanced non-small cell lung cancer in the targeted therapy era.

PubMed

Lwin, Zarnie; Riess, Jonathan W; Gandara, David

2013-10-01

There have been remarkable advances in the targeted treatment of advanced non-small cell lung cancer (NSCLC) over the past several years. Survival outcomes are steadily improving as management paradigms shift in the diagnosis and treatment of advanced NSCLC. Customizing treatment based on histology and molecular typing has become a standard of care in this era of targeted therapy. While new chemotherapeutic agents have proven effective, the pivotal role of platinum-based chemotherapy doublets has been confirmed. Maintenance chemotherapy has become an option, but who to employ it in remains unclear in the real-world setting. Efforts to overcome resistance to targeted agents are ongoing utilizing combination regimens of chemotherapy plus targeted agents, but optimizing combination strategies needs further exploration. This review highlights recent developments in novel chemotherapeutics and in chemotherapy strategies over the past two years. Despite advances in molecular medicine, there remains an essential role for chemotherapy in advanced NSCLC, even in the recent targeted therapy era.

Schools as Tactical Targets in Conflict: What the Case of Nepal Can Teach Us

ERIC Educational Resources Information Center

van Wessel, Margit; van Hirtum, Ruud

2013-01-01

That school grounds, students, and staff can become tactical targets for parties in conflict is widely accepted as a fact by analysts of education and conflict. However, our understanding of the motivations for such targeting remains limited, as does our ability to engage with this matter through policy. In this article we explore tactical…

Adverse drug reaction prediction using scores produced by large-scale drug-protein target docking on high-performance computing machines.

PubMed

LaBute, Montiago X; Zhang, Xiaohua; Lenderman, Jason; Bennion, Brian J; Wong, Sergio E; Lightstone, Felice C

2014-01-01

Late-stage or post-market identification of adverse drug reactions (ADRs) is a significant public health issue and a source of major economic liability for drug development. Thus, reliable in silico screening of drug candidates for possible ADRs would be advantageous. In this work, we introduce a computational approach that predicts ADRs by combining the results of molecular docking and leverages known ADR information from DrugBank and SIDER. We employed a recently parallelized version of AutoDock Vina (VinaLC) to dock 906 small molecule drugs to a virtual panel of 409 DrugBank protein targets. L1-regularized logistic regression models were trained on the resulting docking scores of a 560 compound subset from the initial 906 compounds to predict 85 side effects, grouped into 10 ADR phenotype groups. Only 21% (87 out of 409) of the drug-protein binding features involve known targets of the drug subset, providing a significant probe of off-target effects. As a control, associations of this drug subset with the 555 annotated targets of these compounds, as reported in DrugBank, were used as features to train a separate group of models. The Vina off-target models and the DrugBank on-target models yielded comparable median area-under-the-receiver-operating-characteristic-curves (AUCs) during 10-fold cross-validation (0.60-0.69 and 0.61-0.74, respectively). Evidence was found in the PubMed literature to support several putative ADR-protein associations identified by our analysis. Among them, several associations between neoplasm-related ADRs and known tumor suppressor and tumor invasiveness marker proteins were found. A dual role for interstitial collagenase in both neoplasms and aneurysm formation was also identified. These associations all involve off-target proteins and could not have been found using available drug/on-target interaction data. This study illustrates a path forward to comprehensive ADR virtual screening that can potentially scale with increasing number

Targeting Trypsin-Inflammation Axis for Pancreatitis Therapy in a Humanized Pancreatitis Model

DTIC Science & Technology

2016-10-01

Award Number: W81XWH-15-1-0257 TITLE: Targeting Trypsin-Inflammation Axis for Pancreatitis Therapy in a Humanized Pancreatitis Model PRINCIPAL...AND SUBTITLE Targeting Trypsin-Inflammation Axis for Pancreatitis Therapy in a Humanized Pancreatitis Model 5a. CONTRACT NUMBER 5b. GRANT NUMBER...remains the same since it is covered under the institutional review. We set up monthly video conferences with our partnership PI to discuss any

An integrated workflow to assess the remaining potential of mature hydrocarbon basins: a case study from Northwest Germany (Upper Jurassic/Lower Cretaceous, Lower Saxony Basin)

NASA Astrophysics Data System (ADS)

Seyfang, Björn; Aigner, Thomas; Munsterman, Dirk K.; Irmen, Anton

2017-04-01

Mature hydrocarbon provinces require a high level of geological understanding in order to extend the lives of producing fields, to replace reserves through smaller targets and to reduce the risks of exploring for more and more subtle hydrocarbon traps. Despite a large number of existing wells in the area studied in this paper, the depositional environments and the stratigraphic architecture were still poorly known. In order to improve the geological understanding, we propose a workflow to assess the remaining reservoir potential of mature hydrocarbon areas, integrating cores, cuttings, well-logs, biostratigraphy and seismic data. This workflow was developed for and is exemplified with the northwest of the Lower Saxony Basin (LSB), a mature hydrocarbon province in northwest Germany, but can be applied in a similar fashion to other areas. Systematic integration of lithofacies analysis, chrono- and sequence stratigraphy, combined with electrofacies analysis and modern digital methods like neural network-based lithology determination and 3D facies modelling provides a high-resolution understanding of the spatial facies and reservoir architecture in the study area. Despite widely correlatable litho-units in the Upper Jurassic and Lower Cretaceous in the LSB, complex heterogeneous sedimentary systems can be found in the basin's marginal parts. Two new play types were determined in the study area, showing a remaining potential for stratigraphic hydrocarbon traps. The results of this exploration scale study also provide the basis for re-evaluations on a field development scale. On a basin scale, this study may encourage further data acquisition and re-evaluations to discover previously unknown reservoirs.

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

NASA Astrophysics Data System (ADS)

Neira, José L.; Bintz, Jennifer; Arruebo, María; Rizzuti, Bruno; Bonacci, Thomas; Vega, Sonia; Lanas, Angel; Velázquez-Campoy, Adrián; Iovanna, Juan L.; Abián, Olga

2017-01-01

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

PubMed Central

Neira, José L.; Bintz, Jennifer; Arruebo, María; Rizzuti, Bruno; Bonacci, Thomas; Vega, Sonia; Lanas, Angel; Velázquez-Campoy, Adrián; Iovanna, Juan L.; Abián, Olga

2017-01-01

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs. PMID:28054562

Angiogenic cytokines are antibody targets during graft-versus-leukemia reactions

PubMed Central

Piesche, Matthias; Ho, Vincent T.; Kim, Haesook; Nakazaki, Yukoh; Nehil, Michael; Yaghi, Nasser; Kolodin, Dmitriy; Weiser, Jeremy; Altevogt, Peter; Kiefel, Helena; Alyea, Edwin P.; Antin, Joseph H.; Cutler, Corey; Koreth, John; Canning, Christine; Ritz, Jerome; Soiffer, Robert J.; Dranoff, Glenn

2014-01-01

Purpose The graft-versus-leukemia (GVL) reaction is an important example of immune-mediated tumor destruction. A coordinated humoral and cellular response accomplishes leukemia cell killing, but the specific targets remain largely uncharacterized. To learn more about the antigens that elicit antibodies during GVL reactions, we analyzed advanced myelodysplasia (MDS) and acute myeloid leukemia (AML) patients who received an autologous, granulocyte-macrophage colony stimulating factor (GM-CSF) secreting tumor cell vaccine early after allogeneic hematopoietic stem cell transplantation (HSCT). Experimental Design A combination of tumor-derived cDNA expression library screening, protein microarrays, and antigen-specific ELISAs were employed to characterize sera obtained longitudinally from 15 AML/MDS patients who were vaccinated early after allogeneic HSCT. Results A broad, therapy-induced antibody response was uncovered, which primarily targeted intracellular proteins that function in growth, transcription/translation, metabolism, and homeostasis. Unexpectedly, antibodies were also elicited against eight secreted angiogenic cytokines that play critical roles in leukemogenesis. Antibodies to the angiogenic cytokines were evident early after therapy, and in some patients manifested a diversification in reactivity over time. Patients that developed antibodies to multiple angiogenic cytokines showed prolonged remission and survival. Conclusions These results reveal a potent humoral response during GVL reactions induced with vaccination early after allogeneic HSCT and raise the possibility that antibodies, in conjunction with NK cells and T lymphocytes, may contribute to immune-mediated control of myeloid leukemias. PMID:25538258

Selective Targeting of Brain Tumors with Gold Nanoparticle-Induced Radiosensitization

PubMed Central

Joh, Daniel Y.; Sun, Lova; Stangl, Melissa; Al Zaki, Ajlan; Murty, Surya; Santoiemma, Phillip P.; Davis, James J.; Baumann, Brian C.; Alonso-Basanta, Michelle; Bhang, Dongha; Kao, Gary D.; Tsourkas, Andrew; Dorsey, Jay F.

2013-01-01

Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ∼1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature. PMID:23638079

A new three-dimensional conformal radiotherapy (3DCRT) technique for large breast and/or high body mass index patients: evaluation of a novel fields assessment aimed to reduce extra–target-tissue irradiation

PubMed Central

Stimato, Gerardina; Ippolito, Edy; Silipigni, Sonia; Venanzio, Cristina Di; Gaudino, Diego; Fiore, Michele; Trodella, Lucio; D'Angelillo, Rolando Maria; Ramella, Sara

2016-01-01

Objective: To develop an alternative three-dimensional treatment plan with standardized fields class solution for whole-breast radiotherapy in patients with large/pendulous breast and/or high body mass index (BMI). Methods: Two treatment plans [tangential fields and standardized five-fields technique (S5F)] for a total dose of 50 Gy/25 fractions were generated for patients with large breasts [planning target volume (PTV) >1000 cm3 and/or BMI >25 kg m−2], supine positioned. S5F plans consist of two wedged tangential beams, anteroposterior: 20° for the right breast and 340° for the left breast, and posteroanterior: 181° for the right breast and 179° for the left breast. A field in field in medial–lateral beam and additional fields were added to reduce hot spot areas and extra–target-tissue irradiation and to improve dose distribution. The percentage of PTV receiving 95% of the prescribed dose (PTV V95%), percentage of PTV receiving 105% of the prescribed dose (PTV V105%), maximal dose to PTV (PTV Dmax), homogeneity index (HI) and conformity index were recorded. V10%, V20%, V105% and V107% of a “proper” normal tissue structure (body-PTV healthy tissue) were recorded. Statistical analyses were performed using SYSTAT v.12.0 (SPSS, Chicago, IL). Results: In 38 patients included, S5F improved HI (8.4 vs 10.1; p ≤ 0.001) and significantly reduced PTV Dmax and PTV V105%. The extra–target-tissue irradiation was significantly reduced using S5F for V105% (cm3) and V107% (cm3) with a very high difference in tissue irradiation (46.6 vs 3.0 cm3, p ≤ 0.001 for V105% and 12.2 vs 0.0 cm3, p ≤ 0.001 for V107% for tangential field and S5F plans, respectively). Only a slight increase in low-dose extra–target-tissue irradiation (V10%) was observed (2.2719 vs 1.8261 cm3, p = 0.002). Conclusion: The S5F technique in patients with large breast or high BMI increases HI and decreases hot spots in extra-target-tissues and can therefore be

Target and beam-target spin asymmetries in exclusive π + and π – electroproduction with 1.6- to 5.7-GeV electrons

DOE PAGES

Bosted, P. E.; Biselli, A. S.; Careccia, S.; ...

2016-11-01

Here, beam-target double-spin asymmetries and target single-spin asymmetries in exclusive π + and quasiexclusive π – electroproduction were obtained from scattering of 1.6- to 5.7-GeV longitudinally polarized electrons from longitudinally polarized protons (for π +) and deuterons (for π –) using the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. The kinematic range covered is 1.1 < W < 2.6 GeV and 0.05 < Q 2 < 5GeV 2, with good angular coverage in the forward hemisphere. The asymmetry results were divided into approximately 40 000 kinematic bins for π + from free protons and 15 000 bins for πmore » – production from bound nucleons in the deuteron. The present results are found to be in reasonable agreement with fits to previous world data for W < 1.7 GeV and Q 2 < 0.5GeV 2, with discrepancies increasing at higher values of Q 2, especially for W > 1.5 GeV. Very large target-spin asymmetries are observed for W > 1.6 GeV. When combined with cross-section measurements, the present results can provide powerful constraints on nucleon resonance amplitudes at moderate and large values of Q 2, for resonances with masses as high as 2.3 GeV.« less

Targeting von Willebrand Factor in Ischaemic Stroke: Focus on Clinical Evidence.

PubMed

Buchtele, Nina; Schwameis, Michael; Gilbert, James C; Schörgenhofer, Christian; Jilma, Bernd

2018-06-01

Despite great efforts in stroke research, disability and recurrence rates in ischaemic stroke remain unacceptably high. To address this issue, one potential target for novel therapeutics is the glycoprotein von Willebrand factor (vWF), which increases in thrombogenicity especially under high shear rates as it bridges between vascular sub-endothelial collagen and platelets. The rationale for vWF as a potential target in stroke comes from four bodies of evidence. (1) Animal models which recapitulate the pathogenesis of stroke and validate the concept of targeting vWF for stroke prevention and the use of the vWF cleavage enzyme ADAMTS13 in acute stroke treatment. (2) Extensive epidemiologic data establishing the prognostic role of vWF in the clinical setting showing that high vWF levels are associated with an increased risk of first stroke, stroke recurrence or stroke-associated mortality. As such, vWF levels may be a suitable marker for further risk stratification to potentially fine-tune current risk prediction models which are mainly based on clinical and imaging data. (3) Genetic studies showing an association between vWF levels and stroke risk on genomic levels. Finally, (4) studies of patients with primary disorders of excess or deficiency of function in the vWF axis (e.g. thrombotic thrombocytopenic purpura and von Willebrand disease, respectively) which demonstrate the crucial role of vWF in atherothrombosis. Therapeutic inhibition of VWF by novel agents appears particularly promising for secondary prevention of stroke recurrence in specific sub-groups of patients such as those suffering from large artery atherosclerosis, as designated according to the TOAST classification. Schattauer GmbH Stuttgart.

Acute myeloid leukemia targets for bispecific antibodies

PubMed Central

Hoseini, S S; Cheung, N K

2017-01-01

Despite substantial gains in our understanding of the genomics of acute myelogenous leukemia (AML), patient survival remains unsatisfactory especially among the older age group. T cell-based therapy of lymphoblastic leukemia is rapidly advancing; however, its application in AML is still lagging behind. Bispecific antibodies can redirect polyclonal effector cells to engage chosen targets on leukemia blasts. When the effector cells are natural-killer cells, both antibody-dependent and antibody-independent mechanisms could be exploited. When the effectors are T cells, direct tumor cytotoxicity can be engaged followed by a potential vaccination effect. In this review, we summarize the AML-associated tumor targets and the bispecific antibodies that have been studied. The potentials and limitations of each of these systems will be discussed. PMID:28157217

Identifying mechanism-of-action targets for drugs and probes

PubMed Central

Gregori-Puigjané, Elisabet; Setola, Vincent; Hert, Jérôme; Crews, Brenda A.; Irwin, John J.; Lounkine, Eugen; Marnett, Lawrence; Roth, Bryan L.; Shoichet, Brian K.

2012-01-01

Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to “de-orphanize” drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration—approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. PMID:22711801

A comparison of directed search target detection versus in-scene target detection in Worldview-2 datasets

NASA Astrophysics Data System (ADS)

Grossman, S.

2015-05-01

Since the events of September 11, 2001, the intelligence focus has moved from large order-of-battle targets to small targets of opportunity. Additionally, the business community has discovered the use of remotely sensed data to anticipate demand and derive data on their competition. This requires the finer spectral and spatial fidelity now available to recognize those targets. This work hypothesizes that directed searches using calibrated data perform at least as well as inscene manually intensive target detection searches. It uses calibrated Worldview-2 multispectral images with NEF generated signatures and standard detection algorithms to compare bespoke directed search capabilities against ENVI™ in-scene search capabilities. Multiple execution runs are performed at increasing thresholds to generate detection rates. These rates are plotted and statistically analyzed. While individual head-to-head comparison results vary, 88% of the directed searches performed at least as well as in-scene searches with 50% clearly outperforming in-scene methods. The results strongly support the premise that directed searches perform at least as well as comparable in-scene searches.

Salt Reduction Initiatives around the World - A Systematic Review of Progress towards the Global Target.

PubMed

Trieu, Kathy; Neal, Bruce; Hawkes, Corinna; Dunford, Elizabeth; Campbell, Norm; Rodriguez-Fernandez, Rodrigo; Legetic, Branka; McLaren, Lindsay; Barberio, Amanda; Webster, Jacqui

2015-01-01

To quantify progress with the initiation of salt reduction strategies around the world in the context of the global target to reduce population salt intake by 30% by 2025. A systematic review of the published and grey literature was supplemented by questionnaires sent to country program leaders. Core characteristics of strategies were extracted and categorised according to a pre-defined framework. A total of 75 countries now have a national salt reduction strategy, more than double the number reported in a similar review done in 2010. The majority of programs are multifaceted and include industry engagement to reformulate products (n = 61), establishment of sodium content targets for foods (39), consumer education (71), front-of-pack labelling schemes (31), taxation on high-salt foods (3) and interventions in public institutions (54). Legislative action related to salt reduction such as mandatory targets, front of pack labelling, food procurement policies and taxation have been implemented in 33 countries. 12 countries have reported reductions in population salt intake, 19 reduced salt content in foods and 6 improvements in consumer knowledge, attitudes or behaviours relating to salt. The large and increasing number of countries with salt reduction strategies in place is encouraging although activity remains limited in low- and middle-income regions. The absence of a consistent approach to implementation highlights uncertainty about the elements most important to success. Rigorous evaluation of ongoing programs and initiation of salt reduction programs, particularly in low- and middle- income countries, will be vital to achieving the targeted 30% reduction in salt intake.

Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept.

PubMed

Peyrode, Caroline; Weber, Valérie; Voissière, Aurélien; Maisonial-Besset, Aurélie; Vidal, Aurélien; Auzeloux, Philippe; Gaumet, Vincent; Borel, Michèle; Dauplat, Marie-Mélanie; Quintana, Mercedes; Degoul, Françoise; Rédini, Françoise; Chezal, Jean-Michel; Miot-Noirault, Elisabeth

2016-11-01

To date, surgery remains the only option for the treatment of chondrosarcoma, which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognosis, improving the management of chondrosarcoma still remains a challenge. Our team developed an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan (PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by surface plasmon resonance. In the orthotopic model of Swarm rat chondrosarcoma, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabeled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [ 3 H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA-active targeting of chondrosarcoma. The antitumoral effects were characterized by tumor volume assessment, in vivo 99m Tc-NTP 15-5 scintigraphic imaging of PGs, 1 H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the tolerability of Mel leading to a significant decrease of side effects (hematologic analyses and body weight monitoring). Thus, QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with chondrosarcoma. Mol Cancer Ther; 15(11); 2575-85. ©2016 AACR. ©2016 American Association for Cancer Research.

Willingness to Remain Friends and Attend School with Lesbian and Gay Peers: Relational Expressions of Prejudice among Heterosexual Youth

ERIC Educational Resources Information Center

Poteat, V. Paul; Espelage, Dorothy L.; Koenig, Brian K.

2009-01-01

In this study, heterosexual students' willingness to remain friends with peers who disclose that they are gay or lesbian and their willingness to attend schools that include gay and lesbian students were examined among two large middle school and high school samples (Sample 1: n = 20,509; 50.7% girls; Sample 2: n = 16,917; 50.2% girls). Boys were…

MiRNA-101 inhibits oral squamous-cell carcinoma growth and metastasis by targeting zinc finger E-box binding homeobox 1

PubMed Central

Wu, Baolei; Lei, Delin; Wang, Lei; Yang, Xinjie; Jia, Sen; Yang, Zihui; Shan, Chun; Yang, Xi; Zhang, Chenping; Lu, Bin

2016-01-01

MicroRNAs (miRNAs) are implicated in the pathogenesis of oral squamous-cell carcinoma (OSCC). miR-101 is involved in the development and progression of OSCC, but the biological functions and underlying molecular mechanisms of this miRNA remain largely unknown. In this study, we showed that miR-101 was underexpressed in OSCC tissues and cell lines. miR-101 downregulation was inversely correlated with zinc finger E-box binding homeobox 1 (ZEB1) expression, lymph-node metastasis, and poor prognosis in OSCC patients. Enhanced expression of miR-101 significantly inhibited OSCC cell proliferation, apoptosis resistance, migration and invasion in vitro, and suppressed tumor growth and lung metastasis in vivo. Bioinformatics analyses showed that miR-101 directly targeted ZEB1, as confirmed by a dual-luciferase reporter assay. The inhibitory effects of miR-101 on OSCC growth and metastasis were attenuated and phenocopied by ZEB1 overexpression and knockdown, respectively. Overall, our findings indicated that miRNA-101 reduced OSCC growth and metastasis by targeting ZEB1 and provided new evidence of miR-101 as a potential therapeutic target for OSCC patients. PMID:27429852

Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics.

PubMed

Abubakar, Murtala B; Gan, Siew Hua

2016-01-01

The advent of advanced molecular targeted therapy has resulted in improved prognoses for patients with advanced malignancies. However, despite the significant success and specificity of this advocated targeted therapy, significant on- and off-target adverse effects and inter-individual variability in treatment responses have been reported. The interpatient variability in drug response has been suggested to be partly due to variations in patient genomes. Therefore, the identification of genetic biomarkers by conducting pharmacogenetics studies can help predict patient responses to targeted therapy and may serve as a basis for individualized treatment. In this review, both clinically established and potential molecular targets are highlighted. Overall, current literature suggests that individualization of targeted therapy is promising; however, integrating the clinical benefits of identified biomarkers into clinical practice for personalized medicine remains a major challenge, and further studies to validate these markers and identify novel therapeutic approaches are needed. © 2016 S. Karger AG, Basel.

Decadal climate prediction in the large ensemble limit

NASA Astrophysics Data System (ADS)

Yeager, S. G.; Rosenbloom, N. A.; Strand, G.; Lindsay, K. T.; Danabasoglu, G.; Karspeck, A. R.; Bates, S. C.; Meehl, G. A.

2017-12-01

In order to quantify the benefits of initialization for climate prediction on decadal timescales, two parallel sets of historical simulations are required: one "initialized" ensemble that incorporates observations of past climate states and one "uninitialized" ensemble whose internal climate variations evolve freely and without synchronicity. In the large ensemble limit, ensemble averaging isolates potentially predictable forced and internal variance components in the "initialized" set, but only the forced variance remains after averaging the "uninitialized" set. The ensemble size needed to achieve this variance decomposition, and to robustly distinguish initialized from uninitialized decadal predictions, remains poorly constrained. We examine a large ensemble (LE) of initialized decadal prediction (DP) experiments carried out using the Community Earth System Model (CESM). This 40-member CESM-DP-LE set of experiments represents the "initialized" complement to the CESM large ensemble of 20th century runs (CESM-LE) documented in Kay et al. (2015). Both simulation sets share the same model configuration, historical radiative forcings, and large ensemble sizes. The twin experiments afford an unprecedented opportunity to explore the sensitivity of DP skill assessment, and in particular the skill enhancement associated with initialization, to ensemble size. This talk will highlight the benefits of a large ensemble size for initialized predictions of seasonal climate over land in the Atlantic sector as well as predictions of shifts in the likelihood of climate extremes that have large societal impact.

Mill and the right to remain uninformed.

PubMed

Strasser, M

1986-08-01

In a recent article in the Journal of Medicine and Philosophy, David Ost (1984) claims that patients do not have a right to waive their right to information. He argues that patients cannot make informed rational decisions without full information and thus, a right to waive information would involve a right to avoid one's responsibility to act as an autonomous moral agent. In support of his position, Ost cites a passage from Mill. Yet, a correct interpretation of the passage in question would support one's right to remain uninformed in certain situations. If the information would hurt one's chances for survival or hurt one's ability to make calm, rational decisions, then one not only does not have a duty to find out the information, but one's exercising one's right to remain uninformed may be the only rational course of action to take.

In Situ Target Engagement Studies in Adherent Cells.

PubMed

Axelsson, Hanna; Almqvist, Helena; Otrocka, Magdalena; Vallin, Michaela; Lundqvist, Sara; Hansson, Pia; Karlsson, Ulla; Lundbäck, Thomas; Seashore-Ludlow, Brinton

2018-04-20

A prerequisite for successful drugs is effective binding of the desired target protein in the complex environment of a living system. Drug-target engagement has typically been difficult to monitor in physiologically relevant models, and with current methods, especially, while maintaining spatial information. One recent technique for quantifying drug-target engagement is the cellular thermal shift assay (CETSA), in which ligand-induced protein stabilization is measured after a heat challenge. Here, we describe a CETSA protocol in live A431 cells for p38α (MAPK14), where remaining soluble protein is detected in situ, using high-content imaging in 384-well, microtiter plates. We validate this assay concept using a number of known p38α inhibitors and further demonstrate the potential of this technology for chemical probe and drug discovery purposes by performing a small pilot screen for novel p38α binders. Importantly, this protocol creates a workflow that is amenable to adherent cells in their native state and yields spatially resolved target engagement information measurable at the single-cell level.

Effects of neonicotinoids and fipronil on non-target invertebrates.

PubMed

Pisa, L W; Amaral-Rogers, V; Belzunces, L P; Bonmatin, J M; Downs, C A; Goulson, D; Kreutzweiser, D P; Krupke, C; Liess, M; McField, M; Morrissey, C A; Noome, D A; Settele, J; Simon-Delso, N; Stark, J D; Van der Sluijs, J P; Van Dyck, H; Wiemers, M

2015-01-01

We assessed the state of knowledge regarding the effects of large-scale pollution with neonicotinoid insecticides and fipronil on non-target invertebrate species of terrestrial, freshwater and marine environments. A large section of the assessment is dedicated to the state of knowledge on sublethal effects on honeybees (Apis mellifera) because this important pollinator is the most studied non-target invertebrate species. Lepidoptera (butterflies and moths), Lumbricidae (earthworms), Apoidae sensu lato (bumblebees, solitary bees) and the section "other invertebrates" review available studies on the other terrestrial species. The sections on freshwater and marine species are rather short as little is known so far about the impact of neonicotinoid insecticides and fipronil on the diverse invertebrate fauna of these widely exposed habitats. For terrestrial and aquatic invertebrate species, the known effects of neonicotinoid pesticides and fipronil are described ranging from organismal toxicology and behavioural effects to population-level effects. For earthworms, freshwater and marine species, the relation of findings to regulatory risk assessment is described. Neonicotinoid insecticides exhibit very high toxicity to a wide range of invertebrates, particularly insects, and field-realistic exposure is likely to result in both lethal and a broad range of important sublethal impacts. There is a major knowledge gap regarding impacts on the grand majority of invertebrates, many of which perform essential roles enabling healthy ecosystem functioning. The data on the few non-target species on which field tests have been performed are limited by major flaws in the outdated test protocols. Despite large knowledge gaps and uncertainties, enough knowledge exists to conclude that existing levels of pollution with neonicotinoids and fipronil resulting from presently authorized uses frequently exceed the lowest observed adverse effect concentrations and are thus likely to have large

Forensic considerations when dealing with incinerated human dental remains.

PubMed

Reesu, Gowri Vijay; Augustine, Jeyaseelan; Urs, Aadithya B

2015-01-01

Establishing the human dental identification process relies upon sufficient post-mortem data being recovered to allow for a meaningful comparison with ante-mortem records of the deceased person. Teeth are the most indestructible components of the human body and are structurally unique in their composition. They possess the highest resistance to most environmental effects like fire, desiccation, decomposition and prolonged immersion. In most natural as well as man-made disasters, teeth may provide the only means of positive identification of an otherwise unrecognizable body. It is imperative that dental evidence should not be destroyed through erroneous handling until appropriate radiographs, photographs, or impressions can be fabricated. Proper methods of physical stabilization of incinerated human dental remains should be followed. The maintenance of integrity of extremely fragile structures is crucial to the successful confirmation of identity. In such situations, the forensic dentist must stabilise these teeth before the fragile remains are transported to the mortuary to ensure preservation of possibly vital identification evidence. Thus, while dealing with any incinerated dental remains, a systematic approach must be followed through each stage of evaluation of incinerated dental remains to prevent the loss of potential dental evidence. This paper presents a composite review of various studies on incinerated human dental remains and discusses their impact on the process of human identification and suggests a step by step approach. Copyright © 2014 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Active Targeted Drug Delivery for Microbes Using Nano-Carriers

PubMed Central

Lin, Yung-Sheng; Lee, Ming-Yuan; Yang, Chih-Hui; Huang, Keng-Shiang

2015-01-01

Although vaccines and antibiotics could kill or inhibit microbes, many infectious diseases remain difficult to treat because of acquired resistance and adverse side effects. Nano-carriers-based technology has made significant progress for a long time and is introducing a new paradigm in drug delivery. However, it still has some challenges like lack of specificity toward targeting the infectious site. Nano-carriers utilized targeting ligands on their surface called ‘active target’ provide the promising way to solve the problems like accelerating drug delivery to infectious areas and preventing toxicity or side-effects. In this mini review, we demonstrate the recent studies using the active targeted strategy to kill or inhibit microbes. The four common nano-carriers (e.g. liposomes, nanoparticles, dendrimers and carbon nanotubes) delivering encapsulated drugs are introduced. PMID:25877093

Preclinical PET imaging of EGFR levels: pairing a targeting with a non-targeting Sel-tagged Affibody-based tracer to estimate the specific uptake.

PubMed

Cheng, Qing; Wållberg, Helena; Grafström, Jonas; Lu, Li; Thorell, Jan-Olov; Hägg Olofsson, Maria; Linder, Stig; Johansson, Katarina; Tegnebratt, Tetyana; Arnér, Elias S J; Stone-Elander, Sharon; Ahlzén, Hanna-Stina Martinsson; Ståhl, Stefan

2016-12-01

Though overexpression of epidermal growth factor receptor (EGFR) in several forms of cancer is considered to be an important prognostic biomarker related to poor prognosis, clear correlations between biomarker assays and patient management have been difficult to establish. Here, we utilize a targeting directly followed by a non-targeting tracer-based positron emission tomography (PET) method to examine some of the aspects of determining specific EGFR binding in tumors. The EGFR-binding Affibody molecule ZEGFR:2377 and its size-matched non-binding control ZTaq:3638 were recombinantly fused with a C-terminal selenocysteine-containing Sel-tag (ZEGFR:2377-ST and ZTaq:3638-ST). The proteins were site-specifically labeled with DyLight488 for flow cytometry and ex vivo tissue analyses or with (11)C for in vivo PET studies. Kinetic scans with the (11)C-labeled proteins were performed in healthy mice and in mice bearing xenografts from human FaDu (squamous cell carcinoma) and A431 (epidermoid carcinoma) cell lines. Changes in tracer uptake in A431 xenografts over time were also monitored, followed by ex vivo proximity ligation assays (PLA) of EGFR expressions. Flow cytometry and ex vivo tissue analyses confirmed EGFR targeting by ZEGFR:2377-ST-DyLight488. [Methyl-(11)C]-labeled ZEGFR:2377-ST-CH3 and ZTaq:3638-ST-CH3 showed similar distributions in vivo, except for notably higher concentrations of the former in particularly the liver and the blood. [Methyl-(11)C]-ZEGFR:2377-ST-CH3 successfully visualized FaDu and A431 xenografts with moderate and high EGFR expression levels, respectively. However, in FaDu tumors, the non-specific uptake was large and sometimes equally large, illustrating the importance of proper controls. In the A431 group observed longitudinally, non-specific uptake remained at same level over the observation period. Specific uptake increased with tumor size, but changes varied widely over time in individual tumors. Total (membranous and cytoplasmic) EGFR

Anticipated classes of new medications and molecular targets for pulmonary arterial hypertension

PubMed Central

Morrell, Nicholas W.; Archer, Stephen L.; DeFelice, Albert; Evans, Steven; Fiszman, Monica; Martin, Thomas; Saulnier, Muriel; Rabinovitch, Marlene; Schermuly, Ralph; Stewart, Duncan; Truebel, Hubert; Walker, Gennyne; Stenmark, Kurt R.

2013-01-01

Pulmonary arterial hypertension (PAH) remains a life-limiting condition with a major impact on the ability to lead a normal life. Although existing therapies may improve the outlook in some patients there remains a major unmet need to develop more effective therapies in this condition. There have been significant advances in our understanding of the genetic, cell and molecular basis of PAH over the last few years. This research has identified important new targets that could be explored as potential therapies for PAH. In this review we discuss whether further exploitation of vasoactive agents could bring additional benefits over existing approaches. Approaches to enhance smooth muscle cell apotosis and the potential of receptor tyrosine kinase inhibition are summarised. We evaluate the role of inflammation, epigenetic changes and altered glycolytic metabolism as potential targets for therapy, and whether inherited genetic mutations in PAH have revealed druggable targets. The potential of cell based therapies and gene therapy are also discussed. Potential candidate pathways that could be explored in the context of experimental medicine are identified. PMID:23662201

A high density field reversed configuration (FRC) target for magnetized target fusion: First internal profile measurements of a high density FRC

NASA Astrophysics Data System (ADS)

Intrator, T.; Zhang, S. Y.; Degnan, J. H.; Furno, I.; Grabowski, C.; Hsu, S. C.; Ruden, E. L.; Sanchez, P. G.; Taccetti, J. M.; Tuszewski, M.; Waganaar, W. J.; Wurden, G. A.

2004-05-01

Magnetized target fusion (MTF) is a potentially low cost path to fusion, intermediate in plasma regime between magnetic and inertial fusion energy. It requires compression of a magnetized target plasma and consequent heating to fusion relevant conditions inside a converging flux conserver. To demonstrate the physics basis for MTF, a field reversed configuration (FRC) target plasma has been chosen that will ultimately be compressed within an imploding metal liner. The required FRC will need large density, and this regime is being explored by the FRX-L (FRC-Liner) experiment. All theta pinch formed FRCs have some shock heating during formation, but FRX-L depends further on large ohmic heating from magnetic flux annihilation to heat the high density (2-5×1022m-3), plasma to a temperature of Te+Ti≈500 eV. At the field null, anomalous resistivity is typically invoked to characterize the resistive like flux dissipation process. The first resistivity estimate for a high density collisional FRC is shown here. The flux dissipation process is both a key issue for MTF and an important underlying physics question.

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

PubMed Central

Nguyen, Tri-Hung; Lieu, Linh Thuy; Nguyen, Gary; Bischof, Robert J.; Meeusen, Els N.; Li, Jian; Nation, Roger L.

2016-01-01

ABSTRACT Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research. PMID:27821445

Effect of Patient Set-up and Respiration motion on Defining Biological Targets for Image-Guided Targeted Radiotherapy

NASA Astrophysics Data System (ADS)

McCall, Keisha C.