Variations in backward masking with different masking stimuli: II. The effects of spatially quantised masks in the light of local contour interaction, interchannel inhibition, perceptual retouch, and substitution theories.

PubMed

Bachmann, Talis; Luiga, Iiris; Põder, Endel

2005-01-01

In part I we showed that with spatially non-overlapping targets and masks both local metacontrast-like interactions and attentional processes are involved in backward masking. In this second part we extend the strategy of varying the contents of masks to pattern masking where targets and masks overlap in space, in order to compare different masking theories. Images of human faces were backward-masked by three types of spatially quantised masks (the same faces as targets, faces different from targets, and Gaussian noise with power spectra typical for faces). Configural characteristics, rather than the spectral content of the mask, predicted the extent of masking at relatively long stimulus onset asynchronies (SOAs). This poses difficulties for the theory of transient-on-sustained inhibition as the principal mechanism of masking and also for local contour interaction being a decisive factor in pattern masking. The scale of quantisation had no effect on the masking capacity of noise masks and a strong effect on the capacity of different-face masks. Also, the decrease of configural masking with an increase in the coarseness of the quantisation of the mask highlights ambiguities inherent in the re-entrance-based substitution theory of masking. Different masking theories cannot solve the problems of masking separately. They should be combined in order to create a complex, yet comprehensible mode of interaction for the different mechanisms involved in visual backward masking.

Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules.

PubMed

Okuhira, Keiichiro; Shoda, Takuji; Omura, Risa; Ohoka, Nobumichi; Hattori, Takayuki; Shibata, Norihito; Demizu, Yosuke; Sugihara, Ryo; Ichino, Asato; Kawahara, Haruka; Itoh, Yukihiro; Ishikawa, Minoru; Hashimoto, Yuichi; Kurihara, Masaaki; Itoh, Susumu; Saito, Hiroyuki; Naito, Mikihiko

2017-03-01

Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Switching between global and local levels: the level repetition effect and its hemispheric asymmetry

PubMed Central

Kéïta, Luc; Bedoin, Nathalie; Burack, Jacob A.; Lepore, Franco

2014-01-01

The global level of hierarchical stimuli (Navon’s stimuli) is typically processed quicker and better than the local level; further differential hemispheric dominance is described for local (left hemisphere, LH) and global (right hemisphere, RH) processing. However, neuroimaging and behavioral data indicate that stimulus category (letter or object) could modulate the hemispheric asymmetry for the local level processing. Besides, when the targets are unpredictably displayed at the global or local level, the participant has to switch between levels, and the magnitude of the switch cost increases with the number of repeated-level trials preceding the switch. The hemispheric asymmetries associated with level switching is an unresolved issue. LH areas may be involved in carrying over the target level information in case of level repetition. These areas may also largely participate in the processing of level-changed trials. Here we hypothesized that RH areas underly the inhibitory mechanism performed on the irrelevant level, as one of the components of the level switching process. In an experiment using a within-subject design, hierarchical stimuli were briefly presented either to the right or to the left visual field. 32 adults were instructed to identify the target at the global or local level. We assessed a possible RH dominance for the non-target level inhibition by varying the attentional demands through the manipulation of level repetitions (two or gour repeated-level trials before the switch). The behavioral data confirmed a LH specialization only for the local level processing of letter-based stimuli, and detrimental effect of increased level repetitions before a switch. Further, data provides evidence for a RH advantage in inhibiting the non-target level. Taken together, the data supports the notion of the existence of multiple mechanisms underlying level-switch effects. PMID:24723903

Inter-operative trajectory registration for endoluminal video synchronization: application to biopsy site re-localization.

PubMed

Vemuri, Anant Suraj; Nicolau, Stephane A; Ayache, Nicholas; Marescaux, Jacques; Soler, Luc

2013-01-01

The screening of oesophageal adenocarcinoma involves obtaining biopsies at different regions along the oesophagus. The localization and tracking of these biopsy sites inter-operatively poses a significant challenge for providing targeted treatments. This paper presents a novel framework for providing a guided navigation to the gastro-intestinal specialist for accurate re-positioning of the endoscope at previously targeted sites. Firstly, we explain our approach for the application of electromagnetic tracking in acheiving this objective. Then, we show on three in-vivo porcine interventions that our system can provide accurate guidance information, which was qualitatively evaluated by five experts.

The effect of brain lesions on sound localization in complex acoustic environments.

PubMed

Zündorf, Ida C; Karnath, Hans-Otto; Lewald, Jörg

2014-05-01

Localizing sound sources of interest in cluttered acoustic environments--as in the 'cocktail-party' situation--is one of the most demanding challenges to the human auditory system in everyday life. In this study, stroke patients' ability to localize acoustic targets in a single-source and in a multi-source setup in the free sound field were directly compared. Subsequent voxel-based lesion-behaviour mapping analyses were computed to uncover the brain areas associated with a deficit in localization in the presence of multiple distracter sound sources rather than localization of individually presented sound sources. Analyses revealed a fundamental role of the right planum temporale in this task. The results from the left hemisphere were less straightforward, but suggested an involvement of inferior frontal and pre- and postcentral areas. These areas appear to be particularly involved in the spectrotemporal analyses crucial for effective segregation of multiple sound streams from various locations, beyond the currently known network for localization of isolated sound sources in otherwise silent surroundings.

Texaphyrins: Tumor Localizing Redox Active Expanded Porphyrins

PubMed Central

Arambula, Jonathan F.; Preihs, Christian; Borthwick, Derric; Magda, Darren; Sessler, Jonathan L.

2011-01-01

Texaphyrins, a class of tumor selective expanded porphyrins capable of coordinating large metals, have been found to act as redox mediators within biological systems. This review summarizes studies involving their experimentaluse in cancer chemotherapy. Mechanistic insights involving their presumed mode of action are also described, as well as certain structure activity relationships. Finally, newer texaphyrin-based applications associated with targeted drug delivery are presented. PMID:21355841

Subcellular Localization of a Plant Catalase-Phenol Oxidase, AcCATPO, from Amaranthus and Identification of a Non-canonical Peroxisome Targeting Signal

PubMed Central

Chen, Ning; Teng, Xiao-Lu; Xiao, Xing-Guo

2017-01-01

AcCATPO is a plant catalase-phenol oxidase recently identified from red amaranth. Its physiological function remains unexplored. As the starting step of functional analysis, here we report its subcellular localization and a non-canonical targeting signal. Commonly used bioinformatics programs predicted a peroxisomal localization for AcCATPO, but failed in identification of canonical peroxisomal targeting signals (PTS). The C-terminal GFP tagging led the fusion protein AcCATPO-GFP to the cytosol and the nucleus, but N-terminal tagging directed the GFP-AcCATPO to peroxisomes and nuclei, in transgenic tobacco. Deleting the tripeptide (PTM) at the extreme C-terminus almost ruled out the peroxisomal localization of GFP-AcCATPOΔ3, and removing the C-terminal decapeptide completely excluded peroxisomes as the residence of GFP-AcCATPOΔ10. Furthermore, this decapeptide as a targeting signal could import GFP-10aa to the peroxisome exclusively. Taken together, these results demonstrate that AcCATPO is localized to the peroxisome and the nucleus, and its peroxisomal localization is attributed to a non-canonical PTS1, the C-terminal decapeptide which contains an internal SRL motif and a conserved tripeptide P-S/T-I/M at the extreme of C-terminus. This work may further the study as to the physiological function of AcCATPO, especially clarify its involvement in betalain biosynthesis, and provide a clue to elucidate more non-canonic PTS. PMID:28824680

Subcellular Localization of a Plant Catalase-Phenol Oxidase, AcCATPO, from Amaranthus and Identification of a Non-canonical Peroxisome Targeting Signal.

PubMed

Chen, Ning; Teng, Xiao-Lu; Xiao, Xing-Guo

2017-01-01

AcCATPO is a plant catalase-phenol oxidase recently identified from red amaranth. Its physiological function remains unexplored. As the starting step of functional analysis, here we report its subcellular localization and a non-canonical targeting signal. Commonly used bioinformatics programs predicted a peroxisomal localization for AcCATPO, but failed in identification of canonical peroxisomal targeting signals (PTS). The C-terminal GFP tagging led the fusion protein AcCATPO-GFP to the cytosol and the nucleus, but N-terminal tagging directed the GFP-AcCATPO to peroxisomes and nuclei, in transgenic tobacco. Deleting the tripeptide (PTM) at the extreme C-terminus almost ruled out the peroxisomal localization of GFP-AcCATPOΔ3, and removing the C-terminal decapeptide completely excluded peroxisomes as the residence of GFP-AcCATPOΔ10. Furthermore, this decapeptide as a targeting signal could import GFP-10aa to the peroxisome exclusively. Taken together, these results demonstrate that AcCATPO is localized to the peroxisome and the nucleus, and its peroxisomal localization is attributed to a non-canonical PTS1, the C-terminal decapeptide which contains an internal SRL motif and a conserved tripeptide P-S/T-I/M at the extreme of C-terminus. This work may further the study as to the physiological function of AcCATPO, especially clarify its involvement in betalain biosynthesis, and provide a clue to elucidate more non-canonic PTS.

Laser ablation of Drosophila embryonic motoneurons causes ectopic innervation of target muscle fibers

NASA Technical Reports Server (NTRS)

Chang, T. N.; Keshishian, H.

1996-01-01

We have tested the effects of neuromuscular denervation in Drosophila by laser-ablating the RP motoneurons in intact embryos before synaptogenesis. We examined the consequences of this ablation on local synaptic connectivity in both 1st and 3rd instar larvae. We find that the partial or complete loss of native innervation correlates with the appearance of alternate inputs from neighboring motor endings and axons. These collateral inputs are found at ectopic sites on the denervated target muscle fibers. The foreign motor endings are electrophysiologically functional and are observed on the denervated muscle fibers by the 1st instar larval stage. Our data are consistent with the existence of a local signal from the target environment, which is regulated by innervation and influences synaptic connectivity. Our results show that, despite the stereotypy of Drosophila neuromuscular connections, denervation can induce local changes in connectivity in wild-type Drosophila, suggesting that mechanisms of synaptic plasticity may also be involved in normal Drosophila neuromuscular development.

RRP1B Targets PP1 to Mammalian Cell Nucleoli and Is Associated with Pre-60S Ribosomal Subunits

PubMed Central

Chamousset, Delphine; De Wever, Veerle; Moorhead, Greg B.; Chen, Yan; Boisvert, Francois-Michel; Lamond, Angus I.

2010-01-01

A pool of protein phosphatase 1 (PP1) accumulates within nucleoli and accounts for a large fraction of the serine/threonine protein phosphatase activity in this subnuclear structure. Using a combination of fluorescence imaging with quantitative proteomics, we mapped the subnuclear localization of the three mammalian PP1 isoforms stably expressed as GFP-fusions in live cells and identified RRP1B as a novel nucleolar targeting subunit that shows a specificity for PP1β and PP1γ. RRP1B, one of two mammalian orthologues of the yeast Rrp1p protein, shows an RNAse-dependent localization to the granular component of the nucleolus and distributes in a similar manner throughout the cell cycle to proteins involved in later steps of rRNA processing. Quantitative proteomic analysis of complexes containing both RRP1B and PP1γ revealed enrichment of an overlapping subset of large (60S) ribosomal subunit proteins and pre-60S nonribosomal proteins involved in mid-late processing. Targeting of PP1 to this complex by RRP1B in mammalian cells is likely to contribute to modulation of ribosome biogenesis by mechanisms involving reversible phosphorylation events, thus playing a role in the rapid transduction of cellular signals that call for regulation of ribosome production in response to cellular stress and/or changes in growth conditions. PMID:20926688

Mitochondrial targeting of the human peptide methionine sulfoxide reductase (MSRA), an enzyme involved in the repair of oxidized proteins.

PubMed

Hansel, Alfred; Kuschel, Lioba; Hehl, Solveig; Lemke, Cornelius; Agricola, Hans-Jürgen; Hoshi, Toshinori; Heinemann, Stefan H

2002-06-01

Peptide methionine sulfoxide reductase (MSRA) catalyzes the reduction of methionine sulfoxide to methionine. This widely expressed enzyme constitutes an important repair mechanism for oxidatively damaged proteins, which accumulate during the manifestation of certain degenerative diseases and aging processes. In addition, it is discussed to be involved in regulatory processes. Here we address the question of how the enzyme's diverse functions are reflected in its subcellular localization. Using fusions of the human version of MSRA with the enhanced green fluorescence protein expressed in various mammalian cell lines, we show a distinct localization at mitochondria. The N-terminal 23 amino acid residues contain the signal for this mitochondrial targeting. Activity tests showed that they are not required for enzyme function. Mitochondrial localization of native MSRA in mouse and rat liver slices was verified with an MSRA-specific antibody by using immunohistochemical methods. The protein was located in the mitochondrial matrix, as demonstrated by using pre-embedding immunostaining and electron microscopy. Mitochondria are the major source of reactive oxygen species (ROS). Therefore, MSRA has to be considered an important means for the general reduction of ROS release from mitochondria.

GBNV encoded movement protein (NSm) remodels ER network via C-terminal coiled coil domain

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

Singh, Pratibha; Savithri, H.S., E-mail: bchss@biochem.iisc.ernet.in

Plant viruses exploit the host machinery for targeting the viral genome–movement protein complex to plasmodesmata (PD). The mechanism by which the non-structural protein m (NSm) of Groundnut bud necrosis virus (GBNV) is targeted to PD was investigated using Agrobacterium mediated transient expression of NSm and its fusion proteins in Nicotiana benthamiana. GFP:NSm formed punctuate structures that colocalized with mCherry:plasmodesmata localized protein 1a (PDLP 1a) confirming that GBNV NSm localizes to PD. Unlike in other movement proteins, the C-terminal coiled coil domain of GBNV NSm was shown to be involved in the localization of NSm to PD, as deletion of thismore » domain resulted in the cytoplasmic localization of NSm. Treatment with Brefeldin A demonstrated the role of ER in targeting GFP NSm to PD. Furthermore, mCherry:NSm co-localized with ER–GFP (endoplasmic reticulum targeting peptide (HDEL peptide fused with GFP). Co-expression of NSm with ER–GFP showed that the ER-network was transformed into vesicles indicating that NSm interacts with ER and remodels it. Mutations in the conserved hydrophobic region of NSm (residues 130–138) did not abolish the formation of vesicles. Additionally, the conserved prolines at positions 140 and 142 were found to be essential for targeting the vesicles to the cell membrane. Further, systematic deletion of amino acid residues from N- and C-terminus demonstrated that N-terminal 203 amino acids are dispensable for the vesicle formation. On the other hand, the C-terminal coiled coil domain when expressed alone could also form vesicles. These results suggest that GBNV NSm remodels the ER network by forming vesicles via its interaction through the C-terminal coiled coil domain. Interestingly, NSm interacts with NP in vitro and coexpression of these two proteins in planta resulted in the relocalization of NP to PD and this relocalization was abolished when the N-terminal unfolded region of NSm was deleted. Thus, the NSm interacts with NP via its N-terminal unfolded region and the NSm–NP complex could in turn interact with the ER membrane via the C-terminal coiled coil domain of NSm to form vesicles that are targeted to PD and there by assist the cell to cell movement of the viral genome complex. - Highlights: • GBNV NSm localizes to plasmodesmata via the C-terminal coiled coil domain. • GBNV NSm interacts with endoplasmic reticulum network and remodels it to vesicles. • The C-terminal coiled domain alone is responsible for vesicle formation. • The N-terminal unfolded region of NSm is involved in the re-localization of NP to PD.« less

Arginyltransferase ATE1 is targeted to the neuronal growth cones and regulates neurite outgrowth during brain development.

PubMed

Wang, Junling; Pavlyk, Iuliia; Vedula, Pavan; Sterling, Stephanie; Leu, N Adrian; Dong, Dawei W; Kashina, Anna

2017-10-01

Arginylation is an emerging protein modification mediated by arginyltransferase ATE1, shown to regulate embryogenesis and actin cytoskeleton, however its functions in different physiological systems are not well understood. Here we analyzed the role of ATE1 in brain development and neuronal growth by producing a conditional mouse knockout with Ate1 deletion in the nervous system driven by Nestin promoter (Nes-Ate1 mice). These mice were weaker than wild type, resulting in low postnatal survival rates, and had abnormalities in the brain that suggested defects in neuronal migration. Cultured Ate1 knockout neurons showed a reduction in the neurite outgrowth and the levels of doublecortin and F-actin in the growth cones. In wild type, ATE1 prominently localized to the growth cones, in addition to the cell bodies. Examination of the Ate1 mRNA sequence reveals the existence of putative zipcode-binding sequences involved in mRNA targeting to the cell periphery and local translation at the growth cones. Fluorescence in situ hybridization showed that Ate1 mRNA localized to the tips of the growth cones, likely due to zipcode-mediated targeting, and this localization coincided with spots of localization of arginylated β-actin, which disappeared in the presence of protein synthesis inhibitors. We propose that zipcode-mediated co-targeting of Ate1 and β-actin mRNA leads to localized co-translational arginylation of β-actin that drives the growth cone migration and neurite outgrowth. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Local Stakeholder Perception on Community Participation in Marine Protected Area Management: A Q-Method Approach

NASA Astrophysics Data System (ADS)

Megat Jamual Fawaeed, P. S.; Daim, M. S.

2018-02-01

Local stakeholder involvement in Marine Protected Area (MPA) management can bring to a successful MPA. Generally, participatory research in marine protected area management is exploring the relationship between marine protected area management approach adopted by the management agencies and the level of participation of local stakeholder whom reside within the marine protected areas. However, the scenario of local community participation in MPA management in Malaysia seems discouraging and does not align with the International Aichi Biodiversity Target 2020. In order to achieve the International Aichi Biodiversity Target 2020, this paper attempts to explore the methodology on participatory research towards the local stakeholder of Pulau Perhentian Marine Park (PPMP), Terengganu, Malaysia. A Q-methodology is used to investigate the perspective of local stakeholder who represents different stances on the issues, by having participants rank and sort a series of statements by comply quantitative and qualitative method in collecting the data. A structured questionnaire will be employed across this study by means of face-to-face interview. In total, 210 respondents from Kampung Pasir Hantu are randomly selected. Meanwhile, a workshop with the agency (Department of Marine Park) had been held to discuss about the issues faces on behalf of management that manage the PPMP. Using the Q-method, researcher acknowledged wise viewpoints, reflecting how different stakeholders’ perception and opinion about community participation with highlights the current level of community participation in MPA. Thus, this paper describes the phases involved in this study, methodology and analysis used in making a conclusion .

Evaluation of Prevention Programs: A Basic Guide for Practitioners.

ERIC Educational Resources Information Center

Moberg, D. Paul

This guide is intended for professionals, laypersons, funding agents and others involved in planning and delivering local prevention services. Chapter 1 defines prevention, and differentiates between prevention strategies and programs targeted toward individuals or to general populations. Program evaluation and evaluation research are defined and…

Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets.

PubMed

Peretti, Marta; Angelini, Marina; Savalli, Nicoletta; Florio, Tullio; Yuspa, Stuart H; Mazzanti, Michele

2015-10-01

In recent decades, growing scientific evidence supports the role of ion channels in the development of different cancers. Both potassium selective pores and chloride permeabilities are considered the most active channels during tumorigenesis. High rate of proliferation, active migration, and invasiveness into non-neoplastic tissues are specific properties of neoplastic transformation. All these actions require partial or total involvement of chloride channel activity. In this context, this class of membrane proteins could represent valuable therapeutic targets for the treatment of resistant tumors. However, this encouraging premise has not so far produced any valid new channel-targeted antitumoral molecule for cancer treatment. Problematic for drug design targeting ion channels is their vital role in normal cells for essential physiological functions. By targeting these membrane proteins involved in pathological conditions, it is inevitable to cause relevant side effects in healthy organs. In light of this, a new protein family, the chloride intracellular channels (CLICs), could be a promising class of therapeutic targets for its intrinsic individualities: CLIC1 and CLIC4, in particular, not only are overexpressed in specific tumor types or their corresponding stroma but also change localization and function from hydrophilic cytosolic to integral transmembrane proteins as active ionic channels or signal transducers during cell cycle progression in certain cases. These changes in intracellular localization, tissue compartments, and channel function, uniquely associated with malignant transformation, may offer a unique target for cancer therapy, likely able to spare normal cells. This article is part of a special issue itled "Membrane Channels and Transporters in Cancers." Copyright © 2015 Elsevier B.V. All rights reserved.

The SNARE Protein Syntaxin 3 Confers Specificity for Polarized Axonal Trafficking in Neurons

PubMed Central

Soo Hoo, Linda; Banna, Chris D.; Radeke, Carolyn M.; Sharma, Nikunj; Albertolle, Mary E.; Low, Seng Hui; Weimbs, Thomas; Vandenberg, Carol A.

2016-01-01

Cell polarity and precise subcellular protein localization are pivotal to neuronal function. The SNARE machinery underlies intracellular membrane fusion events, but its role in neuronal polarity and selective protein targeting remain unclear. Here we report that syntaxin 3 is involved in orchestrating polarized trafficking in cultured rat hippocampal neurons. We show that syntaxin 3 localizes to the axonal plasma membrane, particularly to axonal tips, whereas syntaxin 4 localizes to the somatodendritic plasma membrane. Disruption of a conserved N-terminal targeting motif, which causes mislocalization of syntaxin 3, results in coincident mistargeting of the axonal cargos neuron-glia cell adhesion molecule (NgCAM) and neurexin, but not transferrin receptor, a somatodendritic cargo. Similarly, RNAi-mediated knockdown of endogenous syntaxin 3 leads to partial mistargeting of NgCAM, demonstrating that syntaxin 3 plays an important role in its targeting. Additionally, overexpression of syntaxin 3 results in increased axonal growth. Our findings suggest an important role for syntaxin 3 in maintaining neuronal polarity and in the critical task of selective trafficking of membrane protein to axons. PMID:27662481

The SNARE Protein Syntaxin 3 Confers Specificity for Polarized Axonal Trafficking in Neurons.

PubMed

Soo Hoo, Linda; Banna, Chris D; Radeke, Carolyn M; Sharma, Nikunj; Albertolle, Mary E; Low, Seng Hui; Weimbs, Thomas; Vandenberg, Carol A

Cell polarity and precise subcellular protein localization are pivotal to neuronal function. The SNARE machinery underlies intracellular membrane fusion events, but its role in neuronal polarity and selective protein targeting remain unclear. Here we report that syntaxin 3 is involved in orchestrating polarized trafficking in cultured rat hippocampal neurons. We show that syntaxin 3 localizes to the axonal plasma membrane, particularly to axonal tips, whereas syntaxin 4 localizes to the somatodendritic plasma membrane. Disruption of a conserved N-terminal targeting motif, which causes mislocalization of syntaxin 3, results in coincident mistargeting of the axonal cargos neuron-glia cell adhesion molecule (NgCAM) and neurexin, but not transferrin receptor, a somatodendritic cargo. Similarly, RNAi-mediated knockdown of endogenous syntaxin 3 leads to partial mistargeting of NgCAM, demonstrating that syntaxin 3 plays an important role in its targeting. Additionally, overexpression of syntaxin 3 results in increased axonal growth. Our findings suggest an important role for syntaxin 3 in maintaining neuronal polarity and in the critical task of selective trafficking of membrane protein to axons.

Modern Radiation Therapy for Nodal Non-Hodgkin Lymphoma—Target Definition and Dose Guidelines From the International Lymphoma Radiation Oncology Group

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

Illidge, Tim, E-mail: Tim.Illidge@ics.manchester.ac.uk; Specht, Lena; Yahalom, Joachim

2014-05-01

Radiation therapy (RT) is the most effective single modality for local control of non-Hodgkin lymphoma (NHL) and is an important component of therapy for many patients. Many of the historic concepts of dose and volume have recently been challenged by the advent of modern imaging and RT planning tools. The International Lymphoma Radiation Oncology Group (ILROG) has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the ILROG steering committee on the use of RT in NHL in the modern era. The roles of reduced volume and reduced doses aremore » addressed, integrating modern imaging with 3-dimensional planning and advanced techniques of RT delivery. In the modern era, in which combined-modality treatment with systemic therapy is appropriate, the previously applied extended-field and involved-field RT techniques that targeted nodal regions have now been replaced by limiting the RT to smaller volumes based solely on detectable nodal involvement at presentation. A new concept, involved-site RT, defines the clinical target volume. For indolent NHL, often treated with RT alone, larger fields should be considered. Newer treatment techniques, including intensity modulated RT, breath holding, image guided RT, and 4-dimensional imaging, should be implemented, and their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control.« less

Task modulates functional connectivity networks in free viewing behavior.

PubMed

Seidkhani, Hossein; Nikolaev, Andrey R; Meghanathan, Radha Nila; Pezeshk, Hamid; Masoudi-Nejad, Ali; van Leeuwen, Cees

2017-10-01

In free visual exploration, eye-movement is immediately followed by dynamic reconfiguration of brain functional connectivity. We studied the task-dependency of this process in a combined visual search-change detection experiment. Participants viewed two (nearly) same displays in succession. First time they had to find and remember multiple targets among distractors, so the ongoing task involved memory encoding. Second time they had to determine if a target had changed in orientation, so the ongoing task involved memory retrieval. From multichannel EEG recorded during 200 ms intervals time-locked to fixation onsets, we estimated the functional connectivity using a weighted phase lag index at the frequencies of theta, alpha, and beta bands, and derived global and local measures of the functional connectivity graphs. We found differences between both memory task conditions for several network measures, such as mean path length, radius, diameter, closeness and eccentricity, mainly in the alpha band. Both the local and the global measures indicated that encoding involved a more segregated mode of operation than retrieval. These differences arose immediately after fixation onset and persisted for the entire duration of the lambda complex, an evoked potential commonly associated with early visual perception. We concluded that encoding and retrieval differentially shape network configurations involved in early visual perception, affecting the way the visual input is processed at each fixation. These findings demonstrate that task requirements dynamically control the functional connectivity networks involved in early visual perception. Copyright © 2017 Elsevier Inc. All rights reserved.

Membrane Curvature Sensing by Amphipathic Helices Is Modulated by the Surrounding Protein Backbone.

PubMed

Doucet, Christine M; Esmery, Nina; de Saint-Jean, Maud; Antonny, Bruno

2015-01-01

Membrane curvature is involved in numerous biological pathways like vesicle trafficking, endocytosis or nuclear pore complex assembly. In addition to its topological role, membrane curvature is sensed by specific proteins, enabling the coordination of biological processes in space and time. Amongst membrane curvature sensors are the ALPS (Amphipathic Lipid Packing Sensors). ALPS motifs are short peptides with peculiar amphipathic properties. They are found in proteins targeted to distinct curved membranes, mostly in the early secretory pathway. For instance, the ALPS motif of the golgin GMAP210 binds trafficking vesicles, while the ALPS motif of Nup133 targets nuclear pores. It is not clear if, besides curvature sensitivity, ALPS motifs also provide target specificity, or if other domains in the surrounding protein backbone are involved. To elucidate this aspect, we studied the subcellular localization of ALPS motifs outside their natural protein context. The ALPS motifs of GMAP210 or Nup133 were grafted on artificial fluorescent probes. Importantly, ALPS motifs are held in different positions and these contrasting architectures were mimicked by the fluorescent probes. The resulting chimeras recapitulated the original proteins localization, indicating that ALPS motifs are sufficient to specifically localize proteins. Modulating the electrostatic or hydrophobic content of Nup133 ALPS motif modified its avidity for cellular membranes but did not change its organelle targeting properties. In contrast, the structure of the backbone surrounding the helix strongly influenced targeting. In particular, introducing an artificial coiled-coil between ALPS and the fluorescent protein increased membrane curvature sensitivity. This coiled-coil domain also provided membrane curvature sensitivity to the amphipathic helix of Sar1. The degree of curvature sensitivity within the coiled-coil context remains correlated to the natural curvature sensitivity of the helices. This suggests that the chemistry of ALPS motifs is a key parameter for membrane curvature sensitivity, which can be further modulated by the surrounding protein backbone.

Local re-acceleration and a modified thick target model of solar flare electrons

NASA Astrophysics Data System (ADS)

Brown, J. C.; Turkmani, R.; Kontar, E. P.; MacKinnon, A. L.; Vlahos, L.

2009-12-01

Context: The collisional thick target model (CTTM) of solar hard X-ray (HXR) bursts has become an almost “standard model” of flare impulsive phase energy transport and radiation. However, it faces various problems in the light of recent data, particularly the high electron beam density and anisotropy it involves. Aims: We consider how photon yield per electron can be increased, and hence fast electron beam intensity requirements reduced, by local re-acceleration of fast electrons throughout the HXR source itself, after injection. Methods: We show parametrically that, if net re-acceleration rates due to e.g. waves or local current sheet electric (E) fields are a significant fraction of collisional loss rates, electron lifetimes, and hence the net radiative HXR output per electron can be substantially increased over the CTTM values. In this local re-acceleration thick target model (LRTTM) fast electron number requirements and anisotropy are thus reduced. One specific possible scenario involving such re-acceleration is discussed, viz, a current sheet cascade (CSC) in a randomly stressed magnetic loop. Results: Combined MHD and test particle simulations show that local E fields in CSCs can efficiently accelerate electrons in the corona and and re-accelerate them after injection into the chromosphere. In this HXR source scenario, rapid synchronisation and variability of impulsive footpoint emissions can still occur since primary electron acceleration is in the high Alfvén speed corona with fast re-acceleration in chromospheric CSCs. It is also consistent with the energy-dependent time-of-flight delays in HXR features. Conclusions: Including electron re-acceleration in the HXR source allows an LRTTM modification of the CTTM in which beam density and anisotropy are much reduced, and alleviates theoretical problems with the CTTM, while making it more compatible with radio and interplanetary electron numbers. The LRTTM is, however, different in some respects such as spatial distribution of atmospheric heating by fast electrons.

Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group (ILROG)

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

Specht, Lena, E-mail: lena.specht@regionh.dk; Yahalom, Joachim; Illidge, Tim

2014-07-15

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solelymore » on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines.« less

Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG).

PubMed

Specht, Lena; Yahalom, Joachim; Illidge, Tim; Berthelsen, Anne Kiil; Constine, Louis S; Eich, Hans Theodor; Girinsky, Theodore; Hoppe, Richard T; Mauch, Peter; Mikhaeel, N George; Ng, Andrea

2014-07-15

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines. Copyright © 2014 Elsevier Inc. All rights reserved.

HAM-5 functions as a MAP kinase scaffold during cell fusion in Neurospora crassa

DOE PAGES

Jonkers, Wilfried; Leeder, Abigail C.; Ansong, Charles; ...

2014-11-20

Cell fusion in genetically identical Neurospora crassa germlings and in hyphae is a highly regulated process involving the activation of a conserved MAP kinase cascade that includes NRC1, MEK2 and MAK2. During chemotrophic growth in germlings, the MAP kinase cascade members localize to conidial anastomosis tube (CAT) tips every 4 minutes, perfectly out of phase with another protein that is recruited to the tip: SOFT, a protein of unknown biochemical function. How this oscillation process is initiated, maintained and what proteins regulate the MAP kinase cascade is currently unclear. A global phosphoproteomics approach using an allele of mak-2 (mak-2Q100G) thatmore » can be specifically inhibited by the ATP analog 1NM-PP1 was utilized to identify MAK2 kinase targets in germlings that were potentially involved in this process. One such putative target was HAM5, a protein of unknown biochemical function. Previously, Δham-5 mutants were shown to be deficient for hyphal fusion. Here we show that HAM5-GFP co-localized with NRC1, MEK2 and MAK2 and oscillated with identical dynamics from the cytoplasm to CAT tips during chemotropic interactions. In the Δmak-2 strain, HAM5-GFP localized to punctate complexes that did not oscillate, but still localized to the germling tip, suggesting that MAK2 activity influences HAM5 function/localization. However, MAK2-GFP showed only cytoplasmic and nuclear localization in a Δham-5 strain and did not localize to puncta, as observed in wild type germlings. Via co-immunoprecipitation experiments, HAM5 was shown to physically interact with MAK2, MEK2 and NRC1, suggesting that it functions as a scaffold/transport hub for the MAP kinase cascade members during oscillation and chemotropic interactions during both germling and hyphal fusion in N. crassa. The identification of HAM5 as a scaffold-like protein will help to link the activation of MAK2 to upstream factors and other proteins involved in this intriguing process of fungal communication.« less

HAM-5 Functions As a MAP Kinase Scaffold during Cell Fusion in Neurospora crassa

PubMed Central

Jonkers, Wilfried; Leeder, Abigail C.; Ansong, Charles; Wang, Yuexi; Yang, Feng; Starr, Trevor L.; Camp, David G.; Smith, Richard D.; Glass, N. Louise

2014-01-01

Cell fusion in genetically identical Neurospora crassa germlings and in hyphae is a highly regulated process involving the activation of a conserved MAP kinase cascade that includes NRC-1, MEK-2 and MAK-2. During chemotrophic growth in germlings, the MAP kinase cascade members localize to conidial anastomosis tube (CAT) tips every ∼8 minutes, perfectly out of phase with another protein that is recruited to the tip: SOFT, a recently identified scaffold for the MAK-1 MAP kinase pathway in Sordaria macrospora. How the MAK-2 oscillation process is initiated, maintained and what proteins regulate the MAP kinase cascade is currently unclear. A global phosphoproteomics approach using an allele of mak-2 (mak-2Q100G) that can be specifically inhibited by the ATP analog 1NM-PP1 was utilized to identify MAK-2 kinase targets in germlings that were potentially involved in this process. One such putative target was HAM-5, a protein of unknown biochemical function. Previously, Δham-5 mutants were shown to be deficient for hyphal fusion. Here we show that HAM-5-GFP co-localized with NRC-1, MEK-2 and MAK-2 and oscillated with identical dynamics from the cytoplasm to CAT tips during chemotropic interactions. In the Δmak-2 strain, HAM-5-GFP localized to punctate complexes that did not oscillate, but still localized to the germling tip, suggesting that MAK-2 activity influences HAM-5 function/localization. However, MAK-2-GFP showed cytoplasmic and nuclear localization in a Δham-5 strain and did not localize to puncta. Via co-immunoprecipitation experiments, HAM-5 was shown to physically interact with NRC-1, MEK-2 and MAK-2, suggesting that it functions as a scaffold/transport hub for the MAP kinase cascade members for oscillation and chemotropic interactions during germling and hyphal fusion in N. crassa. The identification of HAM-5 as a scaffold-like protein will help to link the activation of MAK-2 cascade to upstream factors and proteins involved in this intriguing process of fungal communication. PMID:25412208

HAM-5 functions as a MAP kinase scaffold during cell fusion in Neurospora crassa

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

Jonkers, Wilfried; Leeder, Abigail C.; Ansong, Charles

Cell fusion in genetically identical Neurospora crassa germlings and in hyphae is a highly regulated process involving the activation of a conserved MAP kinase cascade that includes NRC1, MEK2 and MAK2. During chemotrophic growth in germlings, the MAP kinase cascade members localize to conidial anastomosis tube (CAT) tips every 4 minutes, perfectly out of phase with another protein that is recruited to the tip: SOFT, a protein of unknown biochemical function. How this oscillation process is initiated, maintained and what proteins regulate the MAP kinase cascade is currently unclear. A global phosphoproteomics approach using an allele of mak-2 (mak-2Q100G) thatmore » can be specifically inhibited by the ATP analog 1NM-PP1 was utilized to identify MAK2 kinase targets in germlings that were potentially involved in this process. One such putative target was HAM5, a protein of unknown biochemical function. Previously, Δham-5 mutants were shown to be deficient for hyphal fusion. Here we show that HAM5-GFP co-localized with NRC1, MEK2 and MAK2 and oscillated with identical dynamics from the cytoplasm to CAT tips during chemotropic interactions. In the Δmak-2 strain, HAM5-GFP localized to punctate complexes that did not oscillate, but still localized to the germling tip, suggesting that MAK2 activity influences HAM5 function/localization. However, MAK2-GFP showed only cytoplasmic and nuclear localization in a Δham-5 strain and did not localize to puncta, as observed in wild type germlings. Via co-immunoprecipitation experiments, HAM5 was shown to physically interact with MAK2, MEK2 and NRC1, suggesting that it functions as a scaffold/transport hub for the MAP kinase cascade members during oscillation and chemotropic interactions during both germling and hyphal fusion in N. crassa. The identification of HAM5 as a scaffold-like protein will help to link the activation of MAK2 to upstream factors and other proteins involved in this intriguing process of fungal communication.« less

Brain correlates of the orientation of auditory spatial attention onto speaker location in a "cocktail-party" situation.

PubMed

Lewald, Jörg; Hanenberg, Christina; Getzmann, Stephan

2016-10-01

Successful speech perception in complex auditory scenes with multiple competing speakers requires spatial segregation of auditory streams into perceptually distinct and coherent auditory objects and focusing of attention toward the speaker of interest. Here, we focused on the neural basis of this remarkable capacity of the human auditory system and investigated the spatiotemporal sequence of neural activity within the cortical network engaged in solving the "cocktail-party" problem. Twenty-eight subjects localized a target word in the presence of three competing sound sources. The analysis of the ERPs revealed an anterior contralateral subcomponent of the N2 (N2ac), computed as the difference waveform for targets to the left minus targets to the right. The N2ac peaked at about 500 ms after stimulus onset, and its amplitude was correlated with better localization performance. Cortical source localization for the contrast of left versus right targets at the time of the N2ac revealed a maximum in the region around left superior frontal sulcus and frontal eye field, both of which are known to be involved in processing of auditory spatial information. In addition, a posterior-contralateral late positive subcomponent (LPCpc) occurred at a latency of about 700 ms. Both these subcomponents are potential correlates of allocation of spatial attention to the target under cocktail-party conditions. © 2016 Society for Psychophysiological Research.

Neural Correlates of Sound Localization in Complex Acoustic Environments

PubMed Central

Zündorf, Ida C.; Lewald, Jörg; Karnath, Hans-Otto

2013-01-01

Listening to and understanding people in a “cocktail-party situation” is a remarkable feature of the human auditory system. Here we investigated the neural correlates of the ability to localize a particular sound among others in an acoustically cluttered environment with healthy subjects. In a sound localization task, five different natural sounds were presented from five virtual spatial locations during functional magnetic resonance imaging (fMRI). Activity related to auditory stream segregation was revealed in posterior superior temporal gyrus bilaterally, anterior insula, supplementary motor area, and frontoparietal network. Moreover, the results indicated critical roles of left planum temporale in extracting the sound of interest among acoustical distracters and the precuneus in orienting spatial attention to the target sound. We hypothesized that the left-sided lateralization of the planum temporale activation is related to the higher specialization of the left hemisphere for analysis of spectrotemporal sound features. Furthermore, the precuneus − a brain area known to be involved in the computation of spatial coordinates across diverse frames of reference for reaching to objects − seems to be also a crucial area for accurately determining locations of auditory targets in an acoustically complex scene of multiple sound sources. The precuneus thus may not only be involved in visuo-motor processes, but may also subserve related functions in the auditory modality. PMID:23691185

Assessing school-aged children's inference-making: the effect of story test format in listening comprehension.

PubMed

Freed, Jenny; Cain, Kate

2017-01-01

Comprehension is critical for classroom learning and educational success. Inferences are integral to good comprehension: successful comprehension requires the listener to generate local coherence inferences, which involve integrating information between clauses, and global coherence inferences, which involve integrating textual information with background knowledge to infer motivations, themes, etc. A central priority for the diagnosis of comprehension difficulties and our understanding of why these difficulties arise is the development of valid assessment instruments. We explored typically developing children's ability to make local and global coherence inferences using a novel assessment of listening comprehension. The aims were to determine whether children were more likely to make the target inferences when these were asked during story presentation versus after presentation of the story, and whether there were any age differences between conditions. Children in Years 3 (n = 29) and 5 (n = 31) listened to short stories presented either in a segmented format, in which questions to assess local and global coherence inferences were asked at specific points during story presentation, or in a whole format, when all the questions were asked after the story had been presented. There was developmental progression between age groups for both types of inference question. Children also scored higher on the global coherence inference questions than the local coherence inference questions. There was a benefit of the segmented format for younger children, particularly for the local inference questions. The results suggest that children are more likely to make target inferences if prompted during presentation of the story, and that this format is particularly facilitative for younger children and for local coherence inferences. This has implications for the design of comprehension assessments as well as for supporting children with comprehension difficulties in the classroom. © 2016 Royal College of Speech and Language Therapists.

Morphosyntactic Production and Verbal Working Memory: Evidence From Greek Aphasia and Healthy Aging.

PubMed

Fyndanis, Valantis; Arcara, Giorgio; Christidou, Paraskevi; Caplan, David

2018-05-17

The present work investigated whether verbal working memory (WM) affects morphosyntactic production in configurations that do not involve or favor similarity-based interference and whether WM interacts with verb-related morphosyntactic categories and/or cue-target distance (locality). It also explored whether the findings related to the questions above lend support to a recent account of agrammatic morphosyntactic production: Interpretable Features' Impairment Hypothesis (Fyndanis, Varlokosta, & Tsapkini, 2012). A sentence completion task testing production of subject-verb agreement, tense/time reference, and aspect in local and nonlocal conditions and two verbal WM tasks were administered to 8 Greek-speaking persons with agrammatic aphasia (PWA) and 103 healthy participants. The 3 morphosyntactic categories dissociated in both groups (agreement > tense > aspect). A significant interaction emerged in both groups between the 3 morphosyntactic categories and WM. There was no main effect of locality in either of the 2 groups. At the individual level, all 8 PWA exhibited dissociations between agreement, tense, and aspect, and effects of locality were contradictory. Results suggest that individuals with WM limitations (both PWA and healthy older speakers) show dissociations between the production of verb-related morphosyntactic categories. WM affects performance shaping the pattern of morphosyntactic production (in Greek: subject-verb agreement > tense > aspect). The absence of an effect of locality suggests that executive capacities tapped by WM tasks are involved in morphosyntactic processing of demanding categories even when the cue is adjacent to the target. Results are consistent with the Interpretable Features' Impairment Hypothesis (Fyndanis et al., 2012). https://doi.org/10.23641/asha.6024428.

Intra-plastid protein trafficking: how plant cells adapted prokaryotic mechanisms to the eukaryotic condition.

PubMed

Celedon, Jose M; Cline, Kenneth

2013-02-01

Protein trafficking and localization in plastids involve a complex interplay between ancient (prokaryotic) and novel (eukaryotic) translocases and targeting machineries. During evolution, ancient systems acquired new functions and novel translocation machineries were developed to facilitate the correct localization of nuclear encoded proteins targeted to the chloroplast. Because of its post-translational nature, targeting and integration of membrane proteins posed the biggest challenge to the organelle to avoid aggregation in the aqueous compartments. Soluble proteins faced a different kind of problem since some had to be transported across three membranes to reach their destination. Early studies suggested that chloroplasts addressed these issues by adapting ancient-prokaryotic machineries and integrating them with novel-eukaryotic systems, a process called 'conservative sorting'. In the last decade, detailed biochemical, genetic, and structural studies have unraveled the mechanisms of protein targeting and localization in chloroplasts, suggesting a highly integrated scheme where ancient and novel systems collaborate at different stages of the process. In this review we focus on the differences and similarities between chloroplast ancestral translocases and their prokaryotic relatives to highlight known modifications that adapted them to the eukaryotic situation. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. Copyright © 2012 Elsevier B.V. All rights reserved.

Progress in improving provincial plans for nutrition through targeted technical assistance and local advocacy in Vietnam

PubMed Central

Harris, Jody; Nguyen, Phuong H.; To, Quyen; Frongillo, Edward A.; Menon, Purnima

2016-01-01

Vietnam has been decentralizing nutrition planning to provinces, which could help with local relevance and accountability. Assessment in 2009 found a continuing top-down approach, limited human capacity, and difficulty in integrating multiple sectors. Alive and Thrive (A&T) provided targeted assistance and capacity-building for 15 provincial plans for nutrition (PPNs). We aimed to (i) assess PPN content and quality improvements 2009–2014, and (ii) explain processes through which change occurred. Data consisted of interview-based assessments of provincial planning processes, annual PPN assessments, and tracking of A&T involvement. At endline, some provinces produced higher quality plans. Local planning skills improved, but capacity remained insufficient. Awareness of and support for nutrition improved, but some policy and legal environments were contradictory. Objectives were clearer, but use of data for planning remained inconsistent. Provinces became more proactive and creative, but remained constrained by slow approval processes and insufficient funding. Targeted assistance and local advocacy can improve decentralized planning, with success dependent on policy and programming contexts and ability to overcome constraints around capacity, investment, data use and remnants of centralized planning. We recommend strong engagement with planners at the national level to understand how to unblock major constraints; solutions must take into consideration the particular political, financial and administrative context. PMID:27198978

Determinants for membrane association and permeabilization of the coxsackievirus 2B protein and the identification of the Golgi complex as the target organelle.

PubMed

de Jong, Arjan S; Wessels, Els; Dijkman, Henri B P M; Galama, Jochem M D; Melchers, Willem J G; Willems, Peter H G M; van Kuppeveld, Frank J M

2003-01-10

The 2B protein of enterovirus is responsible for the alterations in the permeability of secretory membranes and the plasma membrane in infected cells. The structural requirements for the membrane association and the subcellular localization of this essential virus protein, however, have not been defined. Here, we provide evidence that the 2B protein is an integral membrane protein in vivo that is predominantly localized at the Golgi complex upon individual expression. Addition of organelle-specific targeting signals to the 2B protein revealed that the Golgi localization is an absolute prerequisite for the ability of the protein to modify plasma membrane permeability. Expression of deletion mutants and heterologous proteins containing specific domains of the 2B protein demonstrated that each of the two hydrophobic regions could mediate membrane binding individually. However, the presence of both hydrophobic regions was required for the correct membrane association, efficient Golgi targeting, and the membrane-permeabilizing activity of the 2B protein, suggesting that the two hydrophobic regions are cooperatively involved in the formation of a membrane-integral complex. The formation of membrane-integral pores by the 2B protein in the Golgi complex and the possible mechanism by which a Golgi-localized virus protein modifies plasma membrane permeability are discussed.

Morphosyntactic Production and Verbal Working Memory: Evidence from Greek Aphasia and Healthy Aging

ERIC Educational Resources Information Center

Fyndanis, Valantis; Arcara, Giorgio; Christidou, Paraskevi; Caplan, David

2018-01-01

Purpose: The present work investigated whether verbal working memory (WM) affects morphosyntactic production in configurations that do not involve or favor similarity-based interference and whether WM interacts with verb-related morphosyntactic categories and/or cue-target distance (locality). It also explored whether the findings related to the…

Measurement of attitudes toward commercial development of geothermal energy in Federal Region IX. Final report

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

Not Available

1981-06-01

A survey was conducted of ten target study groups and subgroups for Klamath Falls, Oregon, and Susanville, California: local government, current and potential industry at the site, relocators to the site, current and potential financial community, regulators, and current and potential promoters and developers. The results of benchmark attitudinal measurement is presented separately for each target group. A literature review was conducted and Macro-environmental attitudes of a sample of local government and industry personnel at the sites were assessed. An assessment of capabilities was made which involved two measurements. The first was a measurement of a sample of promoters, developers,more » and industrial service companies active at the site to determine infrastructure capabilities required by industry for geothermal plants. The second measurement involved analyzing a sample of industry management in the area and defining their requirements for plant retrofit and expansion. Finally, the processes used by the study group to analyze information to reach commitment and regulatory decisions that significantly impact on geothermal energy projects at the site were identified and defined.« less

Target of Rapamycin (TOR)-like 1 Kinase Is Involved in the Control of Polyphosphate Levels and Acidocalcisome Maintenance in Trypanosoma brucei*

PubMed Central

de Jesus, Teresa Cristina Leandro; Tonelli, Renata Rosito; Nardelli, Sheila C.; da Silva Augusto, Leonardo; Motta, Maria Cristina M.; Girard-Dias, Wendell; Miranda, Kildare; Ulrich, Paul; Jimenez, Veronica; Barquilla, Antonio; Navarro, Miguel; Docampo, Roberto; Schenkman, Sergio

2010-01-01

Target of rapamycin (TOR) kinases are highly conserved protein kinases that integrate signals from nutrients and growth factors to coordinate cell growth and cell cycle progression. It has been previously described that two TOR kinases control cell growth in the protozoan parasite Trypanosoma brucei, the causative agent of African trypanosomiasis. Here we studied an unusual TOR-like protein named TbTOR-like 1 containing a PDZ domain and found exclusively in kinetoplastids. TbTOR-like 1 localizes to unique cytosolic granules. After hyperosmotic stress, the localization of the protein shifts to the cell periphery, different from other organelle markers. Ablation of TbTOR-like 1 causes a progressive inhibition of cell proliferation, producing parasites accumulating in the S/G2 phase of the cell cycle. TbTOR-like 1 knocked down cells have an increased area occupied by acidic vacuoles, known as acidocalcisomes, and are enriched in polyphosphate and pyrophosphate. These results suggest that TbTOR-like 1 might be involved in the control of acidocalcisome and polyphosphate metabolism in T. brucei. PMID:20495004

Stakeholder involvement in agri-environmental policy making--learning from a local- and a state-level approach in Germany.

PubMed

Prager, Katrin; Freese, Jan

2009-02-01

Recent European regulations for rural development emphasise the requirement to involve stakeholder groups and other appropriate bodies in the policy-making process. This paper presents two cases involving stakeholder participation in agri-environmental development and policy making, targeted at different policy-making levels. One study was undertaken in Lower Saxony where a local partnership developed and tested an agri-environmental prescription, which was later included in the state's menu of agri-environmental schemes. In Sachsen-Anhalt, state-facilitated stakeholder workshops including a mathematical model were used to optimise the programme planning and budget allocation at the state level. Both studies aimed at improving the acceptance of agri-environmental schemes. The authors gauge the effectiveness of the two approaches and discuss what lessons can be learned. The experience suggests that the approaches can complement one another and could also be applied to rural policy making.

Secondary Cutaneous Involvement in Follicular Diffuse Lymphoma Treated with Helical Tomotherapy

PubMed Central

Dar, A. Rashid; Jordan, Kevin

2017-01-01

Non-Hodgkin’s lymphoma is a complex heterogeneous group of disease entities that involves nodal and extranodal tissues. Cutaneous involvement can occur either as a primary or secondary in course of disease. Radiation therapy with either total body or localized treatments is often used for local control and symptom relief, depending on the target volume. We describe a 60-year-old male with a remote history of stage IA left neck follicular lymphoma treated with radiation 20 years ago and previous relapses aggressively treated by chemotherapy. Treatment to a large volume of back and posterior shoulders on a helical tomotherapy radiotherapy system is reported. The skin lesions responded completely with no toxicity. Palliative radiotherapy to a fairly large and complex volume of skin with modest dose avoiding underlying critical tissues on tomotherapy is feasible, well tolerated with an excellent durable response, without compromising future chemotherapy and stem cell transplant for systemic relapse. PMID:28944110

Whi3, an S. cerevisiae RNA-binding protein, is a component of stress granules that regulates levels of its target mRNAs.

PubMed

Holmes, Kristen J; Klass, Daniel M; Guiney, Evan L; Cyert, Martha S

2013-01-01

RNA binding proteins (RBPs) are vital to the regulation of mRNA transcripts, and can alter mRNA localization, degradation, translation, and storage. Whi3 was originally identified in a screen for small cell size mutants, and has since been characterized as an RBP. The identification of Whi3-interacting mRNAs involved in mediating cellular responses to stress suggested that Whi3 might be involved in stress-responsive RNA processing. We show that Whi3 localizes to stress granules in response to glucose deprivation or heat shock. The kinetics and pattern of Whi3 localization in response to a range of temperatures were subtly but distinctly different from those of known components of RNA processing granules. Deletion of Whi3 resulted in an increase in the relative abundance of Whi3 target RNAs, either in the presence or absence of heat shock. Increased levels of the CLN3 mRNA in whi3Δ cells may explain their decreased cell size. Another mRNA target of Whi3 encodes the zinc-responsive transcription factor Zap1, suggesting a role for Whi3 in response to zinc stress. Indeed, we found that whi3Δ cells have enhanced sensitivity to zinc toxicity. Together our results suggest an expanded model for Whi3 function: in addition to its role as a regulator of the cell cycle, Whi3 may have a role in stress-dependent RNA processing and responses to a variety of stress conditions.

Targeting GLI by GANT61 involves mechanisms dependent on inhibition of both transcription and DNA licensing.

PubMed

Zhang, Ruowen; Wu, Jiahui; Ferrandon, Sylvain; Glowacki, Katie J; Houghton, Janet A

2016-12-06

The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter. Pretreatment of HT29 cells with α-amanitin reduced GANT61-induced γH2AX foci. Co-localization of GLI1 and BrdU foci, inhibited by GANT61, indicated GLI1 and DNA replication to be linked. By co-immunoprecipitation and confocal microscopy, GLI1 co-localized with the DNA licensing factors ORC4, CDT1, and MCM2. Significant co-localization of GLI1 and ORC4 was inhibited by GANT61, and enrichment of ORC4 occurred at the GLI binding site in the FOXM1 promoter. CDT1 was found to be a transcription target of GLI1. Overexpression of CDT1 in HT29 and SW480 cells reduced GANT61-induced cell death, gH2AX foci, and cleavage of caspase-3. Data demonstrate involvement of transcription and of DNA replication licensing factors by non-transcriptional and transcriptional mechanisms in the GLI-dependent mechanism of action of GANT61.

When standards are wide of the mark: nonselective superiority and inferiority biases in comparative judgments of objects and concepts.

PubMed

Giladi, Eilath E; Klar, Yechiel

2002-12-01

People are frequently required to judge how particular group members measure up against others in their group. According to the local-comparisons-general-standards (LOGE) approach, in these member-to-group comparisons, people fail to use the normatively appropriate local (group) standard and are infelicitously affected by a more general standard (involving instances from outside the judged group). Within positive groups, target group members are judged superior to the other members of the group, and within negative groups, inferior. To date, these nonselective superiority and inferiority biases have been demonstrated solely in judgments about human beings. In 6 experiments, nonselective biases were found in perceptual, affective, and cognitive judgments of nonhuman targets, objects, and concepts, thus supporting a cognitive rather than a social account.

Monte Carlo Solution to Find Input Parameters in Systems Design Problems

NASA Astrophysics Data System (ADS)

Arsham, Hossein

2013-06-01

Most engineering system designs, such as product, process, and service design, involve a framework for arriving at a target value for a set of experiments. This paper considers a stochastic approximation algorithm for estimating the controllable input parameter within a desired accuracy, given a target value for the performance function. Two different problems, what-if and goal-seeking problems, are explained and defined in an auxiliary simulation model, which represents a local response surface model in terms of a polynomial. A method of constructing this polynomial by a single run simulation is explained. An algorithm is given to select the design parameter for the local response surface model. Finally, the mean time to failure (MTTF) of a reliability subsystem is computed and compared with its known analytical MTTF value for validation purposes.

Localized redox relays as a privileged mode of cytoplasmic hydrogen peroxide signaling.

PubMed

Travasso, Rui D M; Sampaio Dos Aidos, Fernando; Bayani, Anahita; Abranches, Pedro; Salvador, Armindo

2017-08-01

Hydrogen peroxide (H 2 O 2 ) is a key signaling agent. Its best characterized signaling actions in mammalian cells involve the early oxidation of thiols in cytoplasmic phosphatases, kinases and transcription factors. However, these redox targets are orders of magnitude less H 2 O 2 -reactive and abundant than cytoplasmic peroxiredoxins. How can they be oxidized in a signaling time frame? Here we investigate this question using computational reaction-diffusion models of H 2 O 2 signaling. The results show that at H 2 O 2 supply rates commensurate with mitogenic signaling a H 2 O 2 concentration gradient with a length scale of a few tenths of μm is established. Even near the supply sites H 2 O 2 concentrations are far too low to oxidize typical targets in an early mitogenic signaling time frame. Furthermore, any inhibition of the peroxiredoxin or increase in H 2 O 2 supply able to drastically increase the local H 2 O 2 concentration would collapse the concentration gradient and/or cause an extensive oxidation of the peroxiredoxins I and II, inconsistent with experimental observations. In turn, the local concentrations of peroxiredoxin sulfenate and disulfide forms exceed those of H 2 O 2 by several orders of magnitude. Redox targets reacting with these forms at rate constants much lower than that for, say, thioredoxin could be oxidized within seconds. Moreover, the spatial distribution of the concentrations of these peroxiredoxin forms allows them to reach targets within 1 μm from the H 2 O 2 sites while maintaining signaling localized. The recruitment of peroxiredoxins to specific sites such as caveolae can dramatically increase the local concentrations of the sulfenic and disulfide forms, thus further helping these species to outcompete H 2 O 2 for the oxidation of redox targets. Altogether, these results suggest that H 2 O 2 signaling is mediated by localized redox relays whereby peroxiredoxins are oxidized to sulfenate and disulfide forms at H 2 O 2 supply sites and these forms in turn oxidize the redox targets near these sites. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

NASA Astrophysics Data System (ADS)

Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

2016-01-01

Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

SChloro: directing Viridiplantae proteins to six chloroplastic sub-compartments.

PubMed

Savojardo, Castrense; Martelli, Pier Luigi; Fariselli, Piero; Casadio, Rita

2017-02-01

Chloroplasts are organelles found in plants and involved in several important cell processes. Similarly to other compartments in the cell, chloroplasts have an internal structure comprising several sub-compartments, where different proteins are targeted to perform their functions. Given the relation between protein function and localization, the availability of effective computational tools to predict protein sub-organelle localizations is crucial for large-scale functional studies. In this paper we present SChloro, a novel machine-learning approach to predict protein sub-chloroplastic localization, based on targeting signal detection and membrane protein information. The proposed approach performs multi-label predictions discriminating six chloroplastic sub-compartments that include inner membrane, outer membrane, stroma, thylakoid lumen, plastoglobule and thylakoid membrane. In comparative benchmarks, the proposed method outperforms current state-of-the-art methods in both single- and multi-compartment predictions, with an overall multi-label accuracy of 74%. The results demonstrate the relevance of the approach that is eligible as a good candidate for integration into more general large-scale annotation pipelines of protein subcellular localization. The method is available as web server at http://schloro.biocomp.unibo.it gigi@biocomp.unibo.it.

Nanomedicine Strategies to Target Tumor-Associated Macrophages

PubMed Central

Binnemars-Postma, Karin; Storm, Gert; Prakash, Jai

2017-01-01

In recent years, the influence of the tumor microenvironment (TME) on cancer progression has been better understood. Macrophages, one of the most important cell types in the TME, exist in different subtypes, each of which has a different function. While classically activated M1 macrophages are involved in inflammatory and malignant processes, activated M2 macrophages are more involved in the wound-healing processes occurring in tumors. Tumor-associated macrophages (TAM) display M2 macrophage characteristics and support tumor growth and metastasis by matrix remodeling, neo-angiogenesis, and suppressing local immunity. Due to their detrimental role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer may prove to be beneficial in the treatment of cancer. Due to the plastic nature of macrophages, their activities may be altered to inhibit tumor growth. In this review, we will discuss the therapeutic options for the modulation and targeting of TAM. Different therapeutic strategies to deplete, inhibit recruitment of, or re-educate TAM will be discussed. Current strategies for the targeting of TAM using nanomedicine are reviewed. Passive targeting using different nanoparticle systems is described. Since TAM display a number of upregulated surface proteins compared to non-TAM, specific targeting using targeting ligands coupled to nanoparticles is discussed in detail. PMID:28471401

Interobserver delineation uncertainty in involved-node radiation therapy (INRT) for early-stage Hodgkin lymphoma: on behalf of the Radiotherapy Committee of the EORTC lymphoma group.

PubMed

Aznar, Marianne C; Girinsky, Theodore; Berthelsen, Anne Kiil; Aleman, Berthe; Beijert, Max; Hutchings, Martin; Lievens, Yolande; Meijnders, Paul; Meidahl Petersen, Peter; Schut, Deborah; Maraldo, Maja V; van der Maazen, Richard; Specht, Lena

2017-04-01

In early-stage classical Hodgkin lymphoma (HL) the target volume nowadays consists of the volume of the originally involved nodes. Delineation of this volume on a post-chemotherapy CT-scan is challenging. We report on the interobserver variability in target volume definition and its impact on resulting treatment plans. Two representative cases were selected (1: male, stage IB, localization: left axilla; 2: female, stage IIB, localizations: mediastinum and bilateral neck). Eight experienced observers individually defined the clinical target volume (CTV) using involved-node radiotherapy (INRT) as defined by the EORTC-GELA guidelines for the H10 trial. A consensus contour was generated and the standard deviation computed. We investigated the overlap between observer and consensus contour [Sørensen-Dice coefficient (DSC)] and the magnitude of gross deviations between the surfaces of the observer and consensus contour (Hausdorff distance). 3D-conformal (3D-CRT) and intensity-modulated radiotherapy (IMRT) plans were calculated for each contour in order to investigate the impact of interobserver variability on each treatment modality. Similar target coverage was enforced for all plans. The median CTV was 120 cm 3 (IQR: 95-173 cm 3 ) for Case 1, and 255 cm 3 (IQR: 183-293 cm 3 ) for Case 2. DSC values were generally high (>0.7), and Hausdorff distances were about 30 mm. The SDs between all observer contours, providing an estimate of the systematic error associated with delineation uncertainty, ranged from 1.9 to 3.8 mm (median: 3.2 mm). Variations in mean dose resulting from different observer contours were small and were not higher in IMRT plans than in 3D-CRT plans. We observed considerable differences in target volume delineation, but the systematic delineation uncertainty of around 3 mm is comparable to that reported in other tumour sites. This report is a first step towards calculating an evidence-based planning target volume margin for INRT in HL.

Adding temporally localized noise can enhance the contribution of target knowledge on contrast detection.

PubMed

Silvestre, Daphné; Cavanagh, Patrick; Arleo, Angelo; Allard, Rémy

2017-02-01

External noise paradigms are widely used to characterize sensitivity by comparing the effect of a variable on contrast threshold when it is limited by internal versus external noise. A basic assumption of external noise paradigms is that the processing properties are the same in low and high noise. However, recent studies (e.g., Allard & Cavanagh, 2011; Allard & Faubert, 2014b) suggest that this assumption could be violated when using spatiotemporally localized noise (i.e., appearing simultaneously and at the same location as the target) but not when using spatiotemporally extended noise (i.e., continuously displayed, full-screen, dynamic noise). These previous findings may have been specific to the crowding and 0D noise paradigms that were used, so the purpose of the current study is to test if this violation of noise-invariant processing also occurs in a standard contrast detection task in white noise. The rationale of the current study is that local external noise triggers the use of recognition rather than detection and that a recognition process should be more affected by uncertainty about the shape of the target than one involving detection. To investigate the contribution of target knowledge on contrast detection, the effect of orientation uncertainty was evaluated for a contrast detection task in the absence of noise and in the presence of spatiotemporally localized or extended noise. A larger orientation uncertainty effect was observed with temporally localized noise than with temporally extended noise or with no external noise, indicating a change in the nature of the processing for temporally localized noise. We conclude that the use of temporally localized noise in external noise paradigms risks triggering a shift in process, invalidating the noise-invariant processing required for the paradigm. If, instead, temporally extended external noise is used to match the properties of internal noise, no such processing change occurs.

Optimal use of EEG recordings to target active brain areas with transcranial electrical stimulation.

PubMed

Dmochowski, Jacek P; Koessler, Laurent; Norcia, Anthony M; Bikson, Marom; Parra, Lucas C

2017-08-15

To demonstrate causal relationships between brain and behavior, investigators would like to guide brain stimulation using measurements of neural activity. Particularly promising in this context are electroencephalography (EEG) and transcranial electrical stimulation (TES), as they are linked by a reciprocity principle which, despite being known for decades, has not led to a formalism for relating EEG recordings to optimal stimulation parameters. Here we derive a closed-form expression for the TES configuration that optimally stimulates (i.e., targets) the sources of recorded EEG, without making assumptions about source location or distribution. We also derive a duality between TES targeting and EEG source localization, and demonstrate that in cases where source localization fails, so does the proposed targeting. Numerical simulations with multiple head models confirm these theoretical predictions and quantify the achieved stimulation in terms of focality and intensity. We show that constraining the stimulation currents automatically selects optimal montages that involve only a few (4-7) electrodes, with only incremental loss in performance when targeting focal activations. The proposed technique allows brain scientists and clinicians to rationally target the sources of observed EEG and thus overcomes a major obstacle to the realization of individualized or closed-loop brain stimulation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Optimal use of EEG recordings to target active brain areas with transcranial electrical stimulation

PubMed Central

Dmochowski, Jacek P.; Koessler, Laurent; Norcia, Anthony M.; Bikson, Marom; Parra, Lucas C.

2018-01-01

To demonstrate causal relationships between brain and behavior, investigators would like to guide brain stimulation using measurements of neural activity. Particularly promising in this context are electroencephalography (EEG) and transcranial electrical stimulation (TES), as they are linked by a reciprocity principle which, despite being known for decades, has not led to a formalism for relating EEG recordings to optimal stimulation parameters. Here we derive a closed-form expression for the TES configuration that optimally stimulates (i.e., targets) the sources of recorded EEG, without making assumptions about source location or distribution. We also derive a duality between TES targeting and EEG source localization, and demonstrate that in cases where source localization fails, so does the proposed targeting. Numerical simulations with multiple head models confirm these theoretical predictions and quantify the achieved stimulation in terms of focality and intensity. We show that constraining the stimulation currents automatically selects optimal montages that involve only a few (4–7) electrodes, with only incremental loss in performance when targeting focal activations. The proposed technique allows brain scientists and clinicians to rationally target the sources of observed EEG and thus overcomes a major obstacle to the realization of individualized or closed-loop brain stimulation. PMID:28578130

Synaptotagmin-mediated bending of the target membrane is a critical step in Ca2+-regulated fusion

PubMed Central

Hui, Enfu; Johnson, Colin P.; Yao, Jun; Dunning, F. Mark; Chapman, Edwin R.

2009-01-01

Summary Decades ago it was proposed that exocytosis involves invagination of the target membrane, resulting in a highly localized site of contact between the bilayers destined to fuse. The vesicle protein synaptotagmin-I (syt) bends membranes in response to Ca2+, but whether this drives localized invagination of the target membrane to accelerate fusion has not been determined; previous studies relied on reconstituted vesicles that were already highly curved and used mutations in syt that were not selective for membrane-bending activity. Here, we directly address this question by utilizing vesicles with different degrees of curvature. A tubulation-defective syt mutant was able to promote fusion between highly curved SNARE-bearing liposomes, but exhibited a marked loss of activity when the membranes were relatively flat. Moreover, bending of flat membranes by adding an N-BAR domain rescued the function of the tubulation-deficient syt mutant. Hence, syt-mediated membrane bending is a critical step in membrane fusion. PMID:19703397

Reducing Speckle In One-Look SAR Images

NASA Technical Reports Server (NTRS)

Nathan, K. S.; Curlander, J. C.

1990-01-01

Local-adaptive-filter algorithm incorporated into digital processing of synthetic-aperture-radar (SAR) echo data to reduce speckle in resulting imagery. Involves use of image statistics in vicinity of each picture element, in conjunction with original intensity of element, to estimate brightness more nearly proportional to true radar reflectance of corresponding target. Increases ratio of signal to speckle noise without substantial degradation of resolution common to multilook SAR images. Adapts to local variations of statistics within scene, preserving subtle details. Computationally simple. Lends itself to parallel processing of different segments of image, making possible increased throughput.

Novel incentives and messaging in an online college smoking intervention.

PubMed

Berg, Carla J; Stratton, Erin; Sokol, Michael; Santamaria, Andrew; Bryant, Lawrence; Rodriguez, Rolando

2014-09-01

To examine the feasibility, acceptability, and potential effectiveness of an online intervention targeting college smokers. The incentives involved discounted or free goods and services from businesses proximal to each campus. A randomized controlled trial was conducted with 122 current smokers recruited from 2 Southeastern US universities. The intervention involved health behavior monitoring, targeted messaging, and incentives for healthy goods and services versus the American Cancer Society's Guide to Quitting Smoking online. The intervention achieved greater adherence and utilization (p's < .001). Overall, 55.6% learned about a local business through this program. At end-of-treatment, intervention participants less frequently attempted to quit (p = .02) but smoked fewer cigarettes/day (p = .05). Both groups demonstrated significant end-of-treatment cessation rates. This intervention demonstrated feasibility and acceptability.

Progress in improving provincial plans for nutrition through targeted technical assistance and local advocacy in Vietnam.

PubMed

Harris, Jody; Nguyen, Phuong H; To, Quyen; Frongillo, Edward A; Menon, Purnima

2016-12-01

Vietnam has been decentralizing nutrition planning to provinces, which could help with local relevance and accountability. Assessment in 2009 found a continuing top-down approach, limited human capacity, and difficulty in integrating multiple sectors. Alive and Thrive (A&T) provided targeted assistance and capacity-building for 15 provincial plans for nutrition (PPNs). We aimed to (i) assess PPN content and quality improvements 2009-2014, and (ii) explain processes through which change occurred. Data consisted of interview-based assessments of provincial planning processes, annual PPN assessments, and tracking of A&T involvement. At endline, some provinces produced higher quality plans. Local planning skills improved, but capacity remained insufficient. Awareness of and support for nutrition improved, but some policy and legal environments were contradictory. Objectives were clearer, but use of data for planning remained inconsistent. Provinces became more proactive and creative, but remained constrained by slow approval processes and insufficient funding. Targeted assistance and local advocacy can improve decentralized planning, with success dependent on policy and programming contexts and ability to overcome constraints around capacity, investment, data use and remnants of centralized planning. We recommend strong engagement with planners at the national level to understand how to unblock major constraints; solutions must take into consideration the particular political, financial and administrative context. © The Author 2016. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.

Emodin targets mitochondrial cyclophilin D to induce apoptosis in HepG2 cells.

PubMed

Zhang, Ling; He, Dian; Li, Kun; Liu, Hongli; Wang, Baitao; Zheng, Lifang; Li, Jiazhong

2017-06-01

Emodin has demonstrated potent anticancer activity in human hepatocarcinoma cells and animal models, however, the cellular targets of emodin have not been fully defined. Here we report that emodin induces the dysfunction of mitochondria and the apoptosis in HepG2 cells through an enrichment in mitochondria. Specifically, A mitochondrial matrix protein (cyclophilin D, CyPD) is involved in emodin-induced apoptosis, and the inhibitor of CyPD (cyclosporin A) could almost completely suppressing the apoptosis; Moreover, as the expression of CyPD could be effectively inhibited by antioxidant N-acetyl-l-cysteine and epidermal growth factor (the activator of ERK), reactive oxygen species and ERK might be involved in the relevant role of CyPD. A further molecule-docking discloses the existence of three hydrogen-bonds in CyPD-emodin complex. Thus, target localization and CyPD in mitochondria provides an insight into the action of emodin in the treatment of liver cancer. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

An Approach for Identification of Novel Drug Targets in Streptococcus pyogenes SF370 Through Pathway Analysis.

PubMed

Singh, Satendra; Singh, Dev Bukhsh; Singh, Anamika; Gautam, Budhayash; Ram, Gurudayal; Dwivedi, Seema; Ramteke, Pramod W

2016-12-01

Streptococcus pyogenes is one of the most important pathogens as it is involved in various infections affecting upper respiratory tract and skin. Due to the emergence of multidrug resistance and cross-resistance, S. Pyogenes is becoming more pathogenic and dangerous. In the present study, an in silico comparative analysis of total 65 metabolic pathways of the host (Homo sapiens) and the pathogen was performed. Initially, 486 paralogous enzymes were identified so that they can be removed from possible drug target list. The 105 enzymes of the biochemical pathways of S. pyogenes from the KEGG metabolic pathway database were compared with the proteins from the Homo sapiens by performing a BLASTP search against the non-redundant database restricted to the Homo sapiens subset. Out of these, 83 enzymes were identified as non-human homologous while 30 enzymes of inadequate amino acid length were removed for further processing. Essential enzymes were finally mined from remaining 53 enzymes. Finally, 28 essential enzymes were identified in S. pyogenes SF370 (serotype M1). In subcellular localization study, 18 enzymes were predicted with cytoplasmic localization and ten enzymes with the membrane localization. These ten enzymes with putative membrane localization should be of particular interest. Acyl-carrier-protein S-malonyltransferase, DNA polymerase III subunit beta and dihydropteroate synthase are novel drug targets and thus can be used to design potential inhibitors against S. pyogenes infection. 3D structure of dihydropteroate synthase was modeled and validated that can be used for virtual screening and interaction study of potential inhibitors with the target enzyme.

Isolation and Proteomic Characterization of the Arabidopsis Golgi Defines Functional and Novel Components Involved in Plant Cell Wall Biosynthesis1[W][OA

PubMed Central

Parsons, Harriet T.; Christiansen, Katy; Knierim, Bernhard; Carroll, Andrew; Ito, Jun; Batth, Tanveer S.; Smith-Moritz, Andreia M.; Morrison, Stephanie; McInerney, Peter; Hadi, Masood Z.; Auer, Manfred; Mukhopadhyay, Aindrila; Petzold, Christopher J.; Scheller, Henrik V.; Loqué, Dominique; Heazlewood, Joshua L.

2012-01-01

The plant Golgi plays a pivotal role in the biosynthesis of cell wall matrix polysaccharides, protein glycosylation, and vesicle trafficking. Golgi-localized proteins have become prospective targets for reengineering cell wall biosynthetic pathways for the efficient production of biofuels from plant cell walls. However, proteomic characterization of the Golgi has so far been limited, owing to the technical challenges inherent in Golgi purification. In this study, a combination of density centrifugation and surface charge separation techniques have allowed the reproducible isolation of Golgi membranes from Arabidopsis (Arabidopsis thaliana) at sufficiently high purity levels for in-depth proteomic analysis. Quantitative proteomic analysis, immunoblotting, enzyme activity assays, and electron microscopy all confirm high purity levels. A composition analysis indicated that approximately 19% of proteins were likely derived from contaminating compartments and ribosomes. The localization of 13 newly assigned proteins to the Golgi using transient fluorescent markers further validated the proteome. A collection of 371 proteins consistently identified in all replicates has been proposed to represent the Golgi proteome, marking an appreciable advancement in numbers of Golgi-localized proteins. A significant proportion of proteins likely involved in matrix polysaccharide biosynthesis were identified. The potential within this proteome for advances in understanding Golgi processes has been demonstrated by the identification and functional characterization of the first plant Golgi-resident nucleoside diphosphatase, using a yeast complementation assay. Overall, these data show key proteins involved in primary cell wall synthesis and include a mixture of well-characterized and unknown proteins whose biological roles and importance as targets for future research can now be realized. PMID:22430844

Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery and methods of using same

DOEpatents

Brinker, C. Jeffrey; Carnes, Eric C.; Ashley, Carlee Erin; Willman, Cheryl L.

2017-02-28

The present invention is directed to protocells for specific targeting of hepatocellular and other cancer cells which comprise a nanoporous silica core with a supported lipid bilayer; at least one agent which facilitates cancer cell death (such as a traditional small molecule, a macromolecular cargo (e.g. siRNA or a protein toxin such as ricin toxin A-chain or diphtheria toxin A-chain) and/or a histone-packaged plasmid DNA disposed within the nanoporous silica core (preferably supercoiled in order to more efficiently package the DNA into protocells) which is optionally modified with a nuclear localization sequence to assist in localizing protocells within the nucleus of the cancer cell and the ability to express peptides involved in therapy (apoptosis/cell death) of the cancer cell or as a reporter, a targeting peptide which targets cancer cells in tissue to be treated such that binding of the protocell to the targeted cells is specific and enhanced and a fusogenic peptide that promotes endosomal escape of protocells and encapsulated DNA. Protocells according to the present invention may be used to treat cancer, especially including hepatocellular (liver) cancer using novel binding peptides (c-MET peptides) which selectively bind to hepatocellular tissue or to function in diagnosis of cancer, including cancer treatment and drug discovery.

A domain unique to plant RanGAP is responsible for its targeting to the plant nuclear rim

PubMed Central

Rose, Annkatrin; Meier, Iris

2001-01-01

Ran is a small signaling GTPase that is involved in nucleocytoplasmic transport. Two additional functions of animal Ran in the formation of spindle asters and the reassembly of the nuclear envelope in mitotic cells have been recently reported. In contrast to Ras or Rho, Ran is not associated with membranes. Instead, the spatial sequestering of its accessory proteins, the Ran GTPase-activating protein RanGAP and the nucleotide exchange factor RCC1, appears to define the local concentration of RanGTP vs. RanGDP involved in signaling. Mammalian RanGAP is bound to the nuclear pore by a mechanism involving the attachment of small ubiquitin-related modifier protein (SUMO) to its C terminus and the subsequent binding of the SUMOylated domain to the nucleoporin Nup358. Here we show that plant RanGAP utilizes a different mechanism for nuclear envelope association, involving a novel targeting domain that appears to be unique to plants. The N-terminal WPP domain is highly conserved among plant RanGAPs and the small, plant-specific nuclear envelope-associated protein MAF1, but not present in yeast or animal RanGAP. Confocal laser scanning microscopy of green fluorescent protein (GFP) fusion proteins showed that it is necessary for RanGAP targeting and sufficient to target the heterologous protein GFP to the plant nuclear rim. The highly conserved tryptophan and proline residues of the WPP motif are necessary for its function. The 110-aa WPP domain is the first nuclear-envelope targeting domain identified in plants. Its fundamental difference to its mammalian counterpart implies that different mechanisms have evolved in plants and animals to anchor RanGAP at the nuclear surface. PMID:11752475

Local health and social care responses to implementing the national cold weather plan.

PubMed

Heffernan, C; Jones, L; Ritchie, B; Erens, B; Chalabi, Zaid; Mays, N

2017-09-18

The Cold Weather Plan (CWP) for England was launched by the Department of Health in 2011 to prevent avoidable harm to health by cold weather by enabling individuals to prepare and respond appropriately. This study sought the views of local decision makers involved in the implementation of the CWP in the winter of 2012/13 to establish the effects of the CWP on local planning. It was part of a multi-component independent evaluation of the CWP. Ten LA areas were purposively sampled which varied in level of deprivation and urbanism. Fifty-two semi-structured interviews were held with health and social care managers involved in local planning between November 2012 and May 2013. Thematic analysis revealed that the CWP was considered a useful framework to formalize working arrangements between agencies though local leadership varied across localities. There were difficulties in engaging general practitioners, differences in defining vulnerable individuals and a lack of performance monitoring mechanisms. The CWP was welcomed by local health and social care managers, and improved proactive winter preparedness. Areas for improvement include better integration with general practice, and targeting resources at socially isolated individuals in cold homes with specific interventions aimed at reducing social isolation and building community resilience. © The Author 2017. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Energy-aware scheduling of surveillance in wireless multimedia sensor networks.

PubMed

Wang, Xue; Wang, Sheng; Ma, Junjie; Sun, Xinyao

2010-01-01

Wireless sensor networks involve a large number of sensor nodes with limited energy supply, which impacts the behavior of their application. In wireless multimedia sensor networks, sensor nodes are equipped with audio and visual information collection modules. Multimedia contents are ubiquitously retrieved in surveillance applications. To solve the energy problems during target surveillance with wireless multimedia sensor networks, an energy-aware sensor scheduling method is proposed in this paper. Sensor nodes which acquire acoustic signals are deployed randomly in the sensing fields. Target localization is based on the signal energy feature provided by multiple sensor nodes, employing particle swarm optimization (PSO). During the target surveillance procedure, sensor nodes are adaptively grouped in a totally distributed manner. Specially, the target motion information is extracted by a forecasting algorithm, which is based on the hidden Markov model (HMM). The forecasting results are utilized to awaken sensor node in the vicinity of future target position. According to the two properties, signal energy feature and residual energy, the sensor nodes decide whether to participate in target detection separately with a fuzzy control approach. Meanwhile, the local routing scheme of data transmission towards the observer is discussed. Experimental results demonstrate the efficiency of energy-aware scheduling of surveillance in wireless multimedia sensor network, where significant energy saving is achieved by the sensor awakening approach and data transmission paths are calculated with low computational complexity.

Recent advances in understanding and managing chordomas.

PubMed

Youssef, Carl; Aoun, Salah G; Moreno, Jessica R; Bagley, Carlos A

2016-01-01

Chordomas are rare primary bone tumors arising from embryonic remnants of the notochord. They are slow-growing, locally aggressive, and destructive and typically involve the axial skeleton. Genetic studies have identified several mutations implicated in the pathogenesis of these tumors. Treatment poses a challenge given their insidious progression, degree of local invasion at presentation, and high recurrence rate. They tend to respond poorly to conventional chemotherapy and radiation. This makes radical resection the mainstay of their treatment. Recent advances in targeted chemotherapy and focused particle beam radiation, however, have improved the management and prognosis of these tumors.

L-Ilf3 and L-NF90 Traffic to the Nucleolus Granular Component: Alternatively-Spliced Exon 3 Encodes a Nucleolar Localization Motif

PubMed Central

Viranaicken, Wildriss; Gasmi, Laila; Chaumet, Alexandre; Durieux, Christiane; Georget, Virginie; Denoulet, Philippe; Larcher, Jean-Christophe

2011-01-01

Ilf3 and NF90, two proteins containing double-stranded RNA-binding domains, are generated by alternative splicing and involved in several functions. Their heterogeneity results from posttranscriptional and posttranslational modifications. Alternative splicing of exon 3, coding for a 13 aa N-terminal motif, generates for each protein a long and short isoforms. Subcellular fractionation and localization of recombinant proteins showed that this motif acts as a nucleolar localization signal. Deletion and substitution mutants identified four arginines, essential for nucleolar targeting, and three histidines to stabilize the proteins within the nucleolus. The short isoforms are never found in the nucleoli, whereas the long isoforms are present in the nucleoplasm and the nucleoli. For Ilf3, only the posttranslationally-unmodified long isoform is nucleolar, suggesting that this nucleolar targeting is abrogated by posttranslational modifications. Confocal microscopy and FRAP experiments have shown that the long Ilf3 isoform localizes to the granular component of the nucleolus, and that L-Ilf3 and L-NF90 exchange rapidly between nucleoli. The presence of this 13 aminoacid motif, combined with posttranslational modifications, is responsible for the differences in Ilf3 and NF90 isoforms subcellular localizations. The protein polymorphism of Ilf3/NF90 and the various subcellular localizations of their isoforms may partially explain the various functions previously reported for these proteins. PMID:21811582

Quantification of non-coding RNA target localization diversity and its application in cancers.

PubMed

Cheng, Lixin; Leung, Kwong-Sak

2018-04-01

Subcellular localization is pivotal for RNAs and proteins to implement biological functions. The localization diversity of protein interactions has been studied as a crucial feature of proteins, considering that the protein-protein interactions take place in various subcellular locations. Nevertheless, the localization diversity of non-coding RNA (ncRNA) target proteins has not been systematically studied, especially its characteristics in cancers. In this study, we provide a new algorithm, non-coding RNA target localization coefficient (ncTALENT), to quantify the target localization diversity of ncRNAs based on the ncRNA-protein interaction and protein subcellular localization data. ncTALENT can be used to calculate the target localization coefficient of ncRNAs and measure how diversely their targets are distributed among the subcellular locations in various scenarios. We focus our study on long non-coding RNAs (lncRNAs), and our observations reveal that the target localization diversity is a primary characteristic of lncRNAs in different biotypes. Moreover, we found that lncRNAs in multiple cancers, differentially expressed cancer lncRNAs, and lncRNAs with multiple cancer target proteins are prone to have high target localization diversity. Furthermore, the analysis of gastric cancer helps us to obtain a better understanding that the target localization diversity of lncRNAs is an important feature closely related to clinical prognosis. Overall, we systematically studied the target localization diversity of the lncRNAs and uncovered its association with cancer.

Re-irradiation stereotactic body radiotherapy for spinal metastases: a multi-institutional outcome analysis.

PubMed

Hashmi, Ahmed; Guckenberger, Matthias; Kersh, Ron; Gerszten, Peter C; Mantel, Frederick; Grills, Inga S; Flickinger, John C; Shin, John H; Fahim, Daniel K; Winey, Brian; Oh, Kevin; John Cho, B C; Létourneau, Daniel; Sheehan, Jason; Sahgal, Arjun

2016-11-01

OBJECTIVE This study is a multi-institutional pooled analysis specific to imaging-based local control of spinal metastases in patients previously treated with conventional external beam radiation therapy (cEBRT) and then treated with re-irradiation stereotactic body radiotherapy (SBRT) to the spine as salvage therapy, the largest such study to date. METHODS The authors reviewed cases involving 215 patients with 247 spinal target volumes treated at 7 institutions. Overall survival was calculated on a patient basis, while local control was calculated based on the spinal target volume treated, both using the Kaplan-Meier method. Local control was defined as imaging-based progression within the SBRT target volume. Equivalent dose in 2-Gy fractions (EQD2) was calculated for the cEBRT and SBRT course using an α/β of 10 for tumor and 2 for both spinal cord and cauda equina. RESULTS The median total dose/number of fractions of the initial cEBRT was 30 Gy/10. The median SBRT total dose and number of fractions were 18 Gy and 1, respectively. Sixty percent of spinal target volumes were treated with single-fraction SBRT (median, 16.6 Gy and EQD2/10 = 36.8 Gy), and 40% with multiple-fraction SBRT (median 24 Gy in 3 fractions, EQD2/10 = 36 Gy). The median time interval from cEBRT to re-irradiation SBRT was 13.5 months, and the median duration of patient follow-up was 8.1 months. Kaplan-Meier estimates of 6- and 12-month overall survival rates were 64% and 48%, respectively; 13% of patients suffered a local failure, and the 6- and 12-month local control rates were 93% and 83%, respectively. Multivariate analysis identified Karnofsky Performance Status (KPS) < 70 as a significant prognostic factor for worse overall survival, and single-fraction SBRT as a significant predictive factor for better local control. There were no cases of radiation myelopathy, and the vertebral compression fracture rate was 4.5%. CONCLUSIONS Re-irradiation spine SBRT is effective in yielding imaging-based local control with a clinically acceptable safety profile. A randomized trial would be required to determine the optimal fractionation.

Nanoparticle-mediated local and remote manipulation of protein aggregation.

PubMed

Kogan, Marcelo J; Bastus, Neus G; Amigo, Roger; Grillo-Bosch, Dolors; Araya, Eyleen; Turiel, Antonio; Labarta, Amilcar; Giralt, Ernest; Puntes, Victor F

2006-01-01

The local heat delivered by metallic nanoparticles selectively attached to their target can be used as a molecular surgery to safely remove toxic and clogging aggregates. We apply this principle to protein aggregates, in particular to the amyloid beta protein (Abeta) involved in Alzheimer's disease (AD), a neurodegenerative disease where unnaturally folded Abeta proteins self-assemble and deposit forming amyloid fibrils and plaques. We show the possibility to remotely redissolve these deposits and to interfere with their growth, using the local heat dissipated by gold nanoparticles (AuNP) selectively attached to the aggregates and irradiated with low gigahertz electromagnetic fields. Simultaneous tagging and manipulation by AuNP of Abeta at different stages of aggregation allow both, noninvasive exploration and dissolution of molecular aggregates.

Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal.

PubMed

Unchwaniwala, Nuruddin; Sherer, Nathan M; Loeb, Daniel D

2016-10-01

To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria. The Pol of duck hepatitis B virus (DHBV) also localized to the mitochondria. This result indicates that localization of Pol to mitochondria is likely a feature of all hepadnaviruses. To map the MTS within HBV Pol, we generated a series of Pol-green fluorescent protein (Pol-GFP) fusions and found that a stretch spanning amino acids (aa) 141 to 160 of Pol was sufficient to target GFP to the mitochondria. Surprisingly, deleting aa 141 to 160 in full-length Pol did not fully ablate Pol's mitochondrial localization, suggesting that additional sequences are involved in mitochondrial targeting. Only by deleting the N-terminal 160 amino acids in full-length Pol was mitochondrial localization ablated. Crucial residues for pgRNA packaging are contained within aa 141 to 160, indicating a multifunctional role of this region of Pol in the viral life cycle. Our studies show an unexpected Pol trafficking behavior that is uncoupled from its role in viral DNA synthesis. Chronic infection by HBV is a serious health concern. Existing therapies for chronically infected individuals are not curative, underscoring the need for a better understanding of the viral life cycle to develop better antiviral therapies. To date, the most thoroughly studied function of Pol is to package the pgRNA and reverse transcribe it to double-stranded DNA within capsids. This study provides evidence for mitochondrial localization of Pol and defines the MTS. Recent findings have implicated a non-reverse transcription role for Pol in evading host innate immune responses. Mitochondria play an important role in controlling cellular metabolism, apoptosis, and innate immunity. Pol may alter one or more of these host mitochondrial functions to gain a replicative advantage and persist in chronically infected individuals. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects.

PubMed

Paillas, Salomé; Ladjohounlou, Riad; Lozza, Catherine; Pichard, Alexandre; Boudousq, Vincent; Jarlier, Marta; Sevestre, Samuel; Le Blay, Marion; Deshayes, Emmanuel; Sosabowski, Jane; Chardès, Thierry; Navarro-Teulon, Isabelle; Mairs, Robert J; Pouget, Jean-Pierre

2016-09-10

We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with (125)I [(125)I-mAbs]). We showed that the cytotoxicity of (125)I-mAbs targeting the cell membrane of p53(+/+) HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. (125)I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca(2+) fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2'-deoxyuridine to the nucleus was comparable to that of (125)I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by (125)I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also. Low-energy Auger electrons, such as those emitted by (125)I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with (125)I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting. Our findings describe the mechanisms involved in the efficacy of (125)I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467-484.

Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects

PubMed Central

Paillas, Salomé; Ladjohounlou, Riad; Lozza, Catherine; Pichard, Alexandre; Boudousq, Vincent; Jarlier, Marta; Sevestre, Samuel; Le Blay, Marion; Deshayes, Emmanuel; Sosabowski, Jane; Chardès, Thierry; Navarro-Teulon, Isabelle; Mairs, Robert J.

2016-01-01

Abstract Aims: We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with 125I [125I-mAbs]). Results: We showed that the cytotoxicity of 125I-mAbs targeting the cell membrane of p53+/+ HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. 125I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca2+ fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2′-deoxyuridine to the nucleus was comparable to that of 125I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by 125I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also. Innovation: Low-energy Auger electrons, such as those emitted by 125I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with 125I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting. Conclusion: Our findings describe the mechanisms involved in the efficacy of 125I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467–484. PMID:27224059

Specter: linear deconvolution for targeted analysis of data-independent acquisition mass spectrometry proteomics.

PubMed

Peckner, Ryan; Myers, Samuel A; Jacome, Alvaro Sebastian Vaca; Egertson, Jarrett D; Abelin, Jennifer G; MacCoss, Michael J; Carr, Steven A; Jaffe, Jacob D

2018-05-01

Mass spectrometry with data-independent acquisition (DIA) is a promising method to improve the comprehensiveness and reproducibility of targeted and discovery proteomics, in theory by systematically measuring all peptide precursors in a biological sample. However, the analytical challenges involved in discriminating between peptides with similar sequences in convoluted spectra have limited its applicability in important cases, such as the detection of single-nucleotide polymorphisms (SNPs) and alternative site localizations in phosphoproteomics data. We report Specter (https://github.com/rpeckner-broad/Specter), an open-source software tool that uses linear algebra to deconvolute DIA mixture spectra directly through comparison to a spectral library, thus circumventing the problems associated with typical fragment-correlation-based approaches. We validate the sensitivity of Specter and its performance relative to that of other methods, and show that Specter is able to successfully analyze cases involving highly similar peptides that are typically challenging for DIA analysis methods.

Prolactin-induced Subcellular Targeting of GLUT1 Glucose Transporter in Living Mammary Epithelial Cells

PubMed Central

Riskin, Arieh; Mond, Yehudit

2015-01-01

Background Studying the biological pathways involved in mammalian milk production during lactation could have many clinical implications. The mammary gland is unique in its requirement for transport of free glucose into the cell for the synthesis of lactose, the primary carbohydrate in milk. Objective To study GLUT1 trafficking and subcellular targeting in living mammary epithelial cells (MEC) in culture. Methods Immunocytochemistry was used to study GLUT1 hormonally regulated subcellular targeting in human MEC (HMEC). To study GLUT1 targeting and recycling in living mouse MEC (MMEC) in culture, we constructed fusion proteins of GLUT1 and green fluorescent protein (GFP) and expressed them in CIT3 MMEC. Cells were maintained in growth medium (GM), or exposed to secretion medium (SM), containing prolactin. Results GLUT1 in HMEC localized primarily to the plasma membrane in GM. After exposure to prolactin for 4 days, GLUT1 was targeted intracellularly and demonstrated a perinuclear distribution, co-localizing with lactose synthetase. The dynamic trafficking of GFP-GLUT1 fusion proteins in CIT3 MMEC suggested a basal constitutive GLUT1 recycling pathway between an intracellular pool and the cell surface that targets most GLUT1 to the plasma membrane in GM. Upon exposure to prolactin in SM, GLUT1 was specifically targeted intracellularly within 90–110 minutes. Conclusions Our studies suggest intracellular targeting of GLUT1 to the central vesicular transport system upon exposure to prolactin. The existence of a dynamic prolactin-induced sorting machinery for GLUT1 could be important for transport of free glucose into the Golgi for lactose synthesis during lactation. PMID:26886772

Can involved-field irradiation replace elective nodal irradiation in chemoradiotherapy for esophageal cancer? A systematic review and meta-analysis.

PubMed

Wang, Xiaoyue; Miao, Chuanwang; Chen, Zhen; Li, Wanhu; Yuan, Shuanghu; Yu, Jinming; Hu, Xudong

2017-01-01

Chemoradiotherapy is the most common treatment for inoperable esophageal cancer. However, there is no consensus on the delineation of the clinical target volume. Elective nodal irradiation (ENI) is recommended for inoperable esophageal cancer. A few studies have reported a decrease in the incidence of radiation-related toxicity of involved-field irradiation (IFI) for esophageal cancer. A systematic review and pooled analysis were performed to determine whether IFI in definitive chemoradiotherapy was more beneficial than ENI for esophageal cancer. The results showed no significant differences in the overall survival and local control rates between the IFI and ENI arms. Meanwhile, the incidences of esophageal and lung toxicities were significantly decreased in the IFI arm. These results suggest that IFI is a feasible treatment option for locally advanced esophageal cancer, especially to minimize irradiation-related toxicity.

Can involved-field irradiation replace elective nodal irradiation in chemoradiotherapy for esophageal cancer? A systematic review and meta-analysis

PubMed Central

Wang, Xiaoyue; Miao, Chuanwang; Chen, Zhen; Li, Wanhu; Yuan, Shuanghu; Yu, Jinming; Hu, Xudong

2017-01-01

Chemoradiotherapy is the most common treatment for inoperable esophageal cancer. However, there is no consensus on the delineation of the clinical target volume. Elective nodal irradiation (ENI) is recommended for inoperable esophageal cancer. A few studies have reported a decrease in the incidence of radiation-related toxicity of involved-field irradiation (IFI) for esophageal cancer. A systematic review and pooled analysis were performed to determine whether IFI in definitive chemoradiotherapy was more beneficial than ENI for esophageal cancer. The results showed no significant differences in the overall survival and local control rates between the IFI and ENI arms. Meanwhile, the incidences of esophageal and lung toxicities were significantly decreased in the IFI arm. These results suggest that IFI is a feasible treatment option for locally advanced esophageal cancer, especially to minimize irradiation-related toxicity. PMID:28442917

Improving oncoplastic breast tumor bed localization for radiotherapy planning using image registration algorithms

NASA Astrophysics Data System (ADS)

Wodzinski, Marek; Skalski, Andrzej; Ciepiela, Izabela; Kuszewski, Tomasz; Kedzierawski, Piotr; Gajda, Janusz

2018-02-01

Knowledge about tumor bed localization and its shape analysis is a crucial factor for preventing irradiation of healthy tissues during supportive radiotherapy and as a result, cancer recurrence. The localization process is especially hard for tumors placed nearby soft tissues, which undergo complex, nonrigid deformations. Among them, breast cancer can be considered as the most representative example. A natural approach to improving tumor bed localization is the use of image registration algorithms. However, this involves two unusual aspects which are not common in typical medical image registration: the real deformation field is discontinuous, and there is no direct correspondence between the cancer and its bed in the source and the target 3D images respectively. The tumor no longer exists during radiotherapy planning. Therefore, a traditional evaluation approach based on known, smooth deformations and target registration error are not directly applicable. In this work, we propose alternative artificial deformations which model the tumor bed creation process. We perform a comprehensive evaluation of the most commonly used deformable registration algorithms: B-Splines free form deformations (B-Splines FFD), different variants of the Demons and TV-L1 optical flow. The evaluation procedure includes quantitative assessment of the dedicated artificial deformations, target registration error calculation, 3D contour propagation and medical experts visual judgment. The results demonstrate that the currently, practically applied image registration (rigid registration and B-Splines FFD) are not able to correctly reconstruct discontinuous deformation fields. We show that the symmetric Demons provide the most accurate soft tissues alignment in terms of the ability to reconstruct the deformation field, target registration error and relative tumor volume change, while B-Splines FFD and TV-L1 optical flow are not an appropriate choice for the breast tumor bed localization problem, even though the visual alignment seems to be better than for the Demons algorithm. However, no algorithm could recover the deformation field with sufficient accuracy in terms of vector length and rotation angle differences.

New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response.

PubMed

Szymonowicz, Klaudia; Oeck, Sebastian; Malewicz, Nathalie M; Jendrossek, Verena

2018-03-18

Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors. Here we review current knowledge on the mechanisms dictating Akt's activation and target selection including the involvement of miRNAs and with focus on compartmentalization of the signaling network. Moreover, we discuss recent advances in the cross-talk with DNA damage response highlighting nuclear Akt target proteins with potential involvement in the regulation of DNA double strand break repair.

'Just another incentive scheme': a qualitative interview study of a local pay-for-performance scheme for primary care.

PubMed

Hackett, Julia; Glidewell, Liz; West, Robert; Carder, Paul; Doran, Tim; Foy, Robbie

2014-10-25

A range of policy initiatives have addressed inequalities in healthcare and health outcomes. Local pay-for-performance schemes for primary care have been advocated as means of enhancing clinical ownership of the quality agenda and better targeting local need compared with national schemes such as the UK Quality and Outcomes Framework (QOF). We investigated whether professionals' experience of a local scheme in one English National Health Service (NHS) former primary care trust (PCT) differed from that of the national QOF in relation to the goal of reducing inequalities. We conducted retrospective semi-structured interviews with primary care professionals implementing the scheme and those involved in its development. We purposively sampled practices with varying levels of population socio-economic deprivation and achievement. Interviews explored perceptions of the scheme and indicators, likely mechanisms of influence on practice, perceived benefits and harms, and how future schemes could be improved. We used a framework approach to analysis. Thirty-eight professionals from 16 general practices and six professionals involved in developing local indicators participated. Our findings cover four themes: ownership, credibility of the indicators, influences on behaviour, and exacerbated tensions. We found little evidence that the scheme engendered any distinctive sense of ownership or experiences different from the national scheme. Although the indicators and their evidence base were seldom actively questioned, doubts were expressed about their focus on health promotion given that eventual benefits relied upon patient action and availability of local resources. Whilst practices serving more affluent populations reported status and patient benefit as motivators for participating in the scheme, those serving more deprived populations highlighted financial reward. The scheme exacerbated tensions between patient and professional consultation agendas, general practitioners benefitting directly from incentives and nurses who did much of the work, and practices serving more and less affluent populations which faced different challenges in achieving targets. The contentious nature of pay-for-performance was not necessarily reduced by local adaptation. Those developing future schemes should consider differential rewards and supportive resources for practices serving more deprived populations, and employing a wider range of levers to promote professional understanding and ownership of indicators.

A Simulation Study of a Radiofrequency Localization System for Tracking Patient Motion in Radiotherapy.

PubMed

Ostyn, Mark; Kim, Siyong; Yeo, Woon-Hong

2016-04-13

One of the most widely used tools in cancer treatment is external beam radiotherapy. However, the major risk involved in radiotherapy is excess radiation dose to healthy tissue, exacerbated by patient motion. Here, we present a simulation study of a potential radiofrequency (RF) localization system designed to track intrafraction motion (target motion during the radiation treatment). This system includes skin-wearable RF beacons and an external tracking system. We develop an analytical model for direction of arrival measurement with radio frequencies (GHz range) for use in a localization estimate. We use a Monte Carlo simulation to investigate the relationship between a localization estimate and angular resolution of sensors (signal receivers) in a simulated room. The results indicate that the external sensor needs an angular resolution of about 0.03 degrees to achieve millimeter-level localization accuracy in a treatment room. This fundamental study of a novel RF localization system offers the groundwork to design a radiotherapy-compatible patient positioning system for active motion compensation.

Policy and administrative issues for large-scale clinical interventions following disasters.

PubMed

Scheeringa, Michael S; Cobham, Vanessa E; McDermott, Brett

2014-02-01

Large, programmatic mental health intervention programs for children and adolescents following disasters have become increasingly common; however, little has been written about the key goals and challenges involved. Using available data and the authors' experiences, this article reviews the factors involved in planning and implementing large-scale treatment programs following disasters. These issues include funding, administration, choice of clinical targets, workforce selection, choice of treatment modalities, training, outcome monitoring, and consumer uptake. Ten factors are suggested for choosing among treatment modalities: 1) reach (providing access to the greatest number), 2) retention of patients, 3) privacy, 4) parental involvement, 5) familiarity of the modality to clinicians, 6) intensity (intervention type matches symptom acuity and impairment of patient), 7) burden to the clinician (in terms of time, travel, and inconvenience), 8) cost, 9) technology needs, and 10) effect size. Traditionally, after every new disaster, local leaders who have never done so before have had to be recruited to design, administer, and implement programs. As expertise in all of these areas represents a gap for most local professionals in disaster-affected areas, we propose that a central, nongovernmental agency with national or international scope be created that can consult flexibly with local leaders following disasters on both overarching and specific issues. We propose recommendations and point out areas in greatest need of innovation.

The Assessment of a Model for Determining Community-Based Needs of American Indians with Disabilities through Consumer Involvement in Community Planning and Change. Final Report, 1990.

ERIC Educational Resources Information Center

Marshall, Catherine A.; And Others

This research project sought to identify, at a local community level, the needs and concerns of American Indians with disabilities. The selected target community was Denver, Colorado, and its surrounding metropolitan area. Data were collected through 100 face-to-face interviews with a volunteer population of American Indians with disabilities. The…

Commonsense Investments in a Shared Future: Business Support of Public Schools. The New School Finance Research Agenda: Resource Utilization and School Districts. Finance Collaborative Working Paper #6.

ERIC Educational Resources Information Center

Lewis, Mary Ellen James

A decade ago, the business community began to pursue tentative, new relationships with schools; the focus was on long-term educational improvement, frequently targeted to core academic subjects. Now partnerships are everywhere, involving thousands of schools and hundreds of thousands of local people. This essay discusses the resources brought to…

Village Stability Operations and the Afghan Local Police

DTIC Science & Technology

2014-10-01

government increased the centralization of police recruitment and training. To eliminate the temptations to abuse power arising from deployment in...Defense Initia- tive to the ALP. In June 2010, a Taliban suicide bomber blew himself up at a wedding in Kandahar province attended by numerous...involving ground assaults and suicide bombings aimed at ALP commanders. Some of the strikes claimed the lives of their targets and other ALP

Target volume delineation for radical radiotherapy of early oesophageal carcinoma in elderly patients.

PubMed

Su, J; Zhu, S; Liu, Z; Zhao, Y; Song, C

2017-02-01

To compare the prognosis of elderly patients with early oesophageal carcinoma between radical elective nodal prophylactic irradiation and involved-field irradiation and to estimate the failure modes and adverse effects, then to provide the patients the safe and individual therapeutic regimens. The charts of 96 patients aged 65 and over with early stage oesophageal carcinoma receiving radical radiotherapy in our department were retrospectively analysed. Of all the patients, 49 received elective nodal prophylactic irradiation and the other 47 received involved-field irradiation. After completion of the whole treatment, we analysed short-term effects, tumour local control, overall survival of the patients, failure modes and adverse effects. The 1-, 3-, and 5-year local control rate in elective nodal irradiation and involved-field irradiation groups were 80.6%, 57.4%, 54.0% and 65.4%, 46.5%, 30.5% respectively, and the difference was statistically significant (χ 2 =4.478, P=0.03). The differences of overall survival and progression-free survival were not significant (P>0.05). The difference of 1-, 3-, and 5-years local regional failure rate was statistically significant between elective nodal prophylactic irradiation and involved-field irradiation groups, except for the overall failure and distant metastasis rates. The overall incidence of radiation-induced oesophagitis after elective nodal irradiation or involved-field irradiation was 79.6% and 59.6%, and the difference was statistically significant (χ 2 =4.559, P=0.03). The difference of radiation pneumonitis between elective nodal prophylactic irradiation and involved-field irradiation was not significant (12.2% vs 14.9%; χ 2 =0.144, P=0.7). For elderly patients with early stage oesophageal carcinoma receiving radical radiotherapy, although elective nodal prophylactic irradiation could increase the incidence of radiation-induced oesophagitis, patients could tolerate the treatment and benefit from local control. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Generation and evaluation of an ultra-high-field atlas with applications in DBS planning

NASA Astrophysics Data System (ADS)

Wang, Brian T.; Poirier, Stefan; Guo, Ting; Parrent, Andrew G.; Peters, Terry M.; Khan, Ali R.

2016-03-01

Purpose Deep brain stimulation (DBS) is a common treatment for Parkinson's disease (PD) and involves the use of brain atlases or intrinsic landmarks to estimate the location of target deep brain structures, such as the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi). However, these structures can be difficult to localize with conventional clinical magnetic resonance imaging (MRI), and thus targeting can be prone to error. Ultra-high-field imaging at 7T has the ability to clearly resolve these structures and thus atlases built with these data have the potential to improve targeting accuracy. Methods T1 and T2-weighted images of 12 healthy control subjects were acquired using a 7T MR scanner. These images were then used with groupwise registration to generate an unbiased average template with T1w and T2w contrast. Deep brain structures were manually labelled in each subject by two raters and rater reliability was assessed. We compared the use of this unbiased atlas with two other methods of atlas-based segmentation (single-template and multi-template) for subthalamic nucleus (STN) segmentation on 7T MRI data. We also applied this atlas to clinical DBS data acquired at 1.5T to evaluate its efficacy for DBS target localization as compared to using a standard atlas. Results The unbiased templates provide superb detail of subcortical structures. Through one-way ANOVA tests, the unbiased template is significantly (p <0.05) more accurate than a single-template in atlas-based segmentation and DBS target localization tasks. Conclusion The generated unbiased averaged templates provide better visualization of deep brain nuclei and an increase in accuracy over single-template and lower field strength atlases.

Molecular Analysis of Sarcoidosis Granulomas Reveals Antimicrobial Targets

PubMed Central

Celada, Lindsay J.; Polosukhin, Vasiliy V.; Atkinson, James B.; Drake, Wonder P.

2016-01-01

Sarcoidosis is a granulomatous disease of unknown cause. Prior molecular and immunologic studies have confirmed the presence of mycobacterial virulence factors, such as catalase peroxidase and superoxide dismutase A, within sarcoidosis granulomas. Molecular analysis of granulomas can identify targets of known antibiotics classes. Currently, major antibiotics are directed against DNA synthesis, protein synthesis, and cell wall formation. We conducted molecular analysis of 40 sarcoidosis diagnostic specimens and compared them with 33 disease control specimens for the presence of mycobacterial genes that encode antibiotic targets. We assessed for genes involved in DNA synthesis (DNA gyrase A [gyrA] and DNA gyrase B), protein synthesis (RNA polymerase subunit β), cell wall synthesis (embCAB operon and enoyl reductase), and catalase peroxidase. Immunohistochemical analysis was conducted to investigate the locale of mycobacterial genes such as gyrA within 12 sarcoidosis specimens and 12 disease controls. Mycobacterial DNA was detected in 33 of 39 sarcoidosis specimens by quantitative real-time polymerase chain reaction compared with 2 of 30 disease control specimens (P < 0.001, two-tailed Fisher’s test). Twenty of 39 were positive for three or more mycobacterial genes, compared with 1 of 30 control specimens (P < 0.001, two-tailed Fisher’s test). Immunohistochemistry analysis localized mycobacterial gyrA nucleic acids to sites of granuloma formation in 9 of 12 sarcoidosis specimens compared with 1 of 12 disease controls (P < 0.01). Microbial genes encoding enzymes that can be targeted by currently available antimycobacterial antibiotics are present in sarcoidosis specimens and localize to sites of granulomatous inflammation. Use of antimicrobials directed against target enzymes may be an innovative treatment alternative. PMID:26807608

Pediatric scleroderma: systemic or localized forms.

PubMed

Torok, Kathryn S

2012-04-01

Pediatric scleroderma includes 2 major groups of clinical entities, systemic sclerosis (SSc) and localized scleroderma (LS). Although both share a common pathophysiology, their clinical manifestations differ. LS is typically confined to the skin and underlying subcutis, with up to a quarter of patients showing extracutaneous disease manifestations such as arthritis and uveitis. Vascular, cutaneous, gastrointestinal, pulmonary, and musculoskeletal involvement are most commonly seen in children with SSc. Treatment of both forms targets the active inflammatory stage and halts disease progression; however, progress needs to be made toward the development of more effective antifibrotic therapy to help reverse disease damage. Copyright © 2012 Elsevier Inc. All rights reserved.

Can the elongated hindwing tails of fluttering moths serve as false sonar targets to divert bat attacks?

PubMed

Lee, Wu-Jung; Moss, Cynthia F

2016-05-01

It has long been postulated that the elongated hindwing tails of many saturniid moths have evolved to create false sonar targets to divert the attack of echolocation-guided bat predators. However, rigorous echo-acoustic evidence to support this hypothesis has been lacking. In this study, fluttering luna moths (Actias luna), a species with elongated hindwing tails, were ensonified with frequency modulated chirp signals from all angles of orientation and across the wingbeat cycle. High-speed stereo videography was combined with pulse compression sonar processing to characterize the echo information available to foraging bats. Contrary to previous suggestions, the results show that the tail echoes are weak and do not dominate the sonar returns, compared to the large, planar wings and the moth body. However, the distinctive twisted morphology of the tails create persistent echoes across all angles of orientation, which may induce erroneous sonar target localization and disrupt accurate tracking by echolocating bats. These findings thus suggest a refinement of the false target hypothesis to emphasize sonar localization errors induced by the twisted tails, and highlight the importance of physics-based approaches to study the sensory information involved in the evolutionary arms race between moths and their bat predators.

Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment.

PubMed

Vizi, E S; Fekete, A; Karoly, R; Mike, A

2010-06-01

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the 'what' of brain function, the 'how' of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the 'how' that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic-extrasynaptic receptor trafficking, neuron-glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them.

Detection of multiple airborne targets from multisensor data

NASA Astrophysics Data System (ADS)

Foltz, Mark A.; Srivastava, Anuj; Miller, Michael I.; Grenander, Ulf

1995-08-01

Previously we presented a jump-diffusion based random sampling algorithm for generating conditional mean estimates of scene representations for the tracking and recongition of maneuvering airborne targets. These representations include target positions and orientations along their trajectories and the target type associated with each trajectory. Taking a Bayesian approach, a posterior measure is defined on the parameter space by combining sensor models with a sophisticated prior based on nonlinear airplane dynamics. The jump-diffusion algorithm constructs a Markov process which visits the elements of the parameter space with frequencies proportional to the posterior probability. It consititutes both the infinitesimal, local search via a sample path continuous diffusion transform and the larger, global steps through discrete jump moves. The jump moves involve the addition and deletion of elements from the scene configuration or changes in the target type assoviated with each target trajectory. One such move results in target detection by the addition of a track seed to the inference set. This provides initial track data for the tracking/recognition algorithm to estimate linear graph structures representing tracks using the other jump moves and the diffusion process, as described in our earlier work. Target detection ideally involves a continuous research over a continuum of the observation space. In this work we conclude that for practical implemenations the search space must be discretized with lattice granularity comparable to sensor resolution, and discuss how fast Fourier transforms are utilized for efficient calcuation of sufficient statistics given our array models. Some results are also presented from our implementation on a networked system including a massively parallel machine architecture and a silicon graphics onyx workstation.

Real-Time Multi-Target Localization from Unmanned Aerial Vehicles

PubMed Central

Wang, Xuan; Liu, Jinghong; Zhou, Qianfei

2016-01-01

In order to improve the reconnaissance efficiency of unmanned aerial vehicle (UAV) electro-optical stabilized imaging systems, a real-time multi-target localization scheme based on an UAV electro-optical stabilized imaging system is proposed. First, a target location model is studied. Then, the geodetic coordinates of multi-targets are calculated using the homogeneous coordinate transformation. On the basis of this, two methods which can improve the accuracy of the multi-target localization are proposed: (1) the real-time zoom lens distortion correction method; (2) a recursive least squares (RLS) filtering method based on UAV dead reckoning. The multi-target localization error model is established using Monte Carlo theory. In an actual flight, the UAV flight altitude is 1140 m. The multi-target localization results are within the range of allowable error. After we use a lens distortion correction method in a single image, the circular error probability (CEP) of the multi-target localization is reduced by 7%, and 50 targets can be located at the same time. The RLS algorithm can adaptively estimate the location data based on multiple images. Compared with multi-target localization based on a single image, CEP of the multi-target localization using RLS is reduced by 25%. The proposed method can be implemented on a small circuit board to operate in real time. This research is expected to significantly benefit small UAVs which need multi-target geo-location functions. PMID:28029145

Real-Time Multi-Target Localization from Unmanned Aerial Vehicles.

PubMed

Wang, Xuan; Liu, Jinghong; Zhou, Qianfei

2016-12-25

In order to improve the reconnaissance efficiency of unmanned aerial vehicle (UAV) electro-optical stabilized imaging systems, a real-time multi-target localization scheme based on an UAV electro-optical stabilized imaging system is proposed. First, a target location model is studied. Then, the geodetic coordinates of multi-targets are calculated using the homogeneous coordinate transformation. On the basis of this, two methods which can improve the accuracy of the multi-target localization are proposed: (1) the real-time zoom lens distortion correction method; (2) a recursive least squares (RLS) filtering method based on UAV dead reckoning. The multi-target localization error model is established using Monte Carlo theory. In an actual flight, the UAV flight altitude is 1140 m. The multi-target localization results are within the range of allowable error. After we use a lens distortion correction method in a single image, the circular error probability (CEP) of the multi-target localization is reduced by 7%, and 50 targets can be located at the same time. The RLS algorithm can adaptively estimate the location data based on multiple images. Compared with multi-target localization based on a single image, CEP of the multi-target localization using RLS is reduced by 25%. The proposed method can be implemented on a small circuit board to operate in real time. This research is expected to significantly benefit small UAVs which need multi-target geo-location functions.

A role for a rat homolog of staufen in the transport of RNA to neuronal dendrites.

PubMed

Tang, S J; Meulemans, D; Vazquez, L; Colaco, N; Schuman, E

2001-11-08

RNAs are present in dendrites and may be used for local protein synthesis in response to synaptic activity. To begin to understand dendritic RNA targeting, we cloned a rat homolog of staufen, a Drosophila gene that participates in mRNA targeting during development. In hippocampal neurons, rat staufen protein displays a microtubule-dependent somatodendritic distribution pattern that overlaps with dendritic RNAs. To determine whether r-staufen is required for dendritic RNA targeting, we constructed a mutant version containing the RNA binding domains (stau-RBD) but lacking the C-terminal portion potentially involved in dendritic targeting. Stau-RBD expression was restricted to the cell bodies and proximal dendrites. Expression of stau-RBD significantly decreased, while overexpression of wild-type r-staufen increased, the amount of dendritic mRNA. Taken together, these results suggest that the rat staufen protein plays an important role in the delivery of RNA to dendrites.

Stoichiometry of Nck-dependent actin polymerization in living cells

PubMed Central

Ditlev, Jonathon A.; Michalski, Paul J.; Huber, Greg; Rivera, Gonzalo M.; Mohler, William A.

2012-01-01

Regulation of actin dynamics through the Nck/N-WASp (neural Wiskott–Aldrich syndrome protein)/Arp2/3 pathway is essential for organogenesis, cell invasiveness, and pathogen infection. Although many of the proteins involved in this pathway are known, the detailed mechanism by which it functions remains undetermined. To examine the signaling mechanism, we used a two-pronged strategy involving computational modeling and quantitative experimentation. We developed predictions for Nck-dependent actin polymerization using the Virtual Cell software system. In addition, we used antibody-induced aggregation of membrane-targeted Nck SH3 domains to test these predictions and to determine how the number of molecules in Nck aggregates and the density of aggregates affected localized actin polymerization in living cells. Our results indicate that the density of Nck molecules in aggregates is a critical determinant of actin polymerization. Furthermore, results from both computational simulations and experimentation support a model in which the Nck/N-WASp/Arp2/3 stoichiometry is 4:2:1. These results provide new insight into activities involving localized actin polymerization, including tumor cell invasion, microbial pathogenesis, and T cell activation. PMID:22613834

Chemoradiation for ductal pancreatic carcinoma: principles of combining chemotherapy with radiation, definition of target volume and radiation dose.

PubMed

Wilkowski, Ralf; Thoma, Martin; Weingandt, Helmut; Dühmke, Eckhart; Heinemann, Volker

2005-05-10

Review of the role of chemoradiotherapy in the treatment of locally advanced pancreatic cancer with a specific focus on the technical feasibility and the integration of chemoradiotherapy into multimodal treatment concepts. Combined chemoradiotherapy of pancreatic cancer is a safe treatment with an acceptable profile of side effects when applied with modern planning and radiation techniques as well as considering tissue tolerance. Conventionally fractionated radiation regimens with total doses of 45-50 Gy and small-volume boost radiation with 5.4 Gy have found the greatest acceptance. Locoregional lymphatic drainage should be included in the planning of target volumes because the risk of tumor involvement and local or loco-regional recurrence is high. Up to now, 5-fluorouracil has been considered the "standard" agent for concurrent chemoradiotherapy. The role of gemcitabine given concurrently with radiation has not yet been defined, since high local efficacy may also be accompanied by enhanced toxicities. In addition, no dose or administration form has been determined to be "standard" up to now. The focus of presently ongoing research is to define an effective and feasible regimen of concurrent chemoradiotherapy. While preliminary results indicate promising results using gemcitabine-based chemoradiotherapy, reliable data derived from mature phase III trials are greatly needed. Intensity-modulated radiotherapy has been developed to improve target-specific radiation and to reduce organ toxicity. Its clinical relevance still needs to be defined.

Through-the-Wall Localization of a Moving Target by Two Independent Ultra Wideband (UWB) Radar Systems

PubMed Central

Kocur, Dušan; Švecová, Mária; Rovňáková, Jana

2013-01-01

In the case of through-the-wall localization of moving targets by ultra wideband (UWB) radars, there are applications in which handheld sensors equipped only with one transmitting and two receiving antennas are applied. Sometimes, the radar using such a small antenna array is not able to localize the target with the required accuracy. With a view to improve through-the-wall target localization, cooperative positioning based on a fusion of data retrieved from two independent radar systems can be used. In this paper, the novel method of the cooperative localization referred to as joining intersections of the ellipses is introduced. This method is based on a geometrical interpretation of target localization where the target position is estimated using a properly created cluster of the ellipse intersections representing potential positions of the target. The performance of the proposed method is compared with the direct calculation method and two alternative methods of cooperative localization using data obtained by measurements with the M-sequence UWB radars. The direct calculation method is applied for the target localization by particular radar systems. As alternative methods of cooperative localization, the arithmetic average of the target coordinates estimated by two single independent UWB radars and the Taylor series method is considered. PMID:24021968

Through-the-wall localization of a moving target by two independent ultra wideband (UWB) radar systems.

PubMed

Kocur, Dušan; Svecová, Mária; Rovňáková, Jana

2013-09-09

In the case of through-the-wall localization of moving targets by ultra wideband (UWB) radars, there are applications in which handheld sensors equipped only with one transmitting and two receiving antennas are applied. Sometimes, the radar using such a small antenna array is not able to localize the target with the required accuracy. With a view to improve through-the-wall target localization, cooperative positioning based on a fusion of data retrieved from two independent radar systems can be used. In this paper, the novel method of the cooperative localization referred to as joining intersections of the ellipses is introduced. This method is based on a geometrical interpretation of target localization where the target position is estimated using a properly created cluster of the ellipse intersections representing potential positions of the target. The performance of the proposed method is compared with the direct calculation method and two alternative methods of cooperative localization using data obtained by measurements with the M-sequence UWB radars. The direct calculation method is applied for the target localization by particular radar systems. As alternative methods of cooperative localization, the arithmetic average of the target coordinates estimated by two single independent UWB radars and the Taylor series method is considered.

Elephants in Pyjamas: Testing the Weak Central Coherence Account of Autism Spectrum Disorders Using a Syntactic Disambiguation Task.

PubMed

Riches, N G; Loucas, T; Baird, G; Charman, T; Simonoff, E

2016-01-01

According to the weak central coherence (CC) account individuals with autism spectrum disorders (ASD) exhibit enhanced local processing and weak part-whole integration. CC was investigated in the verbal domain. Adolescents, recruited using a 2 (ASD status) by 2 (language impairment status) design, completed an aural forced choice comprehension task involving syntactically ambiguous sentences. Half the picture targets depicted the least plausible interpretation, resulting in longer RTs across groups. These were assumed to reflect local processing. There was no ASD by plausibility interaction and consequently little evidence for weak CC in the verbal domain when conceptualised as enhanced local processing. Furthermore, there was little evidence that the processing of syntactically ambiguous sentences differed as a function of ASD or language-impairment status.

The Saudi Thoracic Society guidelines for diagnosis and management of noncystic fibrosis bronchiectasis

PubMed Central

Al-Jahdali, Hamdan; Alshimemeri, Abdullah; Mobeireek, Abdullah; Albanna, Amr S.; Al Shirawi, Nehad N.; Wali, Siraj; Alkattan, Khaled; Alrajhi, Abdulrahman A.; Mobaireek, Khalid; Alorainy, Hassan S.; Al-Hajjaj, Mohamed S.; Chang, Anne B.; Aliberti, Stefano

2017-01-01

This is the first guideline developed by the Saudi Thoracic Society for the diagnosis and management of noncystic fibrosis bronchiectasis. Local experts including pulmonologists, infectious disease specialists, thoracic surgeons, respiratory therapists, and others from adult and pediatric departments provided the best practice evidence recommendations based on the available international and local literature. The main objective of this guideline is to utilize the current published evidence to develop recommendations about management of bronchiectasis suitable to our local health-care system and available resources. We aim to provide clinicians with tools to standardize the diagnosis and management of bronchiectasis. This guideline targets primary care physicians, family medicine practitioners, practicing internists and respiratory physicians, and all other health-care providers involved in the care of the patients with bronchiectasis. PMID:28808486

Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells.

PubMed

Thomas, Audrey; Mariani-Floderer, Charlotte; López-Huertas, Maria Rosa; Gros, Nathalie; Hamard-Péron, Elise; Favard, Cyril; Ohlmann, Theophile; Alcamí, José; Muriaux, Delphine

2015-08-01

During HIV-1 assembly, the Gag viral proteins are targeted and assemble at the inner leaflet of the cell plasma membrane. This process could modulate the cortical actin cytoskeleton, located underneath the plasma membrane, since actin dynamics are able to promote localized membrane reorganization. In addition, activated small Rho GTPases are known for regulating actin dynamics and membrane remodeling. Therefore, the modulation of such Rho GTPase activity and of F-actin by the Gag protein during virus particle formation was considered. Here, we studied the implication of the main Rac1, Cdc42, and RhoA small GTPases, and some of their effectors, in this process. The effect of small interfering RNA (siRNA)-mediated Rho GTPases and silencing of their effectors on Gag localization, Gag membrane attachment, and virus-like particle production was analyzed by immunofluorescence coupled to confocal microscopy, membrane flotation assays, and immunoblot assays, respectively. In parallel, the effect of Gag expression on the Rac1 activation level was monitored by G-LISA, and the intracellular F-actin content in T cells was monitored by flow cytometry and fluorescence microscopy. Our results revealed the involvement of activated Rac1 and of the IRSp53-Wave2-Arp2/3 signaling pathway in HIV-1 Gag membrane localization and particle release in T cells as well as a role for actin branching and polymerization, and this was solely dependent on the Gag viral protein. In conclusion, our results highlight a new role for the Rac1-IRSp53-Wave2-Arp2/3 signaling pathway in the late steps of HIV-1 replication in CD4 T lymphocytes. During HIV-1 assembly, the Gag proteins are targeted and assembled at the inner leaflet of the host cell plasma membrane. Gag interacts with specific membrane phospholipids that can also modulate the regulation of cortical actin cytoskeleton dynamics. Actin dynamics can promote localized membrane reorganization and thus can be involved in facilitating Gag assembly and particle formation. Activated small Rho GTPases and effectors are regulators of actin dynamics and membrane remodeling. We thus studied the effects of the Rac1, Cdc42, and RhoA GTPases and their specific effectors on HIV-1 Gag membrane localization and viral particle release in T cells. Our results show that activated Rac1 and the IRSp53-Wave2-Arp2/3 signaling pathway are involved in Gag plasma membrane localization and viral particle production. This work uncovers a role for cortical actin through the activation of Rac1 and the IRSp53/Wave2 signaling pathway in HIV-1 particle formation in CD4 T lymphocytes. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells

PubMed Central

Thomas, Audrey; Mariani-Floderer, Charlotte; López-Huertas, Maria Rosa; Gros, Nathalie; Hamard-Péron, Elise; Favard, Cyril; Ohlmann, Theophile; Alcamí, José

2015-01-01

ABSTRACT During HIV-1 assembly, the Gag viral proteins are targeted and assemble at the inner leaflet of the cell plasma membrane. This process could modulate the cortical actin cytoskeleton, located underneath the plasma membrane, since actin dynamics are able to promote localized membrane reorganization. In addition, activated small Rho GTPases are known for regulating actin dynamics and membrane remodeling. Therefore, the modulation of such Rho GTPase activity and of F-actin by the Gag protein during virus particle formation was considered. Here, we studied the implication of the main Rac1, Cdc42, and RhoA small GTPases, and some of their effectors, in this process. The effect of small interfering RNA (siRNA)-mediated Rho GTPases and silencing of their effectors on Gag localization, Gag membrane attachment, and virus-like particle production was analyzed by immunofluorescence coupled to confocal microscopy, membrane flotation assays, and immunoblot assays, respectively. In parallel, the effect of Gag expression on the Rac1 activation level was monitored by G-LISA, and the intracellular F-actin content in T cells was monitored by flow cytometry and fluorescence microscopy. Our results revealed the involvement of activated Rac1 and of the IRSp53-Wave2-Arp2/3 signaling pathway in HIV-1 Gag membrane localization and particle release in T cells as well as a role for actin branching and polymerization, and this was solely dependent on the Gag viral protein. In conclusion, our results highlight a new role for the Rac1-IRSp53-Wave2-Arp2/3 signaling pathway in the late steps of HIV-1 replication in CD4 T lymphocytes. IMPORTANCE During HIV-1 assembly, the Gag proteins are targeted and assembled at the inner leaflet of the host cell plasma membrane. Gag interacts with specific membrane phospholipids that can also modulate the regulation of cortical actin cytoskeleton dynamics. Actin dynamics can promote localized membrane reorganization and thus can be involved in facilitating Gag assembly and particle formation. Activated small Rho GTPases and effectors are regulators of actin dynamics and membrane remodeling. We thus studied the effects of the Rac1, Cdc42, and RhoA GTPases and their specific effectors on HIV-1 Gag membrane localization and viral particle release in T cells. Our results show that activated Rac1 and the IRSp53-Wave2-Arp2/3 signaling pathway are involved in Gag plasma membrane localization and viral particle production. This work uncovers a role for cortical actin through the activation of Rac1 and the IRSp53/Wave2 signaling pathway in HIV-1 particle formation in CD4 T lymphocytes. PMID:26018170

An Improved Compressive Sensing and Received Signal Strength-Based Target Localization Algorithm with Unknown Target Population for Wireless Local Area Networks.

PubMed

Yan, Jun; Yu, Kegen; Chen, Ruizhi; Chen, Liang

2017-05-30

In this paper a two-phase compressive sensing (CS) and received signal strength (RSS)-based target localization approach is proposed to improve position accuracy by dealing with the unknown target population and the effect of grid dimensions on position error. In the coarse localization phase, by formulating target localization as a sparse signal recovery problem, grids with recovery vector components greater than a threshold are chosen as the candidate target grids. In the fine localization phase, by partitioning each candidate grid, the target position in a grid is iteratively refined by using the minimum residual error rule and the least-squares technique. When all the candidate target grids are iteratively partitioned and the measurement matrix is updated, the recovery vector is re-estimated. Threshold-based detection is employed again to determine the target grids and hence the target population. As a consequence, both the target population and the position estimation accuracy can be significantly improved. Simulation results demonstrate that the proposed approach achieves the best accuracy among all the algorithms compared.

Adaptive optics to enhance target recognition

NASA Astrophysics Data System (ADS)

McAulay, Alastair D.

2012-06-01

Target recognition can be enhanced by reducing image degradation due to atmospheric turbulence. This is accomplished by an adaptive optic system. We discuss the forms of degradation when a target is viewed through the atmosphere1: scintillation from ground targets on a hot day in visible or infrared light; beam spreading and wavering around in time; atmospheric turbulence caused by motion of the target or by weather. In the case of targets we can use a beacon laser that reflects back from the target into a wavefront detector to measure the effects of turbulence on propagation to and from the target before imaging.1 A deformable mirror then corrects the wavefront shape of the transmitted, reflected or scattered data for enhanced imaging. Further, recognition of targets is enhanced by performing accurate distance measurements to localized parts of the target using lidar. Distance is obtained by sending a short pulse to the target and measuring the time for the pulse to return. There is inadequate time to scan the complete field of view so that the beam must be steered to regions of interest such as extremities of the image during image recognition. Distance is particularly valuable to recognize fine features in range along the target or when segmentation is required to separate a target from background or from other targets. We discuss the issues involved.

Towards an Informed Mexican and Mexican-American Citizenry: Bridging the Gap to Increase Human Capacity and Information Dissemination

NASA Astrophysics Data System (ADS)

Ramirez, M. D.; Ramirez, D. M.

2008-12-01

The research translation and community outreach goal of The University of Arizona's (UA) Superfund Basic Research Program and U.S.-Mexico Binational Center for Environmental Sciences and Toxicology is to increase human capacity and information dissemination to diverse stakeholders, including federal, state, and local government agencies as well as northern Mexican and border community stakeholders. Due to Arizona's demographic characteristics and the UA's proximity to the U.S. - Mexico border, activities target primarily Mexican and Mexican-American populations. With this in mind, a model has been established that pulls from human capital, community-based participatory research and public participation theories. The theories applied to our target population have resulted in the creation of a successful model that is used in both research translation and community outreach work. The model contains four components: community needs (participation), science translation (information), engagement (outreach), and training (education). Examples of how this model operates for various stakeholders involved in environmental science and health issues will be discussed. A case in point of how this model has been applied effectively is the partnership with promotoras (community health advocates) to do environmental science and health trainings to increase the knowledge base of specific populations disproportionately exposed to contaminants of concern. Additional case studies and methodologies used to develop innovative communicative tools (that takes into consideration cultural idiosyncrasies) for stakeholders at all levels in Arizona, the border, and Mexico will be highlighted, such as: 1) information sheets regarding local environmental issues for communities neighboring contaminated sites, 2) SciTransfer Bulletins targeting professional level stakeholders such as Project Managers, Community Involvement Coordinators and the general public, 3) coordinating technical and scientific workshops in the U.S and Mexico and 4) participating in local community events. Lessons learned and knowledge gained in the past three years will also be presented.

Handheld single photon emission computed tomography (handheld SPECT) navigated video-assisted thoracoscopic surgery of computer tomography-guided radioactively marked pulmonary lesions.

PubMed

Müller, Joachim; Putora, Paul Martin; Schneider, Tino; Zeisel, Christoph; Brutsche, Martin; Baty, Florent; Markus, Alexander; Kick, Jochen

2016-09-01

Radioactive marking can be a valuable extension to minimally invasive surgery. The technique has been clinically applied in procedures involving sentinel lymph nodes, parathyroidectomy as well as interventions in thoracic surgery. Improvements in equipment and techniques allow one to improve the limits. Pulmonary nodules are frequently surgically removed for diagnostic or therapeutic reasons; here video-assisted thoracoscopic surgery (VATS) is the preferred technique. VATS might be impossible with nodules that are small or located deep in the lung. In this study, we examined the clinical application and safety of employing the newly developed handheld single photon emission tomography (handheld SPECT) device in combination with CT-guided radioactive marking of pulmonary nodules. In this pilot study, 10 subjects requiring surgical resection of a pulmonary nodule were included. The technique involved CT-guided marking of the target nodule with a 20-G needle, with subsequent injection of 25-30 MBq (effective: 7-14 MBq) Tc-99m MAA (Macro Albumin Aggregate). Quality control was made with conventional SPECT-CT to confirm the correct localization and exclude possible complications related to the puncture procedure. VATS was subsequently carried out using the handheld SPECT to localize the radioactivity intraoperatively and therefore the target nodule. A 3D virtual image was superimposed on the intraoperative visual image for surgical guidance. In 9 of the 10 subjects, the radioactive application was successfully placed directly in or in the immediate vicinity of the target nodule. The average size of the involved nodules was 9 mm (range 4-15). All successfully marked nodules were subsequently completely excised (R0) using VATS. The procedure was well tolerated. An asymptomatic clinically insignificant pneumothorax occurred in 5 subjects. Two subjects were found to have non-significant discrete haemorrhage in the infiltration canal of the needle. In a single subject, the radioactive marking was unsuccessful because the radioactivity spread into the pleural space. In our series of 10 patients, it was demonstrated that using handheld SPECT in conjunction with VATS to remove radioactively marked pulmonary nodules is feasible. The combination of proven surgical techniques with a novel localization device (handheld SPECT) allowed successful VATS excision of pulmonary nodules which, due to their localization and small size, would typically have required thoracotomy. ClinicalTrials.gov, NCT02050724, Public 01/29/214, Joachim Müller. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Cortical Recruitment and Nuclear–Cytoplasmic Shuttling of Scd5p, a Protein Phosphatase-1-targeting Protein Involved in Actin Organization and EndocytosisD⃞

PubMed Central

Chang, Ji Suk; Henry, Kenneth; Geli, María Isabel; Lemmon, Sandra K.

2006-01-01

Scd5p regulates endocytosis and cortical actin organization as a targeting subunit for the Ser/Thr protein phosphatase-1 (PP1) in yeast. To identify localization signals in Scd5p required for cell surface recruitment, visualization of GFP-tagged Scd5 truncations and deletions was performed. Scd5p contains a PP1 binding site, a 3-repeat region of 20 amino acids (3R), and a 9-repeat region of 12 amino acids (9R). We found that the 9R is critical for cortical localization of Scd5p, but cortical recruitment is not essential for Scd5p's function in actin organization and endocytosis. We propose that Scd5p can target PP1 to endocytic factors in the cytoplasm that have been disassembled and/or inactivated by phosphorylation. We also found that Scd5p undergoes nuclear-cytoplasmic shuttling in a Crm1p-dependent manner. Scd5p-ΔCT lacking the 9R region and its nuclear export signal (NES) accumulates in the nucleus, causing cortical actin and endocytic defects. Cytoplasmic localization and function of Scd5p-ΔCT is restored by NES addition. However, removal of Scd5p's nuclear localization signal prevents nuclear entry, but endocytosis and actin organization remain relatively normal. These results indicate that nuclear-cytoplasmic shuttling is not required for regulation of Scd5p's cortical function and suggest that Scd5p has an independent nuclear function. PMID:16251346

Multiple-object tracking while driving: the multiple-vehicle tracking task.

PubMed

Lochner, Martin J; Trick, Lana M

2014-11-01

Many contend that driving an automobile involves multiple-object tracking. At this point, no one has tested this idea, and it is unclear how multiple-object tracking would coordinate with the other activities involved in driving. To address some of the initial and most basic questions about multiple-object tracking while driving, we modified the tracking task for use in a driving simulator, creating the multiple-vehicle tracking task. In Experiment 1, we employed a dual-task methodology to determine whether there was interference between tracking and driving. Findings suggest that although it is possible to track multiple vehicles while driving, driving reduces tracking performance, and tracking compromises headway and lane position maintenance while driving. Modified change-detection paradigms were used to assess whether there were change localization advantages for tracked targets in multiple-vehicle tracking. When changes occurred during a blanking interval, drivers were more accurate (Experiment 2a) and ~250 ms faster (Experiment 2b) at locating the vehicle that changed when it was a target rather than a distractor in tracking. In a more realistic driving task where drivers had to brake in response to the sudden onset of brake lights in one of the lead vehicles, drivers were more accurate at localizing the vehicle that braked if it was a tracking target, although there was no advantage in terms of braking response time. Overall, results suggest that multiple-object tracking is possible while driving and perhaps even advantageous in some situations, but further research is required to determine whether multiple-object tracking is actually used in day-to-day driving.

Towards environmentally sustainable human behaviour: targeting non-conscious and conscious processes for effective and acceptable policies

NASA Astrophysics Data System (ADS)

Marteau, Theresa M.

2017-05-01

Meeting climate change targets to limit global warming to 2°C requires rapid and large reductions in demand for products that most contribute to greenhouse gas (GHG) emissions. These include production of bulk materials (e.g. steel and cement), energy supply (e.g. fossil fuels) and animal source foods (particularly ruminants and their products). Effective strategies to meet these targets require transformative changes in supply as well as demand, involving changes in economic, political and legal systems at local, national and international levels, building on evidence from many disciplines. This paper outlines contributions from behavioural science in reducing demand. Grounded in dual-process models of human behaviour (involving non-conscious and conscious processes) this paper considers first why interventions aimed at changing population values towards the environment are usually insufficient or unnecessary for reducing demand although they may be important in increasing public acceptability of policies that could reduce demand. It then outlines two sets of evidence from behavioural science towards effective systems-based strategies, to identify interventions likely to be effective at: (i) reducing demand for products that contribute most to GHG emissions, mainly targeting non-conscious processes and (ii) increasing public acceptability for policy changes to enable these interventions, targeting conscious processes. This article is part of the themed issue 'Material demand reduction'.

Towards environmentally sustainable human behaviour: targeting non-conscious and conscious processes for effective and acceptable policies.

PubMed

Marteau, Theresa M

2017-06-13

Meeting climate change targets to limit global warming to 2°C requires rapid and large reductions in demand for products that most contribute to greenhouse gas (GHG) emissions. These include production of bulk materials (e.g. steel and cement), energy supply (e.g. fossil fuels) and animal source foods (particularly ruminants and their products). Effective strategies to meet these targets require transformative changes in supply as well as demand, involving changes in economic, political and legal systems at local, national and international levels, building on evidence from many disciplines. This paper outlines contributions from behavioural science in reducing demand. Grounded in dual-process models of human behaviour (involving non-conscious and conscious processes) this paper considers first why interventions aimed at changing population values towards the environment are usually insufficient or unnecessary for reducing demand although they may be important in increasing public acceptability of policies that could reduce demand. It then outlines two sets of evidence from behavioural science towards effective systems-based strategies, to identify interventions likely to be effective at: (i) reducing demand for products that contribute most to GHG emissions, mainly targeting non-conscious processes and (ii) increasing public acceptability for policy changes to enable these interventions, targeting conscious processes.This article is part of the themed issue 'Material demand reduction'. © 2017 The Authors.

Towards environmentally sustainable human behaviour: targeting non-conscious and conscious processes for effective and acceptable policies

PubMed Central

2017-01-01

Meeting climate change targets to limit global warming to 2°C requires rapid and large reductions in demand for products that most contribute to greenhouse gas (GHG) emissions. These include production of bulk materials (e.g. steel and cement), energy supply (e.g. fossil fuels) and animal source foods (particularly ruminants and their products). Effective strategies to meet these targets require transformative changes in supply as well as demand, involving changes in economic, political and legal systems at local, national and international levels, building on evidence from many disciplines. This paper outlines contributions from behavioural science in reducing demand. Grounded in dual-process models of human behaviour (involving non-conscious and conscious processes) this paper considers first why interventions aimed at changing population values towards the environment are usually insufficient or unnecessary for reducing demand although they may be important in increasing public acceptability of policies that could reduce demand. It then outlines two sets of evidence from behavioural science towards effective systems-based strategies, to identify interventions likely to be effective at: (i) reducing demand for products that contribute most to GHG emissions, mainly targeting non-conscious processes and (ii) increasing public acceptability for policy changes to enable these interventions, targeting conscious processes. This article is part of the themed issue ‘Material demand reduction’. PMID:28461435

microRNA-122 target sites in the hepatitis C virus RNA NS5B coding region and 3' untranslated region: function in replication and influence of RNA secondary structure.

PubMed

Gerresheim, Gesche K; Dünnes, Nadia; Nieder-Röhrmann, Anika; Shalamova, Lyudmila A; Fricke, Markus; Hofacker, Ivo; Höner Zu Siederdissen, Christian; Marz, Manja; Niepmann, Michael

2017-02-01

We have analyzed the binding of the liver-specific microRNA-122 (miR-122) to three conserved target sites of hepatitis C virus (HCV) RNA, two in the non-structural protein 5B (NS5B) coding region and one in the 3' untranslated region (3'UTR). miR-122 binding efficiency strongly depends on target site accessibility under conditions when the range of flanking sequences available for the formation of local RNA secondary structures changes. Our results indicate that the particular sequence feature that contributes most to the correlation between target site accessibility and binding strength varies between different target sites. This suggests that the dynamics of miRNA/Ago2 binding not only depends on the target site itself but also on flanking sequence context to a considerable extent, in particular in a small viral genome in which strong selection constraints act on coding sequence and overlapping cis-signals and model the accessibility of cis-signals. In full-length genomes, single and combination mutations in the miR-122 target sites reveal that site 5B.2 is positively involved in regulating overall genome replication efficiency, whereas mutation of site 5B.3 showed a weaker effect. Mutation of the 3'UTR site and double or triple mutants showed no significant overall effect on genome replication, whereas in a translation reporter RNA, the 3'UTR target site inhibits translation directed by the HCV 5'UTR. Thus, the miR-122 target sites in the 3'-region of the HCV genome are involved in a complex interplay in regulating different steps of the HCV replication cycle.

Guidelines for Commanders and Staffs: How to Engage With Local Societies During Military Operations

DTIC Science & Technology

2010-11-01

elements (features, traits, hallmarks, etc.) a given society considers the basis of their collective identity. Culture involves a great variety of fields... against a culture may contribute to escalate the conflict and make the personnel become targets in the conflict. 8. WHERE CAN THE KNOWLEDGE ABOUT THE...courtesy); attitudes; confidence; accept food offerings; speak some words in their language; treat women as invisible. 2. Means to

Energetics of impulsive solar flares: Correlating BATSE hard x-ray bursts and the solar atmosphere's soft x-ray response

NASA Technical Reports Server (NTRS)

Newton, Elizabeth

1996-01-01

This investigation has involved the correlation of BATSE-observed solar hard X-ray emission with the characteristics of soft X-ray emitting plasma observed by the Yohkoh Bragg Crystal Spectrometers. The goal was to test the hypothesis that localized electron beam heating is the dominant energy transport mechanism in impulsive flares, as formulated in the thick-target electron-heated model of Brown.

IRF8 Governs Expression of Genes Involved in Innate and Adaptive Immunity in Human and Mouse Germinal Center B Cells

PubMed Central

Morse, Herbert C.

2011-01-01

IRF8 (Interferon Regulatory Factor 8) is a transcription factor expressed throughout B cell differentiation except for mature plasma cells. Previous studies showed it is part of the transcriptional network governing B cell specification and commitment in the bone marrow, regulates the distribution of mature B cells into the splenic follicular and marginal zone compartments, and is expressed at highest levels in germinal center (GC) B cells. Here, we investigated the transcriptional programs and signaling pathways affected by IRF8 in human and mouse GC B cells as defined by ChIP-chip analyses and transcriptional profiling. We show that IRF8 binds a large number of genes by targeting two distinct motifs, half of which are also targeted by PU.1. Over 70% of the binding sites localized to proximal and distal promoter regions with ∼25% being intragenic. There was significant enrichment among targeted genes for those involved in innate and adaptive immunity with over 30% previously defined as interferon stimulated genes. We also showed that IRF8 target genes contributes to multiple aspects of the biology of mature B cells including critical components of the molecular crosstalk among GC B cells, T follicular helper cells, and follicular dendritic cells. PMID:22096565

Therapies targeting cancer stem cells: Current trends and future challenges

PubMed Central

Dragu, Denisa L; Necula, Laura G; Bleotu, Coralia; Diaconu, Carmen C; Chivu-Economescu, Mihaela

2015-01-01

Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells (CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a long-lasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of miRNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers. PMID:26516409

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

Membrane-localized ubiquitin ligase ATL15 functions in sugar-responsive growth regulation in Arabidopsis.

PubMed

Aoyama, Shoki; Terada, Saki; Sanagi, Miho; Hasegawa, Yoko; Lu, Yu; Morita, Yoshie; Chiba, Yukako; Sato, Takeo; Yamaguchi, Junji

2017-09-09

Ubiquitin ligases play important roles in regulating various cellular processes by modulating the protein function of specific ubiquitination targets. The Arabidopsis Tóxicos en Levadura (ATL) family is a group of plant-specific RING-type ubiquitin ligases that localize to membranes via their N-terminal transmembrane-like domains. To date, 91 ATL isoforms have been identified in the Arabidopsis genome, with several ATLs reported to be involved in regulating plant responses to environmental stresses. However, the functions of most ATLs remain unknown. This study, involving transcriptome database analysis, identifies ATL15 as a sugar responsive ATL gene in Arabidopsis. ATL15 expression was rapidly down-regulated in the presence of sugar. The ATL15 protein showed ubiquitin ligase activity in vitro and localized to plasma membrane and endomembrane compartments. Further genetic analyses demonstrated that the atl15 knockout mutants are insensitive to high glucose concentrations, whereas ATL15 overexpression depresses plant growth. In addition, endogenous glucose and starch amounts were reciprocally affected in the atl15 knockout mutants and the ATL15 overexpressors. These results suggest that ATL15 protein plays a significant role as a membrane-localized ubiquitin ligase that regulates sugar-responsive plant growth in Arabidopsis. Copyright © 2017 Elsevier Inc. All rights reserved.

Combining local and global limitations of visual search.

PubMed

Põder, Endel

2017-04-01

There are different opinions about the roles of local interactions and central processing capacity in visual search. This study attempts to clarify the problem using a new version of relevant set cueing. A central precue indicates two symmetrical segments (that may contain a target object) within a circular array of objects presented briefly around the fixation point. The number of objects in the relevant segments, and density of objects in the array were varied independently. Three types of search experiments were run: (a) search for a simple visual feature (color, size, and orientation); (b) conjunctions of simple features; and (c) spatial configuration of simple features (rotated Ts). For spatial configuration stimuli, the results were consistent with a fixed global processing capacity and standard crowding zones. For simple features and their conjunctions, the results were different, dependent on the features involved. While color search exhibits virtually no capacity limits or crowding, search for an orientation target was limited by both. Results for conjunctions of features can be partly explained by the results from the respective features. This study shows that visual search is limited by both local interference and global capacity, and the limitations are different for different visual features.

Bidirectional Lipid Droplet Velocities Are Controlled by Differential Binding Strengths of HCV Core DII Protein

PubMed Central

Lyn, Rodney K.; Hope, Graham; Sherratt, Allison R.; McLauchlan, John; Pezacki, John Paul

2013-01-01

Host cell lipid droplets (LD) are essential in the hepatitis C virus (HCV) life cycle and are targeted by the viral capsid core protein. Core-coated LDs accumulate in the perinuclear region and facilitate viral particle assembly, but it is unclear how mobility of these LDs is directed by core. Herein we used two-photon fluorescence, differential interference contrast imaging, and coherent anti-Stokes Raman scattering microscopies, to reveal novel core-mediated changes to LD dynamics. Expression of core protein’s lipid binding domain II (DII-core) induced slower LD speeds, but did not affect directionality of movement on microtubules. Modulating the LD binding strength of DII-core further impacted LD mobility, revealing the temporal effects of LD-bound DII-core. These results for DII-core coated LDs support a model for core-mediated LD localization that involves core slowing down the rate of movement of LDs until localization at the perinuclear region is accomplished where LD movement ceases. The guided localization of LDs by HCV core protein not only is essential to the viral life cycle but also poses an interesting target for the development of antiviral strategies against HCV. PMID:24223760

WNK4 enhances the degradation of NCC through a sortilin-mediated lysosomal pathway.

PubMed

Zhou, Bo; Zhuang, Jieqiu; Gu, Dingying; Wang, Hua; Cebotaru, Liudmila; Guggino, William B; Cai, Hui

2010-01-01

WNK kinase is a serine/threonine kinase that plays an important role in electrolyte homeostasis. WNK4 significantly inhibits the surface expression of the sodium chloride co-transporter (NCC) by enhancing the degradation of NCC through a lysosomal pathway, but the mechanisms underlying this trafficking are unknown. Here, we investigated the effect of the lysosomal targeting receptor sortilin on NCC expression and degradation. In Cos-7 cells, we observed that the presence of WNK4 reduced the steady-state amount of NCC by approximately half. Co-transfection with truncated sortilin (a dominant negative mutant) prevented this WNK4-induced reduction in NCC. NCC immunoprecipitated with both wild-type sortilin and, to a lesser extent, truncated sortilin. Immunostaining revealed that WNK4 increased the co-localization of NCC with the lysosomal marker cathepsin D, and NCC co-localized with wild-type sortilin, truncated sortilin, and WNK4 in the perinuclear region. These findings suggest that WNK4 promotes NCC targeting to the lysosome for degradation via a mechanism involving sortilin.

Identification of Ski as a target for Aurora A kinase

PubMed Central

Mosquera, Jocelyn; Armisen, Ricardo; Zhao, Hong Ling; Rojas, Diego A.; Maldonado, Edio; Tapia, Julio C; Colombo, Alicia; Hayman, Michael J; Marcelain, Katherine

2011-01-01

Ski is a negative regulator of the transforming growth factor-β and other signalling pathways. The absence of SKI in mouse fibroblasts leads to chromosome segregation defects and genomic instability, suggesting a role for Ski during mitosis. At this stage, Ski is phosphorylated but to date little is known about the kinases involved in this process. Here, we show that Aurora A kinase is able to phosphorylate Ski in vitro. In vivo, Aurora A and Ski co-localized at the centrosomes and co-immunoprecipitated. Conversely, a C-terminal truncation mutant of Ski (SkiΔ491–728) lacking a coiled-coil domain, displayed decreased centrosomal localization. This mutant no longer co-immunoprecipitated with Aurora-A in vivo, but was still phosphorylated in vitro, indicating that the Ski-Aurora A interaction takes place at the centrosomes. These data identify Ski as a novel target of Aurora A and contribute to an understanding of the role of these proteins in the mitotic process. PMID:21600873

Virtual local target method for avoiding local minimum in potential field based robot navigation.

PubMed

Zou, Xi-Yong; Zhu, Jing

2003-01-01

A novel robot navigation algorithm with global path generation capability is presented. Local minimum is a most intractable but is an encountered frequently problem in potential field based robot navigation. Through appointing appropriately some virtual local targets on the journey, it can be solved effectively. The key concept employed in this algorithm are the rules that govern when and how to appoint these virtual local targets. When the robot finds itself in danger of local minimum, a virtual local target is appointed to replace the global goal temporarily according to the rules. After the virtual target is reached, the robot continues on its journey by heading towards the global goal. The algorithm prevents the robot from running into local minima anymore. Simulation results showed that it is very effective in complex obstacle environments.

Operational efficiency and sustainability of vector control of malaria and dengue: descriptive case studies from the Philippines

PubMed Central

2012-01-01

Background Analysis is lacking on the management of vector control systems in disease-endemic countries with respect to the efficiency and sustainability of operations. Methods Three locations were selected, at the scale of province, municipality and barangay (i.e. village). Data on disease incidence, programme activities, and programme management were collected on-site through meetings and focus group discussions. Results Adaptation of disease control strategies to the epidemiological situation per barangay, through micro-stratification, brings gains in efficiency, but should be accompanied by further capacity building on local situational analysis for better selection and targeting of vector control interventions within the barangay. An integrated approach to vector control, aiming to improve the rational use of resources, was evident with a multi-disease strategy for detection and response, and by the use of combinations of vector control methods. Collaboration within the health sector was apparent from the involvement of barangay health workers, re-orientation of job descriptions and the creation of a disease surveillance unit. The engagement of barangay leaders and use of existing community structures helped mobilize local resources and voluntary services for vector control. In one location, local authorities and the community were involved in the planning, implementation and evaluation of malaria control, which triggered local programme ownership. Conclusions Strategies that contributed to an improved efficiency and sustainability of vector control operations were: micro-stratification, integration of vector control within the health sector, a multi-disease approach, involvement of local authorities, and empowerment of communities. Capacity building on situational analysis and vector surveillance should be addressed through national policy and guidelines. PMID:22873707

Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.

PubMed

Toh, Seok-Ming; Xiong, Liqun; Arias, Cesar A; Villegas, Maria V; Lolans, Karen; Quinn, John; Mankin, Alexander S

2007-06-01

Linezolid, which targets the ribosome, is a new synthetic antibiotic that is used for treatment of infections caused by Gram-positive pathogens. Clinical resistance to linezolid, so far, has been developing only slowly and has involved exclusively target site mutations. We have discovered that linezolid resistance in a methicillin-resistant Staphylococcus aureus hospital strain from Colombia is determined by the presence of the cfr gene whose product, Cfr methyltransferase, modifies adenosine at position 2503 in 23S rRNA in the large ribosomal subunit. The molecular model of the linezolid-ribosome complex reveals localization of A2503 within the drug binding site. The natural function of cfr likely involves protection against natural antibiotics whose site of action overlaps that of linezolid. In the chromosome of the clinical strain, cfr is linked to ermB, a gene responsible for dimethylation of A2058 in 23S rRNA. Coexpression of these two genes confers resistance to all the clinically relevant antibiotics that target the large ribosomal subunit. The association of the ermB/cfr operon with transposon and plasmid genetic elements indicates its possible mobile nature. This is the first example of clinical resistance to the synthetic drug linezolid which involves a natural resistance gene with the capability of disseminating among Gram-positive pathogenic strains.

Structural insights into the osteopontin-aptamer complex y molecular dynamics simulations

NASA Astrophysics Data System (ADS)

La Penna, Giovanni; Chelli, Riccardo

2018-01-01

Osteopontin is an intrinsically disordered protein involved in tissue remodeling. As a biomarker for pathological hypertrophy and fibrosis, the protein is targeted by an RNA aptamer. In this work, we model the interactions between osteopontin and its aptamer, including mono- (Na+) and divalent (Mg2+) cations. The molecular dynamics simulations suggest that the presence of divalent cations forces the N-terminus of osteopontin to bind the shell of divalent cations adsorbed over the surface of its RNA aptamer, the latter exposing a high negative charge density. The osteopontin plasticity as a function of the local concentration of Mg is discussed in the frame of the proposed strategies for osteopontin targeting as biomarker and in theranostic.

Policy and Administrative Issues for Large-Scale Clinical Interventions Following Disasters

PubMed Central

Cobham, Vanessa E.; McDermott, Brett

2014-01-01

Abstract Objective: Large, programmatic mental health intervention programs for children and adolescents following disasters have become increasingly common; however, little has been written about the key goals and challenges involved. Methods: Using available data and the authors' experiences, this article reviews the factors involved in planning and implementing large-scale treatment programs following disasters. Results: These issues include funding, administration, choice of clinical targets, workforce selection, choice of treatment modalities, training, outcome monitoring, and consumer uptake. Ten factors are suggested for choosing among treatment modalities: 1) reach (providing access to the greatest number), 2) retention of patients, 3) privacy, 4) parental involvement, 5) familiarity of the modality to clinicians, 6) intensity (intervention type matches symptom acuity and impairment of patient), 7) burden to the clinician (in terms of time, travel, and inconvenience), 8) cost, 9) technology needs, and 10) effect size. Traditionally, after every new disaster, local leaders who have never done so before have had to be recruited to design, administer, and implement programs. Conclusion: As expertise in all of these areas represents a gap for most local professionals in disaster-affected areas, we propose that a central, nongovernmental agency with national or international scope be created that can consult flexibly with local leaders following disasters on both overarching and specific issues. We propose recommendations and point out areas in greatest need of innovation. PMID:24521227

MYCN acts as a direct co-regulator of p53 in MYCN amplified neuroblastoma.

PubMed

Agarwal, Saurabh; Milazzo, Giorgio; Rajapakshe, Kimal; Bernardi, Ronald; Chen, Zaowen; Barberi, Eveline; Koster, Jan; Perini, Giovanni; Coarfa, Cristian; Shohet, Jason M

2018-04-17

The MYC oncogenes and p53 have opposing yet interrelated roles in normal development and tumorigenesis. How MYCN expression alters the biology and clinical responsiveness of pediatric neuroblastoma remains poorly defined. Neuroblastoma is p53 wild type at diagnosis and repression of p53 signaling is required for tumorigenesis. Here, we tested the hypothesis that MYCN amplification alters p53 transcriptional activity in neuroblastoma. Interestingly, we found that MYCN directly binds to the tetrameric form of p53 at its C-terminal domain, and this interaction is independent of MYCN/MAX heterodimer formation. Chromatin analysis of MYCN and p53 targets reveals dramatic changes in binding, as well as co-localization of the MYCN-p53 complex at p53-REs and E-boxes of genes critical to DNA damage responses and cell cycle progression. RNA sequencing studies show that MYCN-p53 co-localization significantly modulated the expression of p53 target genes. Furthermore, MYCN-p53 interaction leads to regulation of alternative p53 targets not regulated in the presence of low MYCN levels. These novel targets include a number of genes involved in lipid metabolism, DNA repair, and apoptosis. Taken together, our findings demonstrate a novel oncogenic role of MYCN as a transcriptional co-regulator of p53 in high-risk MYCN amplified neuroblastoma. Targeting this novel oncogenic function of MYCN may enhance p53-mediated responses and sensitize MYCN amplified tumors to chemotherapy.

Lipid transfer protein 3 as a target of MYB96 mediates freezing and drought stress in Arabidopsis

PubMed Central

Yang, Shuhua

2013-01-01

Several lipid-transfer proteins were reported to modulate the plant response to biotic stress; however, whether lipid-transfer proteins are also involved in abiotic stress remains unknown. This study characterized the function of a lipid-transfer protein, LTP3, during freezing and drought stress. LTP3 was expressed ubiquitously and the LTP3 protein was localized to the cytoplasm. A biochemical study showed that LTP3 was able to bind to lipids. Overexpression of LTP3 resulted in constitutively enhanced freezing tolerance without affecting the expression of CBFs and their target COR genes. Further analyses showed that LTP3 was positively regulated by MYB96 via the direct binding to the LTP3 promoter; consistently, transgenic plants overexpressing MYB96 exhibited enhanced freezing tolerance. This study also found that the loss-of-function mutant ltp3 was sensitive to drought stress, whereas overexpressing plants were drought tolerant, phenotypes reminiscent of myb96 mutant plants and MYB96-overexpressing plants. Taken together, these results demonstrate that LTP3 acts as a target of MYB96 to be involved in plant tolerance to freezing and drought stress. PMID:23404903

Out of the net: An agent-based model to study human movements influence on local-scale malaria transmission.

PubMed

Pizzitutti, Francesco; Pan, William; Feingold, Beth; Zaitchik, Ben; Álvarez, Carlos A; Mena, Carlos F

2018-01-01

Though malaria control initiatives have markedly reduced malaria prevalence in recent decades, global eradication is far from actuality. Recent studies show that environmental and social heterogeneities in low-transmission settings have an increased weight in shaping malaria micro-epidemiology. New integrated and more localized control strategies should be developed and tested. Here we present a set of agent-based models designed to study the influence of local scale human movements on local scale malaria transmission in a typical Amazon environment, where malaria is transmission is low and strongly connected with seasonal riverine flooding. The agent-based simulations show that the overall malaria incidence is essentially not influenced by local scale human movements. In contrast, the locations of malaria high risk spatial hotspots heavily depend on human movements because simulated malaria hotspots are mainly centered on farms, were laborers work during the day. The agent-based models are then used to test the effectiveness of two different malaria control strategies both designed to reduce local scale malaria incidence by targeting hotspots. The first control scenario consists in treat against mosquito bites people that, during the simulation, enter at least once inside hotspots revealed considering the actual sites where human individuals were infected. The second scenario involves the treatment of people entering in hotspots calculated assuming that the infection sites of every infected individual is located in the household where the individual lives. Simulations show that both considered scenarios perform better in controlling malaria than a randomized treatment, although targeting household hotspots shows slightly better performance.

Peripheral nerve catheters and local anesthetic infiltration in perioperative analgesia.

PubMed

Merritt, Christopher K; Mariano, Edward R; Kaye, Alan David; Lissauer, Jonathan; Mancuso, Kenneth; Prabhakar, Amit; Urman, Richard D

2014-03-01

Peripheral nerve catheters (PNCs) and local infiltration analgesia (LIA) represent valuable options for controlling perioperative pain. PNCs have been increasingly utilized to provide both surgical anesthesia and prolonged postoperative analgesia for a wide variety of procedures. PNCs can be more technically challenging to place than typical single-injection nerve blocks (SINB), and familiarity with the indications, contraindications, relevant anatomy, and appropriate technical skills is a prerequisite for the placement of any PNC. PNCs include risks of peripheral nerve injury, damage to adjacent anatomic structures, local anesthetic toxicity, intravascular injection, risks associated with motor block, risks of unnoticed injury to the insensate limb, and risks of sedation associated with PNC placement. In addition to these common risks, there are specific risks unique to each PNC insertion site. LIA strategies have emerged that seek to provide the benefit of targeted local anesthesia while minimizing collateral motor block and increasing the applicability of durable local anesthesia beyond the extremities. LIA involves the injection and/or infusion of a local anesthetic near the site of surgical incision to provide targeted analgesia. A wide variety of techniques have been described, including single-injection intraoperative wound infiltration, indwelling wound infusion catheters, and the recent high-volume LIA technique associated with joint replacement surgery. The efficacy of these techniques varies depending on specific procedures and anatomic locations. The recent incorporation of ultra-long-acting liposomal bupivacaine preparations has the potential to dramatically increase the utility of single-injection LIA. LIA represents a promising yet under-investigated method of postoperative pain control. Copyright © 2014 Elsevier Ltd. All rights reserved.

An infrared small target detection method based on multiscale local homogeneity measure

NASA Astrophysics Data System (ADS)

Nie, Jinyan; Qu, Shaocheng; Wei, Yantao; Zhang, Liming; Deng, Lizhen

2018-05-01

Infrared (IR) small target detection plays an important role in the field of image detection area owing to its intrinsic characteristics. This paper presents a multiscale local homogeneity measure (MLHM) for infrared small target detection, which can enhance the performance of IR small target detection system. Firstly, intra-patch homogeneity of the target itself and the inter-patch heterogeneity between target and the local background regions are integrated to enhance the significant of small target. Secondly, a multiscale measure based on local regions is proposed to obtain the most appropriate response. Finally, an adaptive threshold method is applied to small target segmentation. Experimental results on three different scenarios indicate that the MLHM has good performance under the interference of strong noise.

Disentangling working memory processes during spatial span assessment: a modeling analysis of preferred eye movement strategies.

PubMed

Patt, Virginie M; Thomas, Michael L; Minassian, Arpi; Geyer, Mark A; Brown, Gregory G; Perry, William

2014-01-01

The neurocognitive processes involved during classic spatial working memory (SWM) assessment were investigated by examining naturally preferred eye movement strategies. Cognitively healthy adult volunteers were tested in a computerized version of the Corsi Block-Tapping Task--a spatial span task requiring the short term maintenance of a series of locations presented in a specific order--coupled with eye tracking. Modeling analysis was developed to characterize eye-tracking patterns across all task phases, including encoding, retention, and recall. Results revealed a natural preference for local gaze maintenance during both encoding and retention, with fewer than 40% fixated targets. These findings contrasted with the stimulus retracing pattern expected during recall as a result of task demands, with 80% fixated targets. Along with participants' self-reported strategies of mentally "making shapes," these results suggest the involvement of covert attention shifts and higher order cognitive Gestalt processes during spatial span tasks, challenging instrument validity as a single measure of SWM storage capacity.

The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch.

PubMed

Mauney, Christopher H; Rogers, LeAnn C; Harris, Reuben S; Daniel, Larry W; Devarie-Baez, Nelmi O; Wu, Hanzhi; Furdui, Cristina M; Poole, Leslie B; Perrino, Fred W; Hollis, Thomas

2017-12-01

Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond "redox switch" that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.

Hydrogen peroxide - production, fate and role in redox signaling of tumor cells.

PubMed

Lennicke, Claudia; Rahn, Jette; Lichtenfels, Rudolf; Wessjohann, Ludger A; Seliger, Barbara

2015-09-14

Hydrogen peroxide (H2O2) is involved in various signal transduction pathways and cell fate decisions. The mechanism of the so called "redox signaling" includes the H2O2-mediated reversible oxidation of redox sensitive cysteine residues in enzymes and transcription factors thereby altering their activities. Depending on its intracellular concentration and localization, H2O2 exhibits either pro- or anti-apoptotic activities. In comparison to normal cells, cancer cells are characterized by an increased H2O2 production rate and an impaired redox balance thereby affecting the microenvironment as well as the anti-tumoral immune response. This article reviews the current knowledge about the intracellular production of H2O2 along with redox signaling pathways mediating either the growth or apoptosis of tumor cells. In addition it will be discussed how the targeting of H2O2-linked sources and/or signaling components involved in tumor progression and survival might lead to novel therapeutic targets.

Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment

PubMed Central

Vizi, ES; Fekete, A; Karoly, R; Mike, A

2010-01-01

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the ‘what’ of brain function, the ‘how’ of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the ‘how’ that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic–extrasynaptic receptor trafficking, neuron–glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them. PMID:20136842

Functional involvement of human discs large tumor suppressor in cytokinesis

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

Unno, Kenji; Hanada, Toshihiko; Chishti, Athar H.

2008-10-15

Cytokinesis is the final step of cell division that completes the separation of two daughter cells. We found that the human discs large (hDlg) tumor suppressor homologue is functionally involved in cytokinesis. The guanylate kinase (GUK) domain of hDlg mediates the localization of hDlg to the midbody during cytokinesis, and over-expression of the GUK domain in U2OS and HeLa cells impaired cytokinesis. Mouse embryonic fibroblasts (MEFs) derived from dlg mutant mice contained an increased number of multinucleated cells and showed reduced proliferation in culture. A kinesin-like motor protein, GAKIN, which binds directly to the GUK domain of hDlg, exhibited amore » similar intracellular distribution pattern with hDlg throughout mitosis and localized to the midbody during cytokinesis. However, the targeting of hDlg and GAKIN to the midbody appeared to be independent of each other. The midbody localization of GAKIN required its functional kinesin-motor domain. Treatment of cells with the siRNA specific for hDlg and GAKIN caused formation of multinucleated cells and delayed cytokinesis. Together, these results suggest that hDlg and GAKIN play functional roles in the maintenance of midbody architecture during cytokinesis.« less

Purification and immunolocalization of an annexin-like protein in pea seedlings

NASA Technical Reports Server (NTRS)

Clark, G. B.; Dauwalder, M.; Roux, S. J.

1992-01-01

As part of a study to identify potential targets of calcium action in plant cells, a 35-kDa, annexin-like protein was purified from pea (Pisum sativum L.) plumules by a method used to purify animal annexins. This protein, called p35, binds to a phosphatidylserine affinity column in a calcium-dependent manner and binds 45Ca2+ in a dot-blot assay. Preliminary sequence data confirm a relationship for p35 with the annexin family of proteins. Polyclonal antibodies have been raised which recognize p35 in Western and dot blots. Immunofluorescence and immunogold techniques were used to study the distribution and subcellular localization of p35 in pea plumules and roots. The highest levels of immunostain were found in young developing vascular cells producing wall thickenings and in peripheral root-cap cells releasing slime. This localization in cells which are actively involved in secretion is of interest because one function suggested for the animal annexins is involvement in the mediation of exocytosis.

Pediatric Scleroderma –Systemic and Localized Forms

PubMed Central

Torok, Kathryn S.

2012-01-01

Synopsis statement Pediatric scleroderma includes two major groups of clinical entities, systemic sclerosis (SSc) and localized scleroderma (LS). Although both share a common pathophysiology, with an initial inflammatory phase associated with endothelial activation, and a later fibrotic phase evidenced by collagenization of tissue and appreciable skin thickness, their clinical manifestations differ. LS is typically confined to the skin and underlying subcutis, and though not fatal like SSc, up to a quarter of the patients may have extracutaneous disease manifestations, such as arthritis and uveitis. While any organ may be affected in SSc, vascular (Raynaud’s phenomenon), cutaneous (skin thickening), GI, pulmonary and musculoskeletal involvement are most commonly seen in children. Auto-antibody profiles in childhood onset SSc can assist in predicting internal organ involvement. Treatment for both forms of scleroderma targets the active inflammatory stage and halts disease progression; however, progress still needs to be made towards the development of a more effective anti-fibrotic therapy to help reverse disease damage. PMID:22560576

Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

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

Wada, Takeyoshi; Asahi, Toru; Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480

2016-08-26

The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as amore » thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. - Highlights: • We found that CRBN is a nucleocytoplasmic shutting protein and identified the key domain for nucleocytoplasmic shuttling. • CRBN associates with the transcription factor Ikaros via the N-terminal domain. • CRBN modulates Ikaros-mediated transcriptional regulation and its downstream target, enkephalin.« less

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

NASA Astrophysics Data System (ADS)

Rababaah, Haroun; Shirkhodaie, Amir

2008-04-01

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

Classic Nuclear Localization Signals and a Novel Nuclear Localization Motif Are Required for Nuclear Transport of Porcine Parvovirus Capsid Proteins

PubMed Central

Boisvert, Maude; Bouchard-Lévesque, Véronique; Fernandes, Sandra

2014-01-01

ABSTRACT Nuclear targeting of capsid proteins (VPs) is important for genome delivery and precedes assembly in the replication cycle of porcine parvovirus (PPV). Clusters of basic amino acids, corresponding to potential nuclear localization signals (NLS), were found only in the unique region of VP1 (VP1up, for VP1 unique part). Of the five identified basic regions (BR), three were important for nuclear localization of VP1up: BR1 was a classic Pat7 NLS, and the combination of BR4 and BR5 was a classic bipartite NLS. These NLS were essential for viral replication. VP2, the major capsid protein, lacked these NLS and contained no region with more than two basic amino acids in proximity. However, three regions of basic clusters were identified in the folded protein, assembled into a trimeric structure. Mutagenesis experiments showed that only one of these three regions was involved in VP2 transport to the nucleus. This structural NLS, termed the nuclear localization motif (NLM), is located inside the assembled capsid and thus can be used to transport trimers to the nucleus in late steps of infection but not for virions in initial infection steps. The two NLS of VP1up are located in the N-terminal part of the protein, externalized from the capsid during endosomal transit, exposing them for nuclear targeting during early steps of infection. Globally, the determinants of nuclear transport of structural proteins of PPV were different from those of closely related parvoviruses. IMPORTANCE Most DNA viruses use the nucleus for their replication cycle. Thus, structural proteins need to be targeted to this cellular compartment at two distinct steps of the infection: in early steps to deliver viral genomes to the nucleus and in late steps to assemble new viruses. Nuclear targeting of proteins depends on the recognition of a stretch of basic amino acids by cellular transport proteins. This study reports the identification of two classic nuclear localization signals in the minor capsid protein (VP1) of porcine parvovirus. The major protein (VP2) nuclear localization was shown to depend on a complex structural motif. This motif can be used as a strategy by the virus to avoid transport of incorrectly folded proteins and to selectively import assembled trimers into the nucleus. Structural nuclear localization motifs can also be important for nuclear proteins without a classic basic amino acid stretch, including multimeric cellular proteins. PMID:25078698

Algorithm for Automatic Detection, Localization and Characterization of Magnetic Dipole Targets Using the Laser Scalar Gradiometer

DTIC Science & Technology

2016-06-01

TECHNICAL REPORT Algorithm for Automatic Detection, Localization and Characterization of Magnetic Dipole Targets Using the Laser Scalar...Automatic Detection, Localization and Characterization of Magnetic Dipole Targets Using the Laser Scalar Gradiometer Leon Vaizer, Jesse Angle, Neil...of Magnetic Dipole Targets Using LSG i June 2016 TABLE OF CONTENTS INTRODUCTION

Enhanced flyby science with onboard computer vision: Tracking and surface feature detection at small bodies

NASA Astrophysics Data System (ADS)

Fuchs, Thomas J.; Thompson, David R.; Bue, Brian D.; Castillo-Rogez, Julie; Chien, Steve A.; Gharibian, Dero; Wagstaff, Kiri L.

2015-10-01

Spacecraft autonomy is crucial to increase the science return of optical remote sensing observations at distant primitive bodies. To date, most small bodies exploration has involved short timescale flybys that execute prescripted data collection sequences. Light time delay means that the spacecraft must operate completely autonomously without direct control from the ground, but in most cases the physical properties and morphologies of prospective targets are unknown before the flyby. Surface features of interest are highly localized, and successful observations must account for geometry and illumination constraints. Under these circumstances onboard computer vision can improve science yield by responding immediately to collected imagery. It can reacquire bad data or identify features of opportunity for additional targeted measurements. We present a comprehensive framework for onboard computer vision for flyby missions at small bodies. We introduce novel algorithms for target tracking, target segmentation, surface feature detection, and anomaly detection. The performance and generalization power are evaluated in detail using expert annotations on data sets from previous encounters with primitive bodies.

"Smart inhibition": electrophysiological evidence for the suppression of conflict-generating task rules during task switching.

PubMed

Meiran, Nachshon; Hsieh, Shulan; Chang, Chi-Chih

2011-09-01

A major challenge for task switching is maintaining a balance between high task readiness and effectively ignoring irrelevant task rules. This calls for finely tuned inhibition that targets only the source of interference without adversely influencing other task-related representations. The authors show that irrelevant task rules generating response conflict are inhibited, causing their inefficient execution on the next trial (indicating the presence of competitor rule suppression[CRS];Meiran, Hsieh, & Dimov, Journal of Experimental Psychology: Learning, Memory and Cognition, 36, 992-1002, 2010). To determine whether CRS influences task rules, rather than target stimuli or responses, the authors focused on the processing of the task cue before the target stimulus was presented and before the response could be chosen. As was predicted, CRS was found in the event-related potentials in two time windows during task cue processing. It was also found in three time windows after target presentation. Source localization analyses suggest the involvement of the right dorsal prefrontal cortex in all five time windows.

Testing neuropsychological hypotheses for cognitive deficits in psychopathic criminals: a study of global-local processing.

PubMed

Kosson, David S; Miller, Sarah K; Byrnes, Katherine A; Leveroni, Catherine L

2007-03-01

Competing hypotheses about neuropsychological mechanisms underlying psychopathy are seldom examined in the same study. We tested the left hemisphere activation hypothesis and the response modulation hypothesis of psychopathy in 172 inmates completing a global-local processing task under local bias, global bias, and neutral conditions. Consistent with the left hemisphere activation hypothesis, planned comparisons showed that psychopathic inmates classified local targets more slowly than nonpsychopathic inmates in a local bias condition and exhibited a trend toward similar deficits for global targets in this condition. However, contrary to the response modulation hypothesis, psychopaths were no slower to respond to local targets in a global bias condition. Because psychopathic inmates were not generally slower to respond to local targets, results are also not consistent with a general left hemisphere dysfunction account. Correlational analyses also indicated deficits specific to conditions presenting most targets at the local level initially. Implications for neuropsychological conceptualizations of psychopathy are considered.

PRIMAL: Page Rank-Based Indoor Mapping and Localization Using Gene-Sequenced Unlabeled WLAN Received Signal Strength

PubMed Central

Zhou, Mu; Zhang, Qiao; Xu, Kunjie; Tian, Zengshan; Wang, Yanmeng; He, Wei

2015-01-01

Due to the wide deployment of wireless local area networks (WLAN), received signal strength (RSS)-based indoor WLAN localization has attracted considerable attention in both academia and industry. In this paper, we propose a novel page rank-based indoor mapping and localization (PRIMAL) by using the gene-sequenced unlabeled WLAN RSS for simultaneous localization and mapping (SLAM). Specifically, first of all, based on the observation of the motion patterns of the people in the target environment, we use the Allen logic to construct the mobility graph to characterize the connectivity among different areas of interest. Second, the concept of gene sequencing is utilized to assemble the sporadically-collected RSS sequences into a signal graph based on the transition relations among different RSS sequences. Third, we apply the graph drawing approach to exhibit both the mobility graph and signal graph in a more readable manner. Finally, the page rank (PR) algorithm is proposed to construct the mapping from the signal graph into the mobility graph. The experimental results show that the proposed approach achieves satisfactory localization accuracy and meanwhile avoids the intensive time and labor cost involved in the conventional location fingerprinting-based indoor WLAN localization. PMID:26404274

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

Patel, Pretesh R., E-mail: patel073@mc.duke.edu; Yoo, Sua; Broadwater, Gloria

Purpose: To assess the impact of increasing experience with intensity-modulated radiation therapy (IMRT) after extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM). Methods and Materials: The records of all patients who received IMRT following EPP at Duke University Medical Center between 2005 and 2010 were reviewed. Target volumes included the preoperative extent of the pleural space, chest wall incisions, involved nodal stations, and a boost to close/positive surgical margins if applicable. Patients were typically treated with 9-11 beams with gantry angles, collimator rotations, and beam apertures manually fixed to avoid the contalateral lung and to optimize target coverage. Toxicity wasmore » graded retrospectively using National Cancer Institute common toxicity criteria version 4.0. Target coverage and contralateral lung irradiation were evaluated over time by using linear regression. Local control, disease-free survival, and overall survival rates were estimated using the Kaplan-Meier method. Results: Thirty patients received IMRT following EPP; 21 patients also received systemic chemotherapy. Median follow-up was 15 months. The median dose prescribed to the entire ipsilateral hemithorax was 45 Gy (range, 40-50.4 Gy) with a boost of 8-25 Gy in 9 patients. Median survival was 23.2 months. Two-year local control, disease-free survival, and overall survival rates were 47%, 34%, and 50%, respectively. Increasing experience planning MPM cases was associated with improved coverage of planning target volumes (P=.04). Similarly, mean lung dose (P<.01) and lung V5 (volume receiving 5 Gy or more; P<.01) values decreased with increasing experience. Lung toxicity developed after IMRT in 4 (13%) patients at a median of 2.2 months after RT (three grade 3-4 and one grade 5). Lung toxicity developed in 4 of the initial 15 patients vs none of the last 15 patients treated. Conclusions: With increasing experience, target volume coverage improved and dose to the contralateral lung decreased. Rates of pulmonary toxicity were relatively low. However, both local and distant control rates remained suboptimal.« less

Local linear regression for function learning: an analysis based on sample discrepancy.

PubMed

Cervellera, Cristiano; Macciò, Danilo

2014-11-01

Local linear regression models, a kind of nonparametric structures that locally perform a linear estimation of the target function, are analyzed in the context of empirical risk minimization (ERM) for function learning. The analysis is carried out with emphasis on geometric properties of the available data. In particular, the discrepancy of the observation points used both to build the local regression models and compute the empirical risk is considered. This allows to treat indifferently the case in which the samples come from a random external source and the one in which the input space can be freely explored. Both consistency of the ERM procedure and approximating capabilities of the estimator are analyzed, proving conditions to ensure convergence. Since the theoretical analysis shows that the estimation improves as the discrepancy of the observation points becomes smaller, low-discrepancy sequences, a family of sampling methods commonly employed for efficient numerical integration, are also analyzed. Simulation results involving two different examples of function learning are provided.

AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion

PubMed Central

Cunniff, Brian; McKenzie, Andrew J.; Heintz, Nicholas H.; Howe, Alan K.

2016-01-01

Cell migration is a complex behavior involving many energy-expensive biochemical events that iteratively alter cell shape and location. Mitochondria, the principal producers of cellular ATP, are dynamic organelles that fuse, divide, and relocate to respond to cellular metabolic demands. Using ovarian cancer cells as a model, we show that mitochondria actively infiltrate leading edge lamellipodia, thereby increasing local mitochondrial mass and relative ATP concentration and supporting a localized reversal of the Warburg shift toward aerobic glycolysis. This correlates with increased pseudopodial activity of the AMP-activated protein kinase (AMPK), a critically important cellular energy sensor and metabolic regulator. Furthermore, localized pharmacological activation of AMPK increases leading edge mitochondrial flux, ATP content, and cytoskeletal dynamics, whereas optogenetic inhibition of AMPK halts mitochondrial trafficking during both migration and the invasion of three-dimensional extracellular matrix. These observations indicate that AMPK couples local energy demands to subcellular targeting of mitochondria during cell migration and invasion. PMID:27385336

Cytosolic proteins can exploit membrane localization to trigger functional assembly

PubMed Central

2018-01-01

Cell division, endocytosis, and viral budding would not function without the localization and assembly of protein complexes on membranes. What is poorly appreciated, however, is that by localizing to membranes, proteins search in a reduced space that effectively drives up concentration. Here we derive an accurate and practical analytical theory to quantify the significance of this dimensionality reduction in regulating protein assembly on membranes. We define a simple metric, an effective equilibrium constant, that allows for quantitative comparison of protein-protein interactions with and without membrane present. To test the importance of membrane localization for driving protein assembly, we collected the protein-protein and protein-lipid affinities, protein and lipid concentrations, and volume-to-surface-area ratios for 46 interactions between 37 membrane-targeting proteins in human and yeast cells. We find that many of the protein-protein interactions between pairs of proteins involved in clathrin-mediated endocytosis in human and yeast cells can experience enormous increases in effective protein-protein affinity (10–1000 fold) due to membrane localization. Localization of binding partners thus triggers robust protein complexation, suggesting that it can play an important role in controlling the timing of endocytic protein coat formation. Our analysis shows that several other proteins involved in membrane remodeling at various organelles have similar potential to exploit localization. The theory highlights the master role of phosphoinositide lipid concentration, the volume-to-surface-area ratio, and the ratio of 3D to 2D equilibrium constants in triggering (or preventing) constitutive assembly on membranes. Our simple model provides a novel quantitative framework for interpreting or designing in vitro experiments of protein complexation influenced by membrane binding. PMID:29505559

Patterns of failure after involved field radiotherapy for locally advanced esophageal squamous cell carcinoma.

PubMed

Li, Duo-Jie; Li, Hong-Wei; He, Bin; Wang, Geng-Ming; Cai, Han-Fei; Duan, Shi-Miao; Liu, Jing-Jing; Zhang, Ya-Jun; Cui, Zhen; Jiang, Hao

2016-01-01

To retrospectively analyze the patterns of failure and the treatment effects of involved-field irradiation (IFI) on patients treated with locally advanced esophageal squamous cell carcinoma (ESCC) and to determine whether IFI is practicable in these patients. A total of 79 patients with locally advanced ESCC underwent three dimensional conformal (3D)CRT) or intensity modulated radiotherapy (IMRT) using IFI or elective nodal irradiation (ENI) according to the target volume. The patterns of failure were defined as local/regional, in-field, out)of)field regional lymph node (LN) and distant failure. With a median follow)up of 32.0 months, failures were observed in 66 (83.6%) patients. The cumulative incidence of local/regional failure (55.8 vs 52.8%) and in)field regional lymph node failure (25.6 vs 19.4%) showed no statistically significant difference between the IFI and the ENI group (p=0.526 and 0.215, respectively). Out)of)field nodal relapse rate of only 7.0% was seen in the IFI group. Three)year survival rates for the ENI and IFI group were 22.2 and 18.6%, respectively (p=0.240), and 3)year distant metastasis rates were 27.8 and 32.6%, respectively (p=0.180). The lung V10, V20, V30 and mean lung dose of the ENI group were greater than those of the IFI group, while the mean lung dose and V10 had statistically significant difference. The patterns of failure and survival rates in the IFI group were similar as in the ENI group; the regional recurrence and distant metastasis are the main cause of treatment failure. IFI is feasible for locally advanced ESCC. Further investigation is needed to increase local control and decrease distant metastasis in these patients.

Spectroscopic Imaging of Deep Tissue through Photoacoustic Detection of Molecular Vibration

PubMed Central

Wang, Pu; Rajian, Justin R.; Cheng, Ji-Xin

2013-01-01

The quantized vibration of chemical bonds provides a way of imaging target molecules in a complex tissue environment. Photoacoustic detection of harmonic vibrational transitions provides an approach to visualize tissue content beyond the ballistic photon regime. This method involves pulsed laser excitation of overtone transitions in target molecules inside a tissue. Fast relaxation of the vibrational energy into heat results in a local temperature rise on the order of mK and a subsequent generation of acoustic waves detectable with an ultrasonic transducer. In this perspective, we review recent advances that demonstrate the advantages of vibration-based photoacoustic imaging and illustrate its potential in diagnosing cardiovascular plaques. An outlook into future development of vibrational photoacoustic endoscopy and tomography is provided. PMID:24073304

Strategic Partnerships for Change in an Environmental Justice Community: The ENRRICH Study.

PubMed

Spencer-Hwang, Rhonda; Soret, Sam; Valladares, Johanny; Torres, Xochitl; Pasco-Rubio, Marco; Dougherty, Molly; Kim, Wonha; Montgomery, Susanne

San Bernardino, California, is home to the San Bernardino Railyard (SBR), a major commerce hub with high associated air-pollution, identified as an environmental justice (EJ) issue by local community and air quality agencies. Alarmingly, one elementary school is located only a few hundred yards from SBR. The school, university researchers, and a local community-based organization (CBO) established a partnership to assess potential adverse health impacts in the children and develop interventions and mitigation plans. Study results comparing target school with a demographically matched school verified community concerns finding significantly poorer respiratory health in children attending school near the railyard. Partners are working with local and state collaboratives, the school board, and funding agencies to address the resulting needs of children through education, mitigation, and prevention in an environment where necessary systems changes involving the railyard are elusive. This paper shares lessons learned in moving toward change when addressing an EJ community's health challenges.

Study of plastic strain localization mechanisms caused by nonequilibrium transitions in mesodefect ensembles under high-speed loading

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

Sokovikov, Mikhail, E-mail: sokovikov@icmm.ru; Chudinov, Vasiliy; Bilalov, Dmitry

2015-10-27

The behavior of specimens dynamically loaded during split Hopkinson (Kolsky) bar tests in a regime close to simple shear conditions was studied. The lateral surface of the specimens was investigated in-situ using a high-speed infrared camera CEDIP Silver 450M. The temperature field distribution obtained at different time allowed one to trace the evolution of plastic strain localization. The process of target perforation involving plug formation and ejection was examined using a high-speed infrared camera and a VISAR velocity measurement system. The microstructure of tested specimens was analyzed using an optical interferometer-profiler and a scanning electron microscope. The development of plasticmore » shear instability regions has been simulated numerically.« less

Quantification of DNA cleavage specificity in Hi-C experiments.

PubMed

Meluzzi, Dario; Arya, Gaurav

2016-01-08

Hi-C experiments produce large numbers of DNA sequence read pairs that are typically analyzed to deduce genomewide interactions between arbitrary loci. A key step in these experiments is the cleavage of cross-linked chromatin with a restriction endonuclease. Although this cleavage should happen specifically at the enzyme's recognition sequence, an unknown proportion of cleavage events may involve other sequences, owing to the enzyme's star activity or to random DNA breakage. A quantitative estimation of these non-specific cleavages may enable simulating realistic Hi-C read pairs for validation of downstream analyses, monitoring the reproducibility of experimental conditions and investigating biophysical properties that correlate with DNA cleavage patterns. Here we describe a computational method for analyzing Hi-C read pairs to estimate the fractions of cleavages at different possible targets. The method relies on expressing an observed local target distribution downstream of aligned reads as a linear combination of known conditional local target distributions. We validated this method using Hi-C read pairs obtained by computer simulation. Application of the method to experimental Hi-C datasets from murine cells revealed interesting similarities and differences in patterns of cleavage across the various experiments considered. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Localizing Target Structures in Ultrasound Video

PubMed Central

Kwitt, R.; Vasconcelos, N.; Razzaque, S.; Aylward, S.

2013-01-01

The problem of localizing specific anatomic structures using ultrasound (US) video is considered. This involves automatically determining when an US probe is acquiring images of a previously defined object of interest, during the course of an US examination. Localization using US is motivated by the increased availability of portable, low-cost US probes, which inspire applications where inexperienced personnel and even first-time users acquire US data that is then sent to experts for further assessment. This process is of particular interest for routine examinations in underserved populations as well as for patient triage after natural disasters and large-scale accidents, where experts may be in short supply. The proposed localization approach is motivated by research in the area of dynamic texture analysis and leverages several recent advances in the field of activity recognition. For evaluation, we introduce an annotated and publicly available database of US video, acquired on three phantoms. Several experiments reveal the challenges of applying video analysis approaches to US images and demonstrate that good localization performance is possible with the proposed solution. PMID:23746488

Targeted therapy against EGFR and VEGFR using ZD6474 enhances the therapeutic potential of UV-B phototherapy in breast cancer cells.

PubMed

Sarkar, Siddik; Rajput, Shashi; Tripathi, Amit Kumar; Mandal, Mahitosh

2013-10-20

The hypoxic environment of tumor region stimulated the up regulation of growth factors responsible for angiogenesis and tumor proliferation. Thus, targeting the tumor vasculature along with the proliferation by dual tyrosine kinase inhibitor may be the efficient way of treating advanced breast cancers, which can be further enhanced by combining with radiotherapy. However, the effectiveness of radiotherapy may be severely compromised by toxicities and tumor resistance due to radiation-induced adaptive response contributing to recurrence and metastases of breast cancer. The rational of using ZD6474 is to evaluate the feasibility and efficacy of combined VEGFR2 and EGFR targeting with concurrent targeted and localized UV-B phototherapy in vitro breast cancer cells with the anticipation to cure skin lesions infiltrated with breast cancer cells. Breast cancer cells were exposed to UV-B and ZD6474 and the cell viability, apoptosis, invasion and motility studies were conducted for the combinatorial effect. Graphs and statistical analyses were performed using Graph Pad Prism 5.0. ZD6474 and UV-B decreased cell viability in breast cancers in combinatorial manner without affecting the normal human mammary epithelial cells. ZD6474 inhibited cyclin E expression and induced p53 expression when combined with UV-B. It activated stress induced mitochondrial pathway by inducing translocation of bax and cytochrome-c. The combination of ZD6474 with UV-B vs. either agent alone also more potently down-regulated the anti-apoptotic bcl-2 protein, up-regulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3 and caspase-7 proteins, and induced poly (ADP-ribose) polymerase resulting in apoptosis. ZD6474 combined with UV-B inhibited invasion of breast cancer cells in vitro as compared to either single agent, indicating a potential involvement of pro-angiogenic growth factors in regulating the altered expression and reorganization of cytoskeletal proteins in combinatorial treated breast cancer cells. Involvement of combination therapy in reducing the expression of matrix metalloprotease was also observed. Collectively, our studies indicate that incorporating an anti-EGFR plus VEGFR strategy (ZD6474) with phototherapy (UV-B), an alternative approach to the ongoing conventional radiotherapy for the treatment of infiltrating metastatic breast cancer cells in the skin and for locally recurrence breast cancer than either approach alone.

Leucine-rich-repeat-containing variable lymphocyte receptors as modules to target plant-expressed proteins

DOE PAGES

Velásquez, André C.; Nomura, Kinya; Cooper, Max D.; ...

2017-04-19

The ability to target and manipulate protein-based cellular processes would accelerate plant research; yet, the technology to specifically and selectively target plant-expressed proteins is still in its infancy. Leucine-rich repeats (LRRs) are ubiquitously present protein domains involved in mediating protein–protein interactions. LRRs confer the binding specificity to the highly diverse variable lymphocyte receptor (VLR) antibodies (including VLRA, VLRB and VLRC types) that jawless vertebrates make as the functional equivalents of jawed vertebrate immunoglobulin-based antibodies. Here, VLRBs targeting an effector protein from a plant pathogen, HopM1, were developed by immunizing lampreys and using yeast surface display to select for high-affinity VLRBs.more » HopM1-specific VLRBs (VLRM1) were expressed in planta in the cytosol, the trans-Golgi network, and the apoplast. Expression of VLRM1 was higher when the protein localized to an oxidizing environment that would favor disulfide bridge formation (when VLRM1 was not localized to the cytoplasm), as disulfide bonds are necessary for proper VLR folding. VLRM1 specifically interacted in planta with HopM1 but not with an unrelated bacterial effector protein while HopM1 failed to interact with a non-specific VLRB. Later, VLRs may be used as flexible modules to bind proteins or carbohydrates of interest in planta, with broad possibilities for their use by binding directly to their targets and inhibiting their action, or by creating chimeric proteins with new specificities in which endogenous LRR domains are replaced by those present in VLRs.« less

Leucine-rich-repeat-containing variable lymphocyte receptors as modules to target plant-expressed proteins

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

Velásquez, André C.; Nomura, Kinya; Cooper, Max D.

The ability to target and manipulate protein-based cellular processes would accelerate plant research; yet, the technology to specifically and selectively target plant-expressed proteins is still in its infancy. Leucine-rich repeats (LRRs) are ubiquitously present protein domains involved in mediating protein–protein interactions. LRRs confer the binding specificity to the highly diverse variable lymphocyte receptor (VLR) antibodies (including VLRA, VLRB and VLRC types) that jawless vertebrates make as the functional equivalents of jawed vertebrate immunoglobulin-based antibodies. Here, VLRBs targeting an effector protein from a plant pathogen, HopM1, were developed by immunizing lampreys and using yeast surface display to select for high-affinity VLRBs.more » HopM1-specific VLRBs (VLRM1) were expressed in planta in the cytosol, the trans-Golgi network, and the apoplast. Expression of VLRM1 was higher when the protein localized to an oxidizing environment that would favor disulfide bridge formation (when VLRM1 was not localized to the cytoplasm), as disulfide bonds are necessary for proper VLR folding. VLRM1 specifically interacted in planta with HopM1 but not with an unrelated bacterial effector protein while HopM1 failed to interact with a non-specific VLRB. Later, VLRs may be used as flexible modules to bind proteins or carbohydrates of interest in planta, with broad possibilities for their use by binding directly to their targets and inhibiting their action, or by creating chimeric proteins with new specificities in which endogenous LRR domains are replaced by those present in VLRs.« less

Emergence of Protein Kinase CK2 as a Key Target in Cancer Therapy

PubMed Central

Trembley, Janeen H.; Chen, Zhong; Unger, Gretchen; Slaton, Joel; Kren, Betsy T.; Van Waes, Carter; Ahmed, Khalil

2010-01-01

Protein kinase CK2, a protein serine/threonine kinase, plays a global role in activities related to cell growth, cell death and cell survival. CK2 has a large number of potential substrates localized in diverse locations in the cell including, e.g., NF-κB as an important downstream target of the kinase. In addition to its involvement in cell growth and proliferation it is also a potent suppressor of apoptosis, raising its key importance in cancer cell phenotype. CK2 interacts with diverse pathways which illustrates the breadth of its impact on the cellular machinery of both cell growth and cell death giving it the status of a “master regulator” in the cell. With respect to cancer, CK2 has been found to be dysregulated in all cancers examined demonstrating increased protein expression levels and nuclear localization in cancer cells compared with their normal counterparts. We originally proposed CK2 as a potentially important target for cancer therapy. Given the ubiquitous and essential for cell survival nature of the kinase, an important consideration would be to target it specifically in cancer cells while sparing normal cells. Towards that end, our design of a tenascin based sub-50 nm (i.e., less than 50 nm size) nanocapsule in which an anti-CK2 therapeutic agent can be packaged is highly promising because this formulation can specifically deliver the cargo intracellularly to the cancer cells in vivo. Thus, appropriate strategies to target CK2 especially by molecular approaches may lead to a highly feasible and effective approach to eradication of a given cancer. PMID:20533398

Improvement of Aspergillus nidulans penicillin production by targeting AcvA to peroxisomes.

PubMed

Herr, Andreas; Fischer, Reinhard

2014-09-01

Aspergillus nidulans is able to synthesize penicillin and serves as a model to study the regulation of its biosynthesis. Only three enzymes are required to form the beta lactam ring tripeptide, which is comprised of l-cysteine, l-valine and l-aminoadipic acid. Whereas two enzymes, AcvA and IpnA localize to the cytoplasm, AatA resides in peroxisomes. Here, we tested a novel strategy to improve penicillin production, namely the change of the residence of the enzymes involved in the biosynthesis. We tested if targeting of AcvA or IpnA (or both) to peroxisomes would increase the penicillin yield. Indeed, AcvA peroxisomal targeting led to a 3.2-fold increase. In contrast, targeting IpnA to peroxisomes caused a complete loss of penicillin production. Overexpression of acvA, ipnA or aatA resulted in 1.4, 2.8 and 3.1-fold more penicillin, respectively in comparison to wildtype. Simultaneous overexpression of all three enzymes resulted even in 6-fold more penicillin. Combination of acvA peroxisomal targeting and overexpression of the gene led to 5-fold increase of the penicillin titer. At last, the number of peroxisomes was increased through overexpression of pexK. A strain with the double number of peroxisomes produced 2.3 times more penicillin. These results show that penicillin production can be triggered at several levels of regulation, one of which is the subcellular localization of the enzymes. Copyright © 2014 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Scene-Based Contextual Cueing in Pigeons

PubMed Central

Wasserman, Edward A.; Teng, Yuejia; Brooks, Daniel I.

2014-01-01

Repeated pairings of a particular visual context with a specific location of a target stimulus facilitate target search in humans. We explored an animal model of such contextual cueing. Pigeons had to peck a target which could appear in one of four locations on color photographs of real-world scenes. On half of the trials, each of four scenes was consistently paired with one of four possible target locations; on the other half of the trials, each of four different scenes was randomly paired with the same four possible target locations. In Experiments 1 and 2, pigeons exhibited robust contextual cueing when the context preceded the target by 1 s to 8 s, with reaction times to the target being shorter on predictive-scene trials than on random-scene trials. Pigeons also responded more frequently during the delay on predictive-scene trials than on random-scene trials; indeed, during the delay on predictive-scene trials, pigeons predominately pecked toward the location of the upcoming target, suggesting that attentional guidance contributes to contextual cueing. In Experiment 3, involving left-right and top-bottom scene reversals, pigeons exhibited stronger control by global than by local scene cues. These results attest to the robustness and associative basis of contextual cueing in pigeons. PMID:25546098

Vitamin D metabolism, sex hormones, and male reproductive function.

PubMed

Blomberg Jensen, Martin

2012-08-01

The spectrum of vitamin D (VD)-mediated effects has expanded in recent years, and VD is now recognized as a versatile signaling molecule rather than being solely a regulator of bone health and calcium homeostasis. One of the recently identified target areas of VD is male reproductive function. The VD receptor (VDR) and the VD metabolizing enzyme expression studies documented the presence of this system in the testes, mature spermatozoa, and ejaculatory tract, suggesting that both systemic and local VD metabolism may influence male reproductive function. However, it is still debated which cell is the main VD target in the testis and to what extent VD is important for sex hormone production and function of spermatozoa. This review summarizes descriptive studies on testicular VD metabolism and spatial distribution of VDR and the VD metabolizing enzymes in the mammalian testes and discusses mechanistic and association studies conducted in animals and humans. The reviewed evidence suggests some effects of VD on estrogen and testosterone biosynthesis and implicates involvement of both systemic and local VD metabolism in the regulation of male fertility potential.

Targeting of the Fun30 nucleosome remodeller by the Dpb11 scaffold facilitates cell cycle-regulated DNA end resection

PubMed Central

Bantele, Susanne CS; Ferreira, Pedro; Gritenaite, Dalia; Boos, Dominik; Pfander, Boris

2017-01-01

DNA double strand breaks (DSBs) can be repaired by either recombination-based or direct ligation-based mechanisms. Pathway choice is made at the level of DNA end resection, a nucleolytic processing step, which primes DSBs for repair by recombination. Resection is thus under cell cycle control, but additionally regulated by chromatin and nucleosome remodellers. Here, we show that both layers of control converge in the regulation of resection by the evolutionarily conserved Fun30/SMARCAD1 remodeller. Budding yeast Fun30 and human SMARCAD1 are cell cycle-regulated by interaction with the DSB-localized scaffold protein Dpb11/TOPBP1, respectively. In yeast, this protein assembly additionally comprises the 9-1-1 damage sensor, is involved in localizing Fun30 to damaged chromatin, and thus is required for efficient long-range resection of DSBs. Notably, artificial targeting of Fun30 to DSBs is sufficient to bypass the cell cycle regulation of long-range resection, indicating that chromatin remodelling during resection is underlying DSB repair pathway choice. DOI: http://dx.doi.org/10.7554/eLife.21687.001 PMID:28063255

Relationships Between Divided Attention and Working Memory Impairment in People With Schizophrenia

PubMed Central

Gray, Bradley E.; Hahn, Britta; Robinson, Benjamin; Harvey, Alex; Leonard, Carly J.; Luck, Steven J.; Gold, James M.

2014-01-01

Recent studies suggest that people with schizophrenia (PSZ) have difficulty distributing their attention broadly. Other research suggests that PSZ have reduced working memory (WM) capacity. This study tested whether these findings reflect a common underlying deficit. We measured the ability to distribute attention by means of the Useful Field of View (UFOV) task, in which participants must distribute attention so that they can discriminate a foveal target and simultaneously localize a peripheral target. Participants included 50 PSZ and 52 healthy control subjects. We found that PSZ exhibited severe impairments in UFOV performance, that UFOV performance was highly correlated with WM capacity in PSZ (r = −.61), and that UFOV impairments could not be explained by either impaired low-level processing or a generalized deficit. These results suggest that a common mechanism explains deficits in the ability to distribute attention broadly, reduced WM capacity, and other aspects of impaired cognition in schizophrenia. We hypothesize that this mechanism may involve abnormal local circuit dynamics that cause a hyperfocusing of resources onto a small number of internal representations. PMID:24748559

Identification of 2,4-dihydroxy-5-pyrimidinyl imidothiocarbomate as a novel inhibitor to Y box binding protein-1 (YB-1) and its therapeutic actions against breast cancer.

PubMed

Gunasekaran, Vinoth Prasanna; Nishi, Kumari; Sivakumar, Dakshinamurthy; Sivaraman, Thirunavukkarasu; Mathan, Ganeshan

2018-04-30

In spite of advances in breast cancer treatment and early diagnosis, drug toxicity, cancer relapse, multidrug resistance and metastasis are the major impediment to the developments of efficient drugs. However, unique druggable targets of cancer cells distinct from the normal cells provide new rationale in cancer treatment. Previous reports clearly emphasize the differential expression and localization of Y box binding protein-1 (YB-1) between normal breast tissues and different stages of breast cancer. Y box binding protein-1 is DNA as well as RNA binding protein involved in transcription and translation regulation of various proteins involved in cancer progression, apoptosis, cell cycle, epithelial to mesenchymal transition (EMT) and drug resistance. Particularly, during doxorubicin (DOX) treatment and cancer relapse conditions, YB-1 expression was very high in breast cancer tissues and localized in to nucleus which further favours DOX efflux and metastasis. Moreover, siRNA mediated silencing of YB-1 reduces breast cancer progression and metastasis. In this rationale, using an array of computational methods, 2,4-dihydroxy-5-pyrimidinyl imidothiocarbomate (DPI) has been screened out as a drug-likeness antagonist to the YB-1for cancer treatment. In this study, we determined that DPI was toxic to breast cancer cell lines as individual drug as well as in combination with DOX. Moreover, immunofluorescence and confocal studies showed that DPI decreases DOX induced YB-1 nuclear translocation and increases DOX accumulation in breast cancer cell line. A G1/G0 phase cell cycle arrest and apoptosis was also induced by DPI. Moreover, DPI modulated YB-1 downstream targets such as p53, caspase-3, CDK-1 which are involved in cell cycle progression and apoptosis. Further, metastatic functional analysis revealed that DPI inhibits cell adhesion, migration, invasion in aggressive metastatic cell line and inhibits angiogenesis in chick embryonic chorioallantoic membrane (CAM) model. Meanwhile, DPI alters the expression of YB-1 downstream targets which are involved in metastasis such as VEGFR, caveolin, E-cadherin, cytokeratins, desmin and vimentin in MDA-MB-231 xenograft in chick embryonic CAM membrane. The results clearly demonstrated that DPI inhibited YB-1 nuclear translocation, thereby exhibited anti-apoptotic, anti-proliferative and anti-metastatic activities and increases the therapeutic potential of commercial breast cancer drug doxorubicin. Copyright © 2017 Elsevier B.V. All rights reserved.

Targeted Mutagenesis of Duplicated Genes in Soybean with Zinc-Finger Nucleases1[W][OA

PubMed Central

Curtin, Shaun J.; Zhang, Feng; Sander, Jeffry D.; Haun, William J.; Starker, Colby; Baltes, Nicholas J.; Reyon, Deepak; Dahlborg, Elizabeth J.; Goodwin, Mathew J.; Coffman, Andrew P.; Dobbs, Drena; Joung, J. Keith; Voytas, Daniel F.; Stupar, Robert M.

2011-01-01

We performed targeted mutagenesis of a transgene and nine endogenous soybean (Glycine max) genes using zinc-finger nucleases (ZFNs). A suite of ZFNs were engineered by the recently described context-dependent assembly platform—a rapid, open-source method for generating zinc-finger arrays. Specific ZFNs targeting DICER-LIKE (DCL) genes and other genes involved in RNA silencing were cloned into a vector under an estrogen-inducible promoter. A hairy-root transformation system was employed to investigate the efficiency of ZFN mutagenesis at each target locus. Transgenic roots exhibited somatic mutations localized at the ZFN target sites for seven out of nine targeted genes. We next introduced a ZFN into soybean via whole-plant transformation and generated independent mutations in the paralogous genes DCL4a and DCL4b. The dcl4b mutation showed efficient heritable transmission of the ZFN-induced mutation in the subsequent generation. These findings indicate that ZFN-based mutagenesis provides an efficient method for making mutations in duplicate genes that are otherwise difficult to study due to redundancy. We also developed a publicly accessible Web-based tool to identify sites suitable for engineering context-dependent assembly ZFNs in the soybean genome. PMID:21464476

Local structure preserving sparse coding for infrared target recognition

PubMed Central

Han, Jing; Yue, Jiang; Zhang, Yi; Bai, Lianfa

2017-01-01

Sparse coding performs well in image classification. However, robust target recognition requires a lot of comprehensive template images and the sparse learning process is complex. We incorporate sparsity into a template matching concept to construct a local sparse structure matching (LSSM) model for general infrared target recognition. A local structure preserving sparse coding (LSPSc) formulation is proposed to simultaneously preserve the local sparse and structural information of objects. By adding a spatial local structure constraint into the classical sparse coding algorithm, LSPSc can improve the stability of sparse representation for targets and inhibit background interference in infrared images. Furthermore, a kernel LSPSc (K-LSPSc) formulation is proposed, which extends LSPSc to the kernel space to weaken the influence of the linear structure constraint in nonlinear natural data. Because of the anti-interference and fault-tolerant capabilities, both LSPSc- and K-LSPSc-based LSSM can implement target identification based on a simple template set, which just needs several images containing enough local sparse structures to learn a sufficient sparse structure dictionary of a target class. Specifically, this LSSM approach has stable performance in the target detection with scene, shape and occlusions variations. High performance is demonstrated on several datasets, indicating robust infrared target recognition in diverse environments and imaging conditions. PMID:28323824

Characterization of CD44-Mediated Cancer Cell Uptake and Intracellular Distribution of Hyaluronan-Grafted Liposomes

PubMed Central

Qhattal, Hussaini Syed Sha; Liu, Xinli

2011-01-01

Hyaluronan (HA) is a biocompatible and biodegradable linear polysaccharide which is of interest for tumor targeting through cell surface CD44 receptors. HA binds with high affinity to CD44 receptors, which are overexpressed in many tumors and involved in cancer metastasis. In the present study, we investigated the impact of HA molecular weight (MW), grafting density, and CD44 receptor density on endocytosis of HA-grafted liposomes (HA-liposomes) by cancer cells. Additionally, the intracellular localization of the HA-liposomes was determined. HAs of different MWs (5-8, 10-12, 175-350, and 1600 kDa) were conjugated to liposomes with varying degrees of grafting density. HA surface density was quantified using the hexadecyltrimethylammonium bromide turbidimetric method. Cellular uptake and subcellular localization of HA-liposomes were evaluated by flow cytometry and fluorescence microscopy. Mean particle sizes of HA-liposomes ranged from 120 to 180 nm and increased with the bigger size of HA. HA-liposome uptake correlated with HA MW (5-8 < 10-12 < 175-350 kDa), grafting density, and CD44 receptor density and exceeded that obtained with unconjugated plain liposomes. HA-liposomes were taken up into cells via lipid raft-mediated endocytosis, which is both energy- and cholesterol-dependent. Once within cells, HA-liposomes localized primarily to endosomes and lysosomes. The results demonstrate that cellular targeting efficiency of HA-liposomes depends strongly upon HA MW, grafting density, and cell surface receptor CD44 density. The results support a role of HA-liposomes for targeted drug delivery. PMID:21696190

Specific serine-proline phosphorylation and glycogen synthase kinase 3β-directed subcellular targeting of stathmin 3/Sclip in neurons.

PubMed

Devaux, Sara; Poulain, Fabienne E; Devignot, Véronique; Lachkar, Sylvie; Irinopoulou, Theano; Sobel, André

2012-06-22

During nervous system development, neuronal growth, migration, and functional morphogenesis rely on the appropriate control of the subcellular cytoskeleton including microtubule dynamics. Stathmin family proteins play major roles during the various stages of neuronal differentiation, including axonal growth and branching, or dendritic development. We have shown previously that stathmins 2 (SCG10) and 3 (SCLIP) fulfill distinct, independent and complementary regulatory roles in axonal morphogenesis. Although the two proteins have been proposed to display the four conserved phosphorylation sites originally identified in stathmin 1, we show here that they possess distinct phosphorylation sites within their specific proline-rich domains (PRDs) that are differentially regulated by phosphorylation by proline-directed kinases involved in the control of neuronal differentiation. ERK2 or CDK5 phosphorylate the two proteins but with different site specificities. We also show for the first time that, unlike stathmin 2, stathmin 3 is a substrate for glycogen synthase kinase (GSK) 3β both in vitro and in vivo. Interestingly, stathmin 3 phosphorylated at its GSK-3β target site displays a specific subcellular localization at neuritic tips and within the actin-rich peripheral zone of the growth cone of differentiating hippocampal neurons in culture. Finally, pharmacological inhibition of GSK-3β induces a redistribution of stathmin 3, but not stathmin 2, from the periphery toward the Golgi region of neurons. Stathmin proteins can thus be either regulated locally or locally targeted by specific phosphorylation, each phosphoprotein of the stathmin family fulfilling distinct and specific roles in the control of neuronal differentiation.

The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages

PubMed Central

Das, Anusuya; Segar, Claire E; Hughley, Brian B; Bowers, Daniel T; Botchwey, Edward A

2013-01-01

Endogenous signals originating at the site of injury are involved in the paracrine recruitment, proliferation, and differentiation of circulating progenitor and diverse inflammatory cell types. Here, we investigate a strategy to exploit endogenous cell recruitment mechanisms to regenerate injured bone by local targeting and activation of sphingosine-1-phosphate (S1P) receptors. A mandibular defect model was selected for evaluating regeneration of bone following trauma or congenital disease. The particular challenges of mandibular reconstruction are inherent in the complex anatomy and function of the bone given that the area is highly vascularized and in close proximity to muscle. Nanofibers composed of poly(DL-lactide-co-glycolide) (PLAGA) and polycaprolactone (PCL) were used to delivery FTY720, a targeted agonist of S1P receptors 1 and 3. In vitro culture of bone progenitor cells on drug loaded constructs significantly enhanced SDF1α mediated chemotaxis of bone marrow mononuclear cells. In vivo results show that local delivery of FTY720 from composite nanofibers enhanced blood vessel ingrowth and increased recruitment of M2 alternatively activated macrophages, leading to significant osseous tissue ingrowth into critical sized defects after 12 weeks of treatment. These results demonstrate that local activation of S1P receptors is a regenerative cue resulting in recruitment of wound healing or anti-inflammatory macrophages and bone healing. Use of such small molecule therapy can provide an alternative to biological factors for the clinical treatment of critical size craniofacial defects. PMID:24064148

The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages.

PubMed

Das, Anusuya; Segar, Claire E; Hughley, Brian B; Bowers, Daniel T; Botchwey, Edward A

2013-12-01

Endogenous signals originating at the site of injury are involved in the paracrine recruitment, proliferation, and differentiation of circulating progenitor and diverse inflammatory cell types. Here, we investigate a strategy to exploit endogenous cell recruitment mechanisms to regenerate injured bone by local targeting and activation of sphingosine-1-phosphate (S1P) receptors. A mandibular defect model was selected for evaluating regeneration of bone following trauma or congenital disease. The particular challenges of mandibular reconstruction are inherent in the complex anatomy and function of the bone given that the area is highly vascularized and in close proximity to muscle. Nanofibers composed of poly(DL-lactide-co-glycolide) (PLAGA) and polycaprolactone (PCL) were used to delivery FTY720, a targeted agonist of S1P receptors 1 and 3. In vitro culture of bone progenitor cells on drug-loaded constructs significantly enhanced SDF1α mediated chemotaxis of bone marrow mononuclear cells. In vivo results show that local delivery of FTY720 from composite nanofibers enhanced blood vessel ingrowth and increased recruitment of M2 alternatively activated macrophages, leading to significant osseous tissue ingrowth into critical sized defects after 12 weeks of treatment. These results demonstrate that local activation of S1P receptors is a regenerative cue resulting in recruitment of wound healing or anti-inflammatory macrophages and bone healing. Use of such small molecule therapy can provide an alternative to biological factors for the clinical treatment of critical size craniofacial defects. Copyright © 2013 Elsevier Ltd. All rights reserved.

Model studies in cytochrome P-450-mediated toxicity of halogenated compounds: radical processes involving iron porphyrins.

PubMed Central

Brault, D

1985-01-01

Haloalkane toxicity originates from attack on biological targets by reactive intermediates derived from haloalkane metabolism by a hemoprotein, cytochrome P-450. Carbon-centered radicals and their peroxyl derivatives are most likely involved. The reactions of iron porphyrin--a model for cytochrome P-450--with various carbon-centered and peroxyl radicals generated by pulse radiolysis are examined. Competition between iron porphyrin and unsaturated fatty acids for attack by peroxyl radicals is pointed out. These kinetic data are used to derive a model for toxicity of haloalkanes with particular attention to carbon tetrachloride and halothane. The importance of local oxygen concentration and structural arrangement of fatty acids around cytochrome P-450 is emphasized. PMID:3007100

Nonhistone protein acetylation as cancer therapy targets

PubMed Central

Singh, Brahma N; Zhang, Guanghua; Hwa, Yi L; Li, Jinping; Dowdy, Sean C; Jiang, Shi-Wen

2012-01-01

Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. The significance of histone acetylation in the modification of chromatin structure and dynamics, and thereby gene transcription regulation, has been well recognized. A steadily growing number of nonhistone proteins have been identified as acetylation targets and reversible lysine acetylation in these proteins plays an important role(s) in the regulation of mRNA stability, protein localization and degradation, and protein–protein and protein–DNA interactions. The recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation, differentiation and apoptosis. Many nonhistone proteins targeted by acetylation are the products of oncogenes or tumor-suppressor genes and are directly involved in tumorigenesis, tumor progression and metastasis. Aberrant activity of HDACs has been documented in several types of cancers and HDAC inhibitors (HDACi) have been employed for therapeutic purposes. Here we review the published literature in this field and provide updated information on the regulation and function of nonhistone protein acetylation. While concentrating on the molecular mechanism and pathways involved in the addition and removal of the acetyl moiety, therapeutic modalities of HDACi are also discussed. PMID:20553216

SUMO proteases as potential targets for cancer therapy.

PubMed

Bialik, Piotr; Woźniak, Katarzyna

2017-12-08

Sumoylation is one of the post-translational modifications of proteins, responsible for the regulation of many cellular processes, such as DNA replication and repair, transcription, signal transduction and nuclear transport. During sumoylation, SUMO proteins are covalently attached to the ε-amino group of lysine in target proteins via an enzymatic cascade that requires the sequential action of E1, E2 and E3 enzymes. An important aspect of sumoylation is its reversibility, which involves SUMO-specific proteases called SENPs. SENPs (sentrin/SUMO-specific proteases) catalyze the deconjugation of SUMO proteins using their isopeptidase activity. These enzymes participate through hydrolase activity in the reaction of SUMO protein maturation, which involves the removal of a short fragment on the C-terminus of SUMO inactive form and exposure two glycine residues. SENPs are important for maintaining the balance between sumoylated and desumoylated proteins required for normal cellular physiology. Six SENP isoforms (SENP1, SENP2, SENP3, SENP5, SENP6 and SENP7) have been identified in mammals. These SENPs can be divided into three subfamilies based on their sequence homology, substrate specificity and subcellular localization. Results of studies indicate the role of SUMO proteases in the development of human diseases including cancer, suggesting that these proteins may be attractive targets for new drugs.

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

PubMed

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

2017-06-01

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

The TARGET project in Tuscany: the first disease management model of a regional project for the prevention of hip re-fractures in the elderly.

PubMed

Piscitelli, Prisco; Brandi, Maria Luisa; Nuti, Ranuccio; Rizzuti, Carla; Giorni, Loredano; Giovannini, Valtere; Metozzi, Alessia; Merlotti, Daniela

2010-09-01

The official inquiry on osteoporosis in Italy, promoted by the Italian Senate in 2002 concluded that proper preventive strategies should be adopted at regional level in order to prevent osteoporotic fractures. Tuscany is the first Italian region who has promoted an official program (the TARGET project) aimed to reduce osteoporotic fractures by ensuring adequate treatment to all people aged ≥65 years old who experience a hip fragility fracture. this paper provides information concerning the implementation of TARGET project in Tuscany, assuming that it may represent an useful model for similar experiences to be promoted in other Italian Regions and across Europe. we have examined the model proposed for the regional program, and we have particularly analyzed the in-hospital and post-hospitalization path of hip fractured patients aged >65 years old in Tuscany after the adoption of TARGET project by Tuscany healthcare system and during its ongoing start-up phase. orthopaedic surgeons have been gradually involved in the project and are increasingly fulfilling all the clinical prescriptions and recommendations provided in the project protocol. Different forms of cooperation between orthopaedic surgeons and other clinical specialists have been adopted at each hospital for the treatment of hip fractured elderly patients. GPs involvement needs to be fostered both at regional and local level. The effort of Tuscany region to cope with hip fractures suffered from elderly people must be acknowledged as an interesting way of addressing this critical health problem. Specific preventive strategies modelled on the Tuscany TARGET project should be implemented in other Italian regions.

Acylation-dependent protein export in Leishmania.

PubMed

Denny, P W; Gokool, S; Russell, D G; Field, M C; Smith, D F

2000-04-14

The surface of the protozoan parasite Leishmania is unusual in that it consists predominantly of glycosylphosphatidylinositol-anchored glycoconjugates and proteins. Additionally, a family of hydrophilic acylated surface proteins (HASPs) has been localized to the extracellular face of the plasma membrane in infective parasite stages. These surface polypeptides lack a recognizable endoplasmic reticulum secretory signal sequence, transmembrane spanning domain, or glycosylphosphatidylinositol-anchor consensus sequence, indicating that novel mechanisms are involved in their transport and localization. Here, we show that the N-terminal domain of HASPB contains primary structural information that directs both N-myristoylation and palmitoylation and is essential for correct localization of the protein to the plasma membrane. Furthermore, the N-terminal 18 amino acids of HASPB, encoding the dual acylation site, are sufficient to target the heterologous Aequorea victoria green fluorescent protein to the cell surface of Leishmania. Mutagenesis of the predicted acylated residues confirms that modification by both myristate and palmitate is required for correct trafficking. These data suggest that HASPB is a representative of a novel class of proteins whose translocation onto the surface of eukaryotic cells is dependent upon a "non-classical" pathway involving N-myristoylation/palmitoylation. Significantly, HASPB is also translocated on to the extracellular face of the plasma membrane of transfected mammalian cells, indicating that the export signal for HASPB is recognized by a higher eukaryotic export mechanism.

The cdk7-cyclin H-MAT1 complex associated with TFIIH is localized in coiled bodies.

PubMed Central

Jordan, P; Cunha, C; Carmo-Fonseca, M

1997-01-01

TFIIH is a general transcription factor for RNA polymerase II that in addition is involved in DNA excision repair. TFIIH is composed of eight or nine subunits and we show that at least four of them, namely cdk7, cyclin H, MAT1, and p62 are localized in the coiled body, a distinct subnuclear structure that is transcription dependent and highly enriched in small nuclear ribonucleoproteins. Although coiled bodies do not correspond to sites of transcription, in vivo incorporation of bromo-UTP shows that they are surrounded by transcription foci. Immunofluorescence analysis using antibodies directed against the essential repair factors proliferating cell nuclear antigen and XPG did not reveal labeling of the coiled body in either untreated cells or cells irradiated with UV light, arguing that coiled bodies are probably not involved in DNA repair mechanisms. The localization of cyclin H in the coiled body was predominantly detected during the G1 and S-phases of the cell cycle, whereas in G2 coiled bodies were very small or not detected. Finally, both cyclin H and cdk7 did not colocalize with P80 coilin after disruption of the coiled body, indicating that these proteins are specifically targeted to the small nuclear ribonucleoprotein-containing domain. Images PMID:9243502

The microtubule-associated protein EB1 maintains cell polarity through activation of protein kinase C.

PubMed

Schober, Joseph M; Kwon, Guim; Jayne, Debbie; Cain, Jeanine M

2012-01-06

The plus-ends of microtubules target the cell cortex to modulate actin protrusion dynamics and polarity, but little is known of the molecular mechanism that couples the interaction. EB1 protein associates with the plus-ends of microtubules, placing EB1 in an ideal spatial position to mediate microtubule-actin cross talk. The objective of the current study was to further understand intracellular signaling involved in EB1-dependent cell polarity and motility. B16F10 mouse melanoma cells were depleted of EB1 protein using short hair-pin RNA interference. Correlative live cell-immunofluorescence microscopy was performed to determine localization of WAVE2 and IQGAP1 to protruding versus retracting edges. EB1 knock down caused poor subcellular separation of WAVE2 and IQGAP1, and overall decreased localization. Activation of PKC corrected defects in WAVE2 and IQGAP1 localization, cell spreading and cell shape to levels observed in control cells, but did not correct defects in cell migration. Consistent with these findings, decreased PKC phosphorylation was observed in EB1 knock down cells. These findings support a model where EB1 protein links microtubules to actin protrusion and cell polarity through signaling pathways involving PKC. Copyright © 2011 Elsevier Inc. All rights reserved.

Performing a local barrier operation

DOEpatents

Archer, Charles J; Blocksome, Michael A; Ratterman, Joseph D; Smith, Brian E

2014-03-04

Performing a local barrier operation with parallel tasks executing on a compute node including, for each task: retrieving a present value of a counter; calculating, in dependence upon the present value of the counter and a total number of tasks performing the local barrier operation, a base value, the base value representing the counter's value prior to any task joining the local barrier; calculating, in dependence upon the base value and the total number of tasks performing the local barrier operation, a target value of the counter, the target value representing the counter's value when all tasks have joined the local barrier; joining the local barrier, including atomically incrementing the value of the counter; and repetitively, until the present value of the counter is no less than the target value of the counter: retrieving the present value of the counter and determining whether the present value equals the target value.

Performing a local barrier operation

DOEpatents

Archer, Charles J; Blocksome, Michael A; Ratterman, Joseph D; Smith, Brian E

2014-03-04

Performing a local barrier operation with parallel tasks executing on a compute node including, for each task: retrieving a present value of a counter; calculating, in dependence upon the present value of the counter and a total number of tasks performing the local barrier operation, a base value of the counter, the base value representing the counter's value prior to any task joining the local barrier; calculating, in dependence upon the base value and the total number of tasks performing the local barrier operation, a target value, the target value representing the counter's value when all tasks have joined the local barrier; joining the local barrier, including atomically incrementing the value of the counter; and repetitively, until the present value of the counter is no less than the target value of the counter: retrieving the present value of the counter and determining whether the present value equals the target value.

Proteomic snapshot of the EGF-induced ubiquitin network

PubMed Central

Argenzio, Elisabetta; Bange, Tanja; Oldrini, Barbara; Bianchi, Fabrizio; Peesari, Raghunath; Mari, Sara; Di Fiore, Pier Paolo; Mann, Matthias; Polo, Simona

2011-01-01

The activity, localization and fate of many cellular proteins are regulated through ubiquitination, a process whereby one or more ubiquitin (Ub) monomers or chains are covalently attached to target proteins. While Ub-conjugated and Ub-associated proteomes have been described, we lack a high-resolution picture of the dynamics of ubiquitination in response to signaling. In this study, we describe the epidermal growth factor (EGF)-regulated Ubiproteome, as obtained by two complementary purification strategies coupled to quantitative proteomics. Our results unveil the complex impact of growth factor signaling on Ub-based intracellular networks to levels that extend well beyond what might have been expected. In addition to endocytic proteins, the EGF-regulated Ubiproteome includes a large number of signaling proteins, ubiquitinating and deubiquitinating enzymes, transporters and proteins involved in translation and transcription. The Ub-based signaling network appears to intersect both housekeeping and regulatory circuitries of cellular physiology. Finally, as proof of principle of the biological relevance of the EGF-Ubiproteome, we demonstrated that EphA2 is a novel, downstream ubiquitinated target of epidermal growth factor receptor (EGFR), critically involved in EGFR biological responses. PMID:21245847

An evaluation of the performance of two binaural beamformers in complex and dynamic multitalker environments.

PubMed

Best, Virginia; Mejia, Jorge; Freeston, Katrina; van Hoesel, Richard J; Dillon, Harvey

2015-01-01

Binaural beamformers are super-directional hearing aids created by combining microphone outputs from each side of the head. While they offer substantial improvements in SNR over conventional directional hearing aids, the benefits (and possible limitations) of these devices in realistic, complex listening situations have not yet been fully explored. In this study we evaluated the performance of two experimental binaural beamformers. Testing was carried out using a horizontal loudspeaker array. Background noise was created using recorded conversations. Performance measures included speech intelligibility, localization in noise, acceptable noise level, subjective ratings, and a novel dynamic speech intelligibility measure. Participants were 27 listeners with bilateral hearing loss, fitted with BTE prototypes that could be switched between conventional directional or binaural beamformer microphone modes. Relative to the conventional directional microphones, both binaural beamformer modes were generally superior for tasks involving fixed frontal targets, but not always for situations involving dynamic target locations. Binaural beamformers show promise for enhancing listening in complex situations when the location of the source of interest is predictable.

Improved neovascularization and wound repair by targeting human basic fibroblast growth factor (bFGF) to fibrin.

PubMed

Zhao, Wenxue; Han, Qianqian; Lin, Hang; Gao, Yuan; Sun, Wenjie; Zhao, Yannan; Wang, Bin; Chen, Bing; Xiao, Zhifeng; Dai, Jianwu

2008-10-01

Targeted therapy is a new generation of therapeutics, where two critical factors are involved. One is the particular molecular target, and the other is the specific target-binding drug. In this work, the fibrin, a main component of plasma clot at wound sites, was used as the target for human bFGF, aiming to improve therapeutic neovascularization and wound repair. To endow bFGF with fibrin-targeting ability, a fibrin-binding peptide Kringle1 (K1), derived from human plasminogen, was fused to human bFGF. The recombinant K1bFGF showed high fibrin and plasma-clot-binding ability. When applied to the wound sites with plasma clots, K1bFGF induced robust neovascularization and improved wound healing. To extend the application of K1bFGF to other cases where no plasma clots exist, we developed a fibrin-scaffold/K1bFGF system. This system could induce localized neovascularization by delivery of K1bFGF in a sustained and site-targeting manner, and provide a microenvironment promoting cell growth and tissue regeneration. In summary, we successfully used the pathologic environment fibrin clot as the target for bFGF, and based on which bFGF was designed into a targeting agent by introduction of a fibrin-binding peptide. This provides a potential approach to improve therapeutic neovascularization and wound repair.

A model of muscle atrophy based on live microscopy of muscle remodelling in Drosophila metamorphosis.

PubMed

Kuleesha, Yadav; Puah, Wee Choo; Wasser, Martin

2016-02-01

Genes controlling muscle size and survival play important roles in muscle wasting diseases. In Drosophila melanogaster metamorphosis, larval abdominal muscles undergo two developmental fates. While a doomed population is eliminated by cell death, another persistent group is remodelled and survives into adulthood. To identify and characterize genes involved in the development of remodelled muscles, we devised a workflow consisting of in vivo imaging, targeted gene perturbation and quantitative image analysis. We show that inhibition of TOR signalling and activation of autophagy promote developmental muscle atrophy in early, while TOR and yorkie activation are required for muscle growth in late pupation. We discovered changes in the localization of myonuclei during remodelling that involve anti-polar migration leading to central clustering followed by polar migration resulting in localization along the midline. We demonstrate that the Cathepsin L orthologue Cp1 is required for myonuclear clustering in mid, while autophagy contributes to central positioning of nuclei in late metamorphosis. In conclusion, studying muscle remodelling in metamorphosis can provide new insights into the cell biology of muscle wasting.

A model of muscle atrophy based on live microscopy of muscle remodelling in Drosophila metamorphosis

PubMed Central

Kuleesha, Yadav; Puah, Wee Choo; Wasser, Martin

2016-01-01

Genes controlling muscle size and survival play important roles in muscle wasting diseases. In Drosophila melanogaster metamorphosis, larval abdominal muscles undergo two developmental fates. While a doomed population is eliminated by cell death, another persistent group is remodelled and survives into adulthood. To identify and characterize genes involved in the development of remodelled muscles, we devised a workflow consisting of in vivo imaging, targeted gene perturbation and quantitative image analysis. We show that inhibition of TOR signalling and activation of autophagy promote developmental muscle atrophy in early, while TOR and yorkie activation are required for muscle growth in late pupation. We discovered changes in the localization of myonuclei during remodelling that involve anti-polar migration leading to central clustering followed by polar migration resulting in localization along the midline. We demonstrate that the Cathepsin L orthologue Cp1 is required for myonuclear clustering in mid, while autophagy contributes to central positioning of nuclei in late metamorphosis. In conclusion, studying muscle remodelling in metamorphosis can provide new insights into the cell biology of muscle wasting. PMID:26998322

TLX: A Master Regulator for Neural Stem Cell Maintenance and Neurogenesis

PubMed Central

Islam, Mohammed M.; Zhang, Chun-Li

2014-01-01

The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. PMID:24930777

The intricacies of p21 phosphorylation: protein/protein interactions, subcellular localization and stability.

PubMed

Child, Emma S; Mann, David J

2006-06-01

p21 was originally described as functioning as a cell cycle regulator via inhibition of both cyclin-dependent kinases and processive DNA replication. Nowadays it is recognized to play other fundamental roles including transcriptional regulation and the modulation of apoptosis. Each of these functions of p21 is achieved through direct p21/protein interactions and the subcellular localization of p21 plays an important part in dictating the binding partners to which p21 is exposed. Over recent years, a number of phosphorylation sites in p21 have been identified, these being targeted by several important intracellular signalling protein kinases. Here we review the state of our knowledge of p21 phosphorylation with respect to the kinases involved and the molecular biological effects of each phosphorylation event.

Localization of soluble guanylate cyclase activity in the guinea pig inner ear.

PubMed

Takumida, M; Anniko, M; Popa, R; Zhang, D M

2000-01-01

The aim of this study was to characterize the nitric oxide (NO) receptor soluble guanylate cyclase (sGC), to determine the cells targeted by NO and to elucidate the function of the NO/cGMP pathway in the inner ear. sGC activity in the inner ear was localized by immunohistochemical detection of NO-stimulated cGMP. Soluble guanylate cyclase activity in the cochlea was detected in the nerve endings underneath the outer and inner hair cells, supporting cells, stria vascularis and vessels. In the vestibular organs, sGC activity was detected in the cytoplasm of sensory cells, nerve fibres, dark cells and transitional cells and vessels. These findings suggest that the NO/cGMP pathway may be involved in regulatory processes in neurotransmission, blood flow and inner ear fluid homeostasis.

Scan statistics with local vote for target detection in distributed system

NASA Astrophysics Data System (ADS)

Luo, Junhai; Wu, Qi

2017-12-01

Target detection has occupied a pivotal position in distributed system. Scan statistics, as one of the most efficient detection methods, has been applied to a variety of anomaly detection problems and significantly improves the probability of detection. However, scan statistics cannot achieve the expected performance when the noise intensity is strong, or the signal emitted by the target is weak. The local vote algorithm can also achieve higher target detection rate. After the local vote, the counting rule is always adopted for decision fusion. The counting rule does not use the information about the contiguity of sensors but takes all sensors' data into consideration, which makes the result undesirable. In this paper, we propose a scan statistics with local vote (SSLV) method. This method combines scan statistics with local vote decision. Before scan statistics, each sensor executes local vote decision according to the data of its neighbors and its own. By combining the advantages of both, our method can obtain higher detection rate in low signal-to-noise ratio environment than the scan statistics. After the local vote decision, the distribution of sensors which have detected the target becomes more intensive. To make full use of local vote decision, we introduce a variable-step-parameter for the SSLV. It significantly shortens the scan period especially when the target is absent. Analysis and simulations are presented to demonstrate the performance of our method.

Contextual cueing in naturalistic scenes: Global and local contexts.

PubMed

Brockmole, James R; Castelhano, Monica S; Henderson, John M

2006-07-01

In contextual cueing, the position of a target within a group of distractors is learned over repeated exposure to a display with reference to a few nearby items rather than to the global pattern created by the elements. The authors contrasted the role of global and local contexts for contextual cueing in naturalistic scenes. Experiment 1 showed that learned target positions transfer when local information is altered but not when global information is changed. Experiment 2 showed that scene-target covariation is learned more slowly when local, but not global, information is repeated across trials than when global but not local information is repeated. Thus, in naturalistic scenes, observers are biased to associate target locations with global contexts. Copyright 2006 APA, all rights reserved.

Local cost sharing in Bamako Initiative systems in Benin and Guinea: assuring the financial viability of primary health care.

PubMed

Soucat, A; Levy-Bruhl, D; Gbedonou, P; Drame, K; Lamarque, J P; Diallo, S; Osseni, R; Adovohekpe, P; Ortiz, C; Debeugny, C; Knippenberg, R

1997-06-01

The fourth in a series of five, this article presents and analyses data on cost recovery and community cost-sharing, two key aspects of the Bamako Initiative which have been implemented in Benin and Guinea since 1986. The data come from approximately 400 health centres and result from the six-monthly monitoring sessions conducted from 1989 to 1993. Community involvement in the financing of local operating costs in the two national scale programmes is also described. In Benin and Guinea, a user fee system generates the community financed revenue with the aim of covering local operating costs including drugs. Health worker salaries remain the responsibility of the government and donor funding covers vaccine and investment costs. Village health committees manage and control resources and revenue. The community is also involved in decision making, strategy definition and quality control. In Benin in 1993, community financing revenue amounted to about US$0.6 per capita per year and generally covered all local recurrent non salary costs except vaccines and left a surplus. Although total costs and revenues were slightly lower in Guinea for the same period, over-all user fee revenue (around US$0.3 per capita per year) covered local recurrent costs (not including salaries or vaccines). A comparison of costs and revenue between regions and individual health centres revealed important differences in cost recovery ratios. In Benin, some centres recovered more than twice the local costs targeted for community financing. Twenty-five per cent of centres in Guinea did not manage to cover their designated local recurrent costs. The longitudinal analysis showed that the level of cost recovery remained stable over time even as preventive care (and especially EPI) coverage rose significantly. To better understand the most important characteristics affecting cost recovery levels, best performing health centres in terms of cost-recovery levels in 1993 were compared to worst performing centres. This analysis showed that the size of the target population of the health centre is a key determinant of cost-recovery in both countries. In addition, in Guinea the utilization of curative care linked to geographical access and in Benin the average revenue per case linked to the number of deliveries proved to be additional factors of importance. In best performing centres, financial viability improved over time in both countries between 1990 and 1993. Finally, the implications of these conclusions for the planning of health centre revitalization in West Africa are discussed.

Assisting New York Dairy Farms with Preparing for OSHA Safety Inspections.

PubMed

Tinc, Pamela J; Carrabba, Jim; Meyerhoff, Anna; Horsman, Melissa

2018-01-01

In 2013, the Occupational Safety and Health Administration announced a Local Emphasis Program targeted at New York farmers. This program involved random inspections of dairy farms across the state. This article provides an overview of the efforts made in New York to prepare farmers for these inspections. As a result of this program launch, several safety services offered by the New York Center for Agricultural Medicine and Health were significantly impacted, and required expansion and modification in order to meet the needs of New York farmers.

Consequences of localized frustration for the folding mechanism of the IM7 protein

PubMed Central

Sutto, Ludovico; Lätzer, Joachim; Hegler, Joseph A.; Ferreiro, Diego U.; Wolynes, Peter G.

2007-01-01

In the laboratory, IM7 has been found to have an unusual folding mechanism in which an “on-pathway” intermediate with nonnative interactions is formed. We show that this intermediate is a consequence of an unusual cluster of highly frustrated interactions in the native structure. This cluster is involved in the binding of IM7 to its target, Colicin E7. Redesign of residues in this cluster to eliminate frustration is predicted by simulations to lead to faster folding without the population of an intermediate ensemble. PMID:18077415

[Targeted inactivation of gamma-synuclein gene affects anxiety and exploratory behaviour of mice].

PubMed

Kokhan, V S; Bolkunov, A V; Ustiugov, A A; Van'kin, G I; Shelkovnikova, T A; Redkozubova, O M; Strekalova, T V; Bukhman, V L; Ninkina, N N; Bachurin, S O

2011-01-01

Gamma(gamma)-synuclein is a member of synuclein family of cytoplasmic and predominantly neuronal proteins found only in vertebrates. Gamma-synuclein is abundant in axons and presynaptic terminals of neurons localized in brain regions involved in emotions, learning and memory. However, the role of gamma-synuclein in these brain functions was not previously assessed. We have demonstrated for the first time that the loss of gamma-synuclein results in a significant increase in the level of orientation response in novel environment and decrease in the level of state anxiety.

Contextual cost: when a visual-search target is not where it should be.

PubMed

Makovski, Tal; Jiang, Yuhong V

2010-02-01

Visual search is often facilitated when the search display occasionally repeats, revealing a contextual-cueing effect. According to the associative-learning account, contextual cueing arises from associating the display configuration with the target location. However, recent findings emphasizing the importance of local context near the target have given rise to the possibility that low-level repetition priming may account for the contextual-cueing effect. This study distinguishes associative learning from local repetition priming by testing whether search is directed toward a target's expected location, even when the target is relocated. After participants searched for a T among Ls in displays that repeated 24 times, they completed a transfer session where the target was relocated locally to a previously blank location (Experiment 1) or to an adjacent distractor location (Experiment 2). Results revealed that contextual cueing decreased as the target appeared farther away from its expected location, ultimately resulting in a contextual cost when the target swapped locations with a local distractor. We conclude that target predictability is a key factor in contextual cueing.

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

PubMed

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

2015-07-15

Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. © 2015 American Cancer Society.

Cellular Development Associated with Induced Mycotoxin Synthesis in the Filamentous Fungus Fusarium graminearum

PubMed Central

Menke, Jon; Weber, Jakob; Broz, Karen; Kistler, H. Corby

2013-01-01

Several species of the filamentous fungus Fusarium colonize plants and produce toxic small molecules that contaminate agricultural products, rendering them unsuitable for consumption. Among the most destructive of these species is F. graminearum, which causes disease in wheat and barley and often infests the grain with harmful trichothecene mycotoxins. Synthesis of these secondary metabolites is induced during plant infection or in culture in response to chemical signals. Our results show that trichothecene biosynthesis involves a complex developmental process that includes dynamic changes in cell morphology and the biogenesis of novel subcellular structures. Two cytochrome P-450 oxygenases (Tri4p and Tri1p) involved in early and late steps in trichothecene biosynthesis were tagged with fluorescent proteins and shown to co-localize to vesicles we provisionally call “toxisomes.” Toxisomes, the inferred site of trichothecene biosynthesis, dynamically interact with motile vesicles containing a predicted major facilitator superfamily protein (Tri12p) previously implicated in trichothecene export and tolerance. The immediate isoprenoid precursor of trichothecenes is the primary metabolite farnesyl pyrophosphate. Changes occur in the cellular localization of the isoprenoid biosynthetic enzyme HMG CoA reductase when cultures non-induced for trichothecene biosynthesis are transferred to trichothecene biosynthesis inducing medium. Initially localized in the cellular endomembrane system, HMG CoA reductase, upon induction of trichothecene biosynthesis, increasingly is targeted to toxisomes. Metabolic pathways of primary and secondary metabolism thus may be coordinated and co-localized under conditions when trichothecene biosynthesis occurs. PMID:23667578

Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney.

PubMed

Yang, T; Michele, D E; Park, J; Smart, A M; Lin, Z; Brosius, F C; Schnermann, J B; Briggs, J P

1999-12-01

The discovery that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is a ligand for the gamma-isoform of peroxisome proliferator-activated receptor (PPAR) suggests nuclear signaling by prostaglandins. Studies were undertaken to determine the nephron localization of PPAR isoforms and their heterodimer partners, retinoid X receptors (RXR), and to evaluate the function of this system in the kidney. PPARalpha mRNA, determined by RT-PCR, was found predominately in cortex and further localized to proximal convoluted tubule (PCT); PPARgamma was abundant in renal inner medulla, localized to inner medullary collecting duct (IMCD) and renal medullary interstitial cells (RMIC); PPARbeta, the ubiquitous form of PPAR, was abundant in all nephron segments examined. RXRalpha was localized to PCT and IMCD, whereas RXRbeta was expressed in almost all nephron segments examined. mRNA expression of acyl-CoA synthase (ACS), a known PPAR target gene, was stimulated in renal cortex of rats fed with fenofibrate, but the expression was not significantly altered in either cortex or inner medulla of rats fed with troglitazone. In cultured RMIC cells, both troglitazone and 15d-PGJ2 significantly inhibited cell proliferation and dramatically altered cell shape by induction of cell process formation. We conclude that PPAR and RXR isoforms are expressed in a nephron segment-specific manner, suggesting distinct functions, with PPARalpha being involved in energy metabolism through regulating ACS in PCT and with PPARgamma being involved in modulating RMIC growth and differentiation.

MicroRNA-Related DNA Repair/Cell-Cycle Genes Independently Associated With Relapse After Radiation Therapy for Early Breast Cancer

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

Gee, Harriet E., E-mail: harriet.gee@sydney.edu.au; The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW; Central Clinical School, Sydney Medical School, University of Sydney, NSW

Purpose: Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo. Methods and Materials: With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series ofmore » 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers—TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1—were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis. Results: We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy–treated patients but not in untreated matched control individuals (n=107; P<.05). Conclusions: Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.« less

Multi-target-qubit unconventional geometric phase gate in a multi-cavity system

NASA Astrophysics Data System (ADS)

Liu, Tong; Cao, Xiao-Zhi; Su, Qi-Ping; Xiong, Shao-Jie; Yang, Chui-Ping

2016-02-01

Cavity-based large scale quantum information processing (QIP) may involve multiple cavities and require performing various quantum logic operations on qubits distributed in different cavities. Geometric-phase-based quantum computing has drawn much attention recently, which offers advantages against inaccuracies and local fluctuations. In addition, multiqubit gates are particularly appealing and play important roles in QIP. We here present a simple and efficient scheme for realizing a multi-target-qubit unconventional geometric phase gate in a multi-cavity system. This multiqubit phase gate has a common control qubit but different target qubits distributed in different cavities, which can be achieved using a single-step operation. The gate operation time is independent of the number of qubits and only two levels for each qubit are needed. This multiqubit gate is generic, e.g., by performing single-qubit operations, it can be converted into two types of significant multi-target-qubit phase gates useful in QIP. The proposal is quite general, which can be used to accomplish the same task for a general type of qubits such as atoms, NV centers, quantum dots, and superconducting qubits.

Engineering the First Chimeric Antibody in Targeting Intracellular PRL-3 Oncoprotein for Cancer Therapy in Mice

PubMed Central

Al-Aidaroos, Abdul Qader O.; Hong, Cheng William; Tan, Cheng Peow Bobby; Park, Jung Eun; Varghese, Leyon; Feng, Zhiwei; Zhou, Jianbiao; Chng, Wee Joo; Zeng, Qi

2012-01-01

Antibodies are considered as ‘magic bullets’ because of their high specificity. It is believed that antibodies are too large to routinely enter the cytosol, thus antibody therapeutic approach has been limited to extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are localized within the cell. To explore the possibility of antibody therapies against intracellular targets, we generated a chimeric antibody targeting the intracellular PRL-3 oncoprotein to assess its antitumor activities in mice. Remarkably, we observed that the PRL-3 chimeric antibody could efficiently and specifically reduce the formation of PRL-3 expressing metastatic tumors. We further found that natural killer (NK) cells were important in mediating the therapeutic effect, which was only observed in a nude mouse model (T-cell deficient), but not in a Severe Combined Immunodeficiency’ (scid) mouse model (B- and T-cell deficient), indicating the anticancer effect also depends on host B-cell activity. Our study involving 377 nude and scid mice suggests that antibodies targeting intracellular proteins can be developed to treat cancer. PMID:22374986

Multi-target-qubit unconventional geometric phase gate in a multi-cavity system.

PubMed

Liu, Tong; Cao, Xiao-Zhi; Su, Qi-Ping; Xiong, Shao-Jie; Yang, Chui-Ping

2016-02-22

Cavity-based large scale quantum information processing (QIP) may involve multiple cavities and require performing various quantum logic operations on qubits distributed in different cavities. Geometric-phase-based quantum computing has drawn much attention recently, which offers advantages against inaccuracies and local fluctuations. In addition, multiqubit gates are particularly appealing and play important roles in QIP. We here present a simple and efficient scheme for realizing a multi-target-qubit unconventional geometric phase gate in a multi-cavity system. This multiqubit phase gate has a common control qubit but different target qubits distributed in different cavities, which can be achieved using a single-step operation. The gate operation time is independent of the number of qubits and only two levels for each qubit are needed. This multiqubit gate is generic, e.g., by performing single-qubit operations, it can be converted into two types of significant multi-target-qubit phase gates useful in QIP. The proposal is quite general, which can be used to accomplish the same task for a general type of qubits such as atoms, NV centers, quantum dots, and superconducting qubits.

Identification of candidate houses for the north florida portion of the Florida radon mitigation project. Final report, October 1987-May 1988

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

Roessler, G.S.; Hintenlang, D.E.; Roessler, C.E.

1990-09-01

The report gives results of a study to locate candidate houses for a proposed radon mitigation research and demonstration project in North Florida. The effort involved: identification of target geographical areas, radon monitoring in identified clusters, and house characterization. Selection of target areas with a potential for elevated indoor radon started with a review of a statewide radiation study completed in 1987 and examination of the local geographic pattern observed in a 1986-87 pilot study of the Gainesville area. This effort indicated that North Florida target areas could be selected on the basis of the near-surface occurrence of the Hawthornmore » geological formation. Volunteer houses for radon monitoring in Alachua and Marion counties were obtained by announcing the study in newspaper articles. Screening measurements were made in about 400 target area houses according to EPA protocols using a vendor-supplied charcoal collector method. Results were similar in the two counties, and distributions were similar in both slab and crawl-space houses.« less

Structural and functional insights into the interaction between the Cas family scaffolding protein p130Cas and the focal adhesion-associated protein paxillin

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

Zhang, Chi; Miller, Darcie J.; Guibao, Cristina D.

The Cas family scaffolding protein p130Cas is a Src substrate localized in focal adhesions (FAs) and functions in integrin signaling to promote cell motility, invasion, proliferation, and survival. p130Cas targeting to FAs is essential for its tyrosine phosphorylation and downstream signaling. Although the N-terminal SH3 domain is important for p130Cas localization, it has also been reported that the C-terminal region is involved in p130Cas FA targeting. The C-terminal region of p130Cas or Cas family homology domain (CCHD) has been reported to adopt a structure similar to that of the focal adhesion kinase C-terminal focal adhesion-targeting domain. The mechanism by whichmore » the CCHD promotes FA targeting of p130Cas, however, remains unclear. In this study, using a calorimetry approach, we identified the first LD motif (LD1) of the FA-associated protein paxillin as the binding partner of the p130Cas CCHD (in a 1:1 stoichiometry with a Kd ~4.2 μM) and elucidated the structure of the p130Cas CCHD in complex with the paxillin LD1 motif by X-ray crystallography. Of note, a comparison of the CCHD/LD1 complex with a previously solved structure of CCHD in complex with the SH2-containing protein NSP3 revealed that LD1 had almost identical positioning of key hydrophobic and acidic residues relative to NSP3. Because paxillin is one of the key scaffold molecules in FAs, we propose that the interaction between the p130Cas CCHD and the LD1 motif of paxillin plays an important role in p130Cas FA targeting.« less

Target community foundations to fund family planning.

PubMed

1994-04-01

Practical advice was given on how to secure funding for privately sponsored US family planning programs in local communities. The first step is in identifying community foundations that are directly involved in social service delivery in the local area. For example, Norplant kits were made available to low-income women through a grant from the Baltimore-based Abell Foundation. Another example is that local funds were used to produce a Norplant video, which was needed for outreach programs and for explaining the pros and cons of Norplant use. The short video was designed for multiple audiences, even though it was locally produced and funded in Baltimore. Sometimes the health department can create a consortium of providers for applying for a group grant. The Foundation Center in New York provides information on foundations, including state-by-state analysis of foundations and family planning funded projects. The Foundation Directory and Grants Index publishes by subject a list of foundations funding such areas. These publications are available in network or local libraries. Background information needs to be obtained on the guidelines required for applying for a specific foundation's grant; guidelines may vary widely between foundations and have strict or loose restrictions on form and substance. An important initial step is writing a very brief synthesis of your proposal (2 pages), if there is no prior knowledge of the receptivity of the foundation to the proposed program. If the project is within the scope of the foundation, a larger formal proposal is the next step. Foundations want to see well through out projects, budgeted carefully, with evaluation components. Examples of successful projects conducted elsewhere are good testimonials to the potential success of the proposed venture. Cultural acceptance in the community, pilot projects replicable in other areas, and target populations are important considerations to be included in the proposal.

[Microscopic extensions of head and neck squamous cell carcinomas: impact for clinical target volume definition].

PubMed

Fleury, B; Thariat, J; Barnoud, R; Buiret, G; Lebreton, F; Bancel, B; Poupart, M; Devouassoux-Shisheboran, M

2014-11-01

To assess microscopic extensions of head and neck squamous cell carcinomas aiming at a proposal for target volumes of radiation therapy. Surgical specimens were prospectively analysed macroscopically and microscopically. Tumour borders were identified per macroscopic visual examination and inked on stained slides. Then microscopic implants (perineural or lymphatic involvement, or in situ carcinomas) were looked for with an optic microscope in the macroscopic healthy tissue surrounding the tumour. The maximal length from tumour border was correlated with the maximal length of macroscopically healthy tissues assessable. Twenty-one specimens were analysed and 12 were locally advanced tumours. Mean and median maximal microscopic extensions were 2.9 and 1.0mm (0-15mm), respectively. The 90th and 95th percentiles were 5 and 11mm, respectively. The ratio between healthy tissue length and maximal microscopic tumour extension was 10%. No correlation was found with tumour grade or volume. The presence of microscopic tumour was unlikely after 5mm from macroscopic tumour (≤5% of patients in this series) but should be assessed along with other histoclinical factors and particularities of tumour behaviour by anatomic site. A rigorous terminology should authorize a relevant appreciation of local risk of recurrence, particularly in adjuvant setting or for clinical target volume definition. Larger and more homogenous confirmatory series are needed. Copyright © 2014. Published by Elsevier SAS.

Molecular basis of the specific subcellular localization of the C2-like domain of 5-lipoxygenase.

PubMed

Kulkarni, Shilpa; Das, Sudipto; Funk, Colin D; Murray, Diana; Cho, Wonhwa

2002-04-12

The activation of 5-lipoxygenase (5-LO) involves its calcium-dependent translocation to the nuclear envelope, where it catalyzes the two-step transformation of arachidonic acid into leukotriene A(4), leading to the synthesis of various leukotrienes. To understand the mechanism by which 5-LO is specifically targeted to the nuclear envelope, we studied the membrane binding properties of the amino-terminal domain of 5-LO, which has been proposed to have a C2 domain-like structure. The model building, electrostatic potential calculation, and in vitro membrane binding studies of the isolated C2-like domain of 5-LO and selected mutants show that this Ca(2+)-dependent domain selectively binds zwitterionic phosphatidylcholine, which is conferred by tryptophan residues (Trp(13), Trp(75), and Trp(102)) located in the putative Ca(2+)-binding loops. The spatiotemporal dynamics of the enhanced green fluorescence protein-tagged C2-like domain of 5-LO and mutants in living cells also show that the phosphatidylcholine selectivity of the C2-like domain accounts for the specific targeting of 5-LO to the nuclear envelope. Together, these results show that the C2-like domain of 5-LO is a genuine Ca(2+)-dependent membrane-targeting domain and that the subcellular localization of the domain is governed in large part by its membrane binding properties.

Pathway of cytotoxicity induced by folic acid modified selenium nanoparticles in MCF-7 cells.

PubMed

Pi, Jiang; Jin, Hua; Liu, Ruiying; Song, Bing; Wu, Qing; Liu, Li; Jiang, Jinhuan; Yang, Fen; Cai, Huaihong; Cai, Jiye

2013-02-01

Selenium nanoparticles (Se NPs) have been recognized as promising materials for biomedical applications. To prepare Se NPs which contained cancer targeting methods and to clarify the cellular localization and cytotoxicity mechanisms of these Se NPs against cancer cells, folic acid protected/modified selenium nanoparticles (FA-Se NPs) were first prepared by a one-step method. Some morphologic and spectroscopic methods were obtained to prove the successfully formation of FA-Se NPs while free folate competitive inhibition assay, microscope, and several biological methods were used to determine the in vitro uptake, subcellular localization, and cytotoxicity mechanism of FA-Se NPs in MCF-7 cells. The results indicated that the 70-nm FA-Se NPs were internalized by MCF-7 cells through folate receptor-mediated endocytosis and targeted to mitochondria located regions through endocytic vesicles transporting. Then, the FA-Se NPs entered into mitochondria; triggered the mitochondria-dependent apoptosis of MCF-7 cells which involved oxidative stress, Ca(2)+ stress changes, and mitochondrial dysfunction; and finally caused the damage of mitochondria. FA-Se NPs released from broken mitochondria were transported into nucleus and further into nucleolus which then induced MCF-7 cell cycle arrest. In addition, FA-Se NPs could induce cytoskeleton disorganization and induce MCF-7 cell membrane morphology alterations. These results collectively suggested that FA-Se NPs could be served as potential therapeutic agents and organelle-targeted drug carriers in cancer therapy.

Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer.

PubMed

Du, Shisuo; Lockamy, Virginia; Zhou, Lin; Xue, Christine; LeBlanc, Justin; Glenn, Shonna; Shukla, Gaurav; Yu, Yan; Dicker, Adam P; Leeper, Dennis B; Lu, You; Lu, Bo

2016-11-01

To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics. Copyright © 2016. Published by Elsevier Inc.

A Novel Mutation of Human Liver Alanine:Glyoxylate Aminotransferase Causes Primary Hyperoxaluria Type 1: Immunohistochemical Quantification and Subcellular Distribution

PubMed Central

Kawai, Chikage; Minatogawa, Yohsuke; Akiyoshi, Hidetaka; Hirose, Shinichi; Suehiro, Tsunatoshi; Tone, Shigenobu

2012-01-01

A novel alanine:glyoxylate aminotransferase (AGT) mutation involved in primary hyperoxaluria type 1 (PH1) was studied in Japanese patients. Two mutations in exon 7, c.751T>A and c.752G>A, lead to a W251K amino acid substitution. Proband 1 (patient 1) was homozygous for the W251K mutation allele (DDBJ Accession No. AB292648), and AGT-specific activity in the patient’s liver was very low. To reveal the cause of the low enzymatic activity, the intracellular localization of AGT (W251K) was studied using immunohistochemistry and immunoelectron microscopy. The latter analysis showed that patient 2 had only one-fifth of the normal AGT expression per catalase, suggesting impairment of AGT (W251K) dependent transport into peroxisomes. Peroxisomal transport of human AGT is believed to be dependent on the presence of the type 1 peroxisomal targeting sequence. The C-terminal tripeptide of AGT, KKL is necessary for peroxisomal targeting. In cultured cells, EGFP-AGT (W251K) localized both in the peroxisome and cytosol. These results were consistent with the data obtained from liver analysis of patient 2. The subcellular distribution of AGT (W251K) and the results from a random mutagenesis study suggest that KKL is necessary for peroxisomal targeting of human AGT, but additional signal other than KKL may be necessary. PMID:22685354

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

Du, Shisuo; Lockamy, Virginia; Zhou, Lin

Purpose: To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. Methods and Materials: A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOGmore » protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. Results: The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. Conclusions: It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics.« less

Calreticulin localizes to plant intra/extracellular peripheries of highly specialized cells involved in pollen-pistil interactions.

PubMed

Wasąg, Piotr; Suwińska, Anna; Zakrzewski, Przemysław; Walczewski, Jakub; Lenartowski, Robert; Lenartowska, Marta

2018-01-01

Calcium (Ca 2+ ) plays essential roles in generative reproduction of angiosperms, but the sites and mechanisms of Ca 2+ storage and mobilization during pollen-pistil interactions have not been fully defined. Both external and internal Ca 2+ stores are likely important during male gametophyte communication with the sporophytic and gametophytic cells within the pistil. Given that calreticulin (CRT), a Ca 2+ -buffering protein, is able to bind Ca 2+ reversibly, it can serve as a mobile store of easily releasable Ca 2+ (so called an exchangeable Ca 2+ ) in eukaryotic cells. CRT has typical endoplasmic reticulum (ER) targeting and retention signals and resides primarily in the ER. However, localization of this protein outside the ER has also been revealed in both animal and plant cells, including Golgi/dictyosomes, nucleus, plasma membrane/cell surface, plasmodesmata, and even extracellular matrix. These findings indicate that CRT may function in a variety of different cell compartments and specialized structures. We have recently shown that CRT is highly expressed and accumulated in the ER of plant cells involved in pollen-pistil interactions in Petunia, and we proposed an essential role for CRT in intracellular Ca 2+ storage and mobilization during the key reproductive events. Here, we demonstrate that both CRT and exchangeable Ca 2+ are localized in the intra/extracellular peripheries of highly specialized plant cells, such as the pistil transmitting tract cells, pollen tubes, nucellus cells surrounding the embryo sac, and synergids. Based on our present results, we propose that extracellularly located CRT is also involved in Ca 2+ storage and mobilization during sexual reproduction of angiosperms.

Role of local government in responding to environmental health challenges: a case study of Chungnam.

PubMed

Myung, Hyung-Nam; Lee, Hoo-Young

2017-01-01

The purpose of this study is to introduce the establishment process, policy target, and projects for "Chungnam's master plan on environmental health policy (2017-2020)" as the local government's role in addressing local environmental health challenges. We first analyzed existing studies and social issues on the media related to "Chungnam's master plan" to understand Chungnam's environmental health status and discussed domestic and international policy trends and related plans. An environmental health perception questionnaire survey and a Delphi expert questionnaire survey were conducted among provincial residents to collect various actors' opinions on Chungnam's environmental health issues and policy. An expert advisory panel was launched, and a residents' voice workshop and cities-and-guns-policy-suggestion workshop were held. The vision of Chungnam's environmental health policy is minimizing environmental hazards. We finally selected "Pleasant environment, healthy people, happy Chungnam" to represent the will to shape a pleasant environment and prevent and manage health damages for a happy Chungnam. We selected five strategies based on status analysis and a review of domestic and international policy trends and related plans and identified 2 targets (policy objectives) to accomplish the strategies. The strategies to achieve the first target, "Leader in environmental health policy: Chungnam," include 'Empowering active provincial capabilities,' 'Setting up province-specific systems for environmental health surveys and research,' and 'Preventing and managing newly emerging pollutants.' The strategies for the second target, "Everyone is healthy: Chungnam," include 'Relieving health inequalities among vulnerable regions and residents' and 'Enlarging the resident-friendly environmental health policy.' We developed 29 projects in total, according to these strategies. The establishment of "Chungnam's master plan" is highly valuable; we developed it through discussion involving diverse actors to address environmental health challenges together. It is necessary to continue to strengthen participation, communication, and cooperation among actors to develop an environmental health policy model for the future.

Plastoglobule-Targeting Competence of a Putative Transit Peptide Sequence from Rice Phytoene Synthase 2 in Plastids.

PubMed

You, Min Kyoung; Kim, Jin Hwa; Lee, Yeo Jin; Jeong, Ye Sol; Ha, Sun-Hwa

2016-12-22

Plastoglobules (PGs) are thylakoid membrane microdomains within plastids that are known as specialized locations of carotenogenesis. Three rice phytoene synthase proteins (OsPSYs) involved in carotenoid biosynthesis have been identified. Here, the N-terminal 80-amino-acid portion of OsPSY2 (PTp) was demonstrated to be a chloroplast-targeting peptide by displaying cytosolic localization of OsPSY2(ΔPTp):mCherry in rice protoplast, in contrast to chloroplast localization of OsPSY2:mCherry in a punctate pattern. The peptide sequence of a PTp was predicted to harbor two transmembrane domains eligible for a putative PG-targeting signal. To assess and enhance the PG-targeting ability of PTp, the original PTp DNA sequence ( PTp ) was modified to a synthetic DNA sequence ( stPTp ), which had 84.4% similarity to the original sequence. The motivation of this modification was to reduce the GC ratio from 75% to 65% and to disentangle the hairpin loop structures of PTp . These two DNA sequences were fused to the sequence of the synthetic green fluorescent protein (sGFP) and drove GFP expression with different efficiencies. In particular, the RNA and protein levels of stPTp-sGFP were slightly improved to 1.4-fold and 1.3-fold more than those of sGFP, respectively. The green fluorescent signals of their mature proteins were all observed as speckle-like patterns with slightly blurred stromal signals in chloroplasts. These discrete green speckles of PTp - sGFP and stPTp - sGFP corresponded exactly to the red fluorescent signal displayed by OsPSY2:mCherry in both etiolated and greening protoplasts and it is presumed to correspond to distinct PGs. In conclusion, we identified PTp as a transit peptide sequence facilitating preferential translocation of foreign proteins to PGs, and developed an improved PTp sequence, a s tPTp , which is expected to be very useful for applications in plant biotechnologies requiring precise micro-compartmental localization in plastids.

Registration of MRI to Intraoperative Radiographs for Target Localization in Spinal Interventions

PubMed Central

De Silva, T; Uneri, A; Ketcha, M D; Reaungamornrat, S; Goerres, J; Jacobson, M W; Vogt, S; Kleinszig, G; Khanna, A J; Wolinsky, J-P; Siewerdsen, J H

2017-01-01

Purpose Decision support to assist in target vertebra localization could provide a useful aid to safe and effective spine surgery. Previous solutions have shown 3D-2D registration of preoperative CT to intraoperative radiographs to reliably annotate vertebral labels for assistance during level localization. We present an algorithm (referred to as MR-LevelCheck) to perform 3D-2D registration based on a preoperative MRI to accommodate the increasingly common clinical scenario in which MRI is used instead of CT for preoperative planning. Methods Straightforward adaptation of gradient/intensity-based methods appropriate to CT-to-radiograph registration is confounded by large mismatch and noncorrespondence in image intensity between MRI and radiographs. The proposed method overcomes such challenges with a simple vertebrae segmentation step using vertebra centroids as seed points (automatically defined within existing workflow). Forwards projections are computed using segmented MRI and registered to radiographs via gradient orientation (GO) similarity and the CMA-ES (Covariance-Matrix-Adaptation Evolutionary-Strategy) optimizer. The method was tested in an IRB-approved study involving 10 patients undergoing cervical, thoracic, or lumbar spine surgery following preoperative MRI. Results The method successfully registered each preoperative MRI to intraoperative radiographs and maintained desirable properties of robustness against image content mismatch and large capture range. Robust registration performance was achieved with projection distance error (PDE) (median ± iqr) = 4.3 ± 2.6 mm (median ± iqr) and 0% failure rate. Segmentation accuracy for the continuous max-flow method yielded Dice coefficient = 88.1 ± 5.2, Accuracy = 90.6 ± 5.7, RMSE = 1.8 ± 0.6 mm, and contour affinity ratio (CAR) = 0.82 ± 0.08. Registration performance was found to be robust for segmentation methods exhibiting RMSE < 3 mm and CAR > 0.50. Conclusion The MR-LevelCheck method provides a potentially valuable extension to a previously developed decision support tool for spine surgery target localization by extending its utility to preoperative MRI while maintaining characteristics of accuracy and robustness. PMID:28050972

Metrology Camera System Using Two-Color Interferometry

NASA Technical Reports Server (NTRS)

Dubovitsky, Serge; Liebe, Carl Christian; Peters, Robert; Lay, Oliver

2007-01-01

A metrology system that contains no moving parts simultaneously measures the bearings and ranges of multiple reflective targets in its vicinity, enabling determination of the three-dimensional (3D) positions of the targets with submillimeter accuracy. The system combines a direction-measuring metrology camera and an interferometric range-finding subsystem. Because the system is based partly on a prior instrument denoted the Modulation Sideband Technology for Absolute Ranging (MSTAR) sensor and because of its 3D capability, the system is denoted the MSTAR3D. Developed for use in measuring the shape (for the purpose of compensating for distortion) of large structures like radar antennas, it can also be used to measure positions of multiple targets in the course of conventional terrestrial surveying. A diagram of the system is shown in the figure. One of the targets is a reference target having a known, constant distance with respect to the system. The system comprises a laser for generating local and target beams at a carrier frequency; a frequency shifting unit to introduce a frequency shift offset between the target and local beams; a pair of high-speed modulators that apply modulation to the carrier frequency in the local and target beams to produce a series of modulation sidebands, the highspeed modulators having modulation frequencies of FL and FM; a target beam launcher that illuminates the targets with the target beam; optics and a multipixel photodetector; a local beam launcher that launches the local beam towards the multi-pixel photodetector; a mirror for projecting to the optics a portion of the target beam reflected from the targets, the optics being configured to focus the portion of the target beam at the multi-pixel photodetector; and a signal-processing unit connected to the photodetector. The portion of the target beam reflected from the targets produces spots on the multi-pixel photodetector corresponding to the targets, respectively, and the signal-processing unit centroids the spots to determine bearings of the targets, respectively. As the spots oscillate in intensity because they are mixed with the local laser beam that is flood illuminating the focal plane, the phase of oscillation of each spot is measured, the phase of sidebands in the oscillation of each spot being proportional to a distance to the corresponding target relative to the reference target A.

Efficient Nonlocal M-Control and N-Target Controlled Unitary Gate Using Non-symmetric GHZ States

NASA Astrophysics Data System (ADS)

Chen, Li-Bing; Lu, Hong

2018-03-01

Efficient local implementation of a nonlocal M-control and N-target controlled unitary gate is considered. We first show that with the assistance of two non-symmetric qubit(1)-qutrit(N) Greenberger-Horne-Zeilinger (GHZ) states, a nonlocal 2-control and N-target controlled unitary gate can be constructed from 2 local two-qubit CNOT gates, 2 N local two-qutrit conditional SWAP gates, N local qutrit-qubit controlled unitary gates, and 2 N single-qutrit gates. At each target node, the two third levels of the two GHZ target qutrits are used to expose one and only one initial computational state to the local qutrit-qubit controlled unitary gate, instead of being used to hide certain states from the conditional dynamics. This scheme can be generalized straightforwardly to implement a higher-order nonlocal M-control and N-target controlled unitary gate by using M non-symmetric qubit(1)-qutrit(N) GHZ states as quantum channels. Neither the number of the additional levels of each GHZ target particle nor that of single-qutrit gates needs to increase with M. For certain realistic physical systems, the total gate time may be reduced compared with that required in previous schemes.

One Shot Detection with Laplacian Object and Fast Matrix Cosine Similarity.

PubMed

Biswas, Sujoy Kumar; Milanfar, Peyman

2016-03-01

One shot, generic object detection involves searching for a single query object in a larger target image. Relevant approaches have benefited from features that typically model the local similarity patterns. In this paper, we combine local similarity (encoded by local descriptors) with a global context (i.e., a graph structure) of pairwise affinities among the local descriptors, embedding the query descriptors into a low dimensional but discriminatory subspace. Unlike principal components that preserve global structure of feature space, we actually seek a linear approximation to the Laplacian eigenmap that permits us a locality preserving embedding of high dimensional region descriptors. Our second contribution is an accelerated but exact computation of matrix cosine similarity as the decision rule for detection, obviating the computationally expensive sliding window search. We leverage the power of Fourier transform combined with integral image to achieve superior runtime efficiency that allows us to test multiple hypotheses (for pose estimation) within a reasonably short time. Our approach to one shot detection is training-free, and experiments on the standard data sets confirm the efficacy of our model. Besides, low computation cost of the proposed (codebook-free) object detector facilitates rather straightforward query detection in large data sets including movie videos.

Automatic Localization of Vertebral Levels in X-Ray Fluoroscopy Using 3D-2D Registration: A Tool to Reduce Wrong-Site Surgery

PubMed Central

Otake, Y.; Schafer, S.; Stayman, J. W.; Zbijewski, W.; Kleinszig, G.; Graumann, R.; Khanna, A. J.; Siewerdsen, J. H.

2012-01-01

Surgical targeting of the incorrect vertebral level (“wrong-level” surgery) is among the more common wrong-site surgical errors, attributed primarily to a lack of uniquely identifiable radiographic landmarks in the mid-thoracic spine. Conventional localization method involves manual counting of vertebral bodies under fluoroscopy, is prone to human error, and carries additional time and dose. We propose an image registration and visualization system (referred to as LevelCheck), for decision support in spine surgery by automatically labeling vertebral levels in fluoroscopy using a GPU-accelerated, intensity-based 3D-2D (viz., CT-to-fluoroscopy) registration. A gradient information (GI) similarity metric and CMA-ES optimizer were chosen due to their robustness and inherent suitability for parallelization. Simulation studies involved 10 patient CT datasets from which 50,000 simulated fluoroscopic images were generated from C-arm poses selected to approximate C-arm operator and positioning variability. Physical experiments used an anthropomorphic chest phantom imaged under real fluoroscopy. The registration accuracy was evaluated as the mean projection distance (mPD) between the estimated and true center of vertebral levels. Trials were defined as successful if the estimated position was within the projection of the vertebral body (viz., mPD < 5mm). Simulation studies showed a success rate of 99.998% (1 failure in 50,000 trials) and computation time of 4.7 sec on a midrange GPU. Analysis of failure modes identified cases of false local optima in the search space arising from longitudinal periodicity in vertebral structures. Physical experiments demonstrated robustness of the algorithm against quantum noise and x-ray scatter. The ability to automatically localize target anatomy in fluoroscopy in near-real-time could be valuable in reducing the occurrence of wrong-site surgery while helping to reduce radiation exposure. The method is applicable beyond the specific case of vertebral labeling, since any structure defined in pre-operative (or intra-operative) CT or cone-beam CT can be automatically registered to the fluoroscopic scene. PMID:22864366

Processing Stages Underlying Word Recognition in the Anteroventral Temporal Lobe

PubMed Central

Halgren, Eric; Wang, Chunmao; Schomer, Donald L.; Knake, Susanne; Marinkovic, Ksenija; Wu, Julian; Ulbert, Istvan

2006-01-01

The anteroventral temporal lobe integrates visual, lexical, semantic and mnestic aspects of word-processing, through its reciprocal connections with the ventral visual stream, language areas, and the hippocampal formation. We used linear microelectrode arrays to probe population synaptic currents and neuronal firing in different cortical layers of the anteroventral temporal lobe, during semantic judgments with implicit priming, and overt word recognition. Since different extrinsic and associative inputs preferentially target different cortical layers, this method can help reveal the sequence and nature of local processing stages at a higher resolution than was previously possible. The initial response in inferotemporal and perirhinal cortices is a brief current sink beginning at ~120ms, and peaking at ~170ms. Localization of this initial sink to middle layers suggests that it represents feedforward input from lower visual areas, and simultaneously increased firing implies that it represents excitatory synaptic currents. Until ~800ms, the main focus of transmembrane current sinks alternates between middle and superficial layers, with the superficial focus becoming increasingly dominant after ~550ms. Since superficial layers are the target of local and feedback associative inputs, this suggests an alternation in predominant synaptic input between feedforward and feedback modes. Word repetition does not affect the initial perirhinal and inferotemporal middle layer sink, but does decrease later activity. Entorhinal activity begins later (~200ms), with greater apparent excitatory postsynaptic currents and multiunit activity in neocortically-projecting than hippocampal-projecting layers. In contrast to perirhinal and entorhinal responses, entorhinal responses are larger to repeated words during memory retrieval. These results identify a sequence of physiological activation, beginning with a sharp activation from lower level visual areas carrying specific information to middle layers. This is followed by feedback and associative interactions involving upper cortical layers, which are abbreviated to repeated words. Following bottom-up and associative stages, top-down recollective processes may be driven by entorhinal cortex. Word processing involves a systematic sequence of fast feedforward information transfer from visual areas to anteroventral temporal cortex, followed by prolonged interactions of this feedforward information with local associations, and feedback mnestic information from the medial temporal lobe. PMID:16488158

Behavior analysis in consumer affairs: Retail and consumer response to publicizing food price information

PubMed Central

Greene, Brandon F.; Rouse, Mark; Green, Richard B.; Clay, Connie

1984-01-01

A popular program among consumer action groups involves publicizing comparative food price information (CFPI) gathered from retail stores. Its significance is based on the assumption that publishing CFPI maximizes retail competition (i.e., moderates price levels or price increases) and occasions more frugal store selections among consumers. We tested these assumptions during a 2-year analysis. Specifically, we monitored the prices of two distinct market baskets in the supermarkets of two midwestern cities (target and contrast cities). Following a lengthy baseline, we published the prices of only one of the market baskets at stores in the target city in the local newspaper on five different occasions. The results suggested that reductions in price inflation occurred for both market baskets at the independently operated target stores. The corporate chain stores were not similarly affected. In addition, surveys indicated that many consumers used the CFPI as a basis for store selection. Finally, the analysis included a discussion of the politics, economics, and future of CFPI programs. PMID:16795672

VEGF in nuclear medicine: Clinical application in cancer and future perspectives (Review).

PubMed

Taurone, Samanta; Galli, Filippo; Signore, Alberto; Agostinelli, Enzo; Dierckx, Rudi A J O; Minni, Antonio; Pucci, Marcella; Artico, Marco

2016-08-01

Clinical trials using antiangiogenic drugs revealed their potential against cancer. Unfortunately, a large percentage of patients does not yet benefit from this therapeutic approach highlighting the need of diagnostic tools to non-invasively evaluate and monitor response to therapy. It would also allow to predict which kind of patient will likely benefit of antiangiogenic therapy. Reasons for treatment failure might be due to a low expression of the drug targets or prevalence of other pathways. Molecular imaging has been therefore explored as a diagnostic technique of choice. Since the vascular endothelial growth factor (VEGF/VEGFR) pathway is the main responsible of tumor angiogenesis, several new drugs targeting either the soluble ligand or its receptor to inhibit signaling leading to tumor regression could be involved. Up today, it is difficult to determine VEGF or VEGFR local levels and their non-invasive measurement in tumors might give insight into the available target for VEGF/VEGFR-dependent antiangiogenic therapies, allowing therapy decision making and monitoring of response.

Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK

PubMed Central

Bührmann, Mike; Wiedemann, Bianca M.; Müller, Matthias P.; Hardick, Julia; Ecke, Maria

2017-01-01

In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography. PMID:28892510

The insecticide target in the PSST subunit of complex I.

PubMed

Schuler, F; Casida, J E

2001-10-01

Current insecticides have been selected by sifting and winnowing hundreds of thousands of synthetic chemicals and natural products to obtain commercial preparations of optimal effectiveness and safety. This process has often ended up with compounds of high potency as inhibitors of the electron transport chain and more specifically of complex I (NADH:ubiquinone oxidoreductase). Many classes of chemicals are involved and the enzyme is one of the most complicated known, with 43 subunits catalyzing electron transfer from NADH to ubiquinone through flavin mononucleotide and up to eight iron-sulfur clusters. We used a potent photoaffinity ligand, (trifluoromethyl)diazirinyl[3H]pyridaben, to localize the insecticide target to a single high-affinity site in the PSST subunit that couples electron transfer from iron-sulfur cluster N2 to ubiquinone. Most importantly, all of the potent complex I-inhibiting pesticides, despite their great structural diversity, compete for this same specific binding domain in PSST. Finding their common mode of action and target provides insight into shared toxicological features and potential selection for resistant pests.

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

Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review

PubMed Central

Roberson, DP; Binshtok, AM; Blasl, F; Bean, BP; Woolf, CJ

2011-01-01

BACKGROUND AND PURPOSE We have developed a strategy to target the permanently charged lidocaine derivative lidocaine N-ethyl bromide (QX-314) selectively into nociceptive sensory neurons through the large-pore transient receptor potential cation channel subfamily V (TRPV1) noxious heat detector channel. This involves co-administration of QX-314 and a TRPV1 agonist to produce a long-lasting local analgesia. For potential clinical use we propose using lidocaine as the TRPV1 agonist, because it activates TRPV1 at clinical doses. EXPERIMENTAL APPROACH We conducted experiments in rats to determine optimal concentrations and ratios of lidocaine and QX-314 that produce the greatest degree and duration of pain-selective block when administered nearby the sciatic nerve: reduction in the response to noxious mechanical (pinch) and to radiant heat stimuli, with minimal disruption in motor function (grip strength). KEY RESULTS A combination of 0.5% QX-314 and 2% lidocaine produced 1 h of non-selective sensory and motor block followed by >9 h of pain-selective block, where grip strength was unimpaired. QX-314 at this concentration had no effect by itself, while 2% lidocaine by itself produced 1 h of non-selective block. The combination of 0.5% QX-314 and 2% lidocaine was the best of the many tested, in terms of the duration and selectivity of local analgesia. CONCLUSIONS AND IMPLICATIONS Targeting charged sodium channel blockers into specific sets of axons via activation of differentially expressed large-pore channels provides an opportunity to produce prolonged local analgesia, and represents an example of how exploiting ion channels as a drug delivery port can be used to increase the specificity and efficacy of therapeutics. PMID:21457220

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

Brezovich, I; Wu, X; Popple, R

Purpose: To test spatial and dosimetric accuracy of small cranial target irradiation based on 1.5 T MRI scans using static arcs with MLC-defined fields Methods: A plastic (PMMA) phantom simulating a small brain lesion was mounted on a GammaKnife headframe equipped with MRI localizer. The lesion was a 3 mm long, 3.175 mm diameter cylindrical cavity filled with MRI contrast. Radiochromic film passing through the cavity was marked with pin pricks at the cavity center. The cavity was contoured on an MRI image and fused with CT to simulate treatment of a lesion not visible on CT. The transfer ofmore » the target to CT involved registering the MRI contrast cannels of the localizer that were visible on both modalities. Treatments were planned to deliver 800 cGy to the cavity center using multiple static arcs with 5.0×2.4 mm MLC-defined fields. The phantom was aligned on a STx accelerator by registering the conebeam CT with the planning CT. Films from coronal and sagittal planes were scanned and evaluated using ImageJ software Results: Geographic errors in treatment based on 1.5 T scans agreed within 0.33, −0.27 and 1.21 mm in the vertical, lateral and longitudinal dimensions, respectively. The doses delivered to the cavity center were 7.2% higher than planned. The dose distributions were similar to those of a GammaKnife. Conclusion: Radiation can be delivered with an accelerator at mm accuracy to small cranial targets based on 1.5 MRI scans fused to CTs using a standard GammaKnife headframe and MRI localizer. MLC-defined static arcs produce isodose lines very similar to the GammaKnife.« less

Systemic human CR2-targeted complement alternative pathway inhibitor ameliorates mouse laser-induced choroidal neovascularization.

PubMed

Rohrer, Bärbel; Coughlin, Beth; Bandyopadhyay, Mausumi; Holers, V Michael

2012-08-01

Genetic associations and the presence of complement components within pathological structures of age-related macular degeneration (AMD) have generated the hypothesis that AMD is caused by chronic local complement activation. Since the majority of activity in the common terminal pathway results from engagement of the amplification loop, the alternative pathway has been proposed as a logical therapeutic target. We recently generated a factor H (fH)-based complement inhibitor (CR2-fH) with the capacity to be "targeted" to sites of complement C3 activation. We asked whether the human therapeutic (TT30) is effective in a mouse model of AMD. Choroidal neovascularization (CNV) was induced by argon laser photocoagulation of Bruch's membrane. Every other day, mice received intravenous injections of TT30 or vehicles, and after 6 days, the presence or absence of CNV and CNV-related changes were evaluated. Area of CNV, photoreceptor cell function, gene expression for complement components and cytokines, vascular endothelial growth factor (VEGF) protein levels, and TT30 bioavailability were determined. CNV development, which has previously been shown to require local complement activation, could be reduced by intravenous TT30 delivery. Specific inhibition of the alternative pathway not only reduced angiogenesis in CNV, but also ameliorated changes in several associated disease-related biomarkers, including diminished retinal function and molecular events known to be involved in AMD such as VEGF production. After intravenous injection, TT30 localized to CNV lesion sites in the retinal pigmented epithelium-choroid. Systemic administration of TT30 was found to reduce CNV pathology. These data may open new avenues for novel systemic AMD treatment strategies.

Sustained Attention to Local and Global Target Features Is Different: Performance and Tympanic Membrane Temperature

ERIC Educational Resources Information Center

Helton, William S.; Hayrynen, Lauren; Schaeffer, David

2009-01-01

Vision researchers have investigated the differences between global and local feature perception. No one has, however, examined the role of global and local feature discrimination in sustained attention tasks. In this experiment participants performed a sustained attention task requiring either global or local letter target discriminations or…

Modular elements of the TPR domain in the Mps1 N terminus differentially target Mps1 to the centrosome and kinetochore

PubMed Central

Marquardt, Joseph R.; Perkins, Jennifer L.; Beuoy, Kyle J.; Fisk, Harold A.

2016-01-01

Faithful segregation of chromosomes to two daughter cells is regulated by the formation of a bipolar mitotic spindle and the spindle assembly checkpoint, ensuring proper spindle function. Here we show that the proper localization of the kinase Mps1 (monopolar spindle 1) is critical to both these processes. Separate elements in the Mps1 N-terminal extension (NTE) and tetratricopeptide repeat (TPR) domains govern localization to either the kinetochore or the centrosome. The third TPR (TPR3) and the TPR-capping helix (C-helix) are each sufficient to target Mps1 to the centrosome. TPR3 binds to voltage-dependent anion channel 3, but although this is sufficient for centrosome targeting of Mps1, it is not necessary because of the presence of the C-helix. A version of Mps1 lacking both elements cannot localize to or function at the centrosome, but maintains kinetochore localization and spindle assembly checkpoint function, indicating that TPR3 and the C-helix define a bipartite localization determinant that is both necessary and sufficient to target Mps1 to the centrosome but dispensable for kinetochore targeting. In contrast, elements required for kinetochore targeting (the NTE and first two TPRs) are dispensable for centrosomal localization and function. These data are consistent with a separation of Mps1 function based on localization determinants within the N terminus. PMID:27339139

Modular elements of the TPR domain in the Mps1 N terminus differentially target Mps1 to the centrosome and kinetochore.

PubMed

Marquardt, Joseph R; Perkins, Jennifer L; Beuoy, Kyle J; Fisk, Harold A

2016-07-12

Faithful segregation of chromosomes to two daughter cells is regulated by the formation of a bipolar mitotic spindle and the spindle assembly checkpoint, ensuring proper spindle function. Here we show that the proper localization of the kinase Mps1 (monopolar spindle 1) is critical to both these processes. Separate elements in the Mps1 N-terminal extension (NTE) and tetratricopeptide repeat (TPR) domains govern localization to either the kinetochore or the centrosome. The third TPR (TPR3) and the TPR-capping helix (C-helix) are each sufficient to target Mps1 to the centrosome. TPR3 binds to voltage-dependent anion channel 3, but although this is sufficient for centrosome targeting of Mps1, it is not necessary because of the presence of the C-helix. A version of Mps1 lacking both elements cannot localize to or function at the centrosome, but maintains kinetochore localization and spindle assembly checkpoint function, indicating that TPR3 and the C-helix define a bipartite localization determinant that is both necessary and sufficient to target Mps1 to the centrosome but dispensable for kinetochore targeting. In contrast, elements required for kinetochore targeting (the NTE and first two TPRs) are dispensable for centrosomal localization and function. These data are consistent with a separation of Mps1 function based on localization determinants within the N terminus.

The demonstration of a theory-based approach to the design of localized patient safety interventions

PubMed Central

2013-01-01

Background There is evidence of unsafe care in healthcare systems globally. Interventions to implement recommended practice often have modest and variable effects. Ideally, selecting and adapting interventions according to local contexts should enhance effects. However, the means by which this can happen is seldom systematic, based on theory, or made transparent. This work aimed to demonstrate the applicability, feasibility, and acceptability of a theoretical domains framework implementation (TDFI) approach for co-designing patient safety interventions. Methods We worked with three hospitals to support the implementation of evidence-based guidance to reduce the risk of feeding into misplaced nasogastric feeding tubes. Our stepped process, informed by the TDF and key principles from implementation literature, entailed: involving stakeholders; identifying target behaviors; identifying local factors (barriers and levers) affecting behavior change using a TDF-based questionnaire; working with stakeholders to generate specific local strategies to address key barriers; and supporting stakeholders to implement strategies. Exit interviews and audit data collection were undertaken to assess the feasibility and acceptability of this approach. Results Following audit and discussion, implementation teams for each Trust identified the process of checking the positioning of nasogastric tubes prior to feeding as the key behavior to target. Questionnaire results indicated differences in key barriers between organizations. Focus groups generated innovative, generalizable, and adaptable strategies for overcoming barriers, such as awareness events, screensavers, equipment modifications, and interactive learning resources. Exit interviews identified themes relating to the benefits, challenges, and sustainability of this approach. Time trend audit data were collected for 301 patients over an 18-month period for one Trust, suggesting clinically significant improved use of pH and documentation of practice following the intervention. Conclusions The TDF is a feasible and acceptable framework to guide the implementation of patient safety interventions. The stepped TDFI approach engages healthcare professionals and facilitates contextualization in identifying the target behavior, eliciting local barriers, and selecting strategies to address those barriers. This approach may be of use to implementation teams and policy makers, although our promising findings confirm the need for a more rigorous evaluation; a balanced block evaluation is currently underway. PMID:24131864

Localized delivery of chemotherapy to the cervix for radiosensitization.

PubMed

Hodge, Lucy S; Downs, Levi S; Chura, Justin C; Thomas, Sajeena G; Callery, Patrick S; Soisson, A Patrick; Kramer, Paul; Wolfe, Stephen S; Tracy, Timothy S

2012-10-01

Chemoradiation is the mainstay of therapy for advanced cervical cancer, with the most effective treatment regimens involving combinations of radiosensitizing agents. However, administration of radiosensitizing chemotherapeutics concurrently with pelvic radiation is not without side effects. The aim of this study was to examine the utility of localized drug delivery as a means of improving drug targeting of radiosensitizing chemotherapeutics to the cervix while limiting systemic toxicities. An initial proof-of-concept study was performed in 14 healthy women following local administration of diazepam utilizing a novel cervical delivery device (CerviPrep™). Uterine vein and peripheral blood samples were collected and diazepam was measured using a GC-MS method. In the follow-up study, gemcitabine was applied to the cervix in 17 women undergoing hysterectomy for various gynecological malignancies. Cervical tissue, uterine vein blood samples, and peripheral plasma were collected, and gemcitabine and its deaminated metabolite 2',2'-difluorodeoxyuridine (dFdU) were measured using HPLC-UV and LC/MS methods. Targeted delivery of diazepam to the cervix was consistent with parent drug detectable in the uterine vein of 13 of 14 women. In the second study, pharmacologically relevant concentrations of gemcitabine (0.01-6.6 nmol/g tissue) were detected in the cervical tissue of 11 of 16 available specimens with dFdU measureable in 15 samples (0.04-8.8 nmol/g tissue). Neither gemcitabine nor its metabolites were detected in the peripheral plasma of any subject. Localized drug delivery to the cervix is possible and may be useful in limiting toxicity associated with intravenous administration of chemotherapeutics for radiosensitization. Copyright © 2012 Elsevier Inc. All rights reserved.

Decreasing the metastatic potential in cancers--targeting the heparan sulfate proteoglycans.

PubMed

Fjeldstad, K; Kolset, S O

2005-09-01

The heterogeneity of proteoglycans (PG)s contributes to their functional diversity. Many functions depend on their ability to bind and modulate the activity of components of the extracellular matrix (ECM). The ability of PGs to interact with other molecules, such as growth factors, is largely determined by the fine structure of the glycosaminoglycan (GAG) chains. Tumorigenesis is associated with changes in the PG synthesis. Heparan sulfate (HS) PGs are involved in several aspects of cancer biology including tumor progression, angiogenesis, and metastasis. PGs can have both tumor promoting and tumor suppressing activities depending on the protein core, the GAG attached, molecules they associate with, localization, the tumor subtype, stages, and degree of tumor differentiation. Perlecan is an angiogenic factor involved in tumor invasiveness. The C-terminal domain V of perlecan, named endorepellin, has however been shown to inhibit angiogenesis. Another angiogenic factor is endostatin, the COOH-terminal domain of the part-time PG collagen XVIII. Glypicans and syndecans may promote local cancer cell growth in some cancer tissues, but inhibit tissue invasion and metastasis in others. The GAG hyaluronan (HA) promotes cancer growth by providing a loose matrix for migrating tumor cells and mediates adhesion of cancer cells. HSPG degrading enzymes like heparanase, heparitinase, and other enzymes such as hyaluronidase and MMP are also important in tumor metastasis. Several different treatment strategies that target PGs have been developed. They have the potential to be effective in reducing tumor growth and inhibit the formation of metastases. PGs are also valuable tumor markers in several cancers.

Pseudotachylitic breccia from the Dhala impact structure, north-central India: Texture, mineralogy and geochemical characterization

NASA Astrophysics Data System (ADS)

Pati, J. K.; Reimold, W. U.; Greshake, A.; Schmitt, R. T.; Koeberl, C.; Pati, P.; Prakash, K.

2015-05-01

Pseudotachylitic breccia (PTB) occurs in a drill core from the crater floor of the 11 km diameter, Proterozoic Dhala impact structure, India. PTBs were intersected in late Archean granitoids between 348.15 m and 502.55 m depth in the MCB-10 drill core from the center of the Dhala structure. The breccias comprise both cataclastic-matrix as well as melt breccias. The presence of microlites and vesicles in the groundmass and a widely observed flow fabric in the PTB support the presence of melt in the groundmass of some samples. Clasts in PTB are derived from the Archean granitoid basement. PTB matrix, the matrix of impact melt breccia also occurring between 256.50 m and 502.55 m depth, and the target granitoids vary in terms of silica, total alkali, magnesium and iron oxide contents. Chondrite-normalized REE patterns of PTB and target granitoids are similar, but the elemental abundances in the PTB are lower. The restricted size of PTB as veins and pods of up to 2.5 cm width, their occurrence at varied depths over a core length of 150 m, the clast population, and the chemical relationships between PTB and their host rocks all suggest the derivation of these breccias locally from the fractured basement granitoids involving in-situ melting. We favor that this took place due to rapid decompression during the collapse and modification stage of impact cratering, with, locally, additional energy input from frictional heating. Locally, amphibolite and dioritic mylonite occur in the host granitoids and their admixture could have contributed to the comparatively more mafic composition of PTB. Alteration of these crater floor rocks could have involved preferential reduction of silica and alkali element abundances, possibly due to impact-induced hydrothermal activity at crater floor level. This process, too, could have resulted in more mafic compositions.

Complex background suppression using global-local registration strategy for the detection of small-moving target on moving platform

NASA Astrophysics Data System (ADS)

Zou, Tianhao; Zuo, Zhengrong

2018-02-01

Target detection is a very important and basic problem of computer vision and image processing. The most often case we meet in real world is a detection task for a moving-small target on moving platform. The commonly used methods, such as Registration-based suppression, can hardly achieve a desired result. To crack this hard nut, we introduce a Global-local registration based suppression method. Differ from the traditional ones, the proposed Global-local Registration Strategy consider both the global consistency and the local diversity of the background, obtain a better performance than normal background suppression methods. In this paper, we first discussed the features about the small-moving target detection on unstable platform. Then we introduced a new strategy and conducted an experiment to confirm its noisy stability. In the end, we confirmed the background suppression method based on global-local registration strategy has a better perform in moving target detection on moving platform.

Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs.

PubMed

Hayashi, Teruo

2015-01-01

Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain

PubMed Central

Senapedis, William T.; Kennedy, Caleb J.; Boyle, Patrick M.; Silver, Pamela A.

2011-01-01

Forkhead transcription factors (FOXOs) alter a diverse array of cellular processes including the cell cycle, oxidative stress resistance, and aging. Insulin/Akt activation directs phosphorylation and cytoplasmic sequestration of FOXO away from its target genes and serves as an endpoint of a complex signaling network. Using a human genome small interfering RNA (siRNA) library in a cell-based assay, we identified an extensive network of proteins involved in nuclear export, focal adhesion, and mitochondrial respiration not previously implicated in FOXO localization. Furthermore, a detailed examination of mitochondrial factors revealed that loss of uncoupling protein 5 (UCP5) modifies the energy balance and increases free radicals through up-regulation of uncoupling protein 3 (UCP3). The increased superoxide content induces c-Jun N-terminal kinase 1 (JNK1) kinase activity, which in turn affects FOXO localization through a compensatory dephosphorylation of Akt. The resulting nuclear FOXO increases expression of target genes, including mitochondrial superoxide dismutase. By connecting free radical defense and mitochondrial uncoupling to Akt/FOXO signaling, these results have implications in obesity and type 2 diabetes development and the potential for therapeutic intervention. PMID:21460183

Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain.

PubMed

Senapedis, William T; Kennedy, Caleb J; Boyle, Patrick M; Silver, Pamela A

2011-05-15

Forkhead transcription factors (FOXOs) alter a diverse array of cellular processes including the cell cycle, oxidative stress resistance, and aging. Insulin/Akt activation directs phosphorylation and cytoplasmic sequestration of FOXO away from its target genes and serves as an endpoint of a complex signaling network. Using a human genome small interfering RNA (siRNA) library in a cell-based assay, we identified an extensive network of proteins involved in nuclear export, focal adhesion, and mitochondrial respiration not previously implicated in FOXO localization. Furthermore, a detailed examination of mitochondrial factors revealed that loss of uncoupling protein 5 (UCP5) modifies the energy balance and increases free radicals through up-regulation of uncoupling protein 3 (UCP3). The increased superoxide content induces c-Jun N-terminal kinase 1 (JNK1) kinase activity, which in turn affects FOXO localization through a compensatory dephosphorylation of Akt. The resulting nuclear FOXO increases expression of target genes, including mitochondrial superoxide dismutase. By connecting free radical defense and mitochondrial uncoupling to Akt/FOXO signaling, these results have implications in obesity and type 2 diabetes development and the potential for therapeutic intervention.

Relationships between divided attention and working memory impairment in people with schizophrenia.

PubMed

Gray, Bradley E; Hahn, Britta; Robinson, Benjamin; Harvey, Alex; Leonard, Carly J; Luck, Steven J; Gold, James M

2014-11-01

Recent studies suggest that people with schizophrenia (PSZ) have difficulty distributing their attention broadly. Other research suggests that PSZ have reduced working memory (WM) capacity. This study tested whether these findings reflect a common underlying deficit. We measured the ability to distribute attention by means of the Useful Field of View (UFOV) task, in which participants must distribute attention so that they can discriminate a foveal target and simultaneously localize a peripheral target. Participants included 50 PSZ and 52 healthy control subjects. We found that PSZ exhibited severe impairments in UFOV performance, that UFOV performance was highly correlated with WM capacity in PSZ (r = -.61), and that UFOV impairments could not be explained by either impaired low-level processing or a generalized deficit. These results suggest that a common mechanism explains deficits in the ability to distribute attention broadly, reduced WM capacity, and other aspects of impaired cognition in schizophrenia. We hypothesize that this mechanism may involve abnormal local circuit dynamics that cause a hyperfocusing of resources onto a small number of internal representations. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Ses proteins as possible targets for vaccine development against Staphylococcus epidermidis infections.

PubMed

Hofmans, Dorien; Khodaparast, Laleh; Khodaparast, Ladan; Vanstreels, Els; Shahrooei, Mohammad; Van Eldere, Johan; Van Mellaert, Lieve

2018-05-09

The opportunistic pathogen Staphylococcus epidermidis is progressively involved in device-related infections. Since these infections involve biofilm formation, antibiotics are not effective. Conversely, a vaccine can be advantageous to prevent these infections. In view of vaccine development, predicted surface proteins were evaluated on their potential as a vaccine target. Immunoglobulins directed against S. epidermidis surface proteins SesB, M, O, Q and R, were used to firstly affirm their surface location. Further, inhibitory effects of these IgGs on biofilm formation were determined in vitro on polystyrene and polyurethane surfaces and in vivo using a subcutaneous catheter mouse model. We also examined the opsonophagocytic capacity of these IgGs. Surface localization of the five Ses proteins was demonstrated both for planktonic and sessile cells, though to a variable extent. Ses-specific IgGs added to planktonic cells had a variable inhibitory effect on cell adhesion to polystyrene, while only anti-SesO IgGs decreased cell attachment to polyurethane catheters. Although phagocytic killing was only obtained after opsonisation with SesB-specific IgGs, a significant reduction of in vivo formed biofilms was observed after administration of SesB-, SesM- and SesO-specific IgGs. Regardless of their characterization or function, S. epidermidis surface proteins can be adequate targets for vaccine development aiming the prevention of device-related infections caused by invasive S. epidermidis strains. Copyright © 2018 Elsevier Ltd. All rights reserved.

Neuropeptides in Obesity and Metabolic Disease.

PubMed

van der Klaauw, Agatha A

2018-01-01

The global rise in the prevalence of obesity and associated comorbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. Studies in rodents with the use of global and targeted gene disruption, and mapping of neurocircuitry by using optogenetics and designer receptors exclusively activated by designer drugs (DREADDs) have greatly advanced our understanding of the neural control of body weight. In conjunction with analytical chemistry techniques involving classical immunoassays and mass spectrometry, many neuropeptides that are key to energy homeostasis have been identified. The actions of neuropeptides are diverse, from paracrine modulation of local neurotransmission to hormonal control of distant target organs. Multiple hormones, such as the adipocyte-derived leptin, insulin, and gut hormones, and nutrients signal peripheral energy state to the central nervous system. Neurons in distinct areas of the hypothalamus and brainstem integrate and translate this information by both direct inhibitory/excitatory projections and anorexigenic or orexigenic neuropeptides into actions on food intake and energy expenditure. The importance of these neuropeptides in human energy balance is most powerfully illustrated by genetic forms of obesity that involve neuropeptides such as melanocortin-4-receptor (MC4R) deficiency. Drugs that mimic the actions of neuropeptides are being tested for the treatment of obesity. Successful therapeutic strategies in obesity will require in-depth knowledge of the neuronal circuits they are working in, the downstream targets, and potential compensatory mechanisms. © 2017 American Association for Clinical Chemistry.

Cannabinoids in the Cardiovascular System.

PubMed

Ho, Wing S V; Kelly, Melanie E M

2017-01-01

Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB 1 and CB 2 receptors or non-CB 1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation. © 2017 Elsevier Inc. All rights reserved.

No psychological effect of color context in a low level vision task

PubMed Central

Pedley, Adam; Wade, Alex R

2013-01-01

Background: A remarkable series of recent papers have shown that colour can influence performance in cognitive tasks. In particular, they suggest that viewing a participant number printed in red ink or other red ancillary stimulus elements improves performance in tasks requiring local processing and impedes performance in tasks requiring global processing whilst the reverse is true for the colour blue. The tasks in these experiments require high level cognitive processing such as analogy solving or remote association tests and the chromatic effect on local vs. global processing is presumed to involve widespread activation of the autonomic nervous system. If this is the case, we might expect to see similar effects on all local vs. global task comparisons. To test this hypothesis, we asked whether chromatic cues also influence performance in tasks involving low level visual feature integration. Methods: Subjects performed either local (contrast detection) or global (form detection) tasks on achromatic dynamic Glass pattern stimuli. Coloured instructions, target frames and fixation points were used to attempt to bias performance to different task types. Based on previous literature, we hypothesised that red cues would improve performance in the (local) contrast detection task but would impede performance in the (global) form detection task.  Results: A two-way, repeated measures, analysis of covariance (2×2 ANCOVA) with gender as a covariate, revealed no influence of colour on either task, F(1,29) = 0.289, p = 0.595, partial η 2 = 0.002. Additional analysis revealed no significant differences in only the first attempts of the tasks or in the improvement in performance between trials. Discussion: We conclude that motivational processes elicited by colour perception do not influence neuronal signal processing in the early visual system, in stark contrast to their putative effects on processing in higher areas. PMID:25075280

No psychological effect of color context in a low level vision task.

PubMed

Pedley, Adam; Wade, Alex R

2013-01-01

A remarkable series of recent papers have shown that colour can influence performance in cognitive tasks. In particular, they suggest that viewing a participant number printed in red ink or other red ancillary stimulus elements improves performance in tasks requiring local processing and impedes performance in tasks requiring global processing whilst the reverse is true for the colour blue. The tasks in these experiments require high level cognitive processing such as analogy solving or remote association tests and the chromatic effect on local vs. global processing is presumed to involve widespread activation of the autonomic nervous system. If this is the case, we might expect to see similar effects on all local vs. global task comparisons. To test this hypothesis, we asked whether chromatic cues also influence performance in tasks involving low level visual feature integration. Subjects performed either local (contrast detection) or global (form detection) tasks on achromatic dynamic Glass pattern stimuli. Coloured instructions, target frames and fixation points were used to attempt to bias performance to different task types. Based on previous literature, we hypothesised that red cues would improve performance in the (local) contrast detection task but would impede performance in the (global) form detection task.  A two-way, repeated measures, analysis of covariance (2×2 ANCOVA) with gender as a covariate, revealed no influence of colour on either task, F(1,29) = 0.289, p = 0.595, partial η (2) = 0.002. Additional analysis revealed no significant differences in only the first attempts of the tasks or in the improvement in performance between trials. We conclude that motivational processes elicited by colour perception do not influence neuronal signal processing in the early visual system, in stark contrast to their putative effects on processing in higher areas.

Simulated annealing in orbital flight planning

NASA Technical Reports Server (NTRS)

Soller, Jeffrey

1990-01-01

Simulated annealing is used to solve a minimum fuel trajectory problem in the space station environment. The environment is unique because the space station will define the first true multivehicle environment in space. The optimization yields surfaces which are potentially complex, with multiple local minima. Because of the likelihood of these local minima, descent techniques are unable to offer robust solutions. Other deterministic optimization techniques were explored without success. The simulated annealing optimization is capable of identifying a minimum-fuel, two-burn trajectory subject to four constraints. Furthermore, the computational efforts involved in the optimization are such that missions could be planned on board the space station. Potential applications could include the on-site planning of rendezvous with a target craft of the emergency rescue of an astronaut. Future research will include multiwaypoint maneuvers, using a knowledge base to guide the optimization.

Detection and Immunolabeling of Peroxisomal Proteins.

PubMed

Schrader, Tina A; Islinger, Markus; Schrader, Michael

2017-01-01

Peroxisomes are essential organelles in mammals which contribute to cellular lipid metabolism and redox homeostasis. The spectrum of their functions in human health and disease is far from being complete, and unexpected and novel roles of peroxisomes are being discovered. To date, those include novel biological roles in antiviral defence, as intracellular signaling platforms and as protective organelles in sensory cells. Furthermore, peroxisomes are part of a complex network of interacting subcellular compartments which involves metabolic cooperation, cross-talk and membrane contacts. As potentially novel peroxisomal proteins are continuously discovered, there is great interest in the verification of their peroxisomal localization. Here, we present protocols used successfully in our laboratory for the detection and immunolabeling of peroxisomal proteins in cultured mammalian cells. We present immunofluorescence and fluorescence-based techniques as well as reagents to determine peroxisome-specific targeting and localization of candidate proteins.

Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1.

PubMed

Sarkar, Saumyendra; Jun, Sujung; Simpkins, James W

2015-08-07

Perturbations in dynamic properties of mitochondria including fission, fusion, and movement lead to disruption of energy supply to synapses contributing to neuropathology and cognitive dysfunction in Alzheimer׳s disease (AD). The molecular mechanisms underlying these defects are still unclear. Previously, we have shown that ERβ is localized in the mitochondria and ERβ knock down disrupts mitochondrial functions. Because a selective ERβ modulator (DPN) can activate PKA, and localized PKA signaling in the mitochondrial membrane regulates mitochondrial structure and functions, we reasoned that ERβ signaling in the mitochondrial membrane rescues many of the mitochondrial defects caused by soluble Aβ oligomer. We now report that DPN treatment in primary hippocampal neurons attenuates soluble Aβ-oligomer induced dendritic mitochondrial fission and reduced mobility. Additionally, Aβ treatment reduced the respiratory reserve capacity of hippocampal neuron and inhibited phosphorylation of Drp1 at its PKA site, which induces excessive mitochondrial fission, and DPN treatment ameliorates these inhibitions. Finally, we discovered a direct interaction of ERβ with a mitochondrial resident protein AKAP1, which induces the PKA-mediated local signaling pathway involved in increased oxidative phosphorylation and inhibition of mitochondrial fission. Taken together, our findings highlight the possibility that ERβ signaling pathway may be a useful mitochondria-directed therapeutic target for AD. Copyright © 2015 Elsevier B.V. All rights reserved.

LOCALIZER: subcellular localization prediction of both plant and effector proteins in the plant cell

PubMed Central

Sperschneider, Jana; Catanzariti, Ann-Maree; DeBoer, Kathleen; Petre, Benjamin; Gardiner, Donald M.; Singh, Karam B.; Dodds, Peter N.; Taylor, Jennifer M.

2017-01-01

Pathogens secrete effector proteins and many operate inside plant cells to enable infection. Some effectors have been found to enter subcellular compartments by mimicking host targeting sequences. Although many computational methods exist to predict plant protein subcellular localization, they perform poorly for effectors. We introduce LOCALIZER for predicting plant and effector protein localization to chloroplasts, mitochondria, and nuclei. LOCALIZER shows greater prediction accuracy for chloroplast and mitochondrial targeting compared to other methods for 652 plant proteins. For 107 eukaryotic effectors, LOCALIZER outperforms other methods and predicts a previously unrecognized chloroplast transit peptide for the ToxA effector, which we show translocates into tobacco chloroplasts. Secretome-wide predictions and confocal microscopy reveal that rust fungi might have evolved multiple effectors that target chloroplasts or nuclei. LOCALIZER is the first method for predicting effector localisation in plants and is a valuable tool for prioritizing effector candidates for functional investigations. LOCALIZER is available at http://localizer.csiro.au/. PMID:28300209

Global and local processing near the left and right hands

PubMed Central

Langerak, Robin M.; La Mantia, Carina L.; Brown, Liana E.

2013-01-01

Visual targets can be processed more quickly and reliably when a hand is placed near the target. Both unimodal and bimodal representations of hands are largely lateralized to the contralateral hemisphere, and since each hemisphere demonstrates specialized cognitive processing, it is possible that targets appearing near the left hand may be processed differently than targets appearing near the right hand. The purpose of this study was to determine whether visual processing near the left and right hands interacts with hemispheric specialization. We presented hierarchical-letter stimuli (e.g., small characters used as local elements to compose large characters at the global level) near the left or right hands separately and instructed participants to discriminate the presence of target letters (X and O) from non-target letters (T and U) at either the global or local levels as quickly as possible. Targets appeared at either the global or local level of the display, at both levels, or were absent from the display; participants made foot-press responses. When discriminating target presence at the global level, participants responded more quickly to stimuli presented near the left hand than near either the right hand or in the no-hand condition. Hand presence did not influence target discrimination at the local level. Our interpretation is that left-hand presence may help participants discriminate global information, a right hemisphere (RH) process, and that the left hand may influence visual processing in a way that is distinct from the right hand. PMID:24194725

Randomized phase II--study evaluating EGFR targeting therapy with cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer--PARC: study protocol [ISRCTN56652283].

PubMed

Krempien, R; Muenter, M W; Huber, P E; Nill, S; Friess, H; Timke, C; Didinger, B; Buechler, P; Heeger, S; Herfarth, K K; Abdollahi, A; Buchler, M W; Debus, J

2005-10-11

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrollment. The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.

Primary cilium suppression by SREBP1c involves distortion of vesicular trafficking by PLA2G3

PubMed Central

Gijs, Hannah Laura; Willemarck, Nicolas; Vanderhoydonc, Frank; Khan, Niamat Ali; Dehairs, Jonas; Derua, Rita; Waelkens, Etienne; Taketomi, Yoshitaka; Murakami, Makoto; Agostinis, Patrizia; Annaert, Wim; Swinnen, Johannes V.

2015-01-01

Distortion of primary cilium formation is increasingly recognized as a key event in many human pathologies. One of the underlying mechanisms involves aberrant activation of the lipogenic transcription factor sterol regulatory element–binding protein 1c (SREBP1c), as observed in cancer cells. To gain more insight into the molecular pathways by which SREBP1c suppresses primary ciliogenesis, we searched for overlap between known ciliogenesis regulators and targets of SREBP1. One of the candidate genes that was consistently up-regulated in cellular models of SREBP1c-induced cilium repression was phospholipase A2 group III (PLA2G3), a phospholipase that hydrolyzes the sn-2 position of glycerophospholipids. Use of RNA interference and a chemical inhibitor of PLA2G3 rescued SREBP1c-induced cilium repression. Cilium repression by SREBP1c and PLA2G3 involved alterations in endosomal recycling and vesicular transport toward the cilium, as revealed by aberrant transferrin and Rab11 localization, and was largely mediated by an increase in lysophosphatidylcholine and lysophosphatidylethanolamine levels. Together these findings indicate that aberrant activation of SREBP1c suppresses primary ciliogenesis by PLA2G3-mediated distortion of vesicular trafficking and suggest that PLA2G3 is a novel potential target to normalize ciliogenesis in SREBP1c-overexpressing cells, including cancer cells. PMID:25904332

Dynamic sound localization in cats

PubMed Central

Ruhland, Janet L.; Jones, Amy E.

2015-01-01

Sound localization in cats and humans relies on head-centered acoustic cues. Studies have shown that humans are able to localize sounds during rapid head movements that are directed toward the target or other objects of interest. We studied whether cats are able to utilize similar dynamic acoustic cues to localize acoustic targets delivered during rapid eye-head gaze shifts. We trained cats with visual-auditory two-step tasks in which we presented a brief sound burst during saccadic eye-head gaze shifts toward a prior visual target. No consistent or significant differences in accuracy or precision were found between this dynamic task (2-step saccade) and the comparable static task (single saccade when the head is stable) in either horizontal or vertical direction. Cats appear to be able to process dynamic auditory cues and execute complex motor adjustments to accurately localize auditory targets during rapid eye-head gaze shifts. PMID:26063772

New outlook on the diagnosis, treatment and follow-up of childhood-onset craniopharyngioma.

PubMed

Müller, Hermann L; Merchant, Thomas E; Puget, Stephanie; Martinez-Barbera, Juan-Pedro

2017-05-01

Childhood-onset craniopharyngiomas are rare embryonic tumours of low-grade histological malignancy. Novel insights into the molecular pathogenesis of human adamantinomatous craniopharyngioma have started to unveil the possibility of testing novel treatments targeting pathogenic pathways. Hypothalamic involvement and/or treatment-related lesions result in impaired physical and social functionality and in severe neuroendocrine sequelae. Quality of survival in patients with craniopharyngioma with hypothalamic involvement is impaired by severe obesity, physical fatigue and non-optimal psychosocial development. Patients with craniopharyngioma involving hypothalamic structures have reduced 20-year overall survival, but overall and progression-free survival are not related to the degree of surgical resection. Irradiation is effective in the prevention of tumour progression and recurrence. For favourably localized craniopharyngiomas, the preferred treatment of choice is to attempt complete resection with preservation of visual, hypothalamic and pituitary function. For unfavourably localized tumours in close proximity to optic and/or hypothalamic structures, a radical neurosurgical strategy attempting complete resection is not recommended owing to potential severe sequelae. As expertise has been shown to have an impact on post-treatment morbidity, medical societies should establish criteria for adequate professional expertise for the treatment of craniopharyngioma. On the basis of these criteria, health authorities should organize the certification of centres of excellence that are authorized to treat and care for patients with this chronic disease.

The Rho-GTPase effector ROCK regulates meiotic maturation of the bovine oocyte via myosin light chain phosphorylation and cofilin phosphorylation.

PubMed

Lee, So-Rim; Xu, Yong-Nan; Jo, Yu-Jin; Namgoong, Suk; Kim, Nam-Hyung

2015-11-01

Oocyte meiosis involves a unique asymmetric division involving spindle movement from the central cytoplasm to the cortex, followed by polar body extrusion. ROCK is a Rho-GTPase effector involved in various cellular functions in somatic cells as well as oocyte meiosis. ROCK was previously shown to promote actin organization by phosphorylating several downstream targets, including LIM domain kinase (LIMK), phosphorylated cofilin (p-cofilin), and myosin light chain (MLC). In this study, we investigated the roles of ROCK and MLC during bovine oocyte meiosis. We found that ROCK was localized around the nucleus at the oocyte's germinal-vesicle (GV) stage, but spreads to the rest of the cytoplasm in later developmental stages. On the other hand, phosphorylated MLC (p-MLC) localized at the cortex, and its abundance decreased by the metaphase-II stage. Disrupting ROCK activity, via RNAi or the chemical inhibitor Y-27632, blocked both cell cycle progression and polar body extrusion. ROCK inhibition also resulted in decreased cortical actin, p-cofilin, and p-MLC levels. Similar to the phenotype associated with inhibition of ROCK activity, inhibition of MLC kinase by the chemical inhibitor ML-7 caused defects in polar body extrusion. Collectively, our results suggest that the ROCK/MLC/actomyosin as well as ROCK/LIMK/cofilin pathways regulate meiotic spindle migration and cytokinesis during bovine oocyte maturation. © 2015 Wiley Periodicals, Inc.

A model for safety and health promotion among Danish farmers.

PubMed

Hjort, Charlotte; Højmose, Poul; Sherson, David

2003-01-01

In 1999, a project concerning the prevention of accidents and occupational diseases was started in Vejle County, Denmark. The aim of the project was to increase the safety and health in farming. The project was based on a participatory strategy. The main principles were local involvement in designing the project, multifaceted activities for defined target-groups and respect for occupational skills and integrity. This multilevel approach involved individuals, groups and organisations. Activities were initiated and adjusted throughout the project. This interactive work remodeling the activities throughout the project period and method encouraged empowerment leaving experiences among the participants. Target groups included farmers, farmers' wives, agricultural advisors, agricultural school teachers, employees and part-time assistants. Activities included dialog-meetings, information meetings in larger and smaller groups, as well as designing of educational safety material, e.g., for children and employees. The project is run with a very low degree of central organisational activities, and is also a so called "bottom-up" project with a low budget. Evaluations are undertaken throughout the project period. If this concept can be implemented in Denmark, it may well be useful in other developed as well as less industrialized countries.

Traffic to the malaria parasite food vacuole: a novel pathway involving a phosphatidylinositol 3-phosphate-binding protein.

PubMed

McIntosh, Michael T; Vaid, Ankush; Hosgood, H Dean; Vijay, Justin; Bhattacharya, Anindita; Sahani, Mayurbhai H; Baevova, Pavlina; Joiner, Keith A; Sharma, Pushkar

2007-04-13

Phosphatidylinositol 3-phosphate (PI3P) is a key ligand for recruitment of endosomal regulatory proteins in higher eukaryotes. Subsets of these endosomal proteins possess a highly selective PI3P binding zinc finger motif belonging to the FYVE domain family. We have identified a single FYVE domain-containing protein in Plasmodium falciparum which we term FCP. Expression and mutagenesis studies demonstrate that key residues are involved in specific binding to PI3P. In contrast to FYVE proteins in other organisms, endogenous FCP localizes to a lysosomal compartment, the malaria parasite food vacuole (FV), rather than to cytoplasmic endocytic organelles. Transfections of deletion mutants further indicate that FCP is essential for trophozoite and FV maturation and that it traffics to the FV via a novel constitutive cytoplasmic to vacuole targeting pathway. This newly discovered pathway excludes the secretory pathway and is directed by a C-terminal 44-amino acid peptide domain. We conclude that an FYVE protein that might be expected to participate in vesicle targeting in the parasite cytosol instead has a vital and functional role in the malaria parasite FV.

Recreating communities to support active living: a new role for social marketing.

PubMed

Maibach, Edward W

2003-01-01

The lack of routine physical activity has become an all too pervasive health threat in the United States. Social marketing can be used directly to promote increased physical activity among people who have access to active living options (e.g., safe and convenient sidewalks or bike paths). A second, albeit indirect, use of social marketing to promote physical activity--and the focus of this article--involves promoting behaviors that influence the built environment for the purpose of increasing people's access to active living options. This use of social marketing involves changing the behavior of consumers, developers, distribution channels (e.g., real estate agents) and policy makers. The approach offers public health and other organizations a disciplined, consumer-focused means of mobilizing their available resources in a manner that maximizes the odds of creating active living communities. These means include understanding the competition, understanding target markets, creating mutually beneficial exchanges, segmenting markets and targeting them based on anticipated return. This article identifies specific opportunities for applying the social marketing approach to create active living communities, and identifies opportunities at the state and national level that will enhance the effectiveness of local efforts.

The Nup153-Nup50 Protein Interface and Its Role in Nuclear Import*

PubMed Central

Makise, Masaki; Mackay, Douglas R.; Elgort, Suzanne; Shankaran, Sunita S.; Adam, Stephen A.; Ullman, Katharine S.

2012-01-01

Interactions between Nup50 and soluble transport factors underlie the efficiency of certain nucleocytoplasmic transport pathways. The platform on which these interactions take place is important to building a complete understanding of nucleocytoplasmic trafficking. Nup153 is the nucleoporin that provides this scaffold for Nup50. Here, we have delineated requirements for the interaction between Nup153 and Nup50, revealing a dual interface. An interaction between Nup50 and a region in the unique N-terminal region of Nup153 is critical for the nuclear pore localization of Nup50. A second site of interaction is at the distal tail of Nup153 and is dependent on importin α. Both of these interactions involve the N-terminal domain of Nup50. The configuration of the Nup153-Nup50 partnership suggests that the Nup153 scaffold provides not just a means of pore targeting for Nup50 but also serves to provide a local environment that facilitates bringing Nup50 and importin α together, as well as other soluble factors involved in transport. Consistent with this, disruption of the Nup153-Nup50 interface decreases efficiency of nuclear import. PMID:23007389

Community-based school feeding during Indonesia's economic crisis: implementation, benefits, and sustainability.

PubMed

Studdert, Lisa J; Soekirman; Rasmussen, Kathleen M; Habicht, Jean-Pierre

2004-06-01

The Indonesian Government initiated a community-based national school-feeding program in 1996. Implementation was decentralized and involved multiple participants. In 1998 we evaluated the implementation of the program and the perceived benefits for community stakeholders using a survey of principals in 143 randomly selected schools and follow-up with in-depth interviews and observations in a subsample of 16 communities. The evaluation covered the period of the 1998 Asian economic crisis, affording the opportunity to assess its impact on the program. The program was implemented in all targeted schools, with excellent community participation. Feeding was sustained through the crisis, in spite of a dramatic escalation in food costs. The families of schoolchildren, farmers, and those who prepared food received economic benefits. The snacks replaced those sold at schools and were of better nutritional value. The children benefited because the snacks compensated for losses in the home diet resulting from the economic crisis. Characteristics of the program that may be important in explaining its success include the involvement of a range of community stakeholders, engagement with existing village administrative structures, scope for local community adaptation and innovation, and the use of local foods that dispersed benefits and ensured sustained implementation during the crisis.

ABA, porphyrins and plant TSPO-related protein.

PubMed

Guillaumot, Damien; Guillon, Stéphanie; Morsomme, Pierre; Batoko, Henri

2009-11-01

We have shown that, unexpectedly, AtTSPO (Arabidopsis thaliana TSPO-related protein) is an endoplasmic reticulum and Golgi-localized membrane protein in plant cells.(1) This localization contrasts with that of mammalian 18-kDa translocator protein (at least for the mostly studied isoform, 18-kDa TSPO), a mitochondrial outer membrane protein (reviewed in ref. 2). Whereas the potential functions of 18-kDa TSPO are well documented, involved mainly in mitochondrial physiology,(2) and its interest as drugs target is been explored,(3) the roles of TSPO-related proteins in plant growth and development are yet to be specified. AtTSPO is expressed in dry seeds and can be induced in vegetative tissues by osmotic and salt stress or abscisic acid (ABA) treatment. Moreover, it was shown that the ABA-dependent induction is transient, and that boosting tetrapyrroles biosynthesis through 5-aminolevulinic acid (ALA) feeding enhanced downregulation of AtTSPO, suggesting an inherent post-translational regulation mechanism also involving ABA and likely porphyrins. We present additional evidence that ABA can help stabilize constitutively expressed AtTSPO and that ALA feeding to knockout mutant seeds, induces substantial germination delay. Here we discuss the possible link between ABA and tetrapyrroles in AtTSPO expression and post-translational regulation.

Evidence that the Malaria Parasite Plasmodium falciparum Putative Rhoptry Protein 2 Localizes to the Golgi Apparatus throughout the Erythrocytic Cycle.

PubMed

Hallée, Stéphanie; Richard, Dave

2015-01-01

Invasion of a red blood cell by Plasmodium falciparum merozoites is an essential step in the malaria lifecycle. Several of the proteins involved in this process are stored in the apical complex of the merozoite, a structure containing secretory organelles that are released at specific times during invasion. The molecular players involved in erythrocyte invasion thus represent potential key targets for both therapeutic and vaccine-based strategies to block parasite development. In our quest to identify and characterize new effectors of invasion, we investigated the P. falciparum homologue of a P. berghei protein putatively localized to the rhoptries, the Putative rhoptry protein 2 (PbPRP2). We show that in P. falciparum, the protein colocalizes extensively with the Golgi apparatus across the asexual erythrocytic cycle. Furthermore, imaging of merozoites caught at different times during invasion show that PfPRP2 is not secreted during the process instead staying associated with the Golgi apparatus. Our evidence therefore suggests that PfPRP2 is a Golgi protein and that it is likely not a direct effector in the process of merozoite invasion.

Functional analysis of the Arabidopsis PHT4 family of intracellular phosphate transporters.

PubMed

Guo, B; Jin, Y; Wussler, C; Blancaflor, E B; Motes, C M; Versaw, W K

2008-01-01

The transport of phosphate (Pi) between subcellular compartments is central to metabolic regulation. Although some of the transporters involved in controlling the intracellular distribution of Pi have been identified in plants, others are predicted from genetic, biochemical and bioinformatics studies. Heterologous expression in yeast, and gene expression and localization in plants were used to characterize all six members of an Arabidopsis thaliana membrane transporter family designated here as PHT4. PHT4 proteins share similarity with SLC17/type I Pi transporters, a diverse group of animal proteins involved in the transport of Pi, organic anions and chloride. All of the PHT4 proteins mediate Pi transport in yeast with high specificity. Bioinformatic analysis and localization of PHT4-GFP fusion proteins indicate that five of the proteins are targeted to the plastid envelope, and the sixth resides in the Golgi apparatus. PHT4 genes are expressed in both roots and leaves, although two of the genes are expressed predominantly in leaves and one mostly in roots. These expression patterns, together with Pi transport activities and subcellular locations, suggest roles for PHT4 proteins in the transport of Pi between the cytosol and chloroplasts, heterotrophic plastids and the Golgi apparatus.

Patterns of Primary Tumor Invasion and Regional Lymph Node Spread Based on Magnetic Resonance Imaging in Early-Stage Nasal NK/T-cell Lymphoma: Implications for Clinical Target Volume Definition and Prognostic Significance

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

Wu, Run-Ye; Liu, Kang; Wang, Wei-Hu

Purpose: This study aimed to determine the pathways of primary tumor invasion (PTI) and regional lymph node (LN) spread based on magnetic resonance imaging (MRI) in early-stage nasal NK/T-cell lymphoma (NKTCL), to improve clinical target volume (CTV) delineation and evaluate the prognostic value of locoregional extension patterns. Methods and Materials: A total of 105 patients with newly diagnosed early-stage nasal NKTCL who underwent pretreatment MRI were retrospectively reviewed. All patients received radiation therapy with or without chemotherapy. Results: The incidences of PTI and regional LN involvement were 64.7% and 25.7%, respectively. Based on the incidence of PTI, involved sites surroundingmore » the nasal cavity were classified into 3 risk subgroups: high-risk (>20%), intermediate-risk (5%-20%), and low-risk (<5%). The most frequently involved site was the nasopharynx (35.2%), followed by the maxillary (21.9%) and ethmoid (21.9%) sinuses. Local disease and regional LN spread followed an orderly pattern without LN skipping. The retropharyngeal nodes (RPNs) were most frequently involved (19.0%), followed by level II (11.4%). The 5-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rates for all patients were 72.8%, 65.2%, and 90.0%, respectively. The presence of PTI and regional LN involvement based on MRI significantly and negatively affected PFS and OS. Conclusions: Early-stage nasal NKTCL presents with a high incidence of PTI but a relatively low incidence of regional LN spread. Locoregional spread followed an orderly pattern, and PTI and regional LN spread are powerful prognostic factors for poorer survival outcomes. CTV reduction may be feasible for selected patients.« less

Tracking targeted bimodal nanovaccines: immune responses and routing in cells, tissue, and whole organism.

PubMed

Cruz, Luis J; Tacken, Paul J; Zeelenberg, Ingrid S; Srinivas, Mangala; Bonetto, Fernando; Weigelin, Bettina; Eich, Christina; de Vries, I Jolanda; Figdor, Carl G

2014-12-01

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), involved in the induction of immunity and currently exploited for antitumor immunotherapies. An optimized noninvasive imaging modality capable of determining and quantifying DC-targeted nanoparticle (NP) trajectories could provide valuable information regarding therapeutic vaccine outcome. Here, targeted poly(d,l-lactide-co-glycolide) nanoparticles (PLGA NPs) recognizing DC receptors were equipped with superparamagnetic iron oxide particles (SPIO) or gold nanoparticles with fluorescently labeled antigen. The fluorescent label allowed for rapid analysis and quantification of DC-specific uptake of targeted PLGA NPs in comparison to uptake by other cells. Transmission electron microscopy (TEM) showed that a fraction of the encapsulated antigen reached the lysosomal compartment of DCs, where SPIO and gold were already partially released. However, part of the PLGA NPs localized within the cytoplasm, as confirmed by confocal microscopy. DCs targeted with NPs carrying SPIO or fluorescent antigen were detected within lymph nodes as early as 1 h after injection by magnetic resonance imaging (MRI). Despite the fact that targeting did not markedly affect PLGA NP biodistribution on organism and tissue level, it increased delivery of NPs to DCs residing in peripheral lymph nodes and resulted in enhanced T cell proliferation. In conclusion, two imaging agents within a single carrier allows tracking of targeted PLGA NPs at the subcellular, cellular, and organismal levels, thereby facilitating the rational design of in vivo targeted vaccination strategies.

Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates.

PubMed

Shuvaev, Vladimir V; Muro, Silvia; Arguiri, Evguenia; Khoshnejad, Makan; Tliba, Samira; Christofidou-Solomidou, Melpo; Muzykantov, Vladimir R

2016-07-28

Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemia-reperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Ab/SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extracellular vs. endosomal oxidative stress, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative placental transfer, localization, and effects of radionuclides in experimental animal and human pregnancies

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

Sikov, M.R.; Meznarich, H.K.; Traub, R.J.

1991-11-01

Estimating radiation doses to the human embryo/fetus from radionuclides and predicting effects requires extrapolation of data from studies of laboratory species, with scaling for species-specific developmental stage and gestational time relationships and maturities at birth. Combinations of fetal-to-maternal ratios of concentrations, patterns of deposition, transfer kinetics, and compartmental and physiologic models are used to predict radioactivity levels and radiation doses to the conceptus. There is agreement between values expressing fractional transfer across the placenta ({theta}) with tabulated values for fractional absorption (f{sub 1}) from gastrointestinal (GI) tract or lung for most substances commonly involved in metabolic processes. A tendency towardmore » disagreement for some other materials is thought to involve explanations based on their physicochemistry, toxicity, or the influence of target tissue development on placental transfer kinetics.« less

Complement, a target for therapy in inflammatory and degenerative diseases.

PubMed

Morgan, B Paul; Harris, Claire L

2015-12-01

The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

Mechanisms of Disease: involvement of the urothelium in bladder dysfunction

PubMed Central

Birder, Lori A; de Groat, William C

2011-01-01

SUMMARY Although the urinary bladder urothelium has classically been thought of as a passive barrier to ions and solutes, a number of novel properties have been recently attributed to urothelial cells. Studies have revealed that the urothelium is involved in sensory mechanisms (i.e. the ability to express a number of sensor molecules or respond to thermal, mechanical and chemical stimuli) and can release chemical mediators. Localization of afferent nerves next to the urothelium suggests that urothelial cells could be targets for neurotransmitters released from bladder nerves or that chemicals released by urothelial cells could alter afferent nerve excitability. Taken together, these and other findings highlighted in this article suggest a sensory function for the urothelium. Elucidation of mechanisms that influence urothelial function might provide insights into the pathology of bladder dysfunction. PMID:17211425

Analysis of laterality and percentage of tumor involvement in 1386 prostatectomized specimens for selection of unilateral focal cryotherapy.

PubMed

Mouraviev, Vladimir; Mayes, Janice M; Madden, John F; Sun, Leon; Polascik, Thomas J

2007-04-01

In total, 1386 paraffin embedded radical prostatectomy specimens from patients with clinically localized prostate cancer (PCa) excised between 2002-06 were analyzed. Pathologic assessment paid particular attention to laterality and percentage of tumor involvement (PTI) along with pathologic Gleason Score (pGS). Completely unilateral cancers were identified in 254 (18.3%) patients, and in 39% cases of them the signs of clinically significant PCa were revealed. The majority of unilateral tumors (72%) were low volume with a PTI of < or =5. This study suggests that only a select group of men diagnosed with PCa have completely unilateral cancers that would be amenable to focal ablation therapy targeting 1 lobe. Further study is needed to develop predictive models for those patients likely to have small, unilateral cancers that may be amenable to focal therapy.

Biological Activity of Polynesian Calophyllum inophyllum Oil Extract on Human Skin Cells.

PubMed

Ansel, Jean-Luc; Lupo, Elise; Mijouin, Lily; Guillot, Samuel; Butaud, Jean-François; Ho, Raimana; Lecellier, Gaël; Raharivelomanana, Phila; Pichon, Chantal

2016-07-01

Oil from the nuts of Calophyllum inophyllum, locally called "Tamanu oil" in French Polynesia, was traditionally used for wound healing and to cure various skin problems and ailments. The skin-active effect of "Tamanu oil emulsion" was investigated on human skin cells (keratinocytes and dermal fibroblasts) and showed cell proliferation, glycosaminoglycan and collagen production, and wound healing activity. Transcriptomic analysis of the treated cells revealed gene expression modulation including genes involved in the metabolic process implied in O-glycan biosynthesis, cell adhesion, and cell proliferation. The presence of neoflavonoids as bioactive constituents in Tamanu oil emulsion may contribute to these biological activities. Altogether, consistent data related to targeted histological and cellular functions brought new highlights on the mechanisms involved in these biological processes induced by Tamanu oil effects in skin cells. Georg Thieme Verlag KG Stuttgart · New York.

A computer program to determine the possible daily release window for sky target experiments

NASA Technical Reports Server (NTRS)

Michaud, N. H.

1973-01-01

A computer program is presented which is designed to determine the daily release window for sky target experiments. Factors considered in the program include: (1) target illumination by the sun at release time and during the tracking period; (2) look angle elevation above local horizon from each tracking station to the target; (3) solar depression angle from the local horizon of each tracking station during the experimental period after target release; (4) lunar depression angle from the local horizon of each tracking station during the experimental period after target release; and (5) total sky background brightness as seen from each tracking station while viewing the target. Program output is produced in both graphic and data form. Output data can be plotted for a single calendar month or year. The numerical values used to generate the plots are furnished to permit a more detailed review of the computed daily release windows.

Influence of aging on human sound localization

PubMed Central

Dobreva, Marina S.; O'Neill, William E.

2011-01-01

Errors in sound localization, associated with age-related changes in peripheral and central auditory function, can pose threats to self and others in a commonly encountered environment such as a busy traffic intersection. This study aimed to quantify the accuracy and precision (repeatability) of free-field human sound localization as a function of advancing age. Head-fixed young, middle-aged, and elderly listeners localized band-passed targets using visually guided manual laser pointing in a darkened room. Targets were presented in the frontal field by a robotically controlled loudspeaker assembly hidden behind a screen. Broadband targets (0.1–20 kHz) activated all auditory spatial channels, whereas low-pass and high-pass targets selectively isolated interaural time and intensity difference cues (ITDs and IIDs) for azimuth and high-frequency spectral cues for elevation. In addition, to assess the upper frequency limit of ITD utilization across age groups more thoroughly, narrowband targets were presented at 250-Hz intervals from 250 Hz up to ∼2 kHz. Young subjects generally showed horizontal overestimation (overshoot) and vertical underestimation (undershoot) of auditory target location, and this effect varied with frequency band. Accuracy and/or precision worsened in older individuals for broadband, high-pass, and low-pass targets, reflective of peripheral but also central auditory aging. In addition, compared with young adults, middle-aged, and elderly listeners showed pronounced horizontal localization deficiencies (imprecision) for narrowband targets within 1,250–1,575 Hz, congruent with age-related central decline in auditory temporal processing. Findings underscore the distinct neural processing of the auditory spatial cues in sound localization and their selective deterioration with advancing age. PMID:21368004

A Novel Method of Localization for Moving Objects with an Alternating Magnetic Field

PubMed Central

Gao, Xiang; Yan, Shenggang; Li, Bin

2017-01-01

Magnetic detection technology has wide applications in the fields of geological exploration, biomedical treatment, wreck removal and localization of unexploded ordinance. A large number of methods have been developed to locate targets with static magnetic fields, however, the relation between the problem of localization of moving objectives with alternating magnetic fields and the localization with a static magnetic field is rarely studied. A novel method of target localization based on coherent demodulation was proposed in this paper. The problem of localization of moving objects with an alternating magnetic field was transformed into the localization with a static magnetic field. The Levenberg-Marquardt (L-M) algorithm was applied to calculate the position of the target with magnetic field data measured by a single three-component magnetic sensor. Theoretical simulation and experimental results demonstrate the effectiveness of the proposed method. PMID:28430153

The effects of particle size, shape, density and flow characteristics on particle margination to vascular walls in cardiovascular diseases.

PubMed

Ta, Hang T; Truong, Nghia P; Whittaker, Andrew K; Davis, Thomas P; Peter, Karlheinz

2018-01-01

Vascular-targeted drug delivery is a promising approach for the treatment of atherosclerosis, due to the vast involvement of endothelium in the initiation and growth of plaque, a characteristic of atherosclerosis. One of the major challenges in carrier design for targeting cardiovascular diseases (CVD) is that carriers must be able to navigate the circulation system and efficiently marginate to the endothelium in order to interact with the target receptors. Areas covered: This review draws on studies that have focused on the role of particle size, shape, and density (along with flow hemodynamics and hemorheology) on the localization of the particles to activated endothelial cell surfaces and vascular walls under different flow conditions, especially those relevant to atherosclerosis. Expert opinion: Generally, the size, shape, and density of a particle affect its adhesion to vascular walls synergistically, and these three factors should be considered simultaneously when designing an optimal carrier for targeting CVD. Available preliminary data should encourage more studies to be conducted to investigate the use of nano-constructs, characterized by a sub-micrometer size, a non-spherical shape, and a high material density to maximize vascular wall margination and minimize capillary entrapment, as carriers for targeting CVD.

Affinity-tuning leukocyte integrin for development of safe therapeutics

NASA Astrophysics Data System (ADS)

Park, Spencer

Much attention has been given to the molecular and cellular pathways linking inflammation with cancer and the local tumor environment to identify new target molecules that could lead to improved diagnosis and treatment. Among the many molecular players involved in the complex response, central to the induction of inflammation is intercellular adhesion molecule (ICAM)-1, which is of particular interest for its highly sensitive and localized expression in response to inflammatory signals. ICAM-1, which has been implicated to play a critical role in tumor progression in various types of cancer, has also been linked to cancer metastases, where ICAM-1 facilitates the spread of metastatic cancer cells to secondary sites. This unique expression profile of ICAM-1 throughout solid tumor microenvironment makes ICAM-1 an intriguing molecular target, which holds great potential as an important diagnostic and therapeutic tool. Herein, we have engineered the ligand binding domain, or the inserted (I) domain of a leukocyte integrin, to exhibit a wide range of monovalent affinities to the natural ligand, ICAM-1. Using the resulting I domain variants, we have created drug and gene delivery nanoparticles, as well as targeted immunotherapeutics that have the ability to bind and migrate to inflammatory sites prevalent in tumors and the associated microenvironment. Through the delivery of diagnostic agents, chemotherapeutics, and immunotherapeutics, the following chapters demonstrate that the affinity enhancements achieved by directed evolution bring the affinity of I domains into the range optimal for numerous applications.

A spline-based non-linear diffeomorphism for multimodal prostate registration.

PubMed

Mitra, Jhimli; Kato, Zoltan; Martí, Robert; Oliver, Arnau; Lladó, Xavier; Sidibé, Désiré; Ghose, Soumya; Vilanova, Joan C; Comet, Josep; Meriaudeau, Fabrice

2012-08-01

This paper presents a novel method for non-rigid registration of transrectal ultrasound and magnetic resonance prostate images based on a non-linear regularized framework of point correspondences obtained from a statistical measure of shape-contexts. The segmented prostate shapes are represented by shape-contexts and the Bhattacharyya distance between the shape representations is used to find the point correspondences between the 2D fixed and moving images. The registration method involves parametric estimation of the non-linear diffeomorphism between the multimodal images and has its basis in solving a set of non-linear equations of thin-plate splines. The solution is obtained as the least-squares solution of an over-determined system of non-linear equations constructed by integrating a set of non-linear functions over the fixed and moving images. However, this may not result in clinically acceptable transformations of the anatomical targets. Therefore, the regularized bending energy of the thin-plate splines along with the localization error of established correspondences should be included in the system of equations. The registration accuracies of the proposed method are evaluated in 20 pairs of prostate mid-gland ultrasound and magnetic resonance images. The results obtained in terms of Dice similarity coefficient show an average of 0.980±0.004, average 95% Hausdorff distance of 1.63±0.48 mm and mean target registration and target localization errors of 1.60±1.17 mm and 0.15±0.12 mm respectively. Copyright © 2012 Elsevier B.V. All rights reserved.

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

PubMed

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

2015-08-01

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

Targeting of cytosolic mRNA to mitochondria: naked RNA can bind to the mitochondrial surface.

PubMed

Michaud, Morgane; Maréchal-Drouard, Laurence; Duchêne, Anne-Marie

2014-05-01

Mitochondria contain hundreds of proteins but only a few are encoded by the mitochondrial genome. The other proteins are nuclear-encoded and imported into mitochondria. These proteins can be translated on free cytosolic polysomes, then targeted and imported into mitochondria. Nonetheless, numerous cytosolic mRNAs encoding mitochondrial proteins are detected at the surface of mitochondria in yeast, plants and animals. The localization of mRNAs to the vicinity of mitochondria would be a way for mitochondrial protein sorting. The mechanisms responsible for mRNA targeting to mitochondria are not clearly identified. Sequences within the mRNA molecules (cis-elements), as well as a few trans-acting factors, have been shown to be essential for targeting of some mRNAs. In order to identify receptors involved in mRNA docking to the mitochondrial surface, we have developed an in vitro mRNA binding assay with isolated plant mitochondria. We show that naked mRNAs are able to bind to isolated mitochondria, and our results strongly suggest that mRNA docking to the plant mitochondrial outer membrane requires at least one component of TOM complex. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Expression of membrane targeted aequorin in Xenopus laevis oocytes.

PubMed

Daguzan, C; Nicolas, M T; Mazars, C; Leclerc, C; Moreau, M

1995-08-01

We described here a system for high level of expression of the calcium activated photoprotein aequorin. This protein has been targeted to the plasma membrane of Xenopus oocyte by nuclear microinjection of a plasmid containing a construction of a chimeric cDNA encoding a fusion protein composed of the photoprotein aequorin and the 5-HT1A receptor. The expression of this fusion protein is placed under the control of RSV promoter. Functional photoprotein was reconstituted in the oocyte by incubation with coelenterazine. The amount of photoprotein 24 h after nuclear microinjection of the plasmid was sufficient to trigger a detectable light emission following calcium entry. The efficiency of the expression is correlated with the dose of plasmid injected. Intracytoplasmic injection of the plasmid always failed in photoprotein expression. Targeting of the apoprotein was demonstrated by immunolocalization under confocal microscopy. In our experimental conditions, the apoprotein was always localized at the animal pole above the nucleus. We never observed expression and targeting to the plasma membrane of the vegetal pole. WE suggest that such expression might be of great interest for the study of numerous problems of developmental biology, in which calcium-dependent pathways are involved.

Learning and inference using complex generative models in a spatial localization task.

PubMed

Bejjanki, Vikranth R; Knill, David C; Aslin, Richard N

2016-01-01

A large body of research has established that, under relatively simple task conditions, human observers integrate uncertain sensory information with learned prior knowledge in an approximately Bayes-optimal manner. However, in many natural tasks, observers must perform this sensory-plus-prior integration when the underlying generative model of the environment consists of multiple causes. Here we ask if the Bayes-optimal integration seen with simple tasks also applies to such natural tasks when the generative model is more complex, or whether observers rely instead on a less efficient set of heuristics that approximate ideal performance. Participants localized a "hidden" target whose position on a touch screen was sampled from a location-contingent bimodal generative model with different variances around each mode. Over repeated exposure to this task, participants learned the a priori locations of the target (i.e., the bimodal generative model), and integrated this learned knowledge with uncertain sensory information on a trial-by-trial basis in a manner consistent with the predictions of Bayes-optimal behavior. In particular, participants rapidly learned the locations of the two modes of the generative model, but the relative variances of the modes were learned much more slowly. Taken together, our results suggest that human performance in a more complex localization task, which requires the integration of sensory information with learned knowledge of a bimodal generative model, is consistent with the predictions of Bayes-optimal behavior, but involves a much longer time-course than in simpler tasks.

Immediate Translation of Formin DIAPH1 mRNA after Its Exiting the Nucleus Is Required for Its Perinuclear Localization in Fibroblasts

PubMed Central

Liao, Guoning; Liu, Gang

2013-01-01

DIAPH1 is a formin protein which promotes actin polymerization, stabilizes microtubules and consequently is involved in cytoskeleton dynamics, cell migration and differentiation. In contrast to the relatively well-understood signaling cascades that regulate DIAPH1 activity, its spatial regulation of biogenesis is not understood. A recent report showed that synthesis of DIAPH1 is confined in the perinuclear ER compartment through translation-dependent mRNA targeting. However, the underlying mechanism of DIAPH1 local synthesis is yet to be elucidated. Here, we provide evidence to demonstrate that the 5′-cap-mediated immediate translation of DIAPH1 mRNA upon exiting nucleus is required for localizing the mRNA in the perinuclear ER compartment. This is supported by data: 1) Delayed translation of DIAPH1 mRNA resulted in loss of perinuclear localization of the mRNA; 2) Once delocalized, DIAPH1 mRNA could not be retargeted to the perinuclear region; and 3) The translation of DIAPH1 mRNA is 5′-cap dependent. These results provide new insights into the novel mechanism of DIAPH1 local synthesis. In addition, these findings have led to the development of new approaches for manipulating DIAPH1 mRNA localization and local protein synthesis in cells for functional studies. Furthermore, a correlation of DIAPH1 mRNA and DIAPH1 protein localization has been demonstrated using a new method to quantify the intracellular distribution of protein. PMID:23840831

Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.

PubMed

Paul, Jonathan W; Hua, Susan; Ilicic, Marina; Tolosa, Jorge M; Butler, Trent; Robertson, Sarah; Smith, Roger

2017-03-01

The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs. Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor. We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice. Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor-targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect. Our results demonstrate that oxytocin receptor-targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus. Copyright © 2016. Published by Elsevier Inc.

Task-related modulation of visual neglect in cancellation tasks

PubMed Central

Sarri, Margarita; Greenwood, Richard; Kalra, Lalit; Driver, Jon

2008-01-01

Unilateral neglect involves deficits of spatial exploration and awareness that do not always affect a fixed portion of extrapersonal space, but may vary with current stimulation and possibly with task demands. Here, we assessed any ‘top-down’, task-related influences on visual neglect, with novel experimental variants of the cancellation test. Many different versions of the cancellation test are used clinically, and can differ in the extent of neglect revealed, though the exact factors determining this are not fully understood. Few cancellation studies have isolated the influence of top-down factors, as typically the stimuli are changed also when comparing different tests. Within each of three cancellation studies here, we manipulated task factors, while keeping visual displays identical across conditions to equate purely bottom-up factors. Our results show that top-down task-demands can significantly modulate neglect as revealed by cancellation on the same displays. Varying the target/non-target discrimination required for identical displays has a significant impact. Varying the judgement required can also have an impact on neglect even when all items are targets, so that non-targets no longer need filtering out. Requiring local versus global aspects of shape to be judged for the same displays also has a substantial impact, but the nature of discrimination required by the task still matters even when local/global level is held constant (e.g. for different colour discriminations on the same stimuli). Finally, an exploratory analysis of lesions among our neglect patients suggested that top-down task-related influences on neglect, as revealed by the new cancellation experiments here, might potentially depend on right superior temporal gyrus surviving the lesion. PMID:18790703

Task-related modulation of visual neglect in cancellation tasks.

PubMed

Sarri, Margarita; Greenwood, Richard; Kalra, Lalit; Driver, Jon

2009-01-01

Unilateral neglect involves deficits of spatial exploration and awareness that do not always affect a fixed portion of extrapersonal space, but may vary with current stimulation and possibly with task demands. Here, we assessed any 'top-down', task-related influences on visual neglect, with novel experimental variants of the cancellation test. Many different versions of the cancellation test are used clinically, and can differ in the extent of neglect revealed, though the exact factors determining this are not fully understood. Few cancellation studies have isolated the influence of top-down factors, as typically the stimuli are changed also when comparing different tests. Within each of three cancellation studies here, we manipulated task factors, while keeping visual displays identical across conditions to equate purely bottom-up factors. Our results show that top-down task demands can significantly modulate neglect as revealed by cancellation on the same displays. Varying the target/non-target discrimination required for identical displays has a significant impact. Varying the judgement required can also have an impact on neglect even when all items are targets, so that non-targets no longer need filtering out. Requiring local versus global aspects of shape to be judged for the same displays also has a substantial impact, but the nature of discrimination required by the task still matters even when local/global level is held constant (e.g. for different colour discriminations on the same stimuli). Finally, an exploratory analysis of lesions among our neglect patients suggested that top-down task-related influences on neglect, as revealed by the new cancellation experiments here, might potentially depend on right superior temporal gyrus surviving the lesion.

X11/Mint Genes Control Polarized Localization of Axonal Membrane Proteins in Vivo

PubMed Central

Gross, Garrett G.; Lone, G. Mohiddin; Leung, Lok Kwan; Hartenstein, Volker

2013-01-01

Mislocalization of axonal proteins can result in misassembly and/or miswiring of neural circuits, causing disease. To date, only a handful of genes that control polarized localization of axonal membrane proteins have been identified. Here we report that Drosophila X11/Mint proteins are required for targeting several proteins, including human amyloid precursor protein (APP) and Drosophila APP-like protein (APPL), to axonal membranes and for their exclusion from dendrites of the mushroom body in Drosophila, a brain structure involved in learning and memory. Axonal localization of APP is mediated by an endocytic motif, and loss of X11/Mint results in a dramatic increase in cell-surface levels of APPL, especially on dendrites. Mutations in genes required for endocytosis show similar mislocalization of these proteins to dendrites, and strongly enhance defects seen in X11/Mint mutants. These results suggest that X11/Mint-dependent endocytosis in dendrites may serve to promote the axonal localization of membrane proteins. Since X11/Mint binds to APP, and abnormal trafficking of APP contributes to Alzheimer's disease, deregulation of X11/Mint may be important for Alzheimer's disease pathogenesis. PMID:23658195

Study Abroad in Egypt: Identity, Access, and Arabic Language Learning

ERIC Educational Resources Information Center

Trentman, Emma Gale

2012-01-01

Study abroad is often viewed as an ideal setting to improve target language proficiency due to opportunities for extensive contact with locals in the target language. However, research on study abroad demonstrates that this local contact and target language use can be quite limited, and that there is considerable variation in the linguistic…

Eukaryotic gene regulation by targeted chromatin re-modeling at dispersed, middle-repetitive sequence elements.

PubMed

Hodgetts, Ross

2004-12-01

RNA interference might have evolved to minimize the deleterious impact of transposable elements and viruses on eukaryotic genomes, because mutations in genes within the RNAi pathway cause mobilization of transposons in nematodes and flies. Although the first examples of RNAi involved post-transcriptional gene silencing, recently the pathway has been shown to act at the transcriptional level. It does so by establishing a chromatin configuration on the target DNA that has many of the hallmarks of heterochromatin, thus preventing its transcription. Members of dispersed, repeated sequence families appear to have been utilized by the RNAi machinery to regulate nearby genes in yeast. The unusual genomic distribution of three repeated element families in the chicken, fruit-fly and nematode genomes prompts speculation that some of these repeats have been co-opted to control gene expression, either locally or over extended chromosomal domains.

TLX: A master regulator for neural stem cell maintenance and neurogenesis.

PubMed

Islam, Mohammed M; Zhang, Chun-Li

2015-02-01

The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development. Copyright © 2014 Elsevier B.V. All rights reserved.

Promising landscape for regulating macrophage polarization: epigenetic viewpoint

PubMed Central

Chen, Lu; Zhang, Wen; Xu, Zhenyu; Zuo, Jian; Jiang, Hui; Luan, Jiajie

2017-01-01

Macrophages are critical myeloid cells with the hallmark of phenotypic heterogeneity and functional plasticity. Macrophages phenotypes are commonly described as classically-activated M1 and alternatively-activated M2 macrophages which play an essential role in the tissues homeostasis and diseases pathogenesis. Alternations of macrophage polarization and function states require precise regulation of target-gene expression. Emerging data demonstrate that epigenetic mechanisms and transcriptional factors are becoming increasingly appreciated in the orchestration of macrophage polarization in response to local environmental signals. This review is to focus on the advanced concepts of epigenetics changes involved with the macrophage polarization, including microRNAs, DNA methylation and histone modification, which are responsible for the altered cellular signaling and signature genes expression during M1 or M2 polarization. Eventually, the persistent investigation and understanding of epigenetic mechanisms in tissue macrophage polarization and function will enhance the potential to develop novel therapeutic targets for various diseases. PMID:28915705

N-acetylaspartylglutamate: a transmitter candidate for the retinohypothalamic tract.

PubMed Central

Moffett, J R; Williamson, L; Palkovits, M; Namboodiri, M A

1990-01-01

The retinohypothalamic tract is the neural pathway mediating the photic entrainment of circadian rhythms in mammals. Important targets for these retinal fibers are the suprachiasmatic nuclei (SCN) of the hypothalamus, which are thought to be primary sites for the biological clock. The neurotransmitters that operate in this projection system have not yet been determined. Immunohistochemistry and radioimmunoassay performed with affinity-purified antibodies to N-acetylaspartylglutamate (NAAG) demonstrate that this neuron-specific dipeptide, which may act as an excitatory neurotransmitter, is localized extensively in the retinohypothalamic tract and its target zones, including the SCN. Optic nerve transections resulted in significant reductions in NAAG immunoreactivity in the optic chiasm and SCN. Analysis of NAAG concentrations in micropunches of SCN, by means of radioimmunoassay, showed approximately 50% reductions in NAAG levels. These results suggest that this peptide may act as one of the neurotransmitters involved in retinohypothalamic communication and circadian rhythm entrainment. Images PMID:1978319

Compartmentalization of metabolic pathways in yeast mitochondria improves production of branched chain alcohols

PubMed Central

Avalos, José L.; Fink, Gerald R.; Stephanopoulos, Gregory

2013-01-01

Efforts to improve the production of a compound of interest in Saccharomyces cerevisiae have mainly involved engineering or overexpression of cytoplasmic enzymes. We show that targeted expression of metabolic pathways to mitochondria can increase production levels compared with expression of the same pathways in the cytoplasm. Compartmentalisation of the Ehrlich pathway into mitochondria increased isobutanol production by 260%, whereas overexpression of the same pathway in the cytoplasm only improved yields by 10%, compared with a strain overexpressing only the first three steps of the biosynthetic pathway. Subcellular fractionation of engineered strains reveals that targeting the enzymes of the Ehrlich pathway to the mitochondria achieves higher local enzyme concentrations. Other benefits of compartmentalization may include increased availability of intermediates, removing the need to transport intermediates out of the mitochondrion, and reducing the loss of intermediates to competing pathways. PMID:23417095

Ionospheric Data Assimilation and Targeted Observation Strategies: Proof of Concept Analysis in a Geomagnetic Storm Event

NASA Astrophysics Data System (ADS)

Kostelich, Eric; Durazo, Juan; Mahalov, Alex

2017-11-01

The dynamics of the ionosphere involve complex interactions between the atmosphere, solar wind, cosmic radiation, and Earth's magnetic field. Geomagnetic storms arising from solar activity can perturb these dynamics sufficiently to disrupt radio and satellite communications. Efforts to predict ``space weather,'' including ionospheric dynamics, require the development of a data assimilation system that combines observing systems with appropriate forecast models. This talk will outline a proof-of-concept targeted observation strategy, consisting of the Local Ensemble Transform Kalman Filter, coupled with the Thermosphere Ionosphere Electrodynamics Global Circulation Model, to select optimal locations where additional observations can be made to improve short-term ionospheric forecasts. Initial results using data and forecasts from the geomagnetic storm of 26-27 September 2011 will be described. Work supported by the Air Force Office of Scientific Research (Grant Number FA9550-15-1-0096) and by the National Science Foundation (Grant Number DMS-0940314).

Inactivation of the Parietal Reach Region Causes Optic Ataxia, Impairing Reaches but Not Saccades

PubMed Central

Hwang, Eun Jung; Hauschild, Markus; Wilke, Melanie; Andersen, Richard A.

2013-01-01

SUMMARY Lesions in human posterior parietal cortex can cause optic ataxia (OA), in which reaches but not saccades to visual objects are impaired, suggesting separate visuomotor pathways for the two effectors. In monkeys, one potentially crucial area for reach control is the parietal reach region (PRR), in which neurons respond preferentially during reach planning as compared to saccade planning. However, direct causal evidence linking the monkey PRR to the deficits observed in OA is missing. We thus inactivated part of the macaque PRR, in the medial wall of the intraparietal sulcus, and produced the hallmarks of OA, misreaching for peripheral targets but unimpaired saccades. Furthermore, reach errors were larger for the targets preferred by the neural population local to the injection site. These results demonstrate that PRR is causally involved in reach-specific visuomotor pathways, and reach goal disruption in PRR can be a neural basis of OA. PMID:23217749

5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide.

PubMed

Gresch, Paul J; Barrett, Robert J; Sanders-Bush, Elaine; Smith, Randy L

2007-02-01

d-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systemically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, +/-1.0 mm; DV, -2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 microg/side) or artificial cerebrospinal fluid (n = 3-7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 microg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)(2A) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907; 0.4 mg/kg) blocked the discriminative cue of LSD (0.375 microg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 microg/microl/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT(2A) receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.

Location-based technologies for supporting elderly pedestrian in "getting lost" events.

PubMed

Pulido Herrera, Edith

2017-05-01

Localization-based technologies promise to keep older adults with dementia safe and support them and their caregivers during getting lost events. This paper summarizes mainly technological contributions to support the target group in these events. Moreover, important aspects of the getting lost phenomenon such as its concept and ethical issues are also briefly addressed. Papers were selected from scientific databases and gray literature. Since the topic is still in its infancy, other terms were used to find contributions associated with getting lost e.g. wandering. Trends of applying localization systems were identified as personal locators, perimeter systems and assistance systems. The first system barely considered the older adult's opinion, while assistance systems may involve context awareness to improve the support for both the elderly and the caregiver. Since few studies report multidisciplinary work with a special focus on getting lost, there is not a strong evidence of the real efficiency of localization systems or guidelines to design systems for the target group. Further research about getting lost is required to obtain insights for developing customizable systems. Moreover, considering conditions of the older adult might increase the impact of developments that combine localization technologies and artificial intelligence techniques. Implications for Rehabilitation Whilst there is no cure for dementia such as Alzheimer's, it is feasible to take advantage of technological developments to somewhat diminish its negative impact. For instance, location-based systems may provide information to early diagnose the Alzheimer's disease by assessing navigational impairments of older adults. Assessing the latest supportive technologies and methodologies may provide insights to adopt strategies to properly manage getting lost events. More user-centered designs will provide appropriate assistance to older adults. Namely, customizable systems could assist older adults in their daily walks with the aim to increase their self-confidence, independence and autonomy.

A Robust Wireless Sensor Network Localization Algorithm in Mixed LOS/NLOS Scenario.

PubMed

Li, Bing; Cui, Wei; Wang, Bin

2015-09-16

Localization algorithms based on received signal strength indication (RSSI) are widely used in the field of target localization due to its advantages of convenient application and independent from hardware devices. Unfortunately, the RSSI values are susceptible to fluctuate under the influence of non-line-of-sight (NLOS) in indoor space. Existing algorithms often produce unreliable estimated distances, leading to low accuracy and low effectiveness in indoor target localization. Moreover, these approaches require extra prior knowledge about the propagation model. As such, we focus on the problem of localization in mixed LOS/NLOS scenario and propose a novel localization algorithm: Gaussian mixed model based non-metric Multidimensional (GMDS). In GMDS, the RSSI is estimated using a Gaussian mixed model (GMM). The dissimilarity matrix is built to generate relative coordinates of nodes by a multi-dimensional scaling (MDS) approach. Finally, based on the anchor nodes' actual coordinates and target's relative coordinates, the target's actual coordinates can be computed via coordinate transformation. Our algorithm could perform localization estimation well without being provided with prior knowledge. The experimental verification shows that GMDS effectively reduces NLOS error and is of higher accuracy in indoor mixed LOS/NLOS localization and still remains effective when we extend single NLOS to multiple NLOS.

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

Karakaya, Mahmut; Qi, Hairong

This paper addresses the communication and energy efficiency in collaborative visual sensor networks (VSNs) for people localization, a challenging computer vision problem of its own. We focus on the design of a light-weight and energy efficient solution where people are localized based on distributed camera nodes integrating the so-called certainty map generated at each node, that records the target non-existence information within the camera s field of view. We first present a dynamic itinerary for certainty map integration where not only each sensor node transmits a very limited amount of data but that a limited number of camera nodes ismore » involved. Then, we perform a comprehensive analytical study to evaluate communication and energy efficiency between different integration schemes, i.e., centralized and distributed integration. Based on results obtained from analytical study and real experiments, the distributed method shows effectiveness in detection accuracy as well as energy and bandwidth efficiency.« less

Telomere- and Telomerase-Associated Proteins and Their Functions in the Plant Cell

PubMed Central

Procházková Schrumpfová, Petra; Schořová, Šárka; Fajkus, Jiří

2016-01-01

Telomeres, as physical ends of linear chromosomes, are targets of a number of specific proteins, including primarily telomerase reverse transcriptase. Access of proteins to the telomere may be affected by a number of diverse factors, e.g., protein interaction partners, local DNA or chromatin structures, subcellular localization/trafficking, or simply protein modification. Knowledge of composition of the functional nucleoprotein complex of plant telomeres is only fragmentary. Moreover, the plant telomeric repeat binding proteins that were characterized recently appear to also be involved in non-telomeric processes, e.g., ribosome biogenesis. This interesting finding was not totally unexpected since non-telomeric functions of yeast or animal telomeric proteins, as well as of telomerase subunits, have been reported for almost a decade. Here we summarize known facts about the architecture of plant telomeres and compare them with the well-described composition of telomeres in other organisms. PMID:27446102

Determining the Localization of Carbohydrate Active Enzymes Within Gram-Negative Bacteria.

PubMed

McLean, Richard; Inglis, G Douglas; Mosimann, Steven C; Uwiera, Richard R E; Abbott, D Wade

2017-01-01

Investigating the subcellular location of secreted proteins is valuable for illuminating their biological function. Although several bioinformatics programs currently exist to predict the destination of a trafficked protein using its signal peptide sequence, these programs have limited accuracy and often require experimental validation. Here, we present a systematic method to fractionate gram-negative cells and characterize the subcellular localization of secreted carbohydrate active enzymes (CAZymes). This method involves four parallel approaches that reveal the relative abundance of protein within the cytoplasm, periplasm, outer membrane, and extracellular environment. Cytoplasmic and periplasmic proteins are fractionated by lysis and osmotic shock, respectively. Outer membrane bound proteins are determined by comparing cells before and after exoproteolytic digestion. Extracellularly secreted proteins are collected from the media and concentrated. These four different fractionations can then be probed for the presence and quantity of target proteins using immunochemical methods such as Western blots and ELISAs, or enzyme activity assays.

Models in search of a brain.

PubMed

Love, Bradley C; Gureckis, Todd M

2007-06-01

Mental localization efforts tend to stress the where more than the what. We argue that the proper targets for localization are well-specified cognitive models. We make this case by relating an existing cognitive model of category learning to a learning circuit involving the hippocampus, perirhinal, and prefrontal cortices. Results from groups varying in function along this circuit (e.g., infants, amnesics, and older adults) are successfully simulated by reducing the model's ability to form new clusters in response to surprising events, such as an error in supervised learning or an unfamiliar stimulus in unsupervised learning. Clusters in the model are akin to conjunctive codes that are rooted in an episodic experience (the surprising event) yet can develop to resemble abstract codes as they are updated by subsequent experiences. Thus, the model holds that the line separating episodic and semantic information can become blurred. Dissociations (categorization vs. recognition) are explained in terms of cluster recruitment demands.

An approach to constrained aerodynamic design with application to airfoils

NASA Technical Reports Server (NTRS)

Campbell, Richard L.

1992-01-01

An approach was developed for incorporating flow and geometric constraints into the Direct Iterative Surface Curvature (DISC) design method. In this approach, an initial target pressure distribution is developed using a set of control points. The chordwise locations and pressure levels of these points are initially estimated either from empirical relationships and observed characteristics of pressure distributions for a given class of airfoils or by fitting the points to an existing pressure distribution. These values are then automatically adjusted during the design process to satisfy the flow and geometric constraints. The flow constraints currently available are lift, wave drag, pitching moment, pressure gradient, and local pressure levels. The geometric constraint options include maximum thickness, local thickness, leading-edge radius, and a 'glove' constraint involving inner and outer bounding surfaces. This design method was also extended to include the successive constraint release (SCR) approach to constrained minimization.

Clinic-based intervention projects: STD and family planning programs get involved. Intervention model.

PubMed

Finger, W R

1991-06-01

The sexually transmitted disease (STD) program in Udorn, a popular Thai tourist city, has worked closely with 750 prostitutes for 15 years, incorporating the concerns of brothel managers and prostitutes into service delivery. The program in Udorn is part of a nationwide network of STD clinics. The level of person-to-person interaction was increased once it was determined by 1989 that HIV had infected 6% of prostitutes in the city's brothels. Outreach educators were recruited and trained to ensure that all prostitutes in Udorn had the basic facts about HIV and AIDS. Over the last 2 years, the STD program has trained outreach educators to work in 8 brothels, started a local AIDS prevention foundation supported by local businessmen, and taken other steps to incorporate AIDS prevention into its clinic structure. Such clinic-based programs are an important way of targeting groups at high risk of HIV transmission.

Assessment of sequence dependent geometric distortion in contrast-enhanced MR images employed in stereotactic radiosurgery treatment planning.

PubMed

Pappas, Eleftherios P; Seimenis, Ioannis; Dellios, Dimitrios; Kollias, Georgios; Lampropoulos, Kostas I; Karaiskos, Pantelis

2018-06-25

This work focuses on MR-related sequence dependent geometric distortions, which are associated with B 0 inhomogeneity and patient-induced distortion (susceptibility differences and chemical shift effects), in MR images used in stereotactic radiosurgery (SRS) applications. Emphasis is put on characterizing distortion at target brain areas identified by gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) paramagnetic contrast agent uptake. A custom-made phantom for distortion detection was modified to accommodate two small cylindrical inserts, simulating small brain targets. The inserts were filled with Gd-DTPA solutions of various concentrations (0-20 mM). The phantom was scanned at 1.5 T unit using both the reversed read gradient polarity (to determine the overall distortion as reflected by the inserts centroid offset) and the field mapping (to determine B 0 inhomogeneity related distortion in the vicinity of the inserts) techniques. Post-Gd patient images involving a total of 10 brain metastases/targets were also studied using a similar methodology. For the specific imaging conditions, contrast agent presence was found to evidently affect phantom insert position, with centroid offset extending up to 0.068 mm mM -1 (0.208 ppm mM -1 ). The Gd-DTPA induced distortion in patient images was of the order of 0.5 mm for the MRI protocol used, in agreement with the phantom results. Total localization uncertainty of metastases-targets in patient images ranged from 0.35 mm to 0.87 mm, depending on target location, with an average value of 0.54 mm (2.24 ppm). This relative wide range of target localization uncertainty results from the fact that the B 0 inhomogeneity distortion vector in a specific location may add to or partly counterbalance Gd-DTPA induced distortion, thus increasing or decreasing, respectively, the total sequence dependent distortion. Although relatively small, the sequence dependent distortion in Gd-DTPA enhanced brain images can be easily taken into account for SRS treatment planning and target definition purposes by carefully inspecting both the forward and reversed polarity series.

Targeting Adults Who Provide Alcohol to Underage Youth: Results from a National Survey of Local Law Enforcement Agencies

PubMed Central

Jones-Webb, Rhonda; Toomey, Traci L.; Lenk, Kathleen M.; Nelson, Toben F.; Erickson, Darin J.

2014-01-01

Objective We investigated what local enforcement agencies are doing to target adults who provide alcohol to underage youth; what types of enforcement activities are being conducted to target adult providers; and factors that encourage enforcement activities that target adult providers. Method We surveyed 1056 local law enforcement agencies in the U.S. and measured whether or not the agency conducted enforcement activities that target adults who provide alcohol to underage youth. We also measured whether certain agency and jurisdiction characteristics were associated with enforcement activities that target adults who provide alcohol to underage youth. Results Less than half (42%) of local enforcement agencies conducted enforcement efforts targeting adults who provide alcohol to underage youth. Agencies that conducted the enforcement activities targeting adult providers were significantly more likely to have a full time officer specific to alcohol enforcement, a division specific to alcohol enforcement, a social host law, and to perceive underage drinking was very common. Conclusions Results suggest that targeting social providers (i.e., adults over 21 years of age) will require greater law enforcement resources, implementation of underage drinking laws (e.g., social host policies), and changing perceptions among law enforcement regarding underage drinking. Future studies are needed to identify the most effective enforcement efforts and to examine how enforcement efforts are prospectively linked to alcohol consumption. PMID:25466432

Targeting adults who provide alcohol to underage youth: results from a national survey of local law enforcement agencies.

PubMed

Jones-Webb, Rhonda; Toomey, Traci L; Lenk, Kathleen M; Nelson, Toben F; Erickson, Darin J

2015-06-01

We investigated what local enforcement agencies are doing to target adults who provide alcohol to underage youth; what types of enforcement activities are being conducted to target adult providers; and factors that encourage enforcement activities that target adult providers. We surveyed 1,056 local law enforcement agencies in the US and measured whether or not the agency conducted enforcement activities that target adults who provide alcohol to underage youth. We also measured whether certain agency and jurisdiction characteristics were associated with enforcement activities that target adults who provide alcohol to underage youth. Less than half (42%) of local enforcement agencies conducted enforcement efforts targeting adults who provide alcohol to underage youth. Agencies that conducted the enforcement activities targeting adult providers were significantly more likely to have a full time officer specific to alcohol enforcement, a division specific to alcohol enforcement, a social host law, and to perceive underage drinking was very common. Results suggest that targeting social providers (i.e., adults over 21 years of age) will require greater law enforcement resources, implementation of underage drinking laws (e.g., social host policies), and changing perceptions among law enforcement regarding underage drinking. Future studies are needed to identify the most effective enforcement efforts and to examine how enforcement efforts are prospectively linked to alcohol consumption.

Neuromodulation targets intrinsic cardiac neurons to attenuate neuronally mediated atrial arrhythmias.

PubMed

Gibbons, David D; Southerland, E Marie; Hoover, Donald B; Beaumont, Eric; Armour, J Andrew; Ardell, Jeffrey L

2012-02-01

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T(1)-T(3), 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ∼4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.

Use of exocentric and egocentric representations in the concurrent planning of sequential saccades.

PubMed

Sharika, K M; Ramakrishnan, Arjun; Murthy, Aditya

2014-11-26

The concurrent planning of sequential saccades offers a simple model to study the nature of visuomotor transformations since the second saccade vector needs to be remapped to foveate the second target following the first saccade. Remapping is thought to occur through egocentric mechanisms involving an efference copy of the first saccade that is available around the time of its onset. In contrast, an exocentric representation of the second target relative to the first target, if available, can be used to directly code the second saccade vector. While human volunteers performed a modified double-step task, we examined the role of exocentric encoding in concurrent saccade planning by shifting the first target location well before the efference copy could be used by the oculomotor system. The impact of the first target shift on concurrent processing was tested by examining the end-points of second saccades following a shift of the second target during the first saccade. The frequency of second saccades to the old versus new location of the second target, as well as the propagation of first saccade localization errors, both indices of concurrent processing, were found to be significantly reduced in trials with the first target shift compared to those without it. A similar decrease in concurrent processing was obtained when we shifted the first target but kept constant the second saccade vector. Overall, these results suggest that the brain can use relatively stable visual landmarks, independent of efference copy-based egocentric mechanisms, for concurrent planning of sequential saccades. Copyright © 2014 the authors 0270-6474/14/3416009-13$15.00/0.

New insights into the nucleolar localization of a plant RNA virus-encoded protein that acts in both RNA packaging and RNA silencing suppression: involvement of importins alpha and relevance for viral infection.

PubMed

Pérez-Cañamás, Miryam; Hernández, Carmen

2018-05-21

Despite replication of plus strand RNA viruses takes place in the cytoplasm of host cells, different proteins encoded by these infectious agents have been shown to localize in the nucleus, with high accumulation at the nucleolus. In most cases, the molecular determinants and/or biological significance of such subcellular localization remain elusive. Recently, we reported that protein p37 encoded by Pelargonium line pattern virus (family Tombusviridae) acts in both RNA packaging and RNA silencing suppression. Connsistently with these functions, p37 was detected in the cytoplasm of plant cells though it was also present in the nucleus and, particularly, in the nucleolus. Here, we have aimed to gain further insights into factors influencing p37 nucleolar localization and into its potential relevance for viral infection. Besides mapping the protein region containing the nucleolar localization signal, we have found that p37 interacts with distinct members of the importin alpha family -main cellular transporters for nucleo-cytoplasmic traffic of proteins-, and that these interactions are crucial for nucleolar targeting of p37. Impairment of p37 nucleolar localization through down-regulation of importin alpha expression resulted in a reduction of viral accumulation, suggesting that sorting of the protein to the major subnuclear compartment is advantageous for the infection process.

A COMPARATIVE ANALYSIS BETWEEN FRANCE AND JAPAN ON LOCAL GOVERNMENTS' INVOLVEMENT IN NUCLEAR SAFETY GOVERNANCE

NASA Astrophysics Data System (ADS)

Sugawara, Shin-Etsu; Shiroyama, Hideaki

This paper shows a comparative analysis between France and Japan on the way of the local governments' involvement in nuclear safety governance through some interviews. In France, a law came into force that requires related local governments to establish "Commision Locale d'Information" (CLI), which means the local governments officially involve in nuclear regulatory activity. Meanwhile, in Japan, related local governments substantially involve in the operation of nuclear facilities through the "safety agreements" in spite of the lack of legal authority. As a result of comparative analysis, we can point out some institutional input from French cases as follows: to clarify the local governments' roles in the nuclear regulation system, to establish the official channels of communication among nuclear utilities, national regulatory authorities and local governments, and to stipulate explicitly the transparency as a purpose of safety regulation.

48 CFR 752.225-71 - Local procurement.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Local procurement. 752.225... Local procurement. For use in any USAID contract involving performance overseas. Local Procurement (FEB 1997) (a) Local procurement involves the use of appropriated funds to finance the procurement of goods...

48 CFR 752.225-71 - Local procurement.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Local procurement. 752.225... Local procurement. For use in any USAID contract involving performance overseas. Local Procurement (FEB 1997) (a) Local procurement involves the use of appropriated funds to finance the procurement of goods...

Involvement with Local Television News: Cognitive and Emotional Dimensions.

ERIC Educational Resources Information Center

Perse, Elizabeth M.

1990-01-01

Examines the validity of audience involvement in the context of local television news by testing the relationships among (1) strength of news viewing motivation and involvement intensity; (2) type of news viewing motivation and involvement orientation; and (3) cognitive and emotional involvement. Finds that audience involvement during message…

Effect of spatial nonuniformity of heating on compression and burning of a thermonuclear target under direct multibeam irradiation by a megajoule laser pulse

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

Bel’kov, S. A.; Bondarenko, S. V.; Vergunova, G. A.

Direct-drive fusion targets are considered at present as an alternative to targets of indirect compression at a laser energy level of about 2 MJ. In this approach, the symmetry of compression and ignition of thermonuclear fuel play the major role. We report on the results of theoretical investigation of compression and burning of spherical direct-drive targets in the conditions of spatial nonuniformity of heating associated with a shift of the target from the beam center of focusing and possible laser radiation energy disbalance in the beams. The investigation involves numerous calculations based on a complex of 1D and 2D codesmore » RAPID, SEND (for determining the target illumination and the dynamics of absorption), DIANA, and NUT (1D and multidimensional hydrodynamics of compression and burning of targets). The target under investigation had the form of a two-layer shell (ablator made of inertial material CH and DT ice) filled with DT gas. We have determined the range of admissible variation of compression and combustion parameters of the target depending on the variation of the spatial nonuniformity of its heating by a multibeam laser system. It has been shown that low-mode (long-wavelength) perturbations deteriorate the characteristics of the central region due to less effective conversion of the kinetic energy of the target shell into the internal energy of the center. Local initiation of burning is also observed in off-center regions of the target in the case of substantial asymmetry of irradiation. In this case, burning is not spread over the entire volume of the DT fuel as a rule, which considerably reduces the thermonuclear yield as compared to that in the case of spherical symmetry and central ignition.« less

Visualization of hyperspectral imagery

NASA Astrophysics Data System (ADS)

Hogervorst, Maarten A.; Bijl, Piet; Toet, Alexander

2007-04-01

We developed four new techniques to visualize hyper spectral image data for man-in-the-loop target detection. The methods respectively: (1) display the subsequent bands as a movie ("movie"), (2) map the data onto three channels and display these as a colour image ("colour"), (3) display the correlation between the pixel signatures and a known target signature ("match") and (4) display the output of a standard anomaly detector ("anomaly"). The movie technique requires no assumptions about the target signature and involves no information loss. The colour technique produces a single image that can be displayed in real-time. A disadvantage of this technique is loss of information. A display of the match between a target signature and pixels and can be interpreted easily and fast, but this technique relies on precise knowledge of the target signature. The anomaly detector signifies pixels with signatures that deviate from the (local) background. We performed a target detection experiment with human observers to determine their relative performance with the four techniques,. The results show that the "match" presentation yields the best performance, followed by "movie" and "anomaly", while performance with the "colour" presentation was the poorest. Each scheme has its advantages and disadvantages and is more or less suited for real-time and post-hoc processing. The rationale is that the final interpretation is best done by a human observer. In contrast to automatic target recognition systems, the interpretation of hyper spectral imagery by the human visual system is robust to noise and image transformations and requires a minimal number of assumptions (about signature of target and background, target shape etc.) When more knowledge about target and background is available this may be used to help the observer interpreting the data (aided target detection).

The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision.

PubMed

Yu, R T; Chiang, M Y; Tanabe, T; Kobayashi, M; Yasuda, K; Evans, R M; Umesono, K

2000-03-14

Although the development of the vertebrate eye is well described, the number of transcription factors known to be key to this process is still limited. The localized expression of the orphan nuclear receptor Tlx in the optic cup and discrete parts of the central nervous system suggested the possible role of Tlx in the formation or function of these structures. Analyses of Tlx targeted mice revealed that, in addition to the central nervous system cortical defects, lack of Tlx function results in progressive retinal and optic nerve degeneration with associated blindness. An extensive screen of Tlx-positive and Tlx-negative P19 neural precursors identified Pax2 as a candidate target gene. This identification is significant, because Pax2 is known to be involved in retinal development in both the human and the mouse eye. We find that Pax2 is a direct target and that the Tlx binding site in its promoter is conserved between mouse and human. These studies show that Tlx is a key component of retinal development and vision and an upstream regulator of the Pax2 signaling cascade.

The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision

PubMed Central

Yu, Ruth T.; Chiang, Ming-Yi; Tanabe, Teruyo; Kobayashi, Mime; Yasuda, Kunio; Evans, Ronald M.; Umesono, Kazuhiko

2000-01-01

Although the development of the vertebrate eye is well described, the number of transcription factors known to be key to this process is still limited. The localized expression of the orphan nuclear receptor Tlx in the optic cup and discrete parts of the central nervous system suggested the possible role of Tlx in the formation or function of these structures. Analyses of Tlx targeted mice revealed that, in addition to the central nervous system cortical defects, lack of Tlx function results in progressive retinal and optic nerve degeneration with associated blindness. An extensive screen of Tlx-positive and Tlx-negative P19 neural precursors identified Pax2 as a candidate target gene. This identification is significant, because Pax2 is known to be involved in retinal development in both the human and the mouse eye. We find that Pax2 is a direct target and that the Tlx binding site in its promoter is conserved between mouse and human. These studies show that Tlx is a key component of retinal development and vision and an upstream regulator of the Pax2 signaling cascade. PMID:10706625

p38β, A novel regulatory target of Pokemon in hepatic cells.

PubMed

Chen, Zhe; Liu, Feng; Zhang, Nannan; Cao, Deliang; Liu, Min; Tan, Ying; Jiang, Yuyang

2013-06-27

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells.

p38β, A Novel Regulatory Target of Pokemon in Hepatic Cells

PubMed Central

Chen, Zhe; Liu, Feng; Zhang, Nannan; Cao, Deliang; Liu, Min; Tan, Ying; Jiang, Yuyang

2013-01-01

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells. PMID:23807508

Experimental Proof for the Role of Nonlinear Photoionization in Plasmonic Phototherapy.

PubMed

Minai, Limor; Zeidan, Adel; Yeheskely-Hayon, Daniella; Yudovich, Shimon; Kviatkovsky, Inna; Yelin, Dvir

2016-07-13

Targeting individual cells within a heterogeneous tissue is a key challenge in cancer therapy, encouraging new approaches for cancer treatment that complement the shortcomings of conventional therapies. The highly localized interactions triggered by focused laser beams promise great potential for targeting single cells or small cell clusters; however, most laser-tissue interactions often involve macroscopic processes that may harm healthy nearby tissue and reduce specificity. Specific targeting of living cells using femtosecond pulses and nanoparticles has been demonstrated promising for various potential therapeutic applications including drug delivery via optoporation, drug release, and selective cell death. Here, using an intense resonant femtosecond pulse and cell-specific gold nanorods, we show that at certain irradiation parameters cell death is triggered by nonlinear plasmonic photoionization and not by thermally driven processes. The experimental results are supported by a physical model for the pulse-particle-medium interactions. A good correlation is found between the calculated total number and energy of the generated free electrons and the observed cell death, suggesting that femtosecond photoionization plays the dominant role in cell death.

Effects of the bile acid UDCA on PDT efficacy in vitro and in vivo

NASA Astrophysics Data System (ADS)

Kessel, David; Castelli, Michelle; Sykes, Elizabeth; Garbo, Greta M.

2004-06-01

The phototoxicity of PDT in cell culture can be promoted by the relatively hydrophilic bile acid UDCA (ursodeoxycholic acid). This was attributed to a conformational change in the anti-apoptotic protein Bcl-2, leading to an enhanced sensitivity to photodamage by sensitizers that target sites of Bcl-2 localization. UDCA also promoted the binding and inactivation of Bcl-2 by the non-peptidic antagonist HA14- 1, suggesting that UDCA may also be useful for promoting chemotherapy designed to target Bcl-2. In tumor-bearing animals, addition of UDCA to a PDT protocol involving the tin etiopurpurin SnET2 resulted in enhanced cancer control, but there was no effect on the extent of PDT-induced vascular shut-down. These results are consistent with the propo proposal that UDCA only promotes direct tumor cell kill. In this report, we have sal summarized recent research relating to mode of action of UDCA as it effects the on the efficacy of photodynamic therapy where Bcl-2 is among the PDT targets, and discuss the implications of the results.

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

PubMed Central

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

2015-01-01

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

'Where' and 'what' in visual search.

PubMed

Atkinson, J; Braddick, O J

1989-01-01

A line segment target can be detected among distractors of a different orientation by a fast 'preattentive' process. One view is that this depends on detection of a 'feature gradient', which enables subjects to locate where the target is without necessarily identifying what it is. An alternative view is that a target can be identified as distinctive in a particular 'feature map' without subjects knowing where it is in that map. Experiments are reported in which briefly exposed arrays of line segments were followed by a pattern mask, and the threshold stimulus-mask interval determined for three tasks: 'what'--subjects reported whether the target was vertical or horizontal among oblique distractors; 'coarse where'--subjects reported whether the target was in the upper or lower half of the array; 'fine where'--subjects reported whether or not the target was in a set of four particular array positions. The threshold interval was significantly lower for the 'coarse where' than for the 'what' task, indicating that, even though localization in this task depends on the target's orientation difference, this localization is possible without absolute identification of target orientation. However, for the 'fine where' task, intervals as long as or longer than those for the 'what' task were required. It appears either that different localization processes work at different levels of resolution, or that a single localization process, independent of identification, can increase its resolution at the expense of processing speed. These possibilities are discussed in terms of distinct neural representations of the visual field and fixed or variable localization processes acting upon them.

Dual pancreas- and lung-targeting therapy for local and systemic complications of acute pancreatitis mediated by a phenolic propanediamine moiety.

PubMed

Li, Jianbo; Zhang, Jinjie; Fu, Yao; Sun, Xun; Gong, Tao; Jiang, Jinghui; Zhang, Zhirong

2015-08-28

To inhibit both the local and systemic complications with acute pancreatitis, an effective therapy requires a drug delivery system that can efficiently overcome the blood-pancreas barrier while achieving lung-specific accumulation. Here, we report the first dual pancreas- and lung-targeting therapeutic strategy mediated by a phenolic propanediamine moiety for the treatment of acute pancreatitis. Using the proposed dual-targeting ligand, an anti-inflammatory compound Rhein has been tailored to preferentially accumulate in the pancreas and lungs with rapid distribution kinetics, excellent tissue-penetrating properties and minimum toxicity. Accordingly, the drug-ligand conjugate remarkably downregulated the proinflammatory cytokines in the target organs thus effectively inhibiting local pancreatic and systemic inflammation in rats. The dual-specific targeting therapeutic strategy may help pave the way for targeted drug delivery to treat complicated inflammatory diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Super-resolution optical telescopes with local light diffraction shrinkage

PubMed Central

Wang, Changtao; Tang, Dongliang; Wang, Yanqin; Zhao, Zeyu; Wang, Jiong; Pu, Mingbo; Zhang, Yudong; Yan, Wei; Gao, Ping; Luo, Xiangang

2015-01-01

Suffering from giant size of objective lenses and infeasible manipulations of distant targets, telescopes could not seek helps from present super-resolution imaging, such as scanning near-field optical microscopy, perfect lens and stimulated emission depletion microscopy. In this paper, local light diffraction shrinkage associated with optical super-oscillatory phenomenon is proposed for real-time and optically restoring super-resolution imaging information in a telescope system. It is found that fine target features concealed in diffraction-limited optical images of a telescope could be observed in a small local field of view, benefiting from a relayed metasurface-based super-oscillatory imaging optics in which some local Fourier components beyond the cut-off frequency of telescope could be restored. As experimental examples, a minimal resolution to 0.55 of Rayleigh criterion is obtained, and imaging complex targets and large targets by superimposing multiple local fields of views are demonstrated as well. This investigation provides an access for real-time, incoherent and super-resolution telescopes without the manipulation of distant targets. More importantly, it gives counterintuitive evidence to the common knowledge that relayed optics could not deliver more imaging details than objective systems. PMID:26677820

Locally Bayesian Learning with Applications to Retrospective Revaluation and Highlighting

ERIC Educational Resources Information Center

Kruschke, John K.

2006-01-01

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

The effect of visual context on manual localization of remembered targets

NASA Technical Reports Server (NTRS)

Barry, S. R.; Bloomberg, J. J.; Huebner, W. P.

1997-01-01

This paper examines the contribution of egocentric cues and visual context to manual localization of remembered targets. Subjects pointed in the dark to the remembered position of a target previously viewed without or within a structured visual scene. Without a remembered visual context, subjects pointed to within 2 degrees of the target. The presence of a visual context with cues of straight ahead enhanced pointing performance to the remembered location of central but not off-center targets. Thus, visual context provides strong visual cues of target position and the relationship of body position to target location. Without a visual context, egocentric cues provide sufficient input for accurate pointing to remembered targets.

Anchor-Free Localization Method for Mobile Targets in Coal Mine Wireless Sensor Networks

PubMed Central

Pei, Zhongmin; Deng, Zhidong; Xu, Shuo; Xu, Xiao

2009-01-01

Severe natural conditions and complex terrain make it difficult to apply precise localization in underground mines. In this paper, an anchor-free localization method for mobile targets is proposed based on non-metric multi-dimensional scaling (Multi-dimensional Scaling: MDS) and rank sequence. Firstly, a coal mine wireless sensor network is constructed in underground mines based on the ZigBee technology. Then a non-metric MDS algorithm is imported to estimate the reference nodes’ location. Finally, an improved sequence-based localization algorithm is presented to complete precise localization for mobile targets. The proposed method is tested through simulations with 100 nodes, outdoor experiments with 15 ZigBee physical nodes, and the experiments in the mine gas explosion laboratory with 12 ZigBee nodes. Experimental results show that our method has better localization accuracy and is more robust in underground mines. PMID:22574048

Anchor-free localization method for mobile targets in coal mine wireless sensor networks.

PubMed

Pei, Zhongmin; Deng, Zhidong; Xu, Shuo; Xu, Xiao

2009-01-01

Severe natural conditions and complex terrain make it difficult to apply precise localization in underground mines. In this paper, an anchor-free localization method for mobile targets is proposed based on non-metric multi-dimensional scaling (Multi-dimensional Scaling: MDS) and rank sequence. Firstly, a coal mine wireless sensor network is constructed in underground mines based on the ZigBee technology. Then a non-metric MDS algorithm is imported to estimate the reference nodes' location. Finally, an improved sequence-based localization algorithm is presented to complete precise localization for mobile targets. The proposed method is tested through simulations with 100 nodes, outdoor experiments with 15 ZigBee physical nodes, and the experiments in the mine gas explosion laboratory with 12 ZigBee nodes. Experimental results show that our method has better localization accuracy and is more robust in underground mines.

Student Involvement in Wellness Policies: A Study of Pennsylvania Local Education Agencies

ERIC Educational Resources Information Center

Jomaa, Lamis H.; McDonnell, Elaine; Weirich, Elaine; Hartman, Terryl; Jensen, Leif; Probart, Claudia

2010-01-01

Objective: Explore student-involvement goals in local wellness policies (LWPs) of local education agencies (LEAs) in Pennsylvania (PA) and investigate associations with LEA characteristics. Design: An observational study that helped examine student-involvement goals. Setting: Public PA LEAs. Participants: LWPs submitted by 539 PA public LEAs. Main…

Cytoplasmic sequestration of cyclin D1 associated with cell cycle withdrawal of neuroblastoma cells

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

Sumrejkanchanakij, Piyamas; Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330; Eto, Kazuhiro

2006-02-03

The regulation of D-type cyclin-dependent kinase activity is critical for neuronal differentiation and apoptosis. We recently showed that cyclin D1 is sequestered in the cytoplasm and that its nuclear localization induces apoptosis in postmitotic primary neurons. Here, we further investigated the role of the subcellular localization of cyclin D1 in cell cycle withdrawal during the differentiation of N1E-115 neuroblastoma cells. We show that cyclin D1 became predominantly cytoplasmic after differentiation. Targeting cyclin D1 expression to the nucleus induced phosphorylation of Rb and cdk2 kinase activity. Furthermore, cyclin D1 nuclear localization promoted differentiated N1E-115 cells to reenter the cell cycle, amore » process that was inhibited by p16{sup INK4a}, a specific inhibitor of D-type cyclin activity. These results indicate that cytoplasmic sequestration of cyclin D1 plays a role in neuronal cell cycle withdrawal, and suggests that the abrogation of machinery involved in monitoring aberrant nuclear cyclin D1 activity contributes to neuronal tumorigenesis.« less

Image-interactive orientation in the middle cranial fossa approach to the internal auditory canal: an experimental study.

PubMed

Vrionis, F D; Robertson, J H; Foley, K T; Gardner, G

1997-01-01

Approaches through the middle cranial fossa directed at reaching the internal auditory canal (IAC) invariably employ exposure of the geniculate ganglion, the superior semicircular canal (SSC) or the epitympanum. This involves risk to the facial nerve and hearing apparatus. To minimize this risk, we conducted a laboratory study on 9 cadaver temporal bones by using an image-interactive guidance system (StealthStation) to provide topographic orientation in the middle fossa approach. Surface anatomic fiducials such as the umbo of the tympanic membrane, Henle's spine, the root of the zygoma and various sutures were used as fiducials for registration of CT-images of the temporal bone. Accurate localization of the IAC was achieved in every specimen. Mean target localization error varied from 1.20 to 1.38 mm for critical structures in the temporal bone such as the apex of the cochlea, crus commune, ampula of the SSC and facial hiatus. Our results suggest that frameless stereotaxy may be used as an alternative to current methods in localizing the IAC in patients with small vestibular schwannomas or intractable vertigo undergoing middle fossa surgery.

Cytoplasmic sequestration of cyclin D1 associated with cell cycle withdrawal of neuroblastoma cells.

PubMed

Sumrejkanchanakij, Piyamas; Eto, Kazuhiro; Ikeda, Masa-Aki

2006-02-03

The regulation of D-type cyclin-dependent kinase activity is critical for neuronal differentiation and apoptosis. We recently showed that cyclin D1 is sequestered in the cytoplasm and that its nuclear localization induces apoptosis in postmitotic primary neurons. Here, we further investigated the role of the subcellular localization of cyclin D1 in cell cycle withdrawal during the differentiation of N1E-115 neuroblastoma cells. We show that cyclin D1 became predominantly cytoplasmic after differentiation. Targeting cyclin D1 expression to the nucleus induced phosphorylation of Rb and cdk2 kinase activity. Furthermore, cyclin D1 nuclear localization promoted differentiated N1E-115 cells to reenter the cell cycle, a process that was inhibited by p16(INK4a), a specific inhibitor of D-type cyclin activity. These results indicate that cytoplasmic sequestration of cyclin D1 plays a role in neuronal cell cycle withdrawal, and suggests that the abrogation of machinery involved in monitoring aberrant nuclear cyclin D1 activity contributes to neuronal tumorigenesis.

Anaplasma phagocytophilum in questing Ixodes ricinus ticks from Romania.

PubMed

Matei, Ioana Adriana; Kalmár, Zsuzsa; Magdaş, Cristian; Magdaş, Virginia; Toriay, Hortenzia; Dumitrache, Mirabela Oana; Ionică, Angela Monica; D'Amico, Gianluca; Sándor, Attila D; Mărcuţan, Daniel Ioan; Domşa, Cristian; Gherman, Călin Mircea; Mihalca, Andrei Daniel

2015-04-01

Granulocytic anaplasmosis is a common vector-borne disease of humans and animals with natural transmission cycle that involves tick vectors, among which Ixodes ricinus is the most important. The present paper reports the prevalence and geographical distribution of A. phagocytophilum in 10,438 questing Ixodes ricinus ticks collected at 113 locations from 40 counties of Romania. The unfed ticks were examined for the presence of A. phagocytophilum by PCR targeting a portion of ankA gene. The overall prevalence of infection was 3.42%, with local prevalences ranging between 0.29% and 22.45%, with an average prevalence of 5.39% in the infected localities. The infection with A. phagocytophilum was detected in 72 out of 113 localities and in 34 out of 40 counties. The highest prevalence was recorded in females followed by males and nymphs. The results and the distribution model have shown a large distribution of A. phagocytophilum, covering Romania's entire territory. This study is the first large scale survey of the presence of A. phagocytophilum in questing I. ricinus ticks from Romania. Copyright © 2015 Elsevier GmbH. All rights reserved.

Deep brain stimulation mechanisms: beyond the concept of local functional inhibition.

PubMed

Deniau, Jean-Michel; Degos, Bertrand; Bosch, Clémentine; Maurice, Nicolas

2010-10-01

Deep brain electrical stimulation has become a recognized therapy in the treatment of a variety of motor disorders and has potentially promising applications in a wide range of neurological diseases including neuropsychiatry. Behavioural observation that electrical high-frequency stimulation of a given brain area induces an effect similar to a lesion suggested a mechanism of functional inhibition. In vitro and in vivo experiments as well as per operative recordings in patients have revealed a variety of effects involving local changes of neuronal excitability as well as widespread effects throughout the connected network resulting from activation of axons, including antidromic activation. Here we review current data regarding the local and network activity changes induced by high-frequency stimulation of the subthalamic nucleus and discuss this in the context of motor restoration in Parkinson's disease. Stressing the important functional consequences of axonal activation in deep brain stimulation mechanisms, we highlight the importance of developing anatomical knowledge concerning the fibre connections of the putative therapeutic targets. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Periaqueductal gray knockdown of V2, not V1a and V1b receptor influences nociception in the rat. yj6676@yahoo.com.

PubMed

Yang, Jun; Yang, Yu; Chen, Jian-Min; Wang, Gen; Xu, Hong-Tao; Liu, Wen-Yan; Lin, Bao-Cheng

2007-01-01

Our pervious study has proved that arginine vasopressin (AVP) in periaqueductal gray (PAG) plays a role in antinociception. After establishing a model of local special gene knockdown, the nociceptive effect of vasopressin receptor subunit in PAG was investigated in the rat. Microinjection of short-interfering RNA (siRNA) into PAG, which targeted vasopressin receptor subtypes (V(1a), V(1b) and V(2)), locally weakened the associated mRNA expression and depressed the related receptor synthesis in a dose-dependent manner, in which the significant inhibitive effect occurred on from 7th day to 14th day following 1microg or 2microg siRNA administration. PAG knockdown of V(2) receptor gene markedly decreased pain threshold in from 6th day to 13th day after siRNA administration, whereas local knockdown of either V(1a) or V(1b) receptor gene could not influence pain threshold. The data suggest that V(2) rather than V(1a) and V(1b) receptor in PAG involves in nociception.

Interventions That Target Criminogenic Needs for Justice-Involved Persons With Serious Mental Illnesses: A Targeted Service Delivery Approach.

PubMed

Wilson, Amy Blank; Farkas, Kathleen; Bonfine, Natalie; Duda-Banwar, Janelle

2018-05-01

This research describes the development of a targeted service delivery approach that tailors the delivery of interventions that target criminogenic needs to the specific learning and treatment needs of justice-involved people with serious mental illnesses (SMIs). This targeted service delivery approach includes five service delivery strategies: repetition and summarizing, amplification, active coaching, low-demand practice, and maximizing participation. Examples of how to apply each strategy in session are provided, as well as recommendations on when to use each strategy during the delivery of interventions that target criminogenic needs. This targeted service delivery approach makes an important contribution to the development of interventions for justice-involved people with SMI by increasing the chances that people with SMI can participate fully in and benefit from these interventions that target criminogenic needs. These developments come at a critical time in the field as the next generation of services for justice-involved people with SMI are being developed.

Beta carbonic anhydrases: novel targets for pesticides and anti-parasitic agents in agriculture and livestock husbandry.

PubMed

Zolfaghari Emameh, Reza; Barker, Harlan; Hytönen, Vesa P; Tolvanen, Martti E E; Parkkila, Seppo

2014-08-29

The genomes of many insect and parasite species contain beta carbonic anhydrase (β-CA) protein coding sequences. The lack of β-CA proteins in mammals makes them interesting target proteins for inhibition in treatment of some infectious diseases and pests. Many insects and parasites represent important pests for agriculture and cause enormous economic damage worldwide. Meanwhile, pollution of the environment by old pesticides, emergence of strains resistant to them, and their off-target effects are major challenges for agriculture and society. In this study, we analyzed a multiple sequence alignment of 31 β-CAs from insects, some parasites, and selected plant species relevant to agriculture and livestock husbandry. Using bioinformatics tools a phylogenetic tree was generated and the subcellular localizations and antigenic sites of each protein were predicted. Structural models for β-CAs of Ancylostoma caninum, Ascaris suum, Trichinella spiralis, and Entamoeba histolytica, were built using Pisum sativum and Mycobacterium tuberculosis β-CAs as templates. Six β-CAs of insects and parasites and six β-CAs of plants are predicted to be mitochondrial and chloroplastic, respectively, and thus may be involved in important metabolic functions. All 31 sequences showed the presence of the highly conserved β-CA active site sequence motifs, CXDXR and HXXC (C: cysteine, D: aspartic acid, R: arginine, H: histidine, X: any residue). We discovered that these two motifs are more antigenic than others. Homology models suggested that these motifs are mostly buried and thus not well accessible for recognition by antibodies. The predicted mitochondrial localization of several β-CAs and hidden antigenic epitopes within the protein molecule, suggest that they may not be considered major targets for vaccines. Instead, they are promising candidate enzymes for small-molecule inhibitors which can easily penetrate the cell membrane. Based on current knowledge, we conclude that β-CAs are potential targets for development of small molecule pesticides or anti-parasitic agents with minimal side effects on vertebrates.

The insulator protein Suppressor of Hairy-wing is an essential transcriptional repressor in the Drosophila ovary.

PubMed

Soshnev, Alexey A; Baxley, Ryan M; Manak, J Robert; Tan, Kai; Geyer, Pamela K

2013-09-01

Suppressor of Hairy-wing [Su(Hw)] is a DNA-binding factor required for gypsy insulator function and female germline development in Drosophila. The insulator function of the gypsy retrotransposon depends on Su(Hw) binding to clustered Su(Hw) binding sites (SBSs) and recruitment of the insulator proteins Centrosomal Protein 190 kD (CP190) and Modifier of mdg4 67.2 kD (Mod67.2). By contrast, the Su(Hw) germline function involves binding to non-clustered SBSs and does not require CP190 or Mod67.2. Here, we identify Su(Hw) target genes, using genome-wide analyses in the ovary to uncover genes with an ovary-bound SBS that are misregulated upon Su(Hw) loss. Most Su(Hw) target genes demonstrate enriched expression in the wild-type CNS. Loss of Su(Hw) leads to increased expression of these CNS-enriched target genes in the ovary and other tissues, suggesting that Su(Hw) is a repressor of neural genes in non-neural tissues. Among the Su(Hw) target genes is RNA-binding protein 9 (Rbp9), a member of the ELAV/Hu gene family. Su(Hw) regulation of Rbp9 appears to be insulator independent, as Rbp9 expression is unchanged in a genetic background that compromises the functions of the CP190 and Mod67.2 insulator proteins, even though both localize to Rbp9 SBSs. Rbp9 misregulation is central to su(Hw)(-/-) sterility, as Rbp9(+/-), su(Hw)(-/-) females are fertile. Eggs produced by Rbp9(+/-), su(Hw)(-/-) females show patterning defects, revealing a somatic requirement for Su(Hw) in the ovary. Our studies demonstrate that Su(Hw) is a versatile transcriptional regulatory protein with an essential developmental function involving transcriptional repression.

Extra Large G-Protein Interactome Reveals Multiple Stress Response Function and Partner-Dependent XLG Subcellular Localization

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

Liang, Ying; Gao, Yajun; Jones, Alan M.

The three-member family of Arabidopsis extra-large G proteins (XLG1-3) defines the prototype of an atypical Ga subunit in the heterotrimeric G protein complex. Some recent evidence indicate that XLG subunits operate along with its Gbg dimer in root morphology, stress responsiveness, and cytokinin induced development, however downstream targets of activated XLG proteins in the stress pathways are rarely known. In order to assemble a set of candidate XLG-targeted proteins, a yeast two-hybrid complementation-based screen was performed using XLG protein baits to query interactions between XLG and partner protein found in glucose-treated seedlings, roots, and Arabidopsis cells in culture. Seventy twomore » interactors were identified and >60% of a test set displayed in vivo interaction with XLG proteins. Gene co-expression analysis shows that >70% of the interactors are positively correlated with the corresponding XLG partners. Gene Ontology enrichment for all the candidates indicates stress responses and posits a molecular mechanism involving a specific set of transcription factor partners to XLG. Genes encoding two of these transcription factors, SZF1 and 2, require XLG proteins for full NaCl-induced expression. Furthermore, the subcellular localization of the XLG proteins in the nucleus, endosome, and plasma membrane is dependent on the specific interacting partner.« less

Extra Large G-Protein Interactome Reveals Multiple Stress Response Function and Partner-Dependent XLG Subcellular Localization

DOE PAGES

Liang, Ying; Gao, Yajun; Jones, Alan M.

2017-06-13

The three-member family of Arabidopsis extra-large G proteins (XLG1-3) defines the prototype of an atypical Ga subunit in the heterotrimeric G protein complex. Some recent evidence indicate that XLG subunits operate along with its Gbg dimer in root morphology, stress responsiveness, and cytokinin induced development, however downstream targets of activated XLG proteins in the stress pathways are rarely known. In order to assemble a set of candidate XLG-targeted proteins, a yeast two-hybrid complementation-based screen was performed using XLG protein baits to query interactions between XLG and partner protein found in glucose-treated seedlings, roots, and Arabidopsis cells in culture. Seventy twomore » interactors were identified and >60% of a test set displayed in vivo interaction with XLG proteins. Gene co-expression analysis shows that >70% of the interactors are positively correlated with the corresponding XLG partners. Gene Ontology enrichment for all the candidates indicates stress responses and posits a molecular mechanism involving a specific set of transcription factor partners to XLG. Genes encoding two of these transcription factors, SZF1 and 2, require XLG proteins for full NaCl-induced expression. Furthermore, the subcellular localization of the XLG proteins in the nucleus, endosome, and plasma membrane is dependent on the specific interacting partner.« less

Antiviral Defense Involves AGO4 in an Arabidopsis-Potexvirus Interaction.

PubMed

Brosseau, Chantal; El Oirdi, Mohamed; Adurogbangba, Ayooluwa; Ma, Xiaofang; Moffett, Peter

2016-11-01

In plants, RNA silencing regulates gene expression through the action of Dicer-like (DCL) and Argonaute (AGO) proteins via micro RNAs and RNA-dependent DNA methylation (RdDM). In addition, RNA silencing functions as an antiviral defense mechanism by targeting virus-derived double-stranded RNA. Plants encode multiple AGO proteins with specialized functions, including AGO4-like proteins that affect RdDM and AGO2, AGO5, and AGO1, which have antiviral activities. Here, we show that AGO4 is also required for defense against the potexvirus Plantago asiatica mosaic virus (PlAMV), most likely independent of RdDM components such as DCL3, Pol IV, and Pol V. Transient assays showed that AGO4 has direct antiviral activity on PlAMV and, unlike RdDM, this activity does not require nuclear localization of AGO4. Furthermore, although PlAMV infection causes a decrease in AGO4 expression, PlAMV causes a change in AGO4 localization from a largely nuclear to a largely cytoplasmic distribution. These results indicate an important role for AGO4 in targeting plant RNA viruses as well as demonstrating novel mechanisms of regulation of and by AGO4, independent of its canonical role in regulating gene expression by RdDM.

Structural Basis of Membrane Targeting by the Dock180 Family of Rho Family Guanine Exchange Factors (Rho-GEFs)*

PubMed Central

Premkumar, Lakshmanane; Bobkov, Andrey A.; Patel, Manishha; Jaroszewski, Lukasz; Bankston, Laurie A.; Stec, Boguslaw; Vuori, Kristiina; Côté, Jean-Francois; Liddington, Robert C.

2010-01-01

The Dock180 family of atypical Rho family guanine nucleotide exchange factors (Rho-GEFs) regulate a variety of processes involving cellular or subcellular polarization, including cell migration and phagocytosis. Each contains a Dock homology region-1 (DHR-1) domain that is required to localize its GEF activity to a specific membrane compartment where levels of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) are up-regulated by the local activity of PtdIns 3-kinase. Here we define the structural and energetic bases of phosphoinositide specificity by the DHR-1 domain of Dock1 (a GEF for Rac1), and show that DHR-1 utilizes a C2 domain scaffold and surface loops to create a basic pocket on its upper surface for recognition of the PtdIns(3,4,5)P3 head group. The pocket has many of the characteristics of those observed in pleckstrin homology domains. We show that point mutations in the pocket that abolish phospholipid binding in vitro ablate the ability of Dock1 to induce cell polarization, and propose a model that brings together recent mechanistic and structural studies to rationalize the central role of DHR-1 in dynamic membrane targeting of the Rho-GEF activity of Dock180. PMID:20167601

Role of local government in responding to environmental health challenges: a case study of Chungnam

PubMed Central

Lee, Hoo-Young

2017-01-01

The purpose of this study is to introduce the establishment process, policy target, and projects for “Chungnam’s master plan on environmental health policy (2017-2020)” as the local government’s role in addressing local environmental health challenges. We first analyzed existing studies and social issues on the media related to “Chungnam’s master plan” to understand Chungnam’s environmental health status and discussed domestic and international policy trends and related plans. An environmental health perception questionnaire survey and a Delphi expert questionnaire survey were conducted among provincial residents to collect various actors’ opinions on Chungnam’s environmental health issues and policy. An expert advisory panel was launched, and a residents’ voice workshop and cities-and-guns-policy-suggestion workshop were held. The vision of Chungnam’s environmental health policy is minimizing environmental hazards. We finally selected “Pleasant environment, healthy people, happy Chungnam” to represent the will to shape a pleasant environment and prevent and manage health damages for a happy Chungnam. We selected five strategies based on status analysis and a review of domestic and international policy trends and related plans and identified 2 targets (policy objectives) to accomplish the strategies. The strategies to achieve the first target, “Leader in environmental health policy: Chungnam,” include ‘Empowering active provincial capabilities,’ ‘Setting up province-specific systems for environmental health surveys and research,’ and ‘Preventing and managing newly emerging pollutants.’ The strategies for the second target, “Everyone is healthy: Chungnam,” include ‘Relieving health inequalities among vulnerable regions and residents’ and ‘Enlarging the resident-friendly environmental health policy.’ We developed 29 projects in total, according to these strategies. The establishment of “Chungnam’s master plan” is highly valuable; we developed it through discussion involving diverse actors to address environmental health challenges together. It is necessary to continue to strengthen participation, communication, and cooperation among actors to develop an environmental health policy model for the future. PMID:29198098

Vitamin D receptor is present on the neuronal plasma membrane and is co-localized with amyloid precursor protein, ADAM10 or Nicastrin.

PubMed

Dursun, Erdinç; Gezen-Ak, Duygu

2017-01-01

Our recent study indicated that vitamin D and its receptors are important parts of the amyloid processing pathway in neurons. Yet the role of vitamin D receptor (VDR) in amyloid pathogenesis is complex and all regulations over the production of amyloid beta cannot be explained solely with the transcriptional regulatory properties of VDR. Given that we hypothesized that VDR might exist on the neuronal plasma membrane in close proximity with amyloid precursor protein (APP) and secretase complexes. The present study primarily focused on the localization of VDR in neurons and its interaction with amyloid pathology-related proteins. The localization of VDR on neuronal membranes and its co-localization with target proteins were investigated with cell surface staining followed by immunofluorescence labelling. The FpClass was used for protein-protein interaction prediction. Our results demonstrated the localization of VDR on the neuronal plasma membrane and the co-localization of VDR and APP or ADAM10 or Nicastrin and limited co-localization of VDR and PS1. E-cadherin interaction with APP or the γ-secretase complex may involve NOTCH1, NUMB, or FHL2, according to FpClass. This suggested complex might also include VDR, which greatly contributes to Ca+2 hemostasis with its ligand vitamin D. Consequently, we suggested that VDR might be a member of this complex also with its own non-genomic action and that it can regulate the APP processing pathway in this way in neurons.

Local-global interference is modulated by age, sex and anterior corpus callosum size

PubMed Central

Müller-Oehring, Eva M.; Schulte, Tilman; Raassi, Carla; Pfefferbaum, Adolf; Sullivan, Edith V.

2007-01-01

To identify attentional and neural mechanisms affecting global and local feature extraction, we devised a global-local hierarchical letter paradigm to test the hypothesis that aging reduces functional cerebral lateralization through corpus callosum (CC) degradation. Participants (37 men and women, 26–79 years) performed a task requiring global, local, or global+local attention and underwent structural MRI for CC measurement. Although reaction time (RT) slowed with age, all participants had faster RTs to local than global targets. This local precedence effect together with greater interference from incongruent local information and greater response conflict from local targets each correlated with older age and smaller callosal genu (anterior) areas. These findings support the hypothesis that the CC mediates lateralized local-global processes by inhibition of task-irrelevant information under selective attention conditions. Further, with advancing age smaller genu size leads to less robust inhibition, thereby reducing cerebral lateralization and permitting interference to influence processing. Sex was an additional modifier of interference, in that callosum-interference relationships were evident in women but not in men. Regardless of age, smaller splenium (posterior) areas correlated with less response facilitation from repetition priming of global targets in men, but with greater response facilitation from repetition priming of local targets in women. Our data indicate the following dissociation: Anterior callosal structure was associated with inhibitory processes (i.e., interference from incongruency and response conflict), which are vulnerable to the effects of age and sex, whereas posterior callosal structure was associated with facilitation processes from repetition priming dependent on sex and independent of age. PMID:17335783

Local-global interference is modulated by age, sex and anterior corpus callosum size.

PubMed

Müller-Oehring, Eva M; Schulte, Tilman; Raassi, Carla; Pfefferbaum, Adolf; Sullivan, Edith V

2007-04-20

To identify attentional and neural mechanisms affecting global and local feature extraction, we devised a global-local hierarchical letter paradigm to test the hypothesis that aging reduces functional cerebral lateralization through corpus callosum (CC) degradation. Participants (37 men and women, 26-79 years) performed a task requiring global, local, or global+local attention and underwent structural MRI for CC measurement. Although reaction time (RT) slowed with age, all participants had faster RTs to local than global targets. This local precedence effect together with greater interference from incongruent local information and greater response conflict from local targets each correlated with older age and smaller callosal genu (anterior) areas. These findings support the hypothesis that the CC mediates lateralized local-global processes by inhibition of task-irrelevant information under selective attention conditions. Further, with advancing age smaller genu size leads to less robust inhibition, thereby reducing cerebral lateralization and permitting interference to influence processing. Sex was an additional modifier of interference, in that callosum-interference relationships were evident in women but not in men. Regardless of age, smaller splenium (posterior) areas correlated with less response facilitation from repetition priming of global targets in men, but with greater response facilitation from repetition priming of local targets in women. Our data indicate the following dissociation: anterior callosal structure was associated with inhibitory processes (i.e., interference from incongruency and response conflict), which are vulnerable to the effects of age and sex, whereas posterior callosal structure was associated with facilitation processes from repetition priming dependent on sex and independent of age.

Real-time ultrasound image classification for spine anesthesia using local directional Hadamard features.

PubMed

Pesteie, Mehran; Abolmaesumi, Purang; Ashab, Hussam Al-Deen; Lessoway, Victoria A; Massey, Simon; Gunka, Vit; Rohling, Robert N

2015-06-01

Injection therapy is a commonly used solution for back pain management. This procedure typically involves percutaneous insertion of a needle between or around the vertebrae, to deliver anesthetics near nerve bundles. Most frequently, spinal injections are performed either blindly using palpation or under the guidance of fluoroscopy or computed tomography. Recently, due to the drawbacks of the ionizing radiation of such imaging modalities, there has been a growing interest in using ultrasound imaging as an alternative. However, the complex spinal anatomy with different wave-like structures, affected by speckle noise, makes the accurate identification of the appropriate injection plane difficult. The aim of this study was to propose an automated system that can identify the optimal plane for epidural steroid injections and facet joint injections. A multi-scale and multi-directional feature extraction system to provide automated identification of the appropriate plane is proposed. Local Hadamard coefficients are obtained using the sequency-ordered Hadamard transform at multiple scales. Directional features are extracted from local coefficients which correspond to different regions in the ultrasound images. An artificial neural network is trained based on the local directional Hadamard features for classification. The proposed method yields distinctive features for classification which successfully classified 1032 images out of 1090 for epidural steroid injection and 990 images out of 1052 for facet joint injection. In order to validate the proposed method, a leave-one-out cross-validation was performed. The average classification accuracy for leave-one-out validation was 94 % for epidural and 90 % for facet joint targets. Also, the feature extraction time for the proposed method was 20 ms for a native 2D ultrasound image. A real-time machine learning system based on the local directional Hadamard features extracted by the sequency-ordered Hadamard transform for detecting the laminae and facet joints in ultrasound images has been proposed. The system has the potential to assist the anesthesiologists in quickly finding the target plane for epidural steroid injections and facet joint injections.

Quantitative Expression and Co-Localization of Wnt Signalling Related Proteins in Feline Squamous Cell Carcinoma

PubMed Central

Marote, Georgina; Abramo, Francesca; McKay, Jenny; Thomson, Calum; Beltran, Mariana; Millar, Michael; Priestnall, Simon; Dobson, Jane; Costantino-Casas, Fernando; Petrou, Terry; McGonnell, Imelda M.; Davies, Anthony J.; Weetman, Malcolm; Garden, Oliver A.; Masters, John R.; Thrasivoulou, Christopher; Ahmed, Aamir

2016-01-01

Feline oral squamous cell carcinoma (FOSCC) is an aggressive neoplasm in cats. Little is known about the possible molecular mechanisms that may be involved in the initiation, maintenance and progression of FOSCC. Wnt signalling is critical in development and disease, including many mammalian cancers. In this study, we have investigated the expression of Wnt signalling related proteins using quantitative immunohistochemical techniques on tissue arrays. We constructed tissue arrays with 58 individual replicate tissue samples. We tested for the expression of four key Wnt/ß-catenin transcription targets, namely Cyclin D1 (CCND1 or CD1), FRA1, c-Myc and MMP7. All antibodies showed cross reactivity in feline tissue except MMP7. Quantitative immunohistochemical analysis of single proteins (expressed as area fraction / amount of tissue for normal vs tumor, mean ± SE) showed that the expression of CD1 (3.9 ± 0.5 vs 12.2 ± 0.9), FRA1 (5.5 ± 0.6 vs 16.8 ± 1.1) and c-Myc (5.4 ± 0.5 vs 12.5 ± 0.9) was increased in FOSCC tissue by 2.3 to 3 fold compared to normal controls (p<0.0001). By using a multilabel, quantitative fluorophore technique we further investigated if the co-localization of these proteins (all transcription factors) with each other and in the nucleus (stained with 4',6-diamidino-2-phenylindole, DAPI) was altered in FOSCC compared to normal tissue. The global intersection coefficients, a measure of the proximity of two fluorophore labeled entities, showed that there was a significant change (p < 0.01) in the co-localization for all permutations (e.g. CD1/FRA1 etc), except for the nuclear localization of CD1. Our results show that putative targets of Wnt signalling transcription are up-regulated in FOSCC with alterations in the co-localization of these proteins and could serve as a useful marker for the disease. PMID:27559731

Targeted Nanomaterials for Phototherapy

PubMed Central

Chitgupi, Upendra; Qin, Yiru; Lovell, Jonathan F.

2017-01-01

Phototherapies involve the irradiation of target tissues with light. To further enhance selectivity and potency, numerous molecularly targeted photosensitizers and photoactive nanoparticles have been developed. Active targeting typically involves harnessing the affinity between a ligand and a cell surface receptor for improved accumulation in the targeted tissue. Targeting ligands including peptides, proteins, aptamers and small molecules have been explored for phototherapy. In this review, recent examples of targeted nanomaterials used in phototherapy are summarized. PMID:29071178

The PTI1-like kinase ZmPti1a from maize (Zea mays L.) co-localizes with callose at the plasma membrane of pollen and facilitates a competitive advantage to the male gametophyte.

PubMed

Herrmann, Markus M; Pinto, Sheena; Kluth, Jantjeline; Wienand, Udo; Lorbiecke, René

2006-10-06

The tomato kinase Pto confers resistance to bacterial speck disease caused by Pseudomonas syringae pv. tomato in a gene for gene manner. Upon recognition of specific avirulence factors the Pto kinase activates multiple signal transduction pathways culminating in induction of pathogen defense. The soluble cytoplasmic serine/threonine kinase Pti1 is one target of Pto phosphorylation and is involved in the hypersensitive response (HR) reaction. However, a clear role of Pti1 in plant pathogen resistance is uncertain. So far, no Pti1 homologues from monocotyledonous species have been studied. Here we report the identification and molecular analysis of four Pti1-like kinases from maize (ZmPti1a, -b, -c, -d). These kinase genes showed tissue-specific expression and their corresponding proteins were targeted to different cellular compartments. Sequence similarity, expression pattern and cellular localization of ZmPti1b suggested that this gene is a putative orthologue of Pti1 from tomato. In contrast, ZmPti1a was specifically expressed in pollen and sequestered to the plasma membrane, evidently owing to N-terminal modification by myristoylation and/or S-acylation. The ZmPti1a:GFP fusion protein was not evenly distributed at the pollen plasma membrane but accumulated as an annulus-like structure which co-localized with callose (1,3-beta-glucan) deposition. In addition, co-localization of ZmPti1a and callose was observed during stages of pollen mitosis I and pollen tube germination. Maize plants in which ZmPti1a expression was silenced by RNA interference (RNAi) produced pollen with decreased competitive ability. Hence, our data provide evidence that ZmPti1a plays an important part in a signalling pathway that accelerates pollen performance and male fitness. ZmPti1a from maize is involved in pollen-specific processes during the progamic phase of reproduction, probably in crucial signalling processes associated with regions of callose deposition. Pollen-sporophyte interactions and pathogen induced HR show certain similarities. For example, HR has been shown to be associated with cell wall reinforcement through callose deposition. Hence, it is hypothesized that Pti1 kinases from maize act as general components in evolutionary conserved signalling processes associated with callose, however during different developmental programs and in different tissue types.

An evaluation of talker localization based on direction of arrival estimation and statistical sound source identification

NASA Astrophysics Data System (ADS)

Nishiura, Takanobu; Nakamura, Satoshi

2002-11-01

It is very important to capture distant-talking speech for a hands-free speech interface with high quality. A microphone array is an ideal candidate for this purpose. However, this approach requires localizing the target talker. Conventional talker localization algorithms in multiple sound source environments not only have difficulty localizing the multiple sound sources accurately, but also have difficulty localizing the target talker among known multiple sound source positions. To cope with these problems, we propose a new talker localization algorithm consisting of two algorithms. One is DOA (direction of arrival) estimation algorithm for multiple sound source localization based on CSP (cross-power spectrum phase) coefficient addition method. The other is statistical sound source identification algorithm based on GMM (Gaussian mixture model) for localizing the target talker position among localized multiple sound sources. In this paper, we particularly focus on the talker localization performance based on the combination of these two algorithms with a microphone array. We conducted evaluation experiments in real noisy reverberant environments. As a result, we confirmed that multiple sound signals can be identified accurately between ''speech'' or ''non-speech'' by the proposed algorithm. [Work supported by ATR, and MEXT of Japan.

Fatigue Damage Assessment Leveraging Nondestructive Evaluation Data

NASA Astrophysics Data System (ADS)

Mazur, K.; Wisner, B.; Kontsos, A.

2018-05-01

Fatigue in materials depends on several microstructural parameters. The length and time scales involved in such processes have been investigated by characterization methods that target microstructural effects or that rely on specimen-level observations. Combinations of in situ and ex situ techniques are also used to correlate microstructural changes to bulk properties. We present herein an effort to directly link local changes with specimen-level fatigue damage assessment. To achieve this goal, grain-scale observations in an aluminum alloy are linked with deformation measurements made by digital image correlation and with acoustic emission monitoring obtained from inside the scanning electron microscope. Damage assessment is attempted using a data-processing framework that involves noise removal, data reduction, and classification. The results demonstrate that nondestructive evaluation combined with small-scale testing can provide a means for fatigue damage assessment applicable to a broad range of materials and testing conditions.

The organization of multidisciplinary care teams: modeling internal and external influences on cancer care quality.

PubMed

Fennell, Mary L; Das, Irene Prabhu; Clauser, Steven; Petrelli, Nicholas; Salner, Andrew

2010-01-01

Quality cancer treatment depends upon careful coordination between multiple treatments and treatment providers, the exchange of technical information, and regular communication between all providers and physician disciplines involved in treatment. This article will examine a particular type of organizational structure purported to regularize and streamline the communication between multiple specialists and support services involved in cancer treatment: the multidisciplinary treatment care (MDC) team. We present a targeted review of what is known about various types of MDC team structures and their impact on the quality of treatment care, and we outline a conceptual model of the connections between team context, structure, process, and performance and their subsequent effects on cancer treatment care processes and patient outcomes. Finally, we will discuss future research directions to understand how MDC teams improve patient outcomes and how characteristics of team structure, culture, leadership, and context (organizational setting and local environment) contribute to optimal multidisciplinary cancer care.

Fibrin Clots Are Equilibrium Polymers That Can Be Remodeled Without Proteolytic Digestion

NASA Astrophysics Data System (ADS)

Chernysh, Irina N.; Nagaswami, Chandrasekaran; Purohit, Prashant K.; Weisel, John W.

2012-11-01

Fibrin polymerization is a necessary part of hemostasis but clots can obstruct blood vessels and cause heart attacks and strokes. The polymerization reactions are specific and controlled, involving strong knob-into-hole interactions to convert soluble fibrinogen into insoluble fibrin. It has long been assumed that clots and thrombi are stable structures until proteolytic digestion. On the contrary, using the technique of fluorescence recovery after photobleaching, we demonstrate here that there is turnover of fibrin in an uncrosslinked clot. A peptide representing the knobs involved in fibrin polymerization can compete for the holes and dissolve a preformed fibrin clot, or increase the fraction of soluble oligomers, with striking rearrangements in clot structure. These results imply that in vivo clots or thrombi are more dynamic structures than previously believed that may be remodeled as a result of local environmental conditions, may account for some embolization, and suggest a target for therapeutic intervention.

Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): A comparative analysis of toxicities and clinical outcomes.

PubMed

Fernandes, Annemarie T; Shen, Jason; Finlay, Jarod; Mitra, Nandita; Evans, Tracey; Stevenson, James; Langer, Corey; Lin, Lilie; Hahn, Stephen; Glatstein, Eli; Rengan, Ramesh

2010-05-01

Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT. We assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy. Of the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT. Nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice.

PubMed

Paouri, Evi; Tzara, Ourania; Kartalou, Georgia-Ioanna; Zenelak, Sofia; Georgopoulos, Spiros

2017-05-17

Increasing evidence has suggested that systemic inflammation along with local brain inflammation can play a significant role in Alzheimer's disease (AD) pathogenesis. Identifying key molecules that regulate the crosstalk between the immune and the CNS can provide potential therapeutic targets. TNF-α is a proinflammatory cytokine implicated in the pathogenesis of systemic inflammatory and neurodegenerative diseases, such as rheumatoid arthritis (RA) and AD. Recent studies have reported that anti-TNF-α therapy or RA itself can modulate AD pathology, although the underlying mechanism is unclear. To investigate the role of peripheral TNF-α as a mediator of RA in the pathogenesis of AD, we generated double-transgenic 5XFAD/Tg197 AD/TNF mice that develop amyloid deposits and inflammatory arthritis induced by human TNF-α (huTNF-α) expression. We found that 5XFAD/Tg197 mice display decreased amyloid deposition, compromised neuronal integrity, and robust brain inflammation characterized by extensive gliosis and elevated blood-derived immune cell populations, including phagocytic macrophages and microglia. To evaluate the contribution of peripheral huTNF-α in the observed brain phenotype, we treated 5XFAD/Tg197 mice systemically with infliximab, an anti-huTNF-α antibody that does not penetrate the blood-brain barrier and prevents arthritis. Peripheral inhibition of huTNF-α increases amyloid deposition, rescues neuronal impairment, and suppresses gliosis and recruitment of blood-derived immune cells, without affecting brain huTNF-α levels. Our data report, for the first time, a distinctive role for peripheral TNF-α in the modulation of the amyloid phenotype in mice by regulating blood-derived and local brain inflammatory cell populations involved in β-amyloid clearance. SIGNIFICANCE STATEMENT Mounting evidence supports the active involvement of systemic inflammation, in addition to local brain inflammation, in Alzheimer's disease (AD) progression. TNF-α is a pluripotent cytokine that has been independently involved in the pathogenesis of systemic inflammatory rheumatoid arthritis (RA) and AD. Here we first demonstrate that manipulation of peripheral TNF-α in the context of arthritis modulates the amyloid phenotype by regulating immune cell trafficking in the mouse brain. Our study suggests that additionally to its local actions in the AD brain, TNF-α can also indirectly modulate amyloid pathology as a regulator of peripheral inflammation. Our findings may have significant implications in the treatment of RA patients with anti-TNF-α drugs and in the potential use of TNF-targeted therapies for AD. Copyright © 2017 the authors 0270-6474/17/375155-17$15.00/0.

Chromatin-associated RNA sequencing (ChAR-seq) maps genome-wide RNA-to-DNA contacts

PubMed Central

Jukam, David; Teran, Nicole A; Risca, Viviana I; Smith, Owen K; Johnson, Whitney L; Skotheim, Jan M; Greenleaf, William James

2018-01-01

RNA is a critical component of chromatin in eukaryotes, both as a product of transcription, and as an essential constituent of ribonucleoprotein complexes that regulate both local and global chromatin states. Here, we present a proximity ligation and sequencing method called Chromatin-Associated RNA sequencing (ChAR-seq) that maps all RNA-to-DNA contacts across the genome. Using Drosophila cells, we show that ChAR-seq provides unbiased, de novo identification of targets of chromatin-bound RNAs including nascent transcripts, chromosome-specific dosage compensation ncRNAs, and genome-wide trans-associated RNAs involved in co-transcriptional RNA processing. PMID:29648534

Nature, nurture, and microbes: The development of multiple sclerosis.

PubMed

Wekerle, H

2017-11-01

This paper argues that multiple sclerosis (MS) is the result of an autoimmune attack against components of the central nervous system (CNS). The effector cells involved in the pathogenic process are CNS-autoreactive T cells present in the healthy immune system in a resting state. Upon activation, these cells cross the blood-brain barrier and attack the CNS target tissue. Recent evidence indicates that autoimmune activation may happen in the intestine, following an interaction of bacterial components of the gut flora with local CNS autoreactive T cells. The consequences of this concept are discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Prophylactic Measures During Induction for Acute Myeloid Leukemia.

PubMed

McCarthy, Matthew W; Walsh, Thomas J

2017-03-01

Improved management of infectious complications of acute myeloid leukemia (AML) has contributed substantially to the success of care over the past half century. An important approach to reducing infectious complications during the induction period of chemotherapy involves the use of prophylactic antibacterial, antiviral, and antifungal agents targeting likely pathogens. There is not a one-size-fits-all approach to prophylaxis; every patient undergoing induction therapy should be evaluated individually and within the context of local microbiologic epidemiology and host risk factors. Pharmacologic and non-pharmacologic interventions as well as novel diagnostic platforms can help mitigate the risk of life-threatening infection in patients with AML who undergo induction chemotherapy.

Driving Leadership Style in Leading to Enhance Participation and Involvement in School

ERIC Educational Resources Information Center

Rajbhandari, Mani Man Singh

2011-01-01

"Driving leadership style" enhances local participation and involvement in school in reducing a gap between the school and the local community. As gap filler, leadership role was therefore instigated to drive the local community to participate and involve in the School. The purpose of this exploration was to analyze the driving…

Agent Collaborative Target Localization and Classification in Wireless Sensor Networks

PubMed Central

Wang, Xue; Bi, Dao-wei; Ding, Liang; Wang, Sheng

2007-01-01

Wireless sensor networks (WSNs) are autonomous networks that have been frequently deployed to collaboratively perform target localization and classification tasks. Their autonomous and collaborative features resemble the characteristics of agents. Such similarities inspire the development of heterogeneous agent architecture for WSN in this paper. The proposed agent architecture views WSN as multi-agent systems and mobile agents are employed to reduce in-network communication. According to the architecture, an energy based acoustic localization algorithm is proposed. In localization, estimate of target location is obtained by steepest descent search. The search algorithm adapts to measurement environments by dynamically adjusting its termination condition. With the agent architecture, target classification is accomplished by distributed support vector machine (SVM). Mobile agents are employed for feature extraction and distributed SVM learning to reduce communication load. Desirable learning performance is guaranteed by combining support vectors and convex hull vectors. Fusion algorithms are designed to merge SVM classification decisions made from various modalities. Real world experiments with MICAz sensor nodes are conducted for vehicle localization and classification. Experimental results show the proposed agent architecture remarkably facilitates WSN designs and algorithm implementation. The localization and classification algorithms also prove to be accurate and energy efficient.

Computational Modeling and Neuroimaging Techniques for Targeting during Deep Brain Stimulation

PubMed Central

Sweet, Jennifer A.; Pace, Jonathan; Girgis, Fady; Miller, Jonathan P.

2016-01-01

Accurate surgical localization of the varied targets for deep brain stimulation (DBS) is a process undergoing constant evolution, with increasingly sophisticated techniques to allow for highly precise targeting. However, despite the fastidious placement of electrodes into specific structures within the brain, there is increasing evidence to suggest that the clinical effects of DBS are likely due to the activation of widespread neuronal networks directly and indirectly influenced by the stimulation of a given target. Selective activation of these complex and inter-connected pathways may further improve the outcomes of currently treated diseases by targeting specific fiber tracts responsible for a particular symptom in a patient-specific manner. Moreover, the delivery of such focused stimulation may aid in the discovery of new targets for electrical stimulation to treat additional neurological, psychiatric, and even cognitive disorders. As such, advancements in surgical targeting, computational modeling, engineering designs, and neuroimaging techniques play a critical role in this process. This article reviews the progress of these applications, discussing the importance of target localization for DBS, and the role of computational modeling and novel neuroimaging in improving our understanding of the pathophysiology of diseases, and thus paving the way for improved selective target localization using DBS. PMID:27445709

The Groucho Co-repressor Is Primarily Recruited to Local Target Sites in Active Chromatin to Attenuate Transcription

PubMed Central

Jennings, Barbara H.

2014-01-01

Gene expression is regulated by the complex interaction between transcriptional activators and repressors, which function in part by recruiting histone-modifying enzymes to control accessibility of DNA to RNA polymerase. The evolutionarily conserved family of Groucho/Transducin-Like Enhancer of split (Gro/TLE) proteins act as co-repressors for numerous transcription factors. Gro/TLE proteins act in several key pathways during development (including Notch and Wnt signaling), and are implicated in the pathogenesis of several human cancers. Gro/TLE proteins form oligomers and it has been proposed that their ability to exert long-range repression on target genes involves oligomerization over broad regions of chromatin. However, analysis of an endogenous gro mutation in Drosophila revealed that oligomerization of Gro is not always obligatory for repression in vivo. We have used chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) to profile Gro recruitment in two Drosophila cell lines. We find that Gro predominantly binds at discrete peaks (<1 kilobase). We also demonstrate that blocking Gro oligomerization does not reduce peak width as would be expected if Gro oligomerization induced spreading along the chromatin from the site of recruitment. Gro recruitment is enriched in “active” chromatin containing developmentally regulated genes. However, Gro binding is associated with local regions containing hypoacetylated histones H3 and H4, which is indicative of chromatin that is not fully open for efficient transcription. We also find that peaks of Gro binding frequently overlap the transcription start sites of expressed genes that exhibit strong RNA polymerase pausing and that depletion of Gro leads to release of polymerase pausing and increased transcription at a bona fide target gene. Our results demonstrate that Gro is recruited to local sites by transcription factors to attenuate rather than silence gene expression by promoting histone deacetylation and polymerase pausing. PMID:25165826

The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1

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

Kulebyakin, Konstantin; Penkov, Dmitry; IFOM – the FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, 20139

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to searchmore » new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. - Highlights: • A novel model of liver-specific Prep1 knockout is established. • Ablation of Prep1 in hepatocytes increases insulin sensitivity. • Prep1 controls hepatic insulin sensitivity by regulating localization of FOXO1. • Prep1 regulates localization of FOXO1 via Wnt/β-catenin signaling pathway.« less

Active Electro-Location of Objects in the Underwater Environment Based on the Mixed Polarization Multiple Signal Classification Algorithm

PubMed Central

Guo, Lili; Qi, Junwei; Xue, Wei

2018-01-01

This article proposes a novel active localization method based on the mixed polarization multiple signal classification (MP-MUSIC) algorithm for positioning a metal target or an insulator target in the underwater environment by using a uniform circular antenna (UCA). The boundary element method (BEM) is introduced to analyze the boundary of the target by use of a matrix equation. In this method, an electric dipole source as a part of the locating system is set perpendicularly to the plane of the UCA. As a result, the UCA can only receive the induction field of the target. The potential of each electrode of the UCA is used as spatial-temporal localization data, and it does not need to obtain the field component in each direction compared with the conventional fields-based localization method, which can be easily implemented in practical engineering applications. A simulation model and a physical experiment are constructed. The simulation and the experiment results provide accurate positioning performance, with the help of verifying the effectiveness of the proposed localization method in underwater target locating. PMID:29439495

Experimental investigation of a general real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring.

PubMed

Cho, Byungchul; Poulsen, Per; Ruan, Dan; Sawant, Amit; Keall, Paul J

2012-11-21

The goal of this work was to experimentally quantify the geometric accuracy of a novel real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring for clinically realistic arc and static field treatment delivery and target motion conditions. A general method for real-time target localization using kV imaging and respiratory monitoring was developed. Each dimension of internal target motion T(x, y, z; t) was estimated from the external respiratory signal R(t) through the correlation between R(t(i)) and the projected marker positions p(x(p), y(p); t(i)) on kV images by a state-augmented linear model: T(x, y, z; t) = aR(t) + bR(t - τ) + c. The model parameters, a, b, c, were determined by minimizing the squared fitting error ∑‖p(x(p), y(p); t(i)) - P(θ(i)) · (aR(t(i)) + bR(t(i) - τ) + c)‖(2) with the projection operator P(θ(i)). The model parameters were first initialized based on acquired kV arc images prior to MV beam delivery. This method was implemented on a trilogy linear accelerator consisting of an OBI x-ray imager (operating at 1 Hz) and real-time position monitoring (RPM) system (30 Hz). Arc and static field plans were delivered to a moving phantom programmed with measured lung tumour motion from ten patients. During delivery, the localization method determined the target position and the beam was adjusted in real time via dynamic multileaf collimator (DMLC) adaptation. The beam-target alignment error was quantified by segmenting the beam aperture and a phantom-embedded fiducial marker on MV images and analysing their relative position. With the localization method, the root-mean-squared errors of the ten lung tumour traces ranged from 0.7-1.3 mm and 0.8-1.4 mm during the single arc and five-field static beam delivery, respectively. Without the localization method, these errors ranged from 3.1-7.3 mm. In summary, a general method for real-time target localization using kV imaging and respiratory monitoring has been experimentally investigated for arc and static field delivery. The average beam-target error was 1 mm.

Experimental investigation of a general real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring

NASA Astrophysics Data System (ADS)

Cho, Byungchul; Poulsen, Per; Ruan, Dan; Sawant, Amit; Keall, Paul J.

2012-11-01

The goal of this work was to experimentally quantify the geometric accuracy of a novel real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring for clinically realistic arc and static field treatment delivery and target motion conditions. A general method for real-time target localization using kV imaging and respiratory monitoring was developed. Each dimension of internal target motion T(x, y, z; t) was estimated from the external respiratory signal R(t) through the correlation between R(ti) and the projected marker positions p(xp, yp; ti) on kV images by a state-augmented linear model: T(x, y, z; t) = aR(t) + bR(t - τ) + c. The model parameters, a, b, c, were determined by minimizing the squared fitting error ∑‖p(xp, yp; ti) - P(θi) · (aR(ti) + bR(ti - τ) + c)‖2 with the projection operator P(θi). The model parameters were first initialized based on acquired kV arc images prior to MV beam delivery. This method was implemented on a trilogy linear accelerator consisting of an OBI x-ray imager (operating at 1 Hz) and real-time position monitoring (RPM) system (30 Hz). Arc and static field plans were delivered to a moving phantom programmed with measured lung tumour motion from ten patients. During delivery, the localization method determined the target position and the beam was adjusted in real time via dynamic multileaf collimator (DMLC) adaptation. The beam-target alignment error was quantified by segmenting the beam aperture and a phantom-embedded fiducial marker on MV images and analysing their relative position. With the localization method, the root-mean-squared errors of the ten lung tumour traces ranged from 0.7-1.3 mm and 0.8-1.4 mm during the single arc and five-field static beam delivery, respectively. Without the localization method, these errors ranged from 3.1-7.3 mm. In summary, a general method for real-time target localization using kV imaging and respiratory monitoring has been experimentally investigated for arc and static field delivery. The average beam-target error was 1 mm.

Health promotion activities in annual reports of local governments: 'Health for All' targets as a tool for content analysis.

PubMed

Andersson, Camilla M; Bjärås, Gunilla E M; Tillgren, Per; Ostenson, Claes-Göran

2003-09-01

This article presents an instrument to study the annual reporting of health promotion activities in local governments within the three intervention municipalities of the Stockholm Diabetes Prevention Program (SDPP). The content of health promotion activities are described and the strengths, weaknesses and relevance of the method to health promotion discussed. A content analysis of local governmental reports from 1995-2000 in three Swedish municipalities. A matrix with WHO's 38 'Health for All' (HFA) targets from 1991 was used when coding the local health promotion activities. There are many public health initiatives within the local governmental structure even if they are not always addressed as health promotion. The main focuses in the local governmental reports were environmental issues, unemployment, social care and welfare. Local governmental reports were found to be a useful source of information that could provide knowledge about the priorities and organizational capacities for health promotion within local authorities. Additionally the HFA targets were an effective tool to identify and categorize systematically local health promotion activities in the annual reports of local governments. Identifying local health promotion initiatives by local authorities may ease the development of a health perspective and joint actions within the existing political and administrative structure. This paper provides a complementary method of attaining and structuring information about the local community for developments in health promotion.

Targeting and Localization for Mars Rover Operations

NASA Technical Reports Server (NTRS)

Powell, Mark W.; Crockett, Thomas; Fox, Jason M.; Joswig, Joseph C.; Norris, Jeffrey S.; Rabe, Kenneth J.; McCurdy, Michael; Pyrzak, Guy

2006-01-01

In this work we discuss how the quality of localization knowledge impacts the remote operation of rovers on the surface of Mars. We look at the techniques of localization estimation used in the Mars Pathfinder and Mars Exploration Rover missions. We examine the motivation behind the modes of targeting for different types of activities, such as navigation, remote science, and in situ science. We discuss the virtues and shortcomings of existing approaches and new improvements in the latest operations tools used to support the Mars Exploration Rover missions and rover technology development tasks at the Jet Propulsion Laboratory. We conclude with future directions we plan to explore in improving the localization knowledge available for operations and more effective targeting of rovers and their instrument payloads.

The armadillo repeat region targets ARVCF to cadherin-based cellular junctions.

PubMed

Kaufmann, U; Zuppinger, C; Waibler, Z; Rudiger, M; Urbich, C; Martin, B; Jockusch, B M; Eppenberger, H; Starzinski-Powitz, A

2000-11-01

The cytoplasmic domain of the transmembrane protein M-cadherin is involved in anchoring cytoskeletal elements to the plasma membrane at cell-cell contact sites. Several members of the armadillo repeat protein family mediate this linkage. We show here that ARVCF, a member of the p120 (ctn) subfamily, is a ligand for the cytoplasmic domain of M-cadherin, and characterize the regions involved in this interaction in detail. Complex formation in an in vivo environment was demonstrated in (1) yeast two-hybrid screens, using a cDNA library from differentiating skeletal muscle and part of the cytoplasmic M-cadherin tail as a bait, and (2) mammalian cells, using a novel experimental system, the MOM recruitment assay. Immunoprecipitation and in vitro binding assays confirmed this interaction. Ectopically expressed EGFP-ARVCF-C11, an N-terminal truncated fragment, targets to junctional structures in epithelial MCF7 cells and cardiomyocytes, where it colocalizes with the respective cadherins, beta-catenin and p120 (ctn). Hence, the N terminus of ARVCF is not required for junctional localization. In contrast, deletion of the four N-terminal armadillo repeats abolishes this ability in cardiomyocytes. Detailed mutational analysis revealed the armadillo repeat region of ARVCF as sufficient and necessary for interaction with the 55 membrane-proximal amino acids of the M-cadherin tail.

New discoveries of old SON: a link between RNA splicing and cancer.

PubMed

Hickey, Christopher J; Kim, Jung-Hyun; Ahn, Eun-Young Erin

2014-02-01

The SON protein is a ubiquitously expressed DNA- and RNA-binding protein primarily localized to nuclear speckles. Although several early studies implicated SON in DNA-binding, tumorigenesis and apoptosis, functional significance of this protein had not been recognized until recent studies discovered SON as a novel RNA splicing co-factor. During constitutive RNA splicing, SON ensures efficient intron removal from the transcripts containing suboptimal splice sites. Importantly, SON-mediated splicing is required for proper processing of selective transcripts related to cell cycle, microtubules, centrosome maintenance, and genome stability. Moreover, SON regulates alternative splicing of RNAs from the genes involved in apoptosis and epigenetic modification. In addition to the role in RNA splicing, SON has an ability to suppress transcriptional activation at certain promoter/enhancer DNA sequences. Considering the multiple SON target genes which are directly involved in cell proliferation, genome stability and chromatin modifications, SON is an emerging player in gene regulation during cancer development and progression. Here, we summarize available information from several early studies on SON, and highlight recent discoveries describing molecular mechanisms of SON-mediated gene regulation. We propose that our future effort on better understanding of diverse SON functions would reveal novel targets for cancer therapy. © 2013 Wiley Periodicals, Inc.

A Barley Powdery Mildew Fungus Non-Autonomous Retrotransposon Encodes a Peptide that Supports Penetration Success on Barley.

PubMed

Nottensteiner, Mathias; Zechmann, Bernd; McCollum, Christopher; Hückelhoven, Ralph

2018-05-11

Pathogens overcome plant immunity by the means of secreted effectors. Host effector targets often act in pathogen defense but might also support fungal accommodation or nutrition. The barley ROP GTPase HvRACB is involved in accommodation of fungal haustoria of the powdery mildew fungus Blumeria graminis f.sp. hordei (Bgh) in barley epidermal cells. We found that HvRACB interacts with the ROP-interactive peptide 1 (ROPIP1) that is encoded on the active non-long terminal repeat retroelement Eg-R1 of Bgh. Over-expression of ROPIP1 in barley epidermal cells and host-induced post-transcriptional gene silencing (HIGS) of ROPIP1 suggested that ROPIP1 is involved in virulence of Bgh. Bimolecular fluorescence complementation and co-localization supported that ROPIP1 can interact with activated HvRACB in planta. We show that ROPIP1 is expressed by Bgh on barley and translocated into the cytoplasm of infected barley cells. ROPIP1 is recruited to microtubules upon co-expression of microtubule associated ROP GTPase ACTIVATING PROTEIN (HvMAGAP1) and can destabilize cortical microtubules. Data suggest that Bgh ROPIP targets HvRACB and manipulates host cell microtubule organization for facilitated host cell entry. This points to a possible neo-functionalization of retroelement-derived transcripts for the evolution of a pathogen virulence effector.

7 CFR 799.7 - Early involvement in private and state and local activities requiring Federal approval.

Code of Federal Regulations, 2010 CFR

2010-01-01

... appropriate by FSA to determine the impact of the proposed action on the human environment; (3) Consult with... 7 Agriculture 7 2010-01-01 2010-01-01 false Early involvement in private and state and local... Early involvement in private and state and local activities requiring Federal approval. (a) The NEPA...

7 CFR 799.7 - Early involvement in private and state and local activities requiring Federal approval.

Code of Federal Regulations, 2011 CFR

2011-01-01

... appropriate by FSA to determine the impact of the proposed action on the human environment; (3) Consult with... 7 Agriculture 7 2011-01-01 2011-01-01 false Early involvement in private and state and local... Early involvement in private and state and local activities requiring Federal approval. (a) The NEPA...

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

PubMed

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

2013-05-14

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

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

PubMed Central

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

2013-01-01

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

Implication of oxidative stress in size-dependent toxicity of silica nanoparticles in kidney cells.

PubMed

Passagne, Isabelle; Morille, Marie; Rousset, Marine; Pujalté, Igor; L'azou, Béatrice

2012-09-28

Silica nanoparticles (nano-SiO(2)) are one of the most popular nanomaterials used in industrial manufacturing, synthesis, engineering and medicine. While inhalation of nanoparticles causes pulmonary damage, nano-SiO(2) can be transported into the blood and deposit in target organs where they exert potential toxic effects. Kidney is considered as such a secondary target organ. However, toxicological information of their effect on renal cells and the mechanisms involved remain sparse. In the present study, the cytotoxicity of nano-SiO(2) of different sizes was investigated on two renal proximal tubular cell lines (human HK-2 and porcine LLC-PK(1)). The molecular pathways involved were studied with a focus on the involvement of oxidative stress. Nanoparticle characterization was performed (primary nanoparticle size, surface area, dispersion) in order to investigate a potential relationship between their physical properties and their toxic effects. Firstly, evidence of particle internalization was obtained by transmission electron microscopy and conventional flux cytometry techniques. The use of specific inhibitors of endocytosis pathways showed an internalization process by macropinocytosis and clathrin-mediated endocytosis for 100 nm nano-SiO(2) nanoparticles. These nanoparticles were localized in vesicles. Toxicity was size- and time-dependent (24h, 48 h, 72 h). Indeed, it increased as nanoparticles became smaller. Secondly, analysis of oxidative stress based on the assessment of ROS (reactive oxygen species) production (DHE, dihydroethidium) or lipid peroxidation (MDA, malondialdehyde) clearly demonstrated the involvement of oxidative stress in the toxicity of 20 nm nano-SiO(2). The induction of antioxidant enzymes (catalase, GSTpi, thioredoxin reductase) could explain their lesser toxicity with 100 nm nano-SiO(2). Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Target detection and localization in shallow water: an experimental demonstration of the acoustic barrier problem at the laboratory scale.

PubMed

Marandet, Christian; Roux, Philippe; Nicolas, Barbara; Mars, Jérôme

2011-01-01

This study demonstrates experimentally at the laboratory scale the detection and localization of a wavelength-sized target in a shallow ultrasonic waveguide between two source-receiver arrays at 3 MHz. In the framework of the acoustic barrier problem, at the 1/1000 scale, the waveguide represents a 1.1-km-long, 52-m-deep ocean acoustic channel in the kilohertz frequency range. The two coplanar arrays record in the time-domain the transfer matrix of the waveguide between each pair of source-receiver transducers. Invoking the reciprocity principle, a time-domain double-beamforming algorithm is simultaneously performed on the source and receiver arrays. This array processing projects the multireverberated acoustic echoes into an equivalent set of eigenrays, which are defined by their launch and arrival angles. Comparison is made between the intensity of each eigenray without and with a target for detection in the waveguide. Localization is performed through tomography inversion of the acoustic impedance of the target, using all of the eigenrays extracted from double beamforming. The use of the diffraction-based sensitivity kernel for each eigenray provides both the localization and the signature of the target. Experimental results are shown in the presence of surface waves, and methodological issues are discussed for detection and localization.

Vision-based localization for on-orbit servicing of a partially cooperative satellite

NASA Astrophysics Data System (ADS)

Oumer, Nassir W.; Panin, Giorgio; Mülbauer, Quirin; Tseneklidou, Anastasia

2015-12-01

This paper proposes ground-in-the-loop, model-based visual localization system based on transmitted images to ground, to aid rendezvous and docking maneuvers between a servicer and a target satellite. In particular, we assume to deal with a partially cooperative target, i.e. passive and without fiducial markers, but supposed at least to keep a controlled attitude, up to small fluctuations, so that the approach mainly involves translational motion. For the purpose of localization, video cameras provide an effective and relatively inexpensive solution, working at a wide range of distances with an increasing accuracy and robustness during the approach. However, illumination conditions in space are especially challenging, due to the direct sunlight exposure and to the glossy surface of a satellite, that creates strong reflections and saturations and therefore a high level of background clutter and missing detections. We employ a monocular camera for mid-range tracking (20 - 5 m) and stereo camera at close-range (5 - 0.5 m), with the respective detection and tracking methods, both using intensity edges and robustly dealing with the above issues. Our tracking system has been extensively verified at the facility of the European Proximity Operations Simulator (EPOS) of DLR, which is a very realistic ground simulation able to reproduce sunlight conditions through a high power floodlight source, satellite surface properties using multilayer insulation foils, as well as orbital motion trajectories with ground-truth data, by means of two 6 DOF industrial robots. Results from this large dataset show the effectiveness and robustness of our method against the above difficulties.

Cervical brachytherapy technique for locally advanced carcinoma of the cervix in a patient with septate uterus.

PubMed

Platta, Christopher S; Wallace, Charlie; Gondi, Vinai; Das, Rupak; Straub, Margaret; Al-Niaimi, Ahmed; Applegate, Glenn; Bradley, Kristin A

2014-03-01

To describe an approach to cervical brachytherapy in a patient with congenital septate uterus and locally advanced cervical carcinoma. The patient is a 34-year-old female with septate uterus presenting with pelvic pain. Workup demonstrated a stage IIB cervical adenocarcinoma with imaging evidence of an involved right external iliac lymph node. The patient received whole pelvic radiation, with concurrent weekly cisplatin (40 mg/m(2)), to a dose of 45 Gy in 25 fractions followed by a parametrial boost of 5.4 Gy and an additional nodal boost of 9 Gy. The patient was initiated on cervical brachytherapy following fraction 23 of pelvic radiation. To conform to her septated uterus, a Rotte-Y tandem was used. Additionally, 2 CT-compatible ovoids were placed in the vaginal apex to enhance dose distribution and coverage of the target volume. Each fraction of brachytherapy was performed with CT-based planning. A high-risk clinical target volume (HR-CTV) and normal structures were defined and constrained per American Brachytherapy Society (ABS) and Groupe Européen de Curiethérapie/European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) guidelines. The brachytherapy dose was 27.5 Gy in 5 fractions of 5.5 Gy each, prescribed to the HR-CTV. Herein, we report the first documented case of cervical brachytherapy in a patient with septate uterus and locally advanced cervical carcinoma. Using CT-guided planning, in conjunction with the ABS and GEC-ESTRO guidelines, the patient was effectively treated with adapted cervical brachytherapy, meeting criteria for HR-CTV coverage and normal tissue tolerances.

Effects of TEL Confusers on Operator Target Acquisition Performance with SAR Imagery

DTIC Science & Technology

1998-12-01

processing known as the theory of signal detection (TSD) (Gescheider, 1985; Green & Swets, 1966; Macmillan & Creelman , 1991; Wilson, 1992). A TSD...localizations (Hacker & Ratcliff, 1979; Macmillan & Creelman , 1991). The index of bias in a target localization task provides a measure of the operator’s...of correct localizations substituted for hits (Macmillan & Creelman , 1991). Receiver Operating Characteristic Curves. In addition to the calculation

The grain of spatially referenced economic cost and biodiversity benefit data and the effectiveness of a cost targeting strategy.

PubMed

Sutton, N J; Armsworth, P R

2014-12-01

Facing tight resource constraints, conservation organizations must allocate funds available for habitat protection as effectively as possible. Often, they combine spatially referenced economic and biodiversity data to prioritize land for protection. We tested how sensitive these prioritizations could be to differences in the spatial grain of these data by demonstrating how the conclusion of a classic debate in conservation planning between cost and benefit targeting was altered based on the available information. As a case study, we determined parcel-level acquisition costs and biodiversity benefits of land transactions recently undertaken by a nonprofit conservation organization that seeks to protect forests in the eastern United States. Then, we used hypothetical conservation plans to simulate the types of ex ante priorities that an organization could use to prioritize areas for protection. We found the apparent effectiveness of cost and benefit targeting depended on the spatial grain of the data used when prioritizing parcels based on local species richness. However, when accounting for complementarity, benefit targeting consistently was more efficient than a cost targeting strategy regardless of the spatial grain of the data involved. More pertinently for other studies, we found that combining data collected over different spatial grains inflated the apparent effectiveness of a cost targeting strategy and led to overestimation of the efficiency gain offered by adopting a more integrative return-on-investment approach. © 2014 Society for Conservation Biology.

Comparison of outcomes for MR-guided versus CT-guided high-dose-rate interstitial brachytherapy in women with locally advanced carcinoma of the cervix.

PubMed

Kamran, Sophia C; Manuel, Matthias M; Cho, Linda P; Damato, Antonio L; Schmidt, Ehud J; Tempany, Clare; Cormack, Robert A; Viswanathan, Akila N

2017-05-01

The purpose was to compare local control (LC), overall survival (OS) and dose to the organs at risk (OAR) in women with locally advanced cervical cancer treated with MR-guided versus CT-guided interstitial brachytherapy (BT). 56 patients (29 MR, 27 CT) were treated with high-dose-rate (HDR) interstitial BT between 2005-2015. The MR patients had been prospectively enrolled on a Phase II clinical trial. Data were analyzed using Kaplan-Meier (K-M) and Cox proportional hazards statistical modeling in JMP® & R®. Median follow-up time was 19.7months (MR group) and 18.4months (CT group). There were no statistically significant differences in patient age at diagnosis, histology, percent with tumor size >4cm, grade, FIGO stage or lymph node involvement between the groups. Patients in the MR group had more lymphovascular involvement compared to patients in the CT group (p<0.01). When evaluating plans generated, there were no statistically significant differences in median cumulative dose to the high-risk clinical target volume or the OAR. 2-year K-M LC rates for MR-based and CT-based treatments were 96% and 87%, respectively (log-rank p=0.65). At 2years, OS was significantly better in the MR-guided cohort (84% vs. 56%, p=0.036). On multivariate analysis, squamous histology was associated with longer OS (HR 0.23, 95% CI 0.07-0.72) in a model with MR BT (HR 0.35, 95% CI 0.08-1.18). There was no difference in toxicities between CT and MR BT. In this population of locally advanced cervical-cancer patients, MR-guided HDR BT resulted in estimated 96% 2-year local control and excellent survival and toxicity rates. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of outcomes for MR-guided versus CT-guided high-dose-rate interstitial brachytherapy in women with locally advanced carcinoma of the cervix

PubMed Central

Kamran, Sophia C.; Manuel, Matthias M.; Cho, Linda P.; Damato, Antonio L.; Schmidt, Ehud J.; Tempany, Clare; Cormack, Robert A.; Viswanathan, Akila N.

2017-01-01

Objective The purpose was to compare local control (LC), overall survival (OS) and dose to the organs at risk (OAR) in women with locally advanced cervical cancer treated with MR-guided versus CT-guided interstitial brachytherapy (BT). Methods 56 patients (29 MR, 27 CT) were treated with high-dose-rate (HDR) interstitial BT between 2005–2015. The MR patients had been prospectively enrolled on a Phase II clinical trial. Data were analyzed using Kaplan-Meier (K-M) and Cox proportional hazards statistical modeling in JMP® & R®. Results Median follow-up time was 19.7 months (MR group) and 18.4 months (CT group). There were no statistically significant differences in patient age at diagnosis, histology, percent with tumor size >4 cm, grade, FIGO stage or lymph node involvement between the groups. Patients in the MR group had more lymphovascular involvement compared to patients in the CT group (p<0.01). When evaluating plans generated, there were no statistically significant differences in median cumulative dose to the high-risk clinical target volume or the OAR. 2-year K-M LC rates for MR-based and CT-based treatments were 96% and 87%, respectively (log-rank p=0.65). At 2 years, OS was significantly better in the MR-guided cohort (84% vs. 56%, p=0.036). On multivariate analysis, squamous histology was associated with longer OS (HR 0.23, 95% CI 0.07–0.72) in a model with MR BT (HR 0.35, 95% CI 0.08–1.18). Conclusion In this population of locally advanced cervical-cancer patients, MR-guided HDR BT resulted in estimated 96% 2-year local control and excellent early survival rates. Squamous cell histology was the most significant predictor for survival. PMID:28318644

Biologic treatment in Sjögren's syndrome.

PubMed

Sada, Pablo Ruiz; Isenberg, David; Ciurtin, Coziana

2015-02-01

SS is a chronic systemic autoimmune disease characterized by decreased exocrine gland function. A variety of other disease manifestations may also be present, including general constitutional symptoms and extraglandular features. A multidisciplinary approach focused on both local and systemic medical therapies is needed as the disease has a wide clinical spectrum. The current treatment for SS is mainly symptomatic. However, there is evidence that systemic drugs are effective in controlling extraglandular manifestations of the disease. Overall evidence for the role of conventional immunosuppressive therapy is limited. A number of attempts to use biologic therapies have led to variable results. Biologic agents targeting B cells, such as rituximab, epratuzumab and belimumab, have shown promising results, but further studies are needed to validate the findings. Early-phase studies with abatacept and alefacept proved that T cell stimulation inhibition is another potentially effective target for SS treatment. Modulation or inhibition of other targets such as IFN, IL-6 and Toll-like receptor are also currently being investigated. We have summarized the available evidence regarding the efficacy of biologic treatments and discuss other potential therapies targeting pathways or molecules recognized as being involved in the pathogenesis of SS. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).

PubMed

Ma, Shao; Yin, Ning; Qi, Xiaomei; Pfister, Sandra L; Zhang, Mei-Jie; Ma, Rong; Chen, Guan

2015-05-30

Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.

Computational Identification of Mechanistic Factors That Determine the Timing and Intensity of the Inflammatory Response

PubMed Central

Nagaraja, Sridevi; Reifman, Jaques; Mitrophanov, Alexander Y.

2015-01-01

Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators − tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and the chemokine CXCL8 − as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-α, TGF-β, and CXCL8, may improve the resolution of chronic inflammation. PMID:26633296

A range-based predictive localization algorithm for WSID networks

NASA Astrophysics Data System (ADS)

Liu, Yuan; Chen, Junjie; Li, Gang

2017-11-01

Most studies on localization algorithms are conducted on the sensor networks with densely distributed nodes. However, the non-localizable problems are prone to occur in the network with sparsely distributed sensor nodes. To solve this problem, a range-based predictive localization algorithm (RPLA) is proposed in this paper for the wireless sensor networks syncretizing the RFID (WSID) networks. The Gaussian mixture model is established to predict the trajectory of a mobile target. Then, the received signal strength indication is used to reduce the residence area of the target location based on the approximate point-in-triangulation test algorithm. In addition, collaborative localization schemes are introduced to locate the target in the non-localizable situations. Simulation results verify that the RPLA achieves accurate localization for the network with sparsely distributed sensor nodes. The localization accuracy of the RPLA is 48.7% higher than that of the APIT algorithm, 16.8% higher than that of the single Gaussian model-based algorithm and 10.5% higher than that of the Kalman filtering-based algorithm.

The Treacher Collins syndrome (TCOF1) gene product, treacle, is targeted to the nucleolus by signals in its C-terminus.

PubMed

Winokur, S T; Shiang, R

1998-11-01

The TCOF1 gene product, treacle, responsible for the craniofacial disorder Treacher Collins syndrome, has been predicted to be a member of a class of nucleolar phosphoproteins based on its primary amino acid sequence. Treacle is a low complexity protein with ten repeating units of acidic and basic residues, each of which contains a large number of putative casein kinase 2 and protein kinase C phosphorylation sites. In addition, the C-terminus of treacle contains multiple putative nuclear localization signals. The overall structure of treacle, as well as sequence similarity to several nucleolar phosphoproteins, predicts that treacle is a member of this class of proteins. Using green fluorescent protein fusion constructs with the full-length and deleted domains of the murine homolog of treacle, we demonstrate that the cellular localization of treacle is nucleolar. This localization is mediated by the last 41 residues of the C-terminus (residues 1262-1302). At least two functional nuclear localization signals have been identified in the protein, one between residues 1176 and 1270 and the second within the last 32 residues of the protein (1271-1302). The nucleolar localization signal is disrupted by two constructs that split the C-terminal region between residues 1270 and 1271. This study provides the first direct analysis of treacle and demonstrates that the protein involved in TCOF1 is a nucleolar protein.

Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery

PubMed Central

Gordon, Laurie J.; Wayne, Gareth J.; Almqvist, Helena; Axelsson, Hanna; Seashore-Ludlow, Brinton; Treyer, Andrea; Lundbäck, Thomas; West, Andy; Hann, Michael M.; Artursson, Per

2017-01-01

Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (Fic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined Fic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. Fic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery. PMID:28701380

Local contextual processing of abstract and meaningful real-life images in professional athletes.

PubMed

Fogelson, Noa; Fernandez-Del-Olmo, Miguel; Acero, Rafael Martín

2012-05-01

We investigated the effect of abstract versus real-life meaningful images from sports on local contextual processing in two groups of professional athletes. Local context was defined as the occurrence of a short predictive series of stimuli occurring before delivery of a target event. EEG was recorded in 10 professional basketball players and 9 professional athletes of individual sports during three sessions. In each session, a different set of visual stimuli were presented: triangles facing left, up, right, or down; four images of a basketball player throwing a ball; four images of a baseball player pitching a baseball. Stimuli consisted of 15 % targets and 85 % of equal numbers of three types of standards. Recording blocks consisted of targets preceded by randomized sequences of standards and by sequences including a predictive sequence signaling the occurrence of a subsequent target event. Subjects pressed a button in response to targets. In all three sessions, reaction times and peak P3b latencies were shorter for predicted targets compared with random targets, the last most informative stimulus of the predictive sequence induced a robust P3b, and N2 amplitude was larger for random targets compared with predicted targets. P3b and N2 peak amplitudes were larger in the professional basketball group in comparison with professional athletes of individual sports, across the three sessions. The findings of this study suggest that local contextual information is processed similarly for abstract and for meaningful images and that professional basketball players seem to allocate more attentional resources in the processing of these visual stimuli.

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2017-12-21

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

Involvement of microRNA-181a and Bim in a rat model of retinal ischemia-reperfusion injury.

PubMed

He, Yu; Liu, Jin-Nan; Zhang, Jun-Jun; Fan, Wei

2016-01-01

To investigate the changes in the expression of microRNA-181a (miR-181a) and Bim in a rat model of retinal ischemia-reperfusion (RIR), to explore their target relationship in RIR and their involvement in regulating apoptosis of retinal ganglion cells (RGCs). Target gene prediction for miR-181a was performed with the aid of bioinformatics and Bim was identified as a potential target gene of miR-181a. A rat model of RIR was created by increasing the intraocular pressure. RGCs in the flatmounted retinas were labeled with Brn3, a marker for alive RGCs, by immunofluorescent staining. The changes in the number of RGCs after RIR were recorded. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to determine the expression level of miR-181a in the retina. Bim/Brn3 double immunofluorescence was used to detect the localization of Bim. The expression of Bim in the retina was determined with the aids of Western blot and qRT-PCR. Compared with the negative control group, the density of RGCs was significantly lower in the ischemia/reperfusion (I/R)-24h and I/R-72h groups (P<0.001). The expression level of miR-181a started to decrease at 0h after RIR, and further decreased at 24h and 72h compared with the negative control group (P<0.001). Bim was significantly upregulated at 12h after RIR (P<0.05) and reached peak at 24, 72h compared with the negative control group (P<0.01). Pearson correlation analysis showed that the expression level of Bim was negatively correlated with the expression level of miR-181a and the density of RGCs. Bim may be a potential target gene of miR-181a. Both miR-181a and Bim are involved in RGCs death in RIR. RIR may promote RGCs apoptosis in the retina via downregulation of miR-181a and its inhibition on Bim expression.

Effective dialogue: enhanced public engagement as a legitimising tool for municipal waste management decision-making.

PubMed

Garnett, Kenisha; Cooper, Tim

2014-12-01

The complexity of municipal waste management decision-making has increased in recent years, accompanied by growing scrutiny from stakeholders, including local communities. This complexity reflects a socio-technical framing of the risks and social impacts associated with selecting technologies and sites for waste treatment and disposal facilities. Consequently there is growing pressure on local authorities for stakeholders (including communities) to be given an early opportunity to shape local waste policy in order to encourage swift planning, development and acceptance of the technologies needed to meet statutory targets to divert waste from landfill. This paper presents findings from a research project that explored the use of analytical-deliberative processes as a legitimising tool for waste management decision-making. Adopting a mixed methods approach, the study revealed that communicating the practical benefits of more inclusive forms of engagement is proving difficult even though planning and policy delays are hindering development and implementation of waste management infrastructure. Adopting analytical-deliberative processes at a more strategic level will require local authorities and practitioners to demonstrate how expert-citizen deliberations may foster progress in resolving controversial issues, through change in individuals, communities and institutions. The findings suggest that a significant shift in culture will be necessary for local authorities to realise the potential of more inclusive decision processes. This calls for political actors and civic society to collaborate in institutionalising public involvement in both strategic and local planning structures. Copyright © 2014 Elsevier Ltd. All rights reserved.

The snoRNA domain of vertebrate telomerase RNA functions to localize the RNA within the nucleus.

PubMed Central

Lukowiak, A A; Narayanan, A; Li, Z H; Terns, R M; Terns, M P

2001-01-01

Telomerase RNA is an essential component of the ribonucleoprotein enzyme involved in telomere length maintenance, a process implicated in cellular senescence and cancer. Vertebrate telomerase RNAs contain a box H/ACA snoRNA motif that is not required for telomerase activity in vitro but is essential in vivo. Using the Xenopus oocyte system, we have found that the box H/ACA motif functions in the subcellular localization of telomerase RNA. We have characterized the transport and biogenesis of telomerase RNA by injecting labeled wild-type and variant RNAs into Xenopus oocytes and assaying nucleocytoplasmic distribution, intranuclear localization, modification, and protein binding. Although yeast telomerase RNA shares characteristics of spliceosomal snRNAs, we show that human telomerase RNA is not associated with Sm proteins or efficiently imported into the nucleus. In contrast, the transport properties of vertebrate telomerase RNA resemble those of snoRNAs; telomerase RNA is retained in the nucleus and targeted to nucleoli. Furthermore, both nuclear retention and nucleolar localization depend on the box H/ACA motif. Our findings suggest that the H/ACA motif confers functional localization of vertebrate telomerase RNAs to the nucleus, the compartment where telomeres are synthesized. We have also found that telomerase RNA localizes to Cajal bodies, intranuclear structures where it is thought that assembly of various cellular RNPs takes place. Our results identify the Cajal body as a potential site of telomerase RNP biogenesis. PMID:11780638

Localization of synchronous cortical neural sources.

PubMed

Zerouali, Younes; Herry, Christophe L; Jemel, Boutheina; Lina, Jean-Marc

2013-03-01

Neural synchronization is a key mechanism to a wide variety of brain functions, such as cognition, perception, or memory. High temporal resolution achieved by EEG recordings allows the study of the dynamical properties of synchronous patterns of activity at a very fine temporal scale but with very low spatial resolution. Spatial resolution can be improved by retrieving the neural sources of EEG signal, thus solving the so-called inverse problem. Although many methods have been proposed to solve the inverse problem and localize brain activity, few of them target the synchronous brain regions. In this paper, we propose a novel algorithm aimed at localizing specifically synchronous brain regions and reconstructing the time course of their activity. Using multivariate wavelet ridge analysis, we extract signals capturing the synchronous events buried in the EEG and then solve the inverse problem on these signals. Using simulated data, we compare results of source reconstruction accuracy achieved by our method to a standard source reconstruction approach. We show that the proposed method performs better across a wide range of noise levels and source configurations. In addition, we applied our method on real dataset and identified successfully cortical areas involved in the functional network underlying visual face perception. We conclude that the proposed approach allows an accurate localization of synchronous brain regions and a robust estimation of their activity.

The multi-faceted role of allergen exposure to the local airway mucosa.

PubMed

Golebski, K; Röschmann, K I L; Toppila-Salmi, S; Hammad, H; Lambrecht, B N; Renkonen, R; Fokkens, W J; van Drunen, C M

2013-02-01

Airway epithelial cells are the first to encounter aeroallergens and therefore have recently become an interesting target of many studies investigating their involvement in the modulation of allergic inflammatory responses. Disruption of a passive structural barrier composed of epithelial cells by intrinsic proteolytic activity of allergens may facilitate allergen penetration into local tissues and additionally affect chronic and ongoing inflammatory processes in respiratory tissues. Furthermore, the ability of rhinoviruses to disrupt and interfere with epithelial tight junctions may alter the barrier integrity and enable a passive passage of inhaled allergens through the airway epithelium. On the other hand, epithelial cells are no longer considered to act only as a physical barrier toward inhaled allergens, but also to actively contribute to airway inflammation by detecting and responding to environmental factors. Epithelial cells can produce mediators, which may affect the recruitment and activation of more specialized immune cells to the local tissue and also create a microenvironment in which these activated immune cells may function and propagate the inflammatory processes. This review presents the dual role of epithelium acting as a passive and active barrier when encountering an inhaled allergen and how this double role contributes to the start of local immune responses. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Local and global processing in block design tasks in children with dyslexia or nonverbal learning disability.

PubMed

Cardillo, Ramona; Mammarella, Irene C; Garcia, Ricardo Basso; Cornoldi, Cesare

2017-05-01

Visuo-constructive and perceptual abilities have been poorly investigated in children with learning disabilities. The present study focused on local or global visuospatial processing in children with nonverbal learning disability (NLD) and dyslexia compared with typically-developing (TD) controls. Participants were presented with a modified block design task (BDT), in both a typical visuo-constructive version that involves reconstructing figures from blocks, and a perceptual version in which respondents must rapidly match unfragmented figures with a corresponding fragmented target figure. The figures used in the tasks were devised by manipulating two variables: the perceptual cohesiveness and the task uncertainty, stimulating global or local processes. Our results confirmed that children with NLD had more problems with the visuo-constructive version of the task, whereas those with dyslexia showed only a slight difficulty with the visuo-constructive version, but were in greater difficulty with the perceptual version, especially in terms of response times. These findings are interpreted in relation to the slower visual processing speed of children with dyslexia, and to the visuo-constructive problems and difficulty in using flexibly-experienced global vs local processes of children with NLD. The clinical and educational implications of these findings are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

PubMed Central

Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

2013-01-01

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely 131I-hypericin (131I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications. PMID:23412554

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications.

PubMed

Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

2013-01-01

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely (131)I-hypericin ((131)I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.

Human Cytochrome P450 2E1 Mutations That Alter Mitochondrial Targeting Efficiency and Susceptibility to Ethanol-induced Toxicity in Cellular Models*

PubMed Central

Bansal, Seema; Anandatheerthavarada, Hindupur K.; Prabu, Govindaswamy K.; Milne, Ginger L.; Martin, Martha V.; Guengerich, F. Peter; Avadhani, Narayan G.

2013-01-01

Human polymorphisms in the 5′-upstream regulatory regions and also protein coding regions of cytochrome P450 2E1 (CYP2E1) are known to be associated with several diseases, including cancer and alcohol liver toxicity. In this study, we report novel mutations in the N-terminal protein targeting regions of CYP2E1 that markedly affect subcellular localization of the protein. Variant W23R/W30R protein (termed W23/30R) is preferentially targeted to mitochondria but very poorly to the endoplasmic reticulum, whereas the L32N protein is preferentially targeted to the endoplasmic reticulum and poorly to mitochondria. These results explain the physiological significance of bimodal CYP targeting to the endoplasmic reticulum and mitochondria previously described. COS-7 cells and HepG2 cells stably expressing W23/30R mutations showed markedly increased alcohol toxicity in terms of increased production of reactive oxygen species, respiratory dysfunction, and loss of cytochrome c oxidase subunits and activity. Stable cells expressing the L32N variant, on the other hand, were relatively less responsive to alcohol-induced toxicity and mitochondrial dysfunction. These results further support our previous data, based on mutational studies involving altered targeting, indicating that mitochondria-targeted CYP2E1 plays an important role in alcohol liver toxicity. The results also provide an interesting new link to genetic variations affecting subcellular distribution of CYP2E1 with alcohol-induced toxicity. PMID:23471973

Localization of Ferromagnetic Target with Three Magnetic Sensors in the Movement Considering Angular Rotation

PubMed Central

Gao, Xiang; Yan, Shenggang; Li, Bin

2017-01-01

Magnetic detection techniques have been widely used in many fields, such as virtual reality, surgical robotics systems, and so on. A large number of methods have been developed to obtain the position of a ferromagnetic target. However, the angular rotation of the target relative to the sensor is rarely studied. In this paper, a new method for localization of moving object to determine both the position and rotation angle with three magnetic sensors is proposed. Trajectory localization estimation of three magnetic sensors, which are collinear and noncollinear, were obtained by the simulations, and experimental results demonstrated that the position and rotation angle of ferromagnetic target having roll, pitch or yaw in its movement could be calculated accurately and effectively with three noncollinear vector sensors. PMID:28892006

Mapping a nucleolar targeting sequence of an RNA binding nucleolar protein, Nop25

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

Fujiwara, Takashi; Suzuki, Shunji; Kanno, Motoko

2006-06-10

Nop25 is a putative RNA binding nucleolar protein associated with rRNA transcription. The present study was undertaken to determine the mechanism of Nop25 localization in the nucleolus. Deletion experiments of Nop25 amino acid sequence showed Nop25 to contain a nuclear targeting sequence in the N-terminal and a nucleolar targeting sequence in the C-terminal. By expressing derivative peptides from the C-terminal as GFP-fusion proteins in the cells, a lysine and arginine residue-enriched peptide (KRKHPRRAQDSTKKPPSATRTSKTQRRRR) allowed a GFP-fusion protein to be transported and fully retained in the nucleolus. When the peptide was fused with cMyc epitope and expressed in the cells, amore » cMyc epitope was then detected in the nucleolus. Nop25 did not localize in the nucleolus by deletion of the peptide from Nop25. Furthermore, deletion of a subdomain (KRKHPRRAQ) in the peptide or amino acid substitution of lysine and arginine residues in the subdomain resulted in the loss of Nop25 nucleolar localization. These results suggest that the lysine and arginine residue-enriched peptide is the most prominent nucleolar targeting sequence of Nop25 and that the long stretch of basic residues might play an important role in the nucleolar localization of Nop25. Although Nop25 contained putative SUMOylation, phosphorylation and glycosylation sites, the amino acid substitution in these sites had no effect on the nucleolar localization, thus suggesting that these post-translational modifications did not contribute to the localization of Nop25 in the nucleolus. The treatment of the cells, which expressed a GFP-fusion protein with a nucleolar targeting sequence of Nop25, with RNase A resulted in a complete dislocation of the protein from the nucleolus. These data suggested that the nucleolar targeting sequence might therefore play an important role in the binding of Nop25 to RNA molecules and that the RNA binding of Nop25 might be essential for the nucleolar localization of Nop25.« less

Using State and Local Studies to Teach Geographic Concepts.

ERIC Educational Resources Information Center

Fuller, Michael J.; And Others

1982-01-01

Lessons involve K-12 students in analyzing teacher-developed state and local thematic maps, identifying countries of the world with which their city has a linkage as indicated by local ethnic restaurants, discussing local companies involved in international trade, and learning about foreign-made products in their home and community. (RM)

Identification of Loci Associated with Drought Resistance Traits in Heterozygous Autotetraploid Alfalfa (Medicago sativa L.) Using Genome-Wide Association Studies with Genotyping by Sequencing.

PubMed

Zhang, Tiejun; Yu, Long-Xi; Zheng, Ping; Li, Yajun; Rivera, Martha; Main, Dorrie; Greene, Stephanie L

2015-01-01

Drought resistance is an important breeding target for enhancing alfalfa productivity in arid and semi-arid regions. Identification of genes involved in drought tolerance will facilitate breeding for improving drought resistance and water use efficiency in alfalfa. Our objective was to use a diversity panel of alfalfa accessions comprised of 198 cultivars and landraces to identify genes involved in drought tolerance. The panel was selected from the USDA-ARS National Plant Germplasm System alfalfa collection and genotyped using genotyping by sequencing. A greenhouse procedure was used for phenotyping two important traits associated with drought tolerance: drought resistance index (DRI) and relative leaf water content (RWC). Marker-trait association identified nineteen and fifteen loci associated with DRI and RWC, respectively. Alignments of target sequences flanking to the resistance loci against the reference genome of M. truncatula revealed multiple chromosomal locations. Markers associated with DRI are located on all chromosomes while markers associated with RWC are located on chromosomes 1, 2, 3, 4, 5, 6 and 7. Co-localizations of significant markers between DRI and RWC were found on chromosomes 3, 5 and 7. Most loci associated with DRI in this work overlap with the reported QTLs associated with biomass under drought in alfalfa. Additional significant markers were targeted to several contigs with unknown chromosomal locations. BLAST search using their flanking sequences revealed homology to several annotated genes with functions in stress tolerance. With further validation, these markers may be used for marker-assisted breeding new alfalfa varieties with drought resistance and enhanced water use efficiency.

Potential Proinvasive or Metastatic Effects of Preclinical Antiangiogenic Therapy Are Prevented by Concurrent Chemotherapy.

PubMed

Paez-Ribes, Marta; Man, Shan; Xu, Ping; Kerbel, Robert S

2015-12-15

To resolve a controversy involving the therapeutic impact of antiangiogenic drugs and particularly antibodies targeting the VEGF pathway, namely, a body of preclinical mouse therapy studies showing such drugs can promote invasion and/or distant metastasis when used as monotherapies. In contrast, clinical studies have not shown such promalignancy effects. However, most such clinical studies have involved patients also treated with concurrent chemotherapy highlighting the possibility that chemotherapy may prevent any potential promalignancy effect caused by an antiangiogenic drug treatment. The impact of antiangiogenic therapy using DC101, an antibody targeting mouse VEGFR-2 with or without concurrent chemotherapy was assessed in multiple human breast cancer xenograft models, where impact on orthotopic primary tumors was evaluated. Metastasis was also assessed during adjuvant and neoadjuvant plus adjuvant therapy, after surgical resection of primary tumors, with the same combination therapies. Antiangiogenic therapy, while blunting tumor volume growth, was found to increase local invasion in multiple primary tumor models, including a patient-derived xenograft, but this effect was blocked by concurrent chemotherapy. Similarly, the combination of paclitaxel with DC101 caused a marked reduction of micro- or macrometastatic disease in contrast to DC101 monotherapy, which was associated with small increases in metastatic disease. Conventional wisdom is that targeted biologic antiangiogenic agents such as bevacizumab when used with chemotherapy increase the efficacy of the chemotherapy treatment. Our results suggest the reverse may be true as well-chemotherapy may improve the impact of antiangiogenic drug treatment and, as a result, overall efficacy. Clin Cancer Res; 21(24); 5488-98. ©2015 AACR. ©2015 American Association for Cancer Research.

Effects of non-local electron transport in one-dimensional and two-dimensional simulations of shock-ignited inertial confinement fusion targets

NASA Astrophysics Data System (ADS)

Marocchino, A.; Atzeni, S.; Schiavi, A.

2014-01-01

In some regions of a laser driven inertial fusion target, the electron mean-free path can become comparable to or even longer than the electron temperature gradient scale-length. This can be particularly important in shock-ignited (SI) targets, where the laser-spike heated corona reaches temperatures of several keV. In this case, thermal conduction cannot be described by a simple local conductivity model and a Fick's law. Fluid codes usually employ flux-limited conduction models, which preserve causality, but lose important features of the thermal flow. A more accurate thermal flow modeling requires convolution-like non-local operators. In order to improve the simulation of SI targets, the non-local electron transport operator proposed by Schurtz-Nicolaï-Busquet [G. P. Schurtz et al., Phys. Plasmas 7, 4238 (2000)] has been implemented in the DUED fluid code. Both one-dimensional (1D) and two-dimensional (2D) simulations of SI targets have been performed. 1D simulations of the ablation phase highlight that while the shock profile and timing might be mocked up with a flux-limiter; the electron temperature profiles exhibit a relatively different behavior with no major effects on the final gain. The spike, instead, can only roughly be reproduced with a fixed flux-limiter value. 1D target gain is however unaffected, provided some minor tuning of laser pulses. 2D simulations show that the use of a non-local thermal conduction model does not affect the robustness to mispositioning of targets driven by quasi-uniform laser irradiation. 2D simulations performed with only two final polar intense spikes yield encouraging results and support further studies.

Search asymmetry and eye movements in infants and adults.

PubMed

Adler, Scott A; Gallego, Pamela

2014-08-01

Search asymmetry is characterized by the detection of a feature-present target amidst feature-absent distractors being efficient and unaffected by the number of distractors, whereas detection of a feature-absent target amidst feature-present distractors is typically inefficient and affected by the number of distractors. Although studies have attempted to investigate this phenomenon with infants (e.g., Adler, Inslicht, Rovee-Collier, & Gerhardstein in Infant Behavioral Development, 21, 253-272, 1998; Colombo, Mitchell, Coldren, & Atwater in Journal of Experimental Psychology: Learning, Memory and Cognition, 19, 98-109, 1990), due to methodological limitations, their findings have been unable to definitively establish the development of visual search mechanisms in infants. The present study assessed eye movements as a means to examine an asymmetry in responding to feature-present versus feature-absent targets in 3-month-olds, relative to adults. Saccade latencies to localize a target (or a distractor, as in the homogeneous conditions) were measured as infants and adults randomly viewed feature-present (R among Ps), feature-absent (P among Rs), and homogeneous (either all Rs or all Ps) arrays at set sizes of 1, 3, 5, and 8. Results indicated that neither infants' nor adults' saccade latencies to localize the target in the feature-present arrays were affected by increasing set sizes, suggesting that localization of the target was efficient. In contrast, saccade latencies to localize the target in the feature-absent arrays increased with increasing set sizes for both infants and adults, suggesting an inefficient localization. These findings indicate that infants exhibit an asymmetry consistent with that found with adults, providing support for functional bottom-up selective attention mechanisms in early infancy.

Impact of 'stretch' targets for cardiovascular disease management within a local pay-for-performance programme.

PubMed

Pape, Utz J; Huckvale, Kit; Car, Josip; Majeed, Azeem; Millett, Christopher

2015-01-01

Pay-for-performance programs are often aimed to improve the management of chronic diseases. We evaluate the impact of a local pay for performance programme (QOF+), which rewarded financially more ambitious quality targets ('stretch targets') than those used nationally in the Quality and Outcomes Framework (QOF). We focus on targets for intermediate outcomes in patients with cardiovascular disease and diabetes. A difference-in-difference approach is used to compare practice level achievements before and after the introduction of the local pay for performance program. In addition, we analysed patient-level data on exception reporting and intermediate outcomes utilizing an interrupted time series analysis. The local pay for performance program led to significantly higher target achievements (hypertension: p-value <0.001, coronary heart disease: p-values <0.001, diabetes: p-values <0.061, stroke: p-values <0.003). However, the increase was driven by higher rates of exception reporting (hypertension: p-value <0.001, coronary heart disease: p-values <0.03, diabetes: p-values <0.05) in patients with all conditions except for stroke. Exception reporting allows practitioners to exclude patients from target calculations if certain criteria are met, e.g. informed dissent of the patient for treatment. There were no statistically significant improvements in mean blood pressure, cholesterol or HbA1c levels. Thus, achievement of higher payment thresholds in the local pay for performance scheme was mainly attributed to increased exception reporting by practices with no discernable improvements in overall clinical quality. Hence, active monitoring of exception reporting should be considered when setting more ambitious quality targets. More generally, the study suggests a trade-off between additional incentive for better care and monitoring costs.

Blocking the mineralocorticoid receptor improves effectiveness of steroid treatment for low back pain in rats

PubMed Central

Ye, Ling; Xie, Wenrui; Strong, Judith A.; Zhang, Jun-Ming

2014-01-01

Background Localized inflammation of lumbar dorsal root ganglia (DRG) may contribute to low back pain. Local injections of corticosteroids used for low back pain are sometimes ineffective. Many corticosteroids activate not only the target glucocorticoid receptor (GR) but also the mineralocorticoid receptor (MR), which may have pro-inflammatory effects countering the effects of GR activation. Methods A low back pain model was implemented in rats (n = 6 -10 per group) by locally inflaming the L5 DRG. Sensory neuron excitability and mechanical hypersensitivity of the hind paws were measured. Tested steroids were applied locally to the inflamed DRG or orally. Results The selective MR blocker eplerenone reduced pain behaviors when given orally starting at the time of surgery, or starting 7 days later. The highly GR-selective agonist fluticasone, applied locally to the inflamed DRG, was much more effective in reducing mechanical hypersensitivity. The MR/GR agonist 6-α methylprednisolone, commonly injected for low back pain, reduced mechanical hypersensitivity when applied locally to the DRG, but was less effective than fluticasone. Its effectiveness was improved by combining it with local eplerenone. All tested steroids reduced hyperexcitability of myelinated sensory neurons (n = 71 – 220 cells per group) after inflammation, particularly abnormal spontaneous activity. Conclusions This preclinical study indicates the MR may play an important role in low back pain involving inflammation. Some MR effects may occur at the level of the sensory neuron. It may be useful to consider the action of clinically used steroids at the MR as well as at the GR. PMID:24781496

[What are we doing in neighborhoods? Description of health-promoting community activities in primary care: the FrAC Project].

PubMed

March, Sebastià; Jordán Martín, Matilde; Montaner Gomis, Isabel; Benedé Azagra, Carmen Belén; Elizalde Soto, Lázaro; Ramos, María

2014-01-01

To describe the health-promoting community activities developed in primary health care and compare types of activities and how they are performed among autonomous regions. A descriptive multicenter study was carried out in primary care in 5 Spanish regions. We included community activities consisting of non-sporadic activities, carried out in the previous year, with the participation of the primary care team, and the active participation of the community or as a cross-sector activity. The persons responsible for each of the 194 teams were asked if the team participated in community activities and, if so, a questionnaire was completed by the person responsible for each activity. The variables consisted of the topic addressed, the target population, the professionals involved, the time and scope of implementation, evaluation, theoretical perspectives, network registration, the involvement of the community and other agents, and evaluation of this involvement. A descriptive analysis was performed, stratified by region. We identified 183 community activities in 104 teams. Although there was wide variability among regions, most activities were related to general health, nutrition and emotional-sexual health and targeted the general population, children or parents and were carried out in educational or health centers. Participating professionals had a median of 4 years of experience and a median of 2.8 professionals were involved in each activity. A total of 72.5% of the activities were performed during working hours, 75% were evaluated, and 70% were supported by theoretical and methodological perspectives. Non-health sectors were involved in 65%, local government in 60%, and nongovernmental organizations in 58.5%. Nurses were involved in 85.8% of the activities, physicians in 38.5%, and social workers in 35%. Substantial variability was detected among regions. Wide variability was found in the types of activities and their application among the community activities developed by primary care, as well as in institutional recognition and community involvement in the development and evaluation of these activities. Copyright © 2013 SESPAS. Published by Elsevier Espana. All rights reserved.

The Bioterrorism Threat by Non-State Actors: Hype or Horror?

DTIC Science & Technology

2006-12-01

renamed the town Rajneesh. It took control over the local schools while also converting the only local business into a vegetarian restaurant called...multiple targets. The April 1990 attack was perpetrated from three trucks at multiple locations. The cult targeted Narita Airport, the Diet , the

Career development through local chapter involvement: perspectives from chapter members.

PubMed

Thomas, Melissa; Inniss-Richter, Zipporah; Mata, Holly; Cottrell, Randall R

2013-07-01

The importance of career development in professional organizations has been noted in the literature. Personal and professional benefits of membership regardless of discipline can be found across the career spectrum from student to executive. The benefits of professional membership with respect to career development in local chapter organizations have seldom been studied. Local chapter participation may offer significant career development opportunities for the practitioner, faculty member, and student. The purpose of this study was to explore the importance of local chapter involvement to the career development of health education practitioners. An 18-item questionnaire was disseminated to the membership of three local SOPHE (Society for Public Health Education) chapters that explored the level of local chapter involvement and the impact of how specific professional development activities impacted career development. The results of the survey highlighted the importance of continuing education programs, networking, and leadership experience in developing one's career that are offered by local SOPHE chapter involvement. Making a positive impact in the community and earning the respect of one's peers were most often reported as indicators of career success. These factors can directly impact local chapter participation. Career development can certainly be enhanced by active participation in the local chapter of a professional association.

Auf gute Nachbarschaft!. Verantwortungsübernahme durch Unternehmen für die Stadtteilentwicklung - Haniel und Grillo in Duisburg

NASA Astrophysics Data System (ADS)

Kleine-König, Christiane; Hohn, Uta

2016-03-01

Companies' community involvement turns out to be spatially relevant and-in many cases-to be focused on the near surroundings of the place of business. Some companies strategically align their involvement in order to systematically address local challenges. The essay at hand addresses the subject of corporate social responsibility from a local development perspective. Using the example of two family-owned enterprises based in Duisburg, Haniel and Grillo, it illustrates how socially committed companies can get involved with their local community by acting as good neighbours. Furthermore, it argues that socially committed companies can function as producers of space concerning matters of urban and local development. The specific local settings as well as the economic conditions of the local community serve as an explanatory background of the companies' involvement. The cases presented in this paper prove the firms' specific knowledge of local development needs and possibilities. This makes them qualified partners for local government actors and civil society actors. Thus, in the future, it is worth addressing corporate local responsibility from a governance point of view both in theory and in practice.

'Sly grog' and 'homebrew': a qualitative examination of illicit alcohol and some of its impacts on Indigenous communities with alcohol restrictions in regional and remote Queensland (Australia).

PubMed

Fitts, Michelle S; Robertson, Jan; Towle, Simon; Doran, Chris M; McDermott, Robyn; Miller, Adrian; Margolis, Stephen; Ypinazar, Valmae; Clough, Alan R

2017-08-01

Indigenous communities in Queensland (Australia) have been subject to Alcohol Management Plans since 2002/03, with significant penalties for breaching restrictions. 'Sly grog' and 'homebrew' provide access to alcohol despite restrictions. This paper describes how this alcohol is made available and the risks and impacts involved. In affected towns and communities across a large area of rural and remote Queensland, interviews and focus groups documented experiences and views of 255 long-standing community members and service providers. Using an inductive framework, transcribed interviews were analysed to identify supply mechanisms, community and service provider responses and impacts experienced. 'Homebrew' was reportedly manufactured in just a few localities, in locally-specific forms bringing locally-specific harms. However, 'sly grog' sourced from licensed premises located long distances from communities, is a widespread concern across the region. 'Sly grog' sellers circumvent retailers' takeaway liquor license conditions, stockpile alcohol outside restricted areas, send hoax messages to divert enforcement and take extraordinary risks to avoid apprehension. Police face significant challenges to enforce restrictions. On-selling of 'sly grog' appears more common in remote communities with total prohibition. Despite different motives for involvement in an illicit trade 'sly grog' consumers and sellers receive similar penalties. There is a need for: (a) a more sophisticated regional approach to managing takeaway alcohol sales from licensed suppliers, (b) targeted penalties for 'sly grog' sellers that reflect its significant community impact, (c) strategies to reduce the demand for alcohol and (d) research to assess the effects of these strategies in reducing harms.

Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats

PubMed Central

Jerlhag, Elisabet; Janson, Anna Carin; Waters, Susanna; Engel, Jörgen A.

2012-01-01

Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating. PMID:23166710

Drug Target Prediction and Repositioning Using an Integrated Network-Based Approach

PubMed Central

Emig, Dorothea; Ivliev, Alexander; Pustovalova, Olga; Lancashire, Lee; Bureeva, Svetlana; Nikolsky, Yuri; Bessarabova, Marina

2013-01-01

The discovery of novel drug targets is a significant challenge in drug development. Although the human genome comprises approximately 30,000 genes, proteins encoded by fewer than 400 are used as drug targets in the treatment of diseases. Therefore, novel drug targets are extremely valuable as the source for first in class drugs. On the other hand, many of the currently known drug targets are functionally pleiotropic and involved in multiple pathologies. Several of them are exploited for treating multiple diseases, which highlights the need for methods to reliably reposition drug targets to new indications. Network-based methods have been successfully applied to prioritize novel disease-associated genes. In recent years, several such algorithms have been developed, some focusing on local network properties only, and others taking the complete network topology into account. Common to all approaches is the understanding that novel disease-associated candidates are in close overall proximity to known disease genes. However, the relevance of these methods to the prediction of novel drug targets has not yet been assessed. Here, we present a network-based approach for the prediction of drug targets for a given disease. The method allows both repositioning drug targets known for other diseases to the given disease and the prediction of unexploited drug targets which are not used for treatment of any disease. Our approach takes as input a disease gene expression signature and a high-quality interaction network and outputs a prioritized list of drug targets. We demonstrate the high performance of our method and highlight the usefulness of the predictions in three case studies. We present novel drug targets for scleroderma and different types of cancer with their underlying biological processes. Furthermore, we demonstrate the ability of our method to identify non-suspected repositioning candidates using diabetes type 1 as an example. PMID:23593264

Towards real-time MRI-guided 3D localization of deforming targets for non-invasive cardiac radiosurgery

NASA Astrophysics Data System (ADS)

Ipsen, S.; Blanck, O.; Lowther, N. J.; Liney, G. P.; Rai, R.; Bode, F.; Dunst, J.; Schweikard, A.; Keall, P. J.

2016-11-01

Radiosurgery to the pulmonary vein antrum in the left atrium (LA) has recently been proposed for non-invasive treatment of atrial fibrillation (AF). Precise real-time target localization during treatment is necessary due to complex respiratory and cardiac motion and high radiation doses. To determine the 3D position of the LA for motion compensation during radiosurgery, a tracking method based on orthogonal real-time MRI planes was developed for AF treatments with an MRI-guided radiotherapy system. Four healthy volunteers underwent cardiac MRI of the LA. Contractile motion was quantified on 3D LA models derived from 4D scans with 10 phases acquired in end-exhalation. Three localization strategies were developed and tested retrospectively on 2D real-time scans (sagittal, temporal resolution 100 ms, free breathing). The best-performing method was then used to measure 3D target positions in 2D-2D orthogonal planes (sagittal-coronal, temporal resolution 200-252 ms, free breathing) in 20 configurations of a digital phantom and in the volunteer data. The 3D target localization accuracy was quantified in the phantom and qualitatively assessed in the real data. Mean cardiac contraction was  ⩽  3.9 mm between maximum dilation and contraction but anisotropic. A template matching approach with two distinct template phases and ECG-based selection yielded the highest 2D accuracy of 1.2 mm. 3D target localization showed a mean error of 3.2 mm in the customized digital phantoms. Our algorithms were successfully applied to the 2D-2D volunteer data in which we measured a mean 3D LA motion extent of 16.5 mm (SI), 5.8 mm (AP) and 3.1 mm (LR). Real-time target localization on orthogonal MRI planes was successfully implemented for highly deformable targets treated in cardiac radiosurgery. The developed method measures target shifts caused by respiration and cardiac contraction. If the detected motion can be compensated accordingly, an MRI-guided radiotherapy system could potentially enable completely non-invasive treatment of AF.

Serotonergic neurosecretory synapse targeting is controlled by Netrin-releasing guidepost neurons in C. elegans

PubMed Central

Nelson, Jessica C.; Colón-Ramos, Daniel A.

2013-01-01

Neurosecretory release sites lack distinct post-synaptic partners, yet target to specific circuits. This targeting specificity regulates local release of neurotransmitters and modulation of adjacent circuits. How neurosecretory release sites target to specific regions is not understood. Here we identify a molecular mechanism that governs the spatial specificity of extrasynaptic neurosecretory terminal formation in the serotonergic NSM neurons of C. elegans. We show that post-embryonic arborization and neurosecretory terminal targeting of the C. elegans NSM neuron is dependent on the Netrin receptor UNC-40/DCC. We observe that UNC-40 localizes to specific neurosecretory terminals at the time of axon arbor formation. This localization is dependent on UNC-6/Netrin, which is expressed by nerve ring neurons that act as guideposts to instruct local arbor and release site formation. We find that both UNC-34/Enabled and MIG-10/Lamellipodin are required downstream of UNC-40 to link the sites of ENT formation to nascent axon arbor extensions. Our findings provide a molecular link between release site development and axon arborization, and introduce a novel mechanism that governs the spatial specificity of serotonergic extrasynaptic neurosecretory terminals in vivo. PMID:23345213

Distributed memory approaches for robotic neural controllers

NASA Technical Reports Server (NTRS)

Jorgensen, Charles C.

1990-01-01

The suitability is explored of two varieties of distributed memory neutral networks as trainable controllers for a simulated robotics task. The task requires that two cameras observe an arbitrary target point in space. Coordinates of the target on the camera image planes are passed to a neural controller which must learn to solve the inverse kinematics of a manipulator with one revolute and two prismatic joints. Two new network designs are evaluated. The first, radial basis sparse distributed memory (RBSDM), approximates functional mappings as sums of multivariate gaussians centered around previously learned patterns. The second network types involved variations of Adaptive Vector Quantizers or Self Organizing Maps. In these networks, random N dimensional points are given local connectivities. They are then exposed to training patterns and readjust their locations based on a nearest neighbor rule. Both approaches are tested based on their ability to interpolate manipulator joint coordinates for simulated arm movement while simultaneously performing stereo fusion of the camera data. Comparisons are made with classical k-nearest neighbor pattern recognition techniques.

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

PubMed Central

McCrea, Heather J.; Paradise, Summer; Tomasini, Livia; Addis, Maria; Melis, Maria Antonietta; De Matteis, Maria Antonietta; De Camilli, Pietro

2008-01-01

Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, an X-linked disorder characterized by bilateral cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome, and for Dent disease, another X-linked condition characterized by kidney reabsorption defects. We have previously described an interaction of OCRL with the endocytic adaptor APPL1 that links OCRL to protein networks involved in the disease phenotype. Here we provide new evidence showing that among the interactions which target OCRL to membranes of the endocytic pathway, binding to APPL1 is the only one abolished by all known disease-causing missense mutations in the ASH-RhoGAP domains of the protein. Furthermore, we demonstrate that APPL1 and rab5 independently contribute to recruit OCRL to enlarged endosomes induced by the expression of constitutively active Rab5. Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease. PMID:18307981

Lactosamine-Based Derivatives as Tools to Delineate the Biological Functions of Galectins: Application to Skin Tissue Repair.

PubMed

Dion, Johann; Deshayes, Frédérique; Storozhylova, Nataliya; Advedissian, Tamara; Lambert, Annie; Viguier, Mireille; Tellier, Charles; Dussouy, Christophe; Poirier, Françoise; Grandjean, Cyrille

2017-04-18

Galectins have been recognized as potential novel therapeutic targets for the numerous fundamental biological processes in which they are involved. Galectins are key players in homeostasis, and as such their expression and function are finely tuned in vivo. Thus, their modes of action are complex and remain largely unexplored, partly because of the lack of dedicated tools. We thus designed galectin inhibitors from a lactosamine core, functionalized at key C2 and C3' positions by aromatic substituents to ensure both high affinity and selectivity, and equipped with a spacer that can be modified on demand to further modulate their physico-chemical properties. As a proof-of-concept, galectin-3 was selectively targeted. The efficacy of the synthesized di-aromatic lactosamine tools was shown in cellular assays to modulate collective epithelial cell migration and to interfere with actin/cortactin localization. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

MRI-guided brachytherapy

PubMed Central

Tanderup, Kari; Viswanathan, Akila; Kirisits, Christian; Frank, Steven J.

2014-01-01

The application of MRI-guided brachytherapy has demonstrated significant growth during the last two decades. Clinical improvements in cervix cancer outcomes have been linked to the application of repeated MRI for identification of residual tumor volumes during radiotherapy. This has changed clinical practice in the direction of individualized dose administration, and mounting evidence of improved clinical outcome with regard to local control, overall survival as well as morbidity. MRI-guided prostate HDR and LDR brachytherapy has improved the accuracy of target and organs-at-risk (OAR) delineation, and the potential exists for improved dose prescription and reporting for the prostate gland and organs at risk. Furthermore, MRI-guided prostate brachytherapy has significant potential to identify prostate subvolumes and dominant lesions to allow for dose administration reflecting the differential risk of recurrence. MRI-guided brachytherapy involves advanced imaging, target concepts, and dose planning. The key issue for safe dissemination and implementation of high quality MRI-guided brachytherapy is establishment of qualified multidisciplinary teams and strategies for training and education. PMID:24931089

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

PubMed Central

Tan, Dun-Xian; Manchester, Lucien C.; Qin, Lilan; Reiter, Russel J.

2016-01-01

Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. PMID:27999288

Multiple roles of the Rho GEF ephexin1 in synapse remodeling

PubMed Central

Shi, Lei; Fu, Amy KY

2010-01-01

Synapse remodeling, which involves changes in the synaptic structure and their molecular composition, is required for the maturation and refinement of neural circuits. Although synapse remodeling is known to be tightly dependent on the assembly of local actin cytoskeleton, how actin directs the structural changes of synapse and targeting of synaptic proteins are not fully understood. Recently, we identified ephexin1, a Rho guanine nucleotide exchange factor (GEF) that regulates actin dynamics, to play an essential role in the maturation and functioning of the mammalian neuromuscular junction (NMJ). We showed that ephexin1 regulates the synaptic organization of the neurotransmitter receptor acetylcholine receptor (AChR) clusters through RhoA-dependent actin reorganization. Interestingly, ephexin1 has been implicated in the regulation of postsynaptic structure as well as the presynaptic vesicle release at various types of synapses. Our findings thus establish a novel function of ephexin1 in synapse remodeling through regulating the synaptic targeting of neurotransmitter receptors, revealing a versatile role of ephexin1 at synapses. PMID:21331259

Robust and Rapid Air-Borne Odor Tracking without Casting1,2,3

PubMed Central

Bhattacharyya, Urvashi

2015-01-01

Abstract Casting behavior (zigzagging across an odor stream) is common in air/liquid-borne odor tracking in open fields; however, terrestrial odor localization often involves path selection in a familiar environment. To study this, we trained rats to run toward an odor source in a multi-choice olfactory arena with near-laminar airflow. We find that rather than casting, rats run directly toward an odor port, and if this is incorrect, they serially sample other sources. This behavior is consistent and accurate in the presence of perturbations, such as novel odors, background odor, unilateral nostril stitching, and turbulence. We developed a model that predicts that this run-and-scan tracking of air-borne odors is faster than casting, provided there are a small number of targets at known locations. Thus, the combination of best-guess target selection with fallback serial sampling provides a rapid and robust strategy for finding odor sources in familiar surroundings. PMID:26665165

Preventing falls in residential construction: Effectiveness of engaging partners for a national social marketing campaign.

PubMed

Macario, Everly; Hannon, Sandra Wills; Baker, Robin; Branche, Christine M; Trahan, Christina

2015-08-01

Falls are the leading cause of fatalities in construction. The Safety Pays, Falls Cost campaign aims to prevent falls in residential construction. A critical component of our social marketing approach was to involve 70 partners in reaching target audiences. We assessed partner engagement April 2012-August 2013 through: (1) baseline partnership quality interviews (eight partners); (2) pre-/post-partner "market" readiness in-depth interviews (three partners); (3) a pre-/post- (29/31 partners) online partner engagement survey; and (4) standardized metrics to measure partner activity. We found a high level of interest and engagement that increased with the addition of prompting to action through regular communication and new resources from organizers and formation of local partnerships that were able to tailor their activities to their own communities or regions. It is feasible to leverage government-labor-management partnerships that enjoy trust among target audiences to widely disseminate campaign materials and messages. © 2015 Wiley Periodicals, Inc.

Eye Tracking Dysfunction in Schizophrenia: Characterization and Pathophysiology

PubMed Central

Sereno, Anne B.; Gooding, Diane C.; O’Driscoll, Gilllian A.

2011-01-01

Eye tracking dysfunction (ETD) is one of the most widely replicated behavioral deficits in schizophrenia and is over-represented in clinically unaffected first-degree relatives of schizophrenia patients. Here, we provide an overview of research relevant to the characterization and pathophysiology of this impairment. Deficits are most robust in the maintenance phase of pursuit, particularly during the tracking of predictable target movement. Impairments are also found in pursuit initiation and correlate with performance on tests of motion processing, implicating early sensory processing of motion signals. Taken together, the evidence suggests that ETD involves higher-order structures, including the frontal eye fields, which adjust the gain of the pursuit response to visual and anticipated target movement, as well as early parts of the pursuit pathway, including motion areas (the middle temporal area and the adjacent medial superior temporal area). Broader application of localizing behavioral paradigms in patient and family studies would be advantageous for refining the eye tracking phenotype for genetic studies. PMID:21312405

Structural basis of substrate discrimination and integrin binding by autotaxin

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

Hausmann, Jens; Kamtekar, Satwik; Christodoulou, Evangelos

2013-09-25

Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies including tumor progression and inflammation. However, the molecular basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear. Here, we present the crystal structure of ATX, alone and in complex with a small-molecule inhibitor. We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates.more » We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains, using an atypical mechanism. Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-molecule therapeutic agents.« less

Estrogen receptor-β in mitochondria: implications for mitochondrial bioenergetics and tumorigenesis.

PubMed

Liao, Tien-Ling; Tzeng, Chii-Ruey; Yu, Chao-Lan; Wang, Yi-Pei; Kao, Shu-Huei

2015-09-01

Estrogen enhances mitochondrial function by enhancing mitochondrial biogenesis and sustaining mitochondrial energy-transducing capacity. Shifts in mitochondrial bioenergetic pathways from oxidative phosphorylation to glycolysis have been hypothesized to be involved in estrogen-induced tumorigenesis. Studies have shown that mitochondria are an important target of estrogen. Estrogen receptor-β (ERβ) has been shown to localize to mitochondria in a ligand-dependent or -independent manner and can affect mitochondrial bioenergetics and anti-apoptotic signaling. However, the functional role of mitochondrial ERβ in tumorigenesis remains unclear. Clinical studies of ERβ-related tumorigenesis have shown that ERβ stimulates mitochondrial metabolism to meet the high energy demands of processes such as cell proliferation, cell survival, and transformation. Thus, in elucidating the precise role of mitochondrial ERβ in cell transformation and tumorigenesis, it will be particularly valuable to explore new approaches for the development of medical treatments targeting mitochondrial ERβ-mediated mitochondrial function and preventing apoptosis. © 2015 New York Academy of Sciences.

Structure-Directed and Tailored Diversity Synthetic Antibody Libraries Yield Novel Anti-EGFR Antagonists.

PubMed

Miersch, Shane; Maruthachalam, Bharathikumar Vellalore; Geyer, C Ronald; Sidhu, Sachdev S

2017-05-19

We tested whether grafting an interaction domain into the hypervariable loop of a combinatorial antibody library could promote targeting to a specific epitope. Formation of the epidermal growth factor receptor (EGFR) signaling heterodimer involves extensive contacts mediated by a "dimerization loop." We grafted the dimerization loop into the third hypervariable loop of a synthetic antigen-binding fragment (Fab) library and diversified other loops using a tailored diversity strategy. This structure-directed Fab library and a naı̈ve synthetic Fab library were used to select Fabs against EGFR. Both libraries yielded high affinity Fabs that bound to overlapping epitopes on cell-surface EGFR, inhibited receptor activation, and targeted epitopes distinct from those of cetuximab and panitumumab. Epitope mapping experiments revealed complex sites of interaction, comprised of domains I and II but not exclusively localized to the receptor dimerization loop. These results validate the grafting approach for designing Fab libraries and also underscore the versatility of naı̈ve synthetic libraries.

41 CFR 51-7.2 - Early involvement in private, State, and local activities requiring Federal approval.

Code of Federal Regulations, 2010 CFR

2010-07-01

... environment; (3) Consult with appropriate Federal, regional, State and local agencies and other potentially... private, State, and local activities requiring Federal approval. 51-7.2 Section 51-7.2 Public Contracts... involvement in private, State, and local activities requiring Federal approval. (a) 40 CFR 1501.2(d) requires...

41 CFR 51-7.2 - Early involvement in private, State, and local activities requiring Federal approval.

Code of Federal Regulations, 2011 CFR

2011-07-01

... environment; (3) Consult with appropriate Federal, regional, State and local agencies and other potentially... private, State, and local activities requiring Federal approval. 51-7.2 Section 51-7.2 Public Contracts... involvement in private, State, and local activities requiring Federal approval. (a) 40 CFR 1501.2(d) requires...

Spinal microglia are required for long-term maintenance of neuropathic pain.

PubMed

Echeverry, Stefania; Shi, Xiang Qun; Yang, Mu; Huang, Hao; Wu, YiChen; Lorenzo, Louis-Etienne; Perez-Sanchez, Jimena; Bonin, Robert P; De Koninck, Yves; Zhang, Ji

2017-09-01

While spinal microglia play a role in early stages of neuropathic pain etiology, whether they are useful targets to reverse chronic pain at late stages remains unknown. Here, we show that microglia activation in the spinal cord persists for >3 months following nerve injury in rodents, beyond involvement of proinflammatory cytokine and chemokine signalling. In this chronic phase, selective depletion of spinal microglia in male rats with the targeted immunotoxin Mac1-saporin and blockade of brain-derived neurotrophic factor-TrkB signalling with intrathecal TrkB Fc chimera, but not cytokine inhibition, almost completely reversed pain hypersensitivity. By contrast, local spinal administration of Mac1-saporin did not affect nociceptive withdrawal threshold in control animals nor did it affect the strength of afferent-evoked synaptic activity in the spinal dorsal horn in normal conditions. These findings show that the long-term, chronic phase of nerve injury-induced pain hypersensitivity is maintained by microglia-neuron interactions. The findings also effectively separate the central signalling pathways underlying the maintenance phase of the pathology from the early and peripheral inflammatory reactions to injury, pointing to different targets for the treatment of acute vs chronic injury-induced pain.

Neurostimulation to improve level of consciousness in patients with epilepsy.

PubMed

Gummadavelli, Abhijeet; Kundishora, Adam J; Willie, Jon T; Andrews, John P; Gerrard, Jason L; Spencer, Dennis D; Blumenfeld, Hal

2015-06-01

When drug-resistant epilepsy is poorly localized or surgical resection is contraindicated, current neurostimulation strategies such as deep brain stimulation and vagal nerve stimulation can palliate the frequency or severity of seizures. However, despite medical and neuromodulatory therapy, a significant proportion of patients continue to experience disabling seizures that impair awareness, causing disability and risking injury or sudden unexplained death. We propose a novel strategy in which neuromodulation is used not only to reduce seizures but also to ameliorate impaired consciousness when the patient is in the ictal and postictal states. Improving or preventing alterations in level of consciousness may have an effect on morbidity (e.g., accidents, drownings, falls), risk for death, and quality of life. Recent studies may have elucidated underlying networks and mechanisms of impaired consciousness and yield potential novel targets for neuromodulation. The feasibility, benefits, and pitfalls of potential deep brain stimulation targets are illustrated in human and animal studies involving minimally conscious/vegetative states, movement disorders, depth of anesthesia, sleep-wake regulation, and epilepsy. We review evidence that viable therapeutic targets for impaired consciousness associated with seizures may be provided by key nodes of the consciousness system in the brainstem reticular activating system, hypothalamus, basal ganglia, thalamus, and basal forebrain.

Multiple models guide strategies for agricultural nutrient reductions

USGS Publications Warehouse

Scavia, Donald; Kalcic, Margaret; Muenich, Rebecca Logsdon; Read, Jennifer; Aloysius, Noel; Bertani, Isabella; Boles, Chelsie; Confesor, Remegio; DePinto, Joseph; Gildow, Marie; Martin, Jay; Redder, Todd; Robertson, Dale M.; Sowa, Scott P.; Wang, Yu-Chen; Yen, Haw

2017-01-01

In response to degraded water quality, federal policy makers in the US and Canada called for a 40% reduction in phosphorus (P) loads to Lake Erie, and state and provincial policy makers in the Great Lakes region set a load-reduction target for the year 2025. Here, we configured five separate SWAT (US Department of Agriculture's Soil and Water Assessment Tool) models to assess load reduction strategies for the agriculturally dominated Maumee River watershed, the largest P source contributing to toxic algal blooms in Lake Erie. Although several potential pathways may achieve the target loads, our results show that any successful pathway will require large-scale implementation of multiple practices. For example, one successful pathway involved targeting 50% of row cropland that has the highest P loss in the watershed with a combination of three practices: subsurface application of P fertilizers, planting cereal rye as a winter cover crop, and installing buffer strips. Achieving these levels of implementation will require local, state/provincial, and federal agencies to collaborate with the private sector to set shared implementation goals and to demand innovation and honest assessments of water quality-related programs, policies, and partnerships.

Sumoylation of Rap1 mediates the recruitment of TFIID to promote transcription of ribosomal protein genes

PubMed Central

Chymkowitch, Pierre; Nguéa P, Aurélie; Aanes, Håvard; Koehler, Christian J.; Thiede, Bernd; Lorenz, Susanne; Meza-Zepeda, Leonardo A.; Klungland, Arne; Enserink, Jorrit M.

2015-01-01

Transcription factors are abundant Sumo targets, yet the global distribution of Sumo along the chromatin and its physiological relevance in transcription are poorly understood. Using Saccharomyces cerevisiae, we determined the genome-wide localization of Sumo along the chromatin. We discovered that Sumo-enriched genes are almost exclusively involved in translation, such as tRNA genes and ribosomal protein genes (RPGs). Genome-wide expression analysis showed that Sumo positively regulates their transcription. We also discovered that the Sumo consensus motif at RPG promoters is identical to the DNA binding motif of the transcription factor Rap1. We demonstrate that Rap1 is a molecular target of Sumo and that sumoylation of Rap1 is important for cell viability. Furthermore, Rap1 sumoylation promotes recruitment of the basal transcription machinery, and sumoylation of Rap1 cooperates with the target of rapamycin kinase complex 1 (TORC1) pathway to promote RPG transcription. Strikingly, our data reveal that sumoylation of Rap1 functions in a homeostatic feedback loop that sustains RPG transcription during translational stress. Taken together, Sumo regulates the cellular translational capacity by promoting transcription of tRNA genes and RPGs. PMID:25800674

Mycobacterium tuberculosis surface protein Rv0227c contains high activity binding peptides which inhibit cell invasion.

PubMed

Rodríguez, Diana Marcela; Ocampo, Marisol; Curtidor, Hernando; Vanegas, Magnolia; Patarroyo, Manuel Elkin; Patarroyo, Manuel Alfonso

2012-12-01

Mycobacterium tuberculosis surface proteins involved in target cell invasion may be identified as a strategy for developing subunit-based, chemically-synthesized vaccines. The Rv0227c protein was thus selected to assess its role in the invasion and infection of Mycobacterium tuberculosis target cells. Results revealed Rv0227c localization on mycobacterial surface by immunoelectron microscopy and Western blot. Receptor-ligand assays using 20-mer, non-overlapping peptides covering the complete Rv0227c protein sequence revealed three high activity binding peptides for U937 phagocytic cells and seven for A549 cells. Peptide 16944 significantly inhibited mycobacterial entry to both cell lines while 16943 and 16949 only managed to inhibit entrance to U937 cells and 16951 to A549 cells. The Jnet bioinformatics tool predicted secondary structure elements for the complete protein, agreeing with elements determined for such chemically-synthesized peptides. It was thus concluded that high activity binding peptides which were able to inhibit mycobacterial entry to target cells are of great importance when selecting peptide candidates for inclusion in an anti-tuberculosis vaccine. Copyright © 2012 Elsevier Inc. All rights reserved.

Rapid Processing of a Global Feature in the ON Visual Pathways of Behaving Monkeys.

PubMed

Huang, Jun; Yang, Yan; Zhou, Ke; Zhao, Xudong; Zhou, Quan; Zhu, Hong; Yang, Yingshan; Zhang, Chunming; Zhou, Yifeng; Zhou, Wu

2017-01-01

Visual objects are recognized by their features. Whereas, some features are based on simple components (i.e., local features, such as orientation of line segments), some features are based on the whole object (i.e., global features, such as an object having a hole in it). Over the past five decades, behavioral, physiological, anatomical, and computational studies have established a general model of vision, which starts from extracting local features in the lower visual pathways followed by a feature integration process that extracts global features in the higher visual pathways. This local-to-global model is successful in providing a unified account for a vast sets of perception experiments, but it fails to account for a set of experiments showing human visual systems' superior sensitivity to global features. Understanding the neural mechanisms underlying the "global-first" process will offer critical insights into new models of vision. The goal of the present study was to establish a non-human primate model of rapid processing of global features for elucidating the neural mechanisms underlying differential processing of global and local features. Monkeys were trained to make a saccade to a target in the black background, which was different from the distractors (white circle) in color (e.g., red circle target), local features (e.g., white square target), a global feature (e.g., white ring with a hole target) or their combinations (e.g., red square target). Contrary to the predictions of the prevailing local-to-global model, we found that (1) detecting a distinction or a change in the global feature was faster than detecting a distinction or a change in color or local features; (2) detecting a distinction in color was facilitated by a distinction in the global feature, but not in the local features; and (3) detecting the hole was interfered by the local features of the hole (e.g., white ring with a squared hole). These results suggest that monkey ON visual systems have a subsystem that is more sensitive to distinctions in the global feature than local features. They also provide the behavioral constraints for identifying the underlying neural substrates.

Addressing the social determinants of health: a case study from the Mitanin (community health worker) programme in India

PubMed Central

Schneider, Helen

2014-01-01

The Mitanin Programme, a government community health worker (CHW) programme, was started in Chhattisgarh State of India in 2002. The CHWs (Mitanins) have consistently adopted roles that go beyond health programme-specific interventions to embrace community mobilization and action on local priorities. The aim of this research was to document how and why the Mitanins have been able to act on the social determinants of health, describing the catalysts and processes involved and the enabling programmatic and organizational factors. A qualitative comparative case study of successful action by Mitanin was conducted in two ‘blocks’, purposefully selected as positive exemplars in two districts of Chhattisgarh. One case focused on malnutrition and the other on gender-based violence. Data collection involved 17 in-depth interviews and 10 group interviews with the full range of stakeholders in both blocks, including community members and programme team. Thematic analysis was done using a broad conceptual framework that was further refined. Action on social determinants involved raising awareness on rights, mobilizing women’s collectives, revitalizing local political structures and social action targeting both the community and government service providers. Through these processes, the Mitanins developed identities as agents of change and advocates for the community, both with respect to local cultural and gender norms and in ensuring accountability of service providers. The factors underpinning successful action on social determinants were identified as the significance of the original intent and vision of the programme, and how this was carried through into all aspects of programme design, the role of the Mitanins and their identification with village women, ongoing training and support, and the relative autonomy of the programme. Although the results are not narrowly generalizable and do not necessarily represent the situation of the Mitanin Programme as a whole, the explanatory framework may provide general lessons for programmes in similar contexts. PMID:25274643

Cluster formation in precompound nuclei in the time-dependent framework

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

Schuetrumpf, B.; Nazarewicz, W.

Background: Modern applications of nuclear time-dependent density functional theory (TDDFT) are often capable of providing quantitative description of heavy ion reactions. However, the structures of precompound (preequilibrium, prefission) states produced in heavy ion reactions are difficult to assess theoretically in TDDFT as the single-particle density alone is a weak indicator of shell structure and cluster states. Purpose: We employ the time-dependent nucleon localization function (NLF) to reveal the structure of precompound states in nuclear reactions involving light and medium-mass ions. We primarily focus on spin saturated systems with N = Z . Furthermore, we study reactions with oxygen and carbonmore » ions, for which some experimental evidence for α clustering in precompound states exists. Method: We utilize the symmetry-free TDDFT approach with the Skyrme energy density functional UNEDF1 and compute the time-dependent NLFs to describe 16O + 16O, 40Ca + 16O, 40Ca + 40Ca , and 16,18O + 12C collisions at energies above the Coulomb barrier. Results: We show that NLFs reveal a variety of time-dependent modes involving cluster structures. For instance, the 16O + 16O collision results in a vibrational mode of a quasimolecular α - 12 C - 12 C- α state. For heavier ions, a variety of cluster configurations are predicted. For the collision of 16,18O + 12C, we showed that the precompound system has a tendency to form α clusters. This result supports the experimental findings that the presence of cluster structures in the projectile and target nuclei gives rise to strong entrance channel effects and enhanced α emission. Conclusion: The time-dependent nucleon localization measure is a very good indicator of cluster structures in complex precompound states formed in heavy-ion fusion reactions. Finally, the localization reveals the presence of collective vibrations involving cluster structures, which dominate the initial dynamics of the fusing system.« less

Cluster formation in precompound nuclei in the time-dependent framework

DOE PAGES

Schuetrumpf, B.; Nazarewicz, W.

2017-12-15

Background: Modern applications of nuclear time-dependent density functional theory (TDDFT) are often capable of providing quantitative description of heavy ion reactions. However, the structures of precompound (preequilibrium, prefission) states produced in heavy ion reactions are difficult to assess theoretically in TDDFT as the single-particle density alone is a weak indicator of shell structure and cluster states. Purpose: We employ the time-dependent nucleon localization function (NLF) to reveal the structure of precompound states in nuclear reactions involving light and medium-mass ions. We primarily focus on spin saturated systems with N = Z . Furthermore, we study reactions with oxygen and carbonmore » ions, for which some experimental evidence for α clustering in precompound states exists. Method: We utilize the symmetry-free TDDFT approach with the Skyrme energy density functional UNEDF1 and compute the time-dependent NLFs to describe 16O + 16O, 40Ca + 16O, 40Ca + 40Ca , and 16,18O + 12C collisions at energies above the Coulomb barrier. Results: We show that NLFs reveal a variety of time-dependent modes involving cluster structures. For instance, the 16O + 16O collision results in a vibrational mode of a quasimolecular α - 12 C - 12 C- α state. For heavier ions, a variety of cluster configurations are predicted. For the collision of 16,18O + 12C, we showed that the precompound system has a tendency to form α clusters. This result supports the experimental findings that the presence of cluster structures in the projectile and target nuclei gives rise to strong entrance channel effects and enhanced α emission. Conclusion: The time-dependent nucleon localization measure is a very good indicator of cluster structures in complex precompound states formed in heavy-ion fusion reactions. Finally, the localization reveals the presence of collective vibrations involving cluster structures, which dominate the initial dynamics of the fusing system.« less

Cluster formation in precompound nuclei in the time-dependent framework

NASA Astrophysics Data System (ADS)

Schuetrumpf, B.; Nazarewicz, W.

2017-12-01

Background: Modern applications of nuclear time-dependent density functional theory (TDDFT) are often capable of providing quantitative description of heavy ion reactions. However, the structures of precompound (preequilibrium, prefission) states produced in heavy ion reactions are difficult to assess theoretically in TDDFT as the single-particle density alone is a weak indicator of shell structure and cluster states. Purpose: We employ the time-dependent nucleon localization function (NLF) to reveal the structure of precompound states in nuclear reactions involving light and medium-mass ions. We primarily focus on spin saturated systems with N =Z . Furthermore, we study reactions with oxygen and carbon ions, for which some experimental evidence for α clustering in precompound states exists. Method: We utilize the symmetry-free TDDFT approach with the Skyrme energy density functional UNEDF1 and compute the time-dependent NLFs to describe 16O + 16O,40Ca + 16O, 40Ca + 40Ca, and O,1816 + 12C collisions at energies above the Coulomb barrier. Results: We show that NLFs reveal a variety of time-dependent modes involving cluster structures. For instance, the 16O + 16O collision results in a vibrational mode of a quasimolecular α - 12C - 12C-α state. For heavier ions, a variety of cluster configurations are predicted. For the collision of O,1816 + 12C, we showed that the precompound system has a tendency to form α clusters. This result supports the experimental findings that the presence of cluster structures in the projectile and target nuclei gives rise to strong entrance channel effects and enhanced α emission. Conclusion: The time-dependent nucleon localization measure is a very good indicator of cluster structures in complex precompound states formed in heavy-ion fusion reactions. The localization reveals the presence of collective vibrations involving cluster structures, which dominate the initial dynamics of the fusing system.

Targeted Business Incentives and Local Labor Markets

ERIC Educational Resources Information Center

Freedman, Matthew

2013-01-01

This paper uses a regression discontinuity design to examine the effects of geographically targeted business incentives on local labor markets. Unlike elsewhere in the United States, enterprise zone (EZ) designations in Texas are determined in part by a cutoff rule based on census block group poverty rates. Exploiting this discontinuity as a…

Pivotal response treatment prompts a functional rewiring of the brain among individuals with autism spectrum disorder.

PubMed

Venkataraman, Archana; Yang, Daniel Y-J; Dvornek, Nicha; Staib, Lawrence H; Duncan, James S; Pelphrey, Kevin A; Ventola, Pamela

2016-09-28

Behavioral interventions for autism have gained prominence in recent years; however, the neural-systems-level targets of these interventions remain poorly understood. We use a novel Bayesian framework to extract network-based differences before and after a 16-week pivotal response treatment (PRT) regimen. Our results suggest that the functional changes induced by PRT localize to the posterior cingulate and are marked by a shift in connectivity from the orbitofrontal cortex to the occipital-temporal cortex. Our results illuminate a potential PRT-induced learning mechanism, whereby the neural circuits involved during social perception shift from sensory and attentional systems to higher-level object and face processing areas.

Pivotal Response Treatment Prompts a Functional Rewiring of the Brain amongst Individuals with Autism Spectrum Disorder

PubMed Central

Venkataraman, Archana; Yang, Daniel Y.-J.; Dvornek, Nicha; Staib, Lawrence H.; Duncan, James S.; Pelphrey, Kevin A.; Ventola, Pamela

2016-01-01

Behavioral interventions for autism have gained prominence in recent years; however, the neural-systems-level targets of these interventions remain poorly understood. We use a novel Bayesian framework to extract network-based differences before and after a 16-week Pivotal Response Treatment (PRT) regimen. Our results suggest that functional changes induced by PRT localize to the posterior cingulate and are marked by a shift in connectivity from the orbitofrontal cortex to the occipital temporal cortex. Our results illuminate a potential PRT-induced learning mechanism, whereby the neural circuits involved during social perception shift from sensory and attentional systems to higher-level object and face processing areas. PMID:27532879

Aggregatibacter actinomycetemcomitans Leukotoxin

PubMed Central

Kachlany, S.C.

2010-01-01

Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium that colonizes the human oral cavity and is the causative agent for localized aggressive periodontitis (LAP), an aggressive form of periodontal disease that occurs in adolescents. A. actinomycetemcomitans secretes a protein toxin, leukotoxin (LtxA), which helps the bacterium evade the host immune response during infection. LtxA is a membrane-active toxin that specifically targets white blood cells (WBCs). In this review, we discuss recent developments in this field, including the identification and characterization of genes and proteins involved in secretion, regulation of LtxA, biosynthesis, newly described activities of LtxA, and how LtxA may be used as a therapy for the treatment of diseases. PMID:20200418

Role of NH{sub 2}-terminal hydrophobic motif in the subcellular localization of ATP-binding cassette protein subfamily D: Common features in eukaryotic organisms

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

Lee, Asaka; Asahina, Kota; Okamoto, Takumi

Highlights: • ABCD proteins classifies based on with or without NH{sub 2}-terminal hydrophobic segment. • The ABCD proteins with the segment are targeted peroxisomes. • The ABCD proteins without the segment are targeted to the endoplasmic reticulum. • The role of the segment in organelle targeting is conserved in eukaryotic organisms. - Abstract: In mammals, four ATP-binding cassette (ABC) proteins belonging to subfamily D have been identified. ABCD1–3 possesses the NH{sub 2}-terminal hydrophobic region and are targeted to peroxisomes, while ABCD4 lacking the region is targeted to the endoplasmic reticulum (ER). Based on hydropathy plot analysis, we found that severalmore » eukaryotes have ABCD protein homologs lacking the NH{sub 2}-terminal hydrophobic segment (H0 motif). To investigate whether the role of the NH{sub 2}-terminal H0 motif in subcellular localization is conserved across species, we expressed ABCD proteins from several species (metazoan, plant and fungi) in fusion with GFP in CHO cells and examined their subcellular localization. ABCD proteins possessing the NH{sub 2}-terminal H0 motif were localized to peroxisomes, while ABCD proteins lacking this region lost this capacity. In addition, the deletion of the NH{sub 2}-terminal H0 motif of ABCD protein resulted in their localization to the ER. These results suggest that the role of the NH{sub 2}-terminal H0 motif in organelle targeting is widely conserved in living organisms.« less

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

Li, Mi; University of Chinese Academy of Sciences, Beijing 100049; Liu, Lianqing, E-mail: lqliu@sia.cn

Highlights: •Nanoscale cellular ultra-structures of macrophages were observed. •The binding affinities of FcγRs were measured directly on macrophages. •The nanoscale distributions of FcγRs were mapped on macrophages. -- Abstract: Fc gamma receptors (FcγR), widely expressed on effector cells (e.g., NK cells, macrophages), play an important role in clinical cancer immunotherapy. The binding of FcγRs to the Fc portions of antibodies that are attached to the target cells can activate the antibody-dependent cell-mediated cytotoxicity (ADCC) killing mechanism which leads to the lysis of target cells. In this work, we used atomic force microscopy (AFM) to observe the cellular ultra-structures and measuremore » the biophysical properties (affinity and distribution) of FcγRs on single macrophages in aqueous environments. AFM imaging was used to obtain the topographies of macrophages, revealing the nanoscale cellular fine structures. For molecular interaction recognition, antibody molecules were attached onto AFM tips via a heterobifunctional polyethylene glycol (PEG) crosslinker. With AFM single-molecule force spectroscopy, the binding affinities of FcγRs were quantitatively measured on single macrophages. Adhesion force mapping method was used to localize the FcγRs, revealing the nanoscale distribution of FcγRs on local areas of macrophages. The experimental results can improve our understanding of FcγRs on macrophages; the established approach will facilitate further research on physiological activities involved in antibody-based immunotherapy.« less

Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein

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

Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya

2015-08-15

The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH proteinmore » in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target. - Highlights: • A yeast two-hybrid system (MbY2H) detected BAP31 as a binder of RSV SH protein. • Transfected SH and BAP31 co-localize in lung epithelial cells. • Endogenous BAP31 is pulled down by RSV SH protein. • BAP31 endodomain interacts with the N-terminal α-helix of SH protein in micelles. • This interaction is proposed to be a potential drug target.« less

The ocular albinism type 1 (OA1) GPCR is ubiquitinated and its traffic requires endosomal sorting complex responsible for transport (ESCRT) function

PubMed Central

Giordano, Francesca; Simoes, Sabrina; Raposo, Graça

2011-01-01

The function of signaling receptors is tightly controlled by their intracellular trafficking. One major regulatory mechanism within the endo-lysosomal system required for receptor localization and down-regulation is protein modification by ubiquitination and downstream interactions with the endosomal sorting complex responsible for transport (ESCRT) machinery. Whether and how these mechanisms operate to regulate endosomal sorting of mammalian G protein-coupled receptors (GPCRs) remains unclear. Here, we explore the involvement of ubiquitin and ESCRTs in the trafficking of OA1, a pigment cell-specific GPCR, target of mutations in Ocular Albinism type 1, which localizes intracellularly to melanosomes to regulate their biogenesis. Using biochemical and morphological methods in combination with overexpression and inactivation approaches we show that OA1 is ubiquitinated and that its intracellular sorting and down-regulation requires functional ESCRT components. Depletion or overexpression of subunits of ESCRT-0, -I, and -III markedly inhibits OA1 degradation with concomitant retention within the modified endosomal system. Our data further show that OA1 ubiquitination is uniquely required for targeting to the intralumenal vesicles of multivesicular endosomes, thereby regulating the balance between down-regulation and delivery to melanosomes. This study highlights the role of ubiquitination and the ESCRT machinery in the intracellular trafficking of mammalian GPCRs and has implications for the physiopathology of ocular albinism type 1. PMID:21730137

Greasy tactics in the plant-pathogen molecular arms race.

PubMed

Boyle, Patrick C; Martin, Gregory B

2015-03-01

The modification of proteins by the attachment of fatty acids is a targeting tactic involved in mechanisms of both plant immunity and bacterial pathogenesis. The plant plasma membrane (PM) is a key battleground in the war against disease-causing microbes. This membrane is armed with an array of sensor proteins that function as a surveillance system to detect invading pathogens. Several of these sensor proteins are directed to the plasma membrane through the covalent addition of fatty acids, a process termed fatty acylation. Phytopathogens secrete effector proteins into the plant cell to subvert these surveillance mechanisms, rendering the host susceptible to infection. The targeting of effectors to specific locales within plant cells, particularly the internal face of the host PM, is critical for their virulence function. Several bacterial effectors hijack the host fatty acylation machinery to be modified and directed to this contested locale. To find and fight these fatty acylated effectors the plant leverages lipid-modified intracellular sensors. This review provides examples featuring how fatty acylation is a battle tactic used by both combatants in the molecular arms race between plants and pathogens. Also highlighted is the exploitation of a specific form of host-mediated fatty acid modification, which appears to be exclusively employed by phytopathogenic effector proteins. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Targeted proteome analysis of single-gene deletion strains of Saccharomyces cerevisiae lacking enzymes in the central carbon metabolism.

PubMed

Matsuda, Fumio; Kinoshita, Syohei; Nishino, Shunsuke; Tomita, Atsumi; Shimizu, Hiroshi

2017-01-01

Central carbon metabolism is controlled by modulating the protein abundance profiles of enzymes that maintain the essential systems in living organisms. In this study, metabolic adaptation mechanisms in the model organism Saccharomyces cerevisiae were investigated by direct determination of enzyme abundance levels in 30 wild type and mutant strains. We performed a targeted proteome analysis using S. cerevisiae strains that lack genes encoding the enzymes responsible for central carbon metabolism. Our analysis revealed that at least 30% of the observed variations in enzyme abundance levels could be explained by global regulatory mechanisms. A enzyme-enzyme co-abundance analysis revealed that the abundances of enzyme proteins involved in the trehalose metabolism and glycolysis changed in a coordinated manner under the control of the transcription factors for global regulation. The remaining variations were derived from local mechanisms such as a mutant-specific increase in the abundances of remote enzymes. The proteome data also suggested that, although the functional compensation of the deficient enzyme was attained by using more resources for protein biosynthesis, available resources for the biosynthesis of the enzymes responsible for central metabolism were not abundant in S. cerevisiae cells. These results showed that global and local regulation of enzyme abundance levels shape central carbon metabolism in S. cerevisiae by using a limited resource for protein biosynthesis.

Patterns of Nucleotide Diversity at Photoperiod Related Genes in Norway Spruce [Picea abies (L.) Karst.

PubMed Central

Källman, Thomas; De Mita, Stéphane; Larsson, Hanna; Gyllenstrand, Niclas; Heuertz, Myriam; Parducci, Laura; Suyama, Yoshihisa; Lagercrantz, Ulf; Lascoux, Martin

2014-01-01

The ability of plants to track seasonal changes is largely dependent on genes assigned to the photoperiod pathway, and variation in those genes is thereby important for adaptation to local day length conditions. Extensive physiological data in several temperate conifer species suggest that populations are adapted to local light conditions, but data on the genes underlying this adaptation are more limited. Here we present nucleotide diversity data from 19 genes putatively involved in photoperiodic response in Norway spruce (Picea abies). Based on similarity to model plants the genes were grouped into three categories according to their presumed position in the photoperiod pathway: photoreceptors, circadian clock genes, and downstream targets. An HKA (Hudson, Kreitman and Aquade) test showed a significant excess of diversity at photoreceptor genes, but no departure from neutrality at circadian genes and downstream targets. Departures from neutrality were also tested with Tajima's D and Fay and Wu's H statistics under three demographic scenarios: the standard neutral model, a population expansion model, and a more complex population split model. Only one gene, the circadian clock gene PaPRR3 with a highly positive Tajima's D value, deviates significantly from all tested demographic scenarios. As the PaPRR3 gene harbours multiple non-synonymous variants it appears as an excellent candidate gene for control of photoperiod response in Norway spruce. PMID:24810273

Patterns of nucleotide diversity at photoperiod related genes in Norway spruce [Picea abies (L.) Karst].

PubMed

Källman, Thomas; De Mita, Stéphane; Larsson, Hanna; Gyllenstrand, Niclas; Heuertz, Myriam; Parducci, Laura; Suyama, Yoshihisa; Lagercrantz, Ulf; Lascoux, Martin

2014-01-01

The ability of plants to track seasonal changes is largely dependent on genes assigned to the photoperiod pathway, and variation in those genes is thereby important for adaptation to local day length conditions. Extensive physiological data in several temperate conifer species suggest that populations are adapted to local light conditions, but data on the genes underlying this adaptation are more limited. Here we present nucleotide diversity data from 19 genes putatively involved in photoperiodic response in Norway spruce (Picea abies). Based on similarity to model plants the genes were grouped into three categories according to their presumed position in the photoperiod pathway: photoreceptors, circadian clock genes, and downstream targets. An HKA (Hudson, Kreitman and Aquade) test showed a significant excess of diversity at photoreceptor genes, but no departure from neutrality at circadian genes and downstream targets. Departures from neutrality were also tested with Tajima's D and Fay and Wu's H statistics under three demographic scenarios: the standard neutral model, a population expansion model, and a more complex population split model. Only one gene, the circadian clock gene PaPRR3 with a highly positive Tajima's D value, deviates significantly from all tested demographic scenarios. As the PaPRR3 gene harbours multiple non-synonymous variants it appears as an excellent candidate gene for control of photoperiod response in Norway spruce.

Vaginal dose de-escalation in image guided adaptive brachytherapy for locally advanced cervical cancer.

PubMed

Mohamed, Sandy; Lindegaard, Jacob Christian; de Leeuw, Astrid A C; Jürgenliemk-Schulz, Ina; Kirchheiner, Kathrin; Kirisits, Christian; Pötter, Richard; Tanderup, Kari

2016-09-01

Vaginal stenosis is a major problem following radiotherapy in cervical cancer. We investigated a new dose planning strategy for vaginal dose de-escalation (VDD). Fifty consecutive locally advanced cervical cancer patients without lower or middle vaginal involvement at diagnosis from 3 institutions were analysed. External beam radiotherapy was combined with MRI-guided brachytherapy. VDD was obtained by decreasing dwell times in ovoid/ring and increasing dwell times in tandem/needles. The aim was to maintain the target dose (D90 of HR-CTV⩾85Gy EQD2) while reducing the dose to the surface of the vagina to <140% of the physical fractional brachytherapy dose corresponding to a total EQD2 of 85Gy. The mean vaginal loading (ovoid/ring) was reduced from 51% to 33% of the total loading with VDD, which significantly reduced the dose to the vaginal dose points (p<0.001) without compromising the target dose. The dose to the ICRU recto-vaginal point was reduced by a mean of 4±4Gy EQD2 (p<0.001), while doses to bladder and rectum (D 2cm 3 ) were reduced by 2±2Gy and 3±2Gy, respectively (p<0.001). VDD significantly reduces dose to the upper vagina which is expected to result in reduction of vaginal stenosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Potential of activatable FAP-targeting immunoliposomes in intraoperative imaging of spontaneous metastases.

PubMed

Tansi, Felista L; Rüger, Ronny; Böhm, Claudia; Kontermann, Roland E; Teichgraeber, Ulf K; Fahr, Alfred; Hilger, Ingrid

2016-05-01

Despite intensive research and medical advances met, metastatic disease remains the most common cause of death in cancer patients. This results from late diagnosis, poor therapeutic response and undetected micrometastases and tumor margins during surgery. One approach to overcome these challenges involves fluorescence imaging, which exploits the properties of fluorescent probes for diagnostic detection of molecular structures at the onset of transformation and for intraoperative detection of metastases and tumor margins in real time. Considering these benefits, many contrast agents suitable for fluorescence imaging have been reported. However, most reports only demonstrate the detection of primary tumors and not the detection of metastases or their application in models of image-guided surgery. In this work, we demonstrate the influence of fibroblast activation protein (FAP) on the metastatic potential of fibrosarcoma cells and elucidate the efficacy of activatable FAP-targeting immunoliposomes (FAP-IL) for image-guided detection of the spontaneous metastases in mice models. Furthermore, we characterized the biodistribution and cellular localization of the liposomal fluorescent components in mice organs and traced their excretion over time in urine and feces. Taken together, activatable FAP-IL enhances intraoperative imaging of metastases. Their high accumulation in metastases, subsequent localization in the bile canaliculi and liver kupffer cells and suitable excretion in feces substantiates their potency as contrast agents for intraoperative imaging. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

The macrophage as a Trojan horse for antisense oligonucleotide delivery.

PubMed

Novak, James S; Jaiswal, Jyoti K; Partridge, Terence A

2018-06-04

The gateway to the promised land of gene therapy has been obstructed by the problem of accurate and efficient delivery of therapeutic agents to their target sites. This is true both of constructs designed to directly express proteins of interest, and of constructs or agents aimed at modifying the expression of endogenous genes. It is recognized as a major impediment to the effective application of genetic therapies currently or incipiently in clinical trial. Our recent study has examined the mechanism underlying delivery of therapeutic antisense oligonucleotides (ASO) for treating the devastating muscle disease Duchenne muscular dystrophy [1]. Working to understand the mode of ASO delivery in DMD, we discovered that inflammatory cells act as a depot that locally stores the intravenously administered ASO. This local depot of ASO then becomes available to the muscle fibres by way of satellite cells that deliver their cargo by fusion with damaged fibres during muscle repair. This finding points to a potentially novel strategy for systemic ASO delivery, involving the use of the inflammatory cell as a Trojan horse. Such an approach would have the benefit not only of enhancing tissue-specific delivery of ASO, but also of reducing the impact of their rapid clearance from the circulation. Here, we discuss the issues surrounding ASO-mediated exon skipping efficacy for DMD, and outline research aimed at improving targeted ASO delivery.

Remodeling of ribosomal genes in somatic cells by Xenopus egg extract

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

Ostrup, Olga, E-mail: osvarcova@gmail.com; Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo; Norwegian Center for Stem Cell Research, Oslo

Highlights: {yields} Xenopus egg extract remodels nuclei and alter cell growth characteristics. {yields} Ribosomal genes are reprogrammed within 6 h after extract exposure. {yields} rDNA reprogramming involves promoter targeting of SNF2H remodeling complex. {yields} Xenopus egg extract does not initiate stress-related response in somatic cells. {yields} Aza-cytidine elicits a stress-induced response in reprogrammed cells. -- Abstract: Extracts from Xenopus eggs can reprogram gene expression in somatic nuclei, however little is known about the earliest processes associated with the switch in the transcriptional program. We show here that an early reprogramming event is the remodeling of ribosomal chromatin and gene expression.more » This occurs within hours of extract treatment and is distinct from a stress response. Egg extract elicits remodeling of the nuclear envelope, chromatin and nucleolus. Nucleolar remodeling involves a rapid and stable decrease in ribosomal gene transcription, and promoter targeting of the nucleolar remodeling complex component SNF2H without affecting occupancy of the transcription factor UBF and the stress silencers SUV39H1 and SIRT1. During this process, nucleolar localization of UBF and SIRT1 is not altered. On contrary, azacytidine pre-treatment has an adverse effect on rDNA remodeling induced by extract and elicits a stress-type nuclear response. Thus, an early event of Xenopus egg extract-mediated nuclear reprogramming is the remodeling of ribosomal genes involving nucleolar remodeling complex. Condition-specific and rapid silencing of ribosomal genes may serve as a sensitive marker for evaluation of various reprogramming methods.« less

Herpes simplex virus 2-induced activation in vaginal cells involves Toll-like receptors 2 and 9 and DNA sensors DAI and IFI16.

PubMed

Triantafilou, Kathy; Eryilmazlar, Dilan; Triantafilou, Martha

2014-02-01

The pathway by which herpes simplex virus 2 (HSV2) triggers the innate immune system in the urogenital system has not as yet been fully elucidated. In this study, we aimed to determine which pattern recognition receptors (PRRs) recognize HSV2 in primary vaginal epithelial cells. Once we deciphered the receptors involved, we aimed to target them to immunomodulate innate responses as a prophylactic or therapeutic intervention for early HSV2 infection. To determine which PRRs are involved, receptor silencing as well as confocal microscopy was utilized. For immunomodulation, PRR agonists were utilized to induce a strong, local response to limit the infection, and we used 2 quantitative methods, flow cytometry and plaque assays, to determine their effect on HSV2 replication. Our results show that HSV2 is detected by a plethora of PRRs: Toll-like receptors (TLR) 2 as well as deoxyribonucleic acid (DNA) sensors TLR9, DNA-dependent activator of interferon regulatory factors, and to a lesser extent interferon-inducible 16, which trigger cytokine secretion to protect the host. Using PRR agonists, such as lipoproteins, CpG DNA, and cyclic dinucleotides, we could significantly limit HSV2 replication. Different PRRs are strategically placed in different cell locations to detect virus invasion. Use of agonists that target and activate these PRRs appeared to be effective in preventing primary HSV2 infection in vaginal cells and could provide new insights in defense against HSV2 urogenital infections. Copyright © 2014 Mosby, Inc. All rights reserved.

Use of social networking sites in online sex crimes against minors: an examination of national incidence and means of utilization.

PubMed

Mitchell, Kimberly J; Finkelhor, David; Jones, Lisa M; Wolak, Janis

2010-08-01

To describe the variety of ways social networking sites (SNSs) are used to facilitate the sexual exploitation of youth, as well as identify victim, offender, and case differences between arrests, with and without a SNS nexus. Mail surveys were sent to a nationally representative sample of over 2,500 local, state, and federal law enforcement agencies in the United States. Follow-up detailed telephone interviews were conducted for 1,051 individual cases ending in an arrest for Internet-related sex crimes against minors in 2006. In the United States, an estimated 2,322 arrests (unweighted n = 291) for Internet sex crimes against minors involved SNSs in some way, including an estimated 503 arrests (unweighted n = 93) in cases involving identified victims and the use of SNSs by offenders (the majority of arrests involved undercover operations undertaken by police). SNSs were used to initiate sexual relationships, to provide a means of communication between victim and offender, to access information about the victim, to disseminate information or pictures about the victim, and to get in touch with victim's friends. A considerable number of arrests for Internet sex crimes against minors have a SNS nexus to them. The findings support previous claims that prevention messages should target youth behaviors rather than specific online locations where these crimes occur. In targeting behaviors, youth can take this knowledge with them online, regardless of whether they are using SNSs, chat rooms, or instant messaging. (c) 2010 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

An inhibitory gate for state transition in cortex

PubMed Central

Zucca, Stefano; D’Urso, Giulia; Pasquale, Valentina; Vecchia, Dania; Pica, Giuseppe; Bovetti, Serena; Moretti, Claudio; Varani, Stefano; Molano-Mazón, Manuel; Chiappalone, Michela; Panzeri, Stefano; Fellin, Tommaso

2017-01-01

Large scale transitions between active (up) and silent (down) states during quiet wakefulness or NREM sleep regulate fundamental cortical functions and are known to involve both excitatory and inhibitory cells. However, if and how inhibition regulates these activity transitions is unclear. Using fluorescence-targeted electrophysiological recording and cell-specific optogenetic manipulation in both anesthetized and non-anesthetized mice, we found that two major classes of interneurons, the parvalbumin and the somatostatin positive cells, tightly control both up-to-down and down-to-up state transitions. Inhibitory regulation of state transition was observed under both natural and optogenetically-evoked conditions. Moreover, perturbative optogenetic experiments revealed that the inhibitory control of state transition was interneuron-type specific. Finally, local manipulation of small ensembles of interneurons affected cortical populations millimetres away from the modulated region. Together, these results demonstrate that inhibition potently gates transitions between cortical activity states, and reveal the cellular mechanisms by which local inhibitory microcircuits regulate state transitions at the mesoscale. DOI: http://dx.doi.org/10.7554/eLife.26177.001 PMID:28509666

Oral health promotion and education messages in Live.Learn.Laugh. projects.

PubMed

Horn, Virginie; Phantumvanit, Prathip

2014-10-01

The FDI-Unilever Live.Learn.Laugh. phase 2 partnership involved dissemination of the key oral health message of encouraging 'twice-daily toothbrushing with fluoride toothpaste' and education of people worldwide by FDI, National Dental Associations, the Unilever Oral Care global team and local brands. The dissemination and education process used different methodologies, each targeting specific groups, namely: mother and child (Project option A); schoolchildren (Project option B); dentists and patients (Project option C); and specific communities (Project option D). Altogether, the partnership implemented 29 projects in 27 countries. These consisted of educational interventions, evaluations including (in some cases) clinical assessment, together with communication activities at both global and local levels, to increase the reach of the message to a broader population worldwide. The phase 2 experience reveals the strength of such a public-private partnership approach in tackling global oral health issues by creating synergies between partners and optimising the promotion and education process. © 2014 FDI World Dental Federation.

City Governments and Aging in Place: Community Design, Transportation and Housing Innovation Adoption

PubMed Central

Lehning, Amanda J.

2012-01-01

Purpose of the study: To examine the characteristics associated with city government adoption of community design, housing, and transportation innovations that could benefit older adults. Design and methods: A mixed-methods study with quantitative data collected via online surveys from 62 city planners combined with qualitative data collected via telephone interviews with a subsample of 18 survey respondents. Results: Results indicate that advocacy is an effective strategy to encourage city government adoption of these innovations. Percent of the population with a disability was positively associated, whereas percent of the population aged 65 and older was not associated or negatively associated, with innovation adoption in the regression models. Qualitative interviews suggest that younger individuals with disabilities are more active in local advocacy efforts. Implications: Results suggest that successful advocacy strategies for local government adoption include facilitating the involvement of older residents, targeting key decision makers within government, emphasizing the financial benefits to the city, and focusing on cities whose aging residents are vulnerable to disease and disability. PMID:21900505

Lessons Learned From Transitioning PEPFAR Track 1.0 Care and Treatment Programs: Case Studies in Financial Management Capacity Building in Zambia and Botswana.

PubMed

Kuehn, Chuck; Tidwell, George; Vhugen, Jann; Sharma, Anjali

2015-01-01

In 2008, the United States government mandated transition of internationally managed HIV care and treatment programs to local country ownership. Three case studies illustrate the US Health Resources Services Administration's fiscal assessment and technical assistance (TA) processes to strengthen local organizations' capabilities to absorb and manage United States government funding. Review of initial, TA and follow-up reports reveal that the 1 Botswanan and 2 Zambian organizations closed 10 of 17 financial capacity gaps, with Health Resources Services Administration assisting on 2. Zambian organizations requested and absorbed targeted TA on the basis of the consultant's desk review, their finance staff revised fiscal policies and procedures, and accordingly trained other staff. In Botswana, delays in integrating recommendations necessitated on-site TA for knowledge building and role modeling. Organizational maturity may explain differences in responsiveness, ownership, and required TA approaches. Clarifying expectations of capacity building, funding agreement, and nonmonetary donor involvement can help new organizations determine and act on intervening actions.

Pressure/temperature fluid cell apparatus for the neutron powder diffractometer instrument: probing atomic structure in situ.

PubMed

Wang, Hsiu-Wen; Fanelli, Victor R; Reiche, Helmut M; Larson, Eric; Taylor, Mark A; Xu, Hongwu; Zhu, Jinlong; Siewenie, Joan; Page, Katharine

2014-12-01

This contribution describes a new local structure compatible gas/liquid cell apparatus for probing disordered materials at high pressures and variable temperatures in the Neutron Powder Diffraction instrument at the Lujan Neutron Scattering Center, Los Alamos National Laboratory. The new sample environment offers choices for sample canister thickness and canister material type. Finite element modeling is utilized to establish maximum allowable working pressures of 414 MPa at 15 K and 121 MPa at 600 K. High quality atomic pair distribution function data extraction and modeling have been demonstrated for a calibration standard (Si powder) and for supercritical and subcritical CO2 measurements. The new sample environment was designed to specifically target experimental studies of the local atomic structures involved in geologic CO2 sequestration, but will be equally applicable to a wide variety of energy applications, including sorption of fluids on nano/meso-porous solids, clathrate hydrate formation, catalysis, carbon capture, and H2 and natural gas uptake/storage.

Social Work Field Training for the Community: A Student Self-Directed Approach in the Environmental Domain in Jordan

PubMed Central

Al-Makhamreh, Sahar; Alnabulsi, Hana; Asfour, Hana

2016-01-01

This article outlines innovative field training methods that foster the abilities of undergraduate social work students so that they are able to empower the local community and raise awareness of environmental issues. In this study, students were engaged in a local community assessment that sought to understand their views on environmental and community impacts of the Synchrotron-Light for Experimental Science and Applications in the Middle East (SESAME) Project on the lives of the host village's residents. A students' self-directed approach was applied for the fieldwork out of which interventions were developed ( Garrison, 1997). Quantitative data were gathered by eighteen students through a survey of 361 questionnaires targeting Allan society. In addition to students' field notes, pre and post focus groups were used to collect qualitative information. Study findings highlighted the effectiveness of students' self-directed projects in cultivating culturally competent practices; ensuring sustainable development; and providing evidence-based knowledge on social work practice involving environmental issues. PMID:27559202

Social Work Field Training for the Community: A Student Self-Directed Approach in the Environmental Domain in Jordan.

PubMed

Al-Makhamreh, Sahar; Alnabulsi, Hana; Asfour, Hana

2016-06-01

This article outlines innovative field training methods that foster the abilities of undergraduate social work students so that they are able to empower the local community and raise awareness of environmental issues. In this study, students were engaged in a local community assessment that sought to understand their views on environmental and community impacts of the Synchrotron-Light for Experimental Science and Applications in the Middle East (SESAME) Project on the lives of the host village's residents. A students' self-directed approach was applied for the fieldwork out of which interventions were developed ( Garrison, 1997). Quantitative data were gathered by eighteen students through a survey of 361 questionnaires targeting Allan society. In addition to students' field notes, pre and post focus groups were used to collect qualitative information. Study findings highlighted the effectiveness of students' self-directed projects in cultivating culturally competent practices; ensuring sustainable development; and providing evidence-based knowledge on social work practice involving environmental issues.

Nanomaterial-Enabled Neural Stimulation

PubMed Central

Wang, Yongchen; Guo, Liang

2016-01-01

Neural stimulation is a critical technique in treating neurological diseases and investigating brain functions. Traditional electrical stimulation uses electrodes to directly create intervening electric fields in the immediate vicinity of neural tissues. Second-generation stimulation techniques directly use light, magnetic fields or ultrasound in a non-contact manner. An emerging generation of non- or minimally invasive neural stimulation techniques is enabled by nanotechnology to achieve a high spatial resolution and cell-type specificity. In these techniques, a nanomaterial converts a remotely transmitted primary stimulus such as a light, magnetic or ultrasonic signal to a localized secondary stimulus such as an electric field or heat to stimulate neurons. The ease of surface modification and bio-conjugation of nanomaterials facilitates cell-type-specific targeting, designated placement and highly localized membrane activation. This review focuses on nanomaterial-enabled neural stimulation techniques primarily involving opto-electric, opto-thermal, magneto-electric, magneto-thermal and acousto-electric transduction mechanisms. Stimulation techniques based on other possible transduction schemes and general consideration for these emerging neurotechnologies are also discussed. PMID:27013938

Plant nutrition: root transporters on the move.

PubMed

Zelazny, Enric; Vert, Grégory

2014-10-01

Nutrient and water uptake from the soil is essential for plant growth and development. In the root, absorption and radial transport of nutrients and water toward the vascular tissues is achieved by a battery of specialized transporters and channels. Modulating the amount and the localization of these membrane transport proteins appears as a way to drive their activity and is essential to maintain nutrient homeostasis in plants. This control first involves the delivery of newly synthesized proteins to the plasma membrane by establishing check points along the secretory pathway, especially during the export from the endoplasmic reticulum. Plasma membrane-localized transport proteins are internalized through endocytosis followed by recycling to the cell surface or targeting to the vacuole for degradation, hence constituting another layer of control. These intricate mechanisms are often regulated by nutrient availability, stresses, and endogenous cues, allowing plants to rapidly adjust to their environment and adapt their development. © 2014 American Society of Plant Biologists. All Rights Reserved.

Community based ecological restoration of peatland in Central Mongolia for climate change mitigation and adaptation

NASA Astrophysics Data System (ADS)

Minayeva, Tatiana; Chultem, Dugarjav; Grootjans, Ab; Yamkhin, Jambaljav; Sirin, Andrey; Suvorov, Gennady; Batdorj, Oyunbileg; Tsamba, Batdorj

2017-04-01

Peatlands cover almost 2 % of Mongolia. They play crucial role in regulation of key natural processes in ecosystems and provide unique resources to maintain traditional way of life and livelihoods of herders. During the last decades, Mongolian peatlands severely degraded both due to the climate related events and due to overgrazing. The peat degradation causes significant losses of carbon store, GHG emissions and is followed by changes in water balance and water composition. The issue arises if such a type of ecosystems as peatlands could be a subject for ecosystem restoration in this arid and subhumid climate. Could it be considered as measure for climate change mitigation and adaptation? With funding opportunities from the Asian Development Bank a pilot project for peatland restoration had been launched in 2016 in Khashaat soum, Arkhangai aimag in Central Mongolia. The pilot aimed to merge local interests of herders with global targets of climate change mitigation. The following questions are addressed: what are the losses of natural functions and ecosystem services of peatland; what are expectations and demands of local communities and incentives for their involvement; how should and could look the target ecosystem; what are the technical solutions in order to achieve the target ecosystem characteristics; and what are the parameters for monitoring to assess the success of the project? The comprehensive baseline study addressed both natural and social aspects. The conclusions are: most of peat in the study area had been mineralised and has turned to organic rich soil with carbon content between 20 to 40 %, the key sources of water - small springs - are partly destroyed by cattle; the permafrost disappeared in this area and could not be the subject for restoration; local herders understand the value of peatland as water source and had carried out some voluntary activities for water storage and regulation such as dam construction; nevertheless there is no understanding of functional particularities of peatland ecosystem and restoration efforts are not effective. Following the baseline study the concept for ecosystem restoration project had been developed. The approach was to merge community based solution with scientific approaches. Restoration in subhumid conditions should avoid creation of open water surfaces, like channels or reservoirs, and deal with integrative ecosystem management. The restoration concept involved fencing of springs, preventing erosion and enhancing water accumulation in soil by cascades of small dams and other small scale ecological solutions. At the same time to meet the needs of local herders, it was decided to repair the dam, constructed by herders, even if it has little value for peatland restoration. The engineering design is now ready and will be implemented next months. The last part of the pilot is monitoring. The parameters determined in the baseline study are included in monitoring program to help to evaluate: carbon sequestration rate, GHG emission reduction, water retention, soil humidity, pasture productivity, social integrity and impact on livelihoods.

An Improved Aerial Target Localization Method with a Single Vector Sensor

PubMed Central

Zhao, Anbang; Bi, Xuejie; Hui, Juan; Zeng, Caigao; Ma, Lin

2017-01-01

This paper focuses on the problems encountered in the actual data processing with the use of the existing aerial target localization methods, analyzes the causes of the problems, and proposes an improved algorithm. Through the processing of the sea experiment data, it is found that the existing algorithms have higher requirements for the accuracy of the angle estimation. The improved algorithm reduces the requirements of the angle estimation accuracy and obtains the robust estimation results. The closest distance matching estimation algorithm and the horizontal distance estimation compensation algorithm are proposed. The smoothing effect of the data after being post-processed by using the forward and backward two-direction double-filtering method has been improved, thus the initial stage data can be filtered, so that the filtering results retain more useful information. In this paper, the aerial target height measurement methods are studied, the estimation results of the aerial target are given, so as to realize the three-dimensional localization of the aerial target and increase the understanding of the underwater platform to the aerial target, so that the underwater platform has better mobility and concealment. PMID:29135956

Investigating the Human Dimension of Unprecedented Global Climate Change in northeastern Siberia, Russia: Understandings, Perceptions and Responses

NASA Astrophysics Data System (ADS)

Crate, S.

2009-12-01

An urgent challenge of the 21st century is to investigate understandings, perceptions and responses of populations confronting the local effects of global climate change. This paper describes the most recent results of one such project working with rural native Viliui Sakha communities, Turkic-speaking horse & cattle breeders in northeastern Siberia, Russia. The research questions are: 1) What local effects of global climate change are Viliui Sakha communities observing, how are Viliui Sakha perceiving these changes and how are the changes affecting both their subsistence survival and their cultural orientations? 2) What local knowledge exists about past climate perturbations and how does that knowledge influence contemporary adaptation to global climate change? 3) How can anecdotal (local) knowledge and regional scientific knowledge about the local effects of global climate change be integrated to enhance both local adaptive responses and policy efforts? The four-village, three-year study is a collaborative effort involving the active participation of the targeted communities, field assistants, native specialists, an in-country research team and an international collaborator. The project is founded on the PI’s 20 years of ongoing research and work with rural Viliui Sakha communities and on her fluency in both the Sakha and Russian languages. A central focus of this project is the integration of local and scientific knowledges. We are documenting local knowledge on the community, elder and archival levels. We are collaborating with scientists in Yakutsk for regional scientific data. Our project team has just returned from the second summer of field work and this presentation will cover the project results to date. Hayfields are inundated with water.

Molecular pathways and targets in prostate cancer

PubMed Central

Shtivelman, Emma; Beer, Tomasz M.; Evans, Christopher P.

2014-01-01

Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease. The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors. It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways. Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies. The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer. This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge. PMID:25277175

Implementing local projects to reduce the stigma of mental illness.

PubMed

Warner, Richard

2008-01-01

This editorial describes strategies used and the lessons learned in implementing two local anti-stigma projects. The WPA Programme to Reduce Stigma and Discrimination Because of Schizophrenia established projects to fight stigma in 20 countries, using social-marketing techniques to enhance their effectiveness. First steps at each site were to establish an action committee and conduct a survey of perceived stigma. Based on survey results, the action committees selected a few homogeneous and accessible target groups, such as employers, and criminal justice personnel. Messages and media were selected, tested, and refined. Guidelines are provided for setting up a consumer (service-user) speakers' bureau and for establishing a media-watch organization, which can lobby news and entertainment media to exclude negative portrayals of people with mental illness. Improvements in knowledge about mental illness were effected in high school students and criminal justice personnel. Positive changes in attitude towards people with mental illness were achieved with high school students, but were more difficult to achieve with police officers. Local antistigma projects can be effective in reducing stigma and relatively inexpensive. The involvement of consumers is important in working with police officers. Project organizers should be on the lookout for useful changes that can become permanent.

Cell Penetrating Capacity and Internalization Mechanisms Used by the Synthetic Peptide CIGB-552 and Its Relationship with Tumor Cell Line Sensitivity.

PubMed

Astrada, Soledad; Fernández Massó, Julio Raúl; Vallespí, Maribel G; Bollati-Fogolín, Mariela

2018-03-30

CIGB-552 is a twenty-amino-acid novel synthetic peptide that has proven to be effective in reducing tumor size and increasing lifespan in tumor-bearing mice. Such capability is conferred by its cell-penetrating peptide character, which allows it to enter cells and elicit a pro-apoptotic effect through its major mediator, COMMD1 protein. Cell-penetrating peptides are able to use different internalization mechanisms, such as endocytosis or direct transduction through the plasma membrane. Although CIGB-552 cytotoxicity has been evaluated in several non-tumor- and tumor-derived cell lines, no data regarding the relationship between cell line sensitivity, cell penetrating capacity, the internalization mechanisms involved, COMMD1 expression levels, or its subcellular localization has yet been produced. Here, we present the results obtained from a comparative analysis of CIGB-552 sensitivity, internalization capacity and the mechanisms involved in three human tumor-derived cell lines from different origins: mammary gland, colon and lung (MCF-7, HT-29 and H460, respectively). Furthermore, cell surface markers relevant for internalization processes such as phosphatidylserine, as well as CIGB-552 target COMMD1 expression/localization, were also evaluated. We found that both endocytosis and transduction are involved in CIGB-552 internalization in the three cell lines evaluated. However, CIGB-552 incorporation efficiency and contribution of each mechanism is cell-line dependent. Finally, sensitivity was directly correlated with high internalization capacity in those cell lines where endocytosis had a major contribution on CIGB-552 internalization.