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…

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…

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

Mechanisms involved in the transport of mercuric ions in target tissues

PubMed Central

Bridges, Christy C.; Zalups, Rudolfs K.

2016-01-01

Mercury exists in the environment in various forms, all of which pose a risk to human health. Despite guidelines regulating the industrial release of mercury into the environment, humans continue to be exposed regularly to various forms of this metal via inhalation or ingestion. Following exposure, mercuric ions are taken up by and accumulate in numerous organs, including brain, intestine, kidney, liver, and placenta. In order to understand the toxicological effects of exposure to mercury, a thorough understanding of the mechanisms that facilitate entry of mercuric ions into target cells must first be obtained. A number of mechanisms for the transport of mercuric ions into target cells and organs have been proposed in recent years. However, the ability of these mechanisms to transport mercuric ions and the regulatory features of these carriers have not been characterized completely. The purpose of this review is to summarize the current findings related to the mechanisms that may be involved in the transport of inorganic and organic forms of mercury in target tissues and organs. This review will describe mechanisms known to be involved in the transport of mercury and will also propose additional mechanisms that may potentially be involved in the transport of mercuric ions into target cells. PMID:27422290

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.

Targeted manipulation of leaf form via local growth repression.

PubMed

Malinowski, Robert; Kasprzewska, Ania; Fleming, Andrew J

2011-06-01

A classical view is that leaf shape is the result of local promotion of growth linked to cell proliferation. However, an alternative hypothesis is that leaf form is the result of local repression of growth in an otherwise growing system. Here we show that leaf form can indeed be manipulated in a directed fashion by local repression of growth. We show that targeting expression of an inhibitor of a cyclin-dependent kinase (KRP1) to the sinus area of developing leaves of Arabidopsis leads to local growth repression and the formation of organs with extreme lobing, including generation of leaflet-like organs. Directing KRP1 expression to other regions of the leaf using an miRNA target sequence tagging approach also leads to predictable novel leaf forms, and repression of growth in the leaf margin blocks the outgrowth of lobes, leading to a smoother perimeter. In addition, we show that decreased growth around the perimeter and across the leaf abaxial surface leads to a change in 3D form, as predicted by mechanical models of leaf growth. Our analysis provides experimental evidence that local repression of growth influences leaf shape, suggesting that it could be part of the mechanism of morphogenesis in plants in the context of an otherwise growing system. © 2011 The Authors. The Plant Journal © 2011 Blackwell Publishing Ltd.

Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies.

PubMed

Ruiz Salas, Veronica; Alegre, Marta; Garcés, Joan Ramón; Puig, Lluis

2014-06-01

The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development.

Contribution of self-motion perception to acoustic target localization.

PubMed

Pettorossi, V E; Brosch, M; Panichi, R; Botti, F; Grassi, S; Troiani, D

2005-05-01

The findings of this study suggest that acoustic spatial perception during head movement is achieved by the vestibular system, which is responsible for the correct dynamic of acoustic target pursuit. The ability to localize sounds in space during whole-body rotation relies on the auditory localization system, which recognizes the position of sound in a head-related frame, and on the sensory systems, namely the vestibular system, which perceive head and body movement. The aim of this study was to analyse the contribution of head motion cues to the spatial representation of acoustic targets in humans. Healthy subjects standing on a rotating platform in the dark were asked to pursue with a laser pointer an acoustic target which was horizontally rotated while the body was kept stationary or maintained stationary while the whole body was rotated. The contribution of head motion to the spatial acoustic representation could be inferred by comparing the gains and phases of the pursuit in the two experimental conditions when the frequency was varied. During acoustic target rotation there was a reduction in the gain and an increase in the phase lag, while during whole-body rotations the gain tended to increase and the phase remained constant. The different contributions of the vestibular and acoustic systems were confirmed by analysing the acoustic pursuit during asymmetric body rotation. In this particular condition, in which self-motion perception gradually diminished, an increasing delay in target pursuit was observed.

Contraceptive Vaccines Targeting Factors Involved in Establishment of Pregnancy

PubMed Central

Lemons, Angela R.; Naz, Rajesh K.

2011-01-01

Problem Current methods of contraception lack specificity and are accompanied with serious side effects. A more specific method of contraception is needed. Contraceptive vaccines can provide most, if not all, the desired characteristics of an ideal contraceptive. Approach This article reviews several factors involved in the establishment of pregnancy, focusing on those that are essential for successful implantation. Factors that are both essential and pregnancy-specific can provide potential targets for contraception. Conclusion Using database search, 76 factors (cytokines/chemokines/growth factors/others) were identified that are involved in various steps of the establishment of pregnancy. Among these factors, three, namely chorionic gonadotropin (CG), leukemia inhibitory factor (LIF), and preimplantation factor (PIF), are found to be unique and exciting molecules. Human CG is a well-known pregnancy-specific protein that has undergone phase I and phase II clinical trials, in women, as a contraceptive vaccine with encouraging results. LIF and PIF are pregnancy-specific and essential for successful implantation. These molecules are intriguing and may provide viable targets for immunocontraception. A multiepitope vaccine combining factors/antigens involved in various steps of the fertilization cascade and pregnancy establishment, may provide a highly immunogenic and efficacious modality for contraception in humans. PMID:21481058

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

Systemic involvement in localized scleroderma/morphea.

PubMed

Gorkiewicz-Petkow, Anna; Kalinska-Bienias, Agnieszka

2015-01-01

Localized scleroderma (LoSc), also known as morphea, is a rare fibrosing disorder of the skin and underlying tissues. Sclerosis is mainly limited to the skin, but subcutaneous tissue, fascia, and underlying muscles and bone may also be involved. In some cases, systemic manifestation with visceral abnormalities may occur. Several publications have focused on significant aspects of LoSc: genetics, immunity, epidemiology, scoring systems, and unification of classifications. Clinical studies featuring large cohorts with the disease published by various international study groups have been of great value in furthering the diagnostic and therapeutic management of LoSc. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

A Modified Magnetic Gradient Contraction Based Method for Ferromagnetic Target Localization

PubMed Central

Wang, Chen; Zhang, Xiaojuan; Qu, Xiaodong; Pan, Xiao; Fang, Guangyou; Chen, Luzhao

2016-01-01

The Scalar Triangulation and Ranging (STAR) method, which is based upon the unique properties of magnetic gradient contraction, is a high real-time ferromagnetic target localization method. Only one measurement point is required in the STAR method and it is not sensitive to changes in sensing platform orientation. However, the localization accuracy of the method is limited by the asphericity errors and the inaccurate value of position leads to larger errors in the estimation of magnetic moment. To improve the localization accuracy, a modified STAR method is proposed. In the proposed method, the asphericity errors of the traditional STAR method are compensated with an iterative algorithm. The proposed method has a fast convergence rate which meets the requirement of high real-time localization. Simulations and field experiments have been done to evaluate the performance of the proposed method. The results indicate that target parameters estimated by the modified STAR method are more accurate than the traditional STAR method. PMID:27999322

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.

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.

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.

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

36 CFR 219.14 - Involvement of State and local governments.

Code of Federal Regulations, 2011 CFR

2011-07-01

... OF AGRICULTURE PLANNING National Forest System Land and Resource Management Planning Collaborative Planning for Sustainability § 219.14 Involvement of State and local governments. The responsible official... coordination of resource management plans or programs. ...

36 CFR 219.14 - Involvement of State and local governments.

Code of Federal Regulations, 2010 CFR

2010-07-01

... OF AGRICULTURE PLANNING National Forest System Land and Resource Management Planning Collaborative Planning for Sustainability § 219.14 Involvement of State and local governments. The responsible official... coordination of resource management plans or programs. ...

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.

LuciPHOr: Algorithm for Phosphorylation Site Localization with False Localization Rate Estimation Using Modified Target-Decoy Approach*

PubMed Central

Fermin, Damian; Walmsley, Scott J.; Gingras, Anne-Claude; Choi, Hyungwon; Nesvizhskii, Alexey I.

2013-01-01

The localization of phosphorylation sites in peptide sequences is a challenging problem in large-scale phosphoproteomics analysis. The intense neutral loss peaks and the coexistence of multiple serine/threonine and/or tyrosine residues are limiting factors for objectively scoring site patterns across thousands of peptides. Various computational approaches for phosphorylation site localization have been proposed, including Ascore, Mascot Delta score, and ProteinProspector, yet few address direct estimation of the false localization rate (FLR) in each experiment. Here we propose LuciPHOr, a modified target-decoy-based approach that uses mass accuracy and peak intensities for site localization scoring and FLR estimation. Accurate estimation of the FLR is a difficult task at the individual-site level because the degree of uncertainty in localization varies significantly across different peptides. LuciPHOr carries out simultaneous localization on all candidate sites in each peptide and estimates the FLR based on the target-decoy framework, where decoy phosphopeptides generated by placing artificial phosphorylation(s) on non-candidate residues compete with the non-decoy phosphopeptides. LuciPHOr also reports approximate site-level confidence scores for all candidate sites as a means to localize additional sites from multiphosphorylated peptides in which localization can be partially achieved. Unlike the existing tools, LuciPHOr is compatible with any search engine output processed through the Trans-Proteomic Pipeline. We evaluated the performance of LuciPHOr in terms of the sensitivity and accuracy of FLR estimates using two synthetic phosphopeptide libraries and a phosphoproteomic dataset generated from complex mouse brain samples. PMID:23918812

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

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.

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.

Distributed MIMO Radar for Imaging and High Resolution Target Localization

DTIC Science & Technology

2012-02-02

Reduction in Distributed MIMO Radar with Multi-Carrier OFDM Signals Carl Georgeson 11/23/2010 Approved 17 • 10-019 Algorithms for Target Location and...28-2012 Final Report 04/15/2009 - 11/30/2011 Distributed MIMO Radar for Imaging and High Resolution Target Localization FA9550-09-1-0303 Alexander M...error for the general case of MIMO radar with multiple waveforms with non-coherent and coherent observations; (b) finds a closed-form solution for the

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

Student involvement in wellness policies: a study of Pennsylvania local education agencies.

PubMed

Jomaa, Lamis H; McDonnell, Elaine; Weirich, Elaine; Hartman, Terryl; Jensen, Leif; Probart, Claudia

2010-01-01

Explore student-involvement goals in local wellness policies (LWPs) of local education agencies (LEAs) in Pennsylvania (PA) and investigate associations with LEA characteristics. An observational study that helped examine student-involvement goals. Public PA LEAs. LWPs submitted by 539 PA public LEAs. Six student-involvement goals analyzed as dependent variables. Correlations between demographic and policy characteristics of LEAs and student-involvement goals were measured. Policies developed by LEAs were abstracted and analyzed. Logistic regression models were developed to analyze relationships between student-involvement goals and the demographic and policy characteristics of LEAs. Majority of LEAs included policy goals that address student involvement in an array of activities related to wellness policy, food service, and role modeling. Regression models showed that LEAs with comprehensive and strong policies were most likely to include student-involvement goals regardless of LEA location, enrollment, or socioeconomic status of students. Student engagement in school nutrition policies has been shown to increase student acceptance in an array of health-related areas and is therefore promising in the area of obesity prevention. Comprehensiveness and rigor of LWPs were strongly correlated with the inclusion of student-involvement goals on LWPs. The upcoming reauthorization of the Child Nutrition programs in 2010 creates a good opportunity to address student involvement in LWPs. Copyright © 2010 Society for Nutrition Education. Published by Elsevier Inc. All rights reserved.

Targeted therapy for localized non-small-cell lung cancer: a review

PubMed Central

Paleiron, Nicolas; Bylicki, Olivier; André, Michel; Rivière, Emilie; Grassin, Frederic; Robinet, Gilles; Chouaïd, Christos

2016-01-01

Targeted therapies have markedly improved the management of patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy in localized NSCLC is less well established. The aim of this review is to analyze trials of targeted therapies in localized NSCLC. In patients with wild-type EGFR, tyrosine kinase inhibitors have shown no efficacy in Phase III trials. Few data are available for EGFR-mutated localized NSCLC, as routine biological profiling is not recommended. Available studies are small, often retrospectives, and/or conducted in a single-center making it difficult to draw firm conclusions. Ongoing prospective Phase III trials are comparing adjuvant tyrosine kinase inhibitor administration versus adjuvant chemotherapy. By analogy with the indication of bevacizumab in advanced NSCLC, use of antiangiogenic agents in the perioperative setting is currently restricted to nonsquamous NSCLC. Several trials of adjuvant or neoadjuvant bevacizumab are planned or ongoing, but for the moment there is no evidence of efficacy. Data on perioperative use of biomarkers in early-stage NSCLC come mainly from small, retrospective, uncontrolled studies. Assessment of customized adjuvant or neoadjuvant therapy in localized NSCLC (with or without oncogenic driver mutations) is a major challenge. PMID:27462164

Systematic study of target localization for bioluminescence tomography guided radiation therapy

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

Yu, Jingjing; Zhang, Bin; Reyes, Juvenal

Purpose: To overcome the limitation of CT/cone-beam CT (CBCT) in guiding radiation for soft tissue targets, the authors developed a spectrally resolved bioluminescence tomography (BLT) system for the small animal radiation research platform. The authors systematically assessed the performance of the BLT system in terms of target localization and the ability to resolve two neighboring sources in simulations, tissue-mimicking phantom, and in vivo environments. Methods: Multispectral measurements acquired in a single projection were used for the BLT reconstruction. The incomplete variables truncated conjugate gradient algorithm with an iterative permissible region shrinking strategy was employed as the optimization scheme to reconstructmore » source distributions. Simulation studies were conducted for single spherical sources with sizes from 0.5 to 3 mm radius at depth of 3–12 mm. The same configuration was also applied for the double source simulation with source separations varying from 3 to 9 mm. Experiments were performed in a standalone BLT/CBCT system. Two self-illuminated sources with 3 and 4.7 mm separations placed inside a tissue-mimicking phantom were chosen as the test cases. Live mice implanted with single-source at 6 and 9 mm depth, two sources at 3 and 5 mm separation at depth of 5 mm, or three sources in the abdomen were also used to illustrate the localization capability of the BLT system for multiple targets in vivo. Results: For simulation study, approximate 1 mm accuracy can be achieved at localizing center of mass (CoM) for single-source and grouped CoM for double source cases. For the case of 1.5 mm radius source, a common tumor size used in preclinical study, their simulation shows that for all the source separations considered, except for the 3 mm separation at 9 and 12 mm depth, the two neighboring sources can be resolved at depths from 3 to 12 mm. Phantom experiments illustrated that 2D bioluminescence imaging failed to distinguish two

Systematic study of target localization for bioluminescence tomography guided radiation therapy

PubMed Central

Yu, Jingjing; Zhang, Bin; Iordachita, Iulian I.; Reyes, Juvenal; Lu, Zhihao; Brock, Malcolm V.; Patterson, Michael S.; Wong, John W.

2016-01-01

Purpose: To overcome the limitation of CT/cone-beam CT (CBCT) in guiding radiation for soft tissue targets, the authors developed a spectrally resolved bioluminescence tomography (BLT) system for the small animal radiation research platform. The authors systematically assessed the performance of the BLT system in terms of target localization and the ability to resolve two neighboring sources in simulations, tissue-mimicking phantom, and in vivo environments. Methods: Multispectral measurements acquired in a single projection were used for the BLT reconstruction. The incomplete variables truncated conjugate gradient algorithm with an iterative permissible region shrinking strategy was employed as the optimization scheme to reconstruct source distributions. Simulation studies were conducted for single spherical sources with sizes from 0.5 to 3 mm radius at depth of 3–12 mm. The same configuration was also applied for the double source simulation with source separations varying from 3 to 9 mm. Experiments were performed in a standalone BLT/CBCT system. Two self-illuminated sources with 3 and 4.7 mm separations placed inside a tissue-mimicking phantom were chosen as the test cases. Live mice implanted with single-source at 6 and 9 mm depth, two sources at 3 and 5 mm separation at depth of 5 mm, or three sources in the abdomen were also used to illustrate the localization capability of the BLT system for multiple targets in vivo. Results: For simulation study, approximate 1 mm accuracy can be achieved at localizing center of mass (CoM) for single-source and grouped CoM for double source cases. For the case of 1.5 mm radius source, a common tumor size used in preclinical study, their simulation shows that for all the source separations considered, except for the 3 mm separation at 9 and 12 mm depth, the two neighboring sources can be resolved at depths from 3 to 12 mm. Phantom experiments illustrated that 2D bioluminescence imaging failed to distinguish two sources

Systemic sclerosis and localized scleroderma--current concepts and novel targets for therapy.

PubMed

Distler, Oliver; Cozzio, Antonio

2016-01-01

Systemic sclerosis (SSc) is a chronic autoimmune disease with a high morbidity and mortality. Skin and organ fibrosis are key manifestations of SSc, for which no generally accepted therapy is available. Thus, there is a high unmet need for novel anti-fibrotic therapeutic strategies in SSc. At the same time, important progress has been made in the identification and characterization of potential molecular targets in fibrotic diseases over the recent years. In this review, we have selected four targeted therapies, which are tested in clinical trials in SSc, for in depths discussion of their preclinical characterization. Soluble guanylate cyclase (sGC) stimulators such as riociguat might target both vascular remodeling and tissue fibrosis. Blockade of interleukin-6 might be particularly promising for early inflammatory stages of SSc. Inhibition of serotonin receptor 2b signaling links platelet activation to tissue fibrosis. Targeting simultaneously multiple key molecules with the multityrosine kinase-inhibitor nintedanib might be a promising approach in complex fibrotic diseases such as SSc, in which many partially independent pathways are activated. Herein, we also give a state of the art overview of the current classification, clinical presentation, diagnostic approach, and treatment options of localized scleroderma. Finally, we discuss whether the novel targeted therapies currently tested in SSc could be used for localized scleroderma.

[Local involvement of the optic nerve by acute lymphoblastic leukemia].

PubMed

Bernardczyk-Meller, Jadwiga; Stefańska, Katarzyna

2005-01-01

The leucemias quite commonly involve the eyes and adnexa. In some cases it causes visual complants. Both, the anterior chamber of the eye and the posterior portion of the globe may sites of acute or chronic leukemia and leucemic relapse. We report an unique case of a 14 years old leucemic patient who suffered visual loss and papilloedema, due to a unilateral local involvement within optic nerve, during second relapse of acute lymphocytic leuemia. In spite of typical treatment of main disease, the boy had died. The authors present typical ophthalmic features of the leucemia, too.

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.

Effects of adaptation of vestibulo-ocular reflex function on manual target localization

NASA Technical Reports Server (NTRS)

Bloomberg, J. J.; Merkle, L. A.; Barry, S. R.; Huebner, W. P.; Cohen, H. S.; Mueller, S. A.; Fordice, J.

2000-01-01

The goal of the present study was to determine if adaptive modulation of vestibulo-ocular reflex (VOR) function is associated with commensurate alterations in manual target localization. To measure the effects of adapted VOR on manual responses we developed the Vestibular-Contingent Pointing Test (VCP). In the VCP test, subjects pointed to a remembered target following passive whole body rotation in the dark. In the first experiment, subjects performed VCP before and after wearing 0.5X minifying lenses that adaptively attenuate horizontal VOR gain. Results showed that adaptive reduction in horizontal VOR gain was accompanied by a commensurate change in VCP performance. In the second experiment, bilaterally labyrinthine deficient (LD) subjects were tested to confirm that vestibular cues were central to the spatial coding of both eye and hand movements during VCP. LD subjects performed significantly worse than normal subjects. These results demonstrate that adaptive change in VOR can lead to alterations in manual target localization.

Registration of MRI to intraoperative radiographs for target localization in spinal interventions

NASA Astrophysics Data System (ADS)

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

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. 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. 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

Image-guided ex-vivo targeting accuracy using a laparoscopic tissue localization system

NASA Astrophysics Data System (ADS)

Bieszczad, Jerry; Friets, Eric; Knaus, Darin; Rauth, Thomas; Herline, Alan; Miga, Michael; Galloway, Robert; Kynor, David

2007-03-01

In image-guided surgery, discrete fiducials are used to determine a spatial registration between the location of surgical tools in the operating theater and the location of targeted subsurface lesions and critical anatomic features depicted in preoperative tomographic image data. However, the lack of readily localized anatomic landmarks has greatly hindered the use of image-guided surgery in minimally invasive abdominal procedures. To address these needs, we have previously described a laser-based system for localization of internal surface anatomy using conventional laparoscopes. During a procedure, this system generates a digitized, three-dimensional representation of visible anatomic surfaces in the abdominal cavity. This paper presents the results of an experiment utilizing an ex-vivo bovine liver to assess subsurface targeting accuracy achieved using our system. During the experiment, several radiopaque targets were inserted into the liver parenchyma. The location of each target was recorded using an optically-tracked insertion probe. The liver surface was digitized using our system, and registered with the liver surface extracted from post-procedure CT images. This surface-based registration was then used to transform the position of the inserted targets into the CT image volume. The target registration error (TRE) achieved using our surface-based registration (given a suitable registration algorithm initialization) was 2.4 mm +/- 1.0 mm. A comparable TRE (2.6 mm +/- 1.7 mm) was obtained using a registration based on traditional fiducial markers placed on the surface of the same liver. These results indicate the potential of fiducial-free, surface-to-surface registration for image-guided lesion targeting in minimally invasive abdominal surgery.

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

On Target Localization Using Combined RSS and AoA Measurements

PubMed Central

Beko, Marko; Dinis, Rui

2018-01-01

This work revises existing solutions for a problem of target localization in wireless sensor networks (WSNs), utilizing integrated measurements, namely received signal strength (RSS) and angle of arrival (AoA). The problem of RSS/AoA-based target localization became very popular in the research community recently, owing to its great applicability potential and relatively low implementation cost. Therefore, here, a comprehensive study of the state-of-the-art (SoA) solutions and their detailed analysis is presented. The beginning of this work starts by considering the SoA approaches based on convex relaxation techniques (more computationally complex in general), and it goes through other (less computationally complex) approaches, as well, such as the ones based on the generalized trust region sub-problems framework and linear least squares. Furthermore, a detailed analysis of the computational complexity of each solution is reviewed. Furthermore, an extensive set of simulation results is presented. Finally, the main conclusions are summarized, and a set of future aspects and trends that might be interesting for future research in this area is identified. PMID:29671832

Prediction of margin involvement and local recurrence after skin-sparing and simple mastectomy.

PubMed

Al-Himdani, S; Timbrell, S; Tan, K T; Morris, J; Bundred, N J

2016-07-01

Skin-sparing mastectomy (SSM) facilitates immediate breast reconstruction. We investigated locoregional recurrence rates after SSM compared with simple mastectomy and the factors predicting oncological failure. Patients with early breast cancer that underwent mastectomy between 2000 and 2005 at a single institution were studied to ascertain local and systemic recurrence rates between groups. Kaplan-Meier curves and log-rank test were used to evaluate disease-free survival. Patients (n = 577) underwent simple mastectomy (80%) or SSM (20%). Median follow up was 80 months. Patients undergoing SSM were of younger average age, less often had involved lymph nodes (22% vs 44%, p < 0.001), more often had DCIS present (79% vs 53%, p < 0.001) and involved margins (29% vs 15%, p = 0.001). Involved surgical margins were associated with large size (p = 0.001). The 8-year local recurrence (LR) rates were 7.9% for SSM and 5% for simple mastectomy respectively (p = 0.35). Predictors of locoregional recurrence were lymph node involvement (HR 8.0, for >4 nodes, p < 0.001) and involved surgical margins (HR 3.3, p = 0.002). In node negative patients, SSM was a predictor of locoregional recurrence (HR 4.8 [1.1, 19.9], p = 0.033). Delayed reconstruction is more appropriate for node positive early breast cancer after post-mastectomy radiotherapy. Re-excision of involved margins is essential to prevent local recurrence after mastectomy. Copyright © 2016 Elsevier Ltd, BASO ~ the Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

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...

Intraoperative Radiation Therapy Reduces Local Recurrence Rates in Patients With Microscopically Involved Circumferential Resection Margins After Resection of Locally Advanced Rectal Cancer

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

Alberda, Wijnand J.; Verhoef, Cornelis; Nuyttens, Joost J.

Purpose: Intraoperative radiation therapy (IORT) is advocated by some for patients with locally advanced rectal cancer (LARC) who have involved or narrow circumferential resection margins (CRM) after rectal surgery. This study evaluates the potentially beneficial effect of IORT on local control. Methods and Materials: All surgically treated patients with LARC treated in a tertiary referral center between 1996 and 2012 were analyzed retrospectively. The outcome in patients treated with IORT with a clear but narrow CRM (≤2 mm) or a microscopically involved CRM was compared with the outcome in patients who were not treated with IORT. Results: A total of 409 patients underwent resectionmore » of LARC, and 95 patients (23%) had a CRM ≤ 2 mm. Four patients were excluded from further analysis because of a macroscopically involved resection margin. In 43 patients with clear but narrow CRMs, there was no difference in the cumulative 5-year local recurrence-free survival of patients treated with (n=21) or without (n=22) IORT (70% vs 79%, P=.63). In 48 patients with a microscopically involved CRM, there was a significant difference in the cumulative 5-year local recurrence-free survival in favor of the patients treated with IORT (n=31) compared with patients treated without IORT (n=17) (84 vs 41%, P=.01). Multivariable analysis confirmed that IORT was independently associated with a decreased local recurrence rate (hazard ratio 0.24, 95% confidence interval 0.07-0.86). There was no significant difference in complication rate of patients treated with or without IORT (65% vs 52%, P=.18) Conclusion: The current study suggests that IORT reduces local recurrence rates in patients with LARC with a microscopically involved CRM.« less

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

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…

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.

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.

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.

Subcellular localization and vacuolar targeting of sorbitol dehydrogenase in apple seed.

PubMed

Wang, Xiu-Ling; Hu, Zi-Ying; You, Chun-Xiang; Kong, Xiu-Zhen; Shi, Xiao-Pu

2013-09-01

Sorbitol is the primary photosynthate and translocated carbohydrate in fruit trees of the Rosaceae family. NAD(+)-dependent sorbitol dehydrogenase (NAD-SDH, EC 1.1.1.14), which mainly catalyzes the oxidation of sorbitol to fructose, plays a key role in regulating sink strength in apple. In this study, we found that apple NAD-SDH was ubiquitously distributed in epidermis, parenchyma, and vascular bundle in developing cotyledon. NAD-SDH was localized in the cytosol, the membranes of endoplasmic reticulum and vesicles, and the vacuolar lumen in the cotyledon at the middle stage of seed development. In contrast, NAD-SDH was mainly distributed in the protein storage vacuoles in cotyledon at the late stage of seed development. Sequence analysis revealed there is a putative signal peptide (SP), also being predicated to be a transmembrane domain, in the middle of proteins of apple NAD-SDH isoforms. To investigate whether the putative internal SP functions in the vacuolar targeting of NAD-SDH, we analyzed the localization of the SP-deletion mutants of MdSDH5 and MdSDH6 (two NAD-SDH isoforms in apple) by the transient expression system in Arabidopsis protoplasts. MdSDH5 and MdSDH6 were not localized in the vacuoles after their SPs were deleted, suggesting the internal SP functions in the vacuolar targeting of apple NAD-SDH. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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.

A methodology to link national and local information for spatial targeting of ammonia mitigation efforts

NASA Astrophysics Data System (ADS)

Carnell, E. J.; Misselbrook, T. H.; Dore, A. J.; Sutton, M. A.; Dragosits, U.

2017-09-01

The effects of atmospheric nitrogen (N) deposition are evident in terrestrial ecosystems worldwide, with eutrophication and acidification leading to significant changes in species composition. Substantial reductions in N deposition from nitrogen oxides emissions have been achieved in recent decades. By contrast, ammonia (NH3) emissions from agriculture have not decreased substantially and are typically highly spatially variable, making efficient mitigation challenging. One solution is to target NH3 mitigation measures spatially in source landscapes to maximize the benefits for nature conservation. The paper develops an approach to link national scale data and detailed local data to help identify suitable measures for spatial targeting of local sources near designated Special Areas of Conservation (SACs). The methodology combines high-resolution national data on emissions, deposition and source attribution with local data on agricultural management and site conditions. Application of the methodology for the full set of 240 SACs in England found that agriculture contributes ∼45 % of total N deposition. Activities associated with cattle farming represented 54 % of agricultural NH3 emissions within 2 km of the SACs, making them a major contributor to local N deposition, followed by mineral fertiliser application (21 %). Incorporation of local information on agricultural management practices at seven example SACs provided the means to correct outcomes compared with national-scale emission factors. The outcomes show how national scale datasets can provide information on N deposition threats at landscape to national scales, while local-scale information helps to understand the feasibility of mitigation measures, including the impact of detailed spatial targeting on N deposition rates to designated sites.

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...

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

The effect of types of banner ad, Web localization, and customer involvement on Internet users' attitudes.

PubMed

Chen, Jengchung Victor; Ross, William H; Yen, David C; Akhapon, Lerdsuwankij

2009-02-01

In this study, three characteristics of Web sites were varied: types of banner ad, Web localization, and involvement in purchasing a product. The dependent variable was attitude toward the site. In laboratory experiments conducted in Thailand and Taiwan, participants browsed versions of a Web site containing different types of banner ads and products. As a within-participants factor, each participant browsed both a standardized English-language Web site and a localized Web site. Results showed that animated (rather than static) banner ads, localized versions (rather than a standardized version) of Web sites, and high (rather than low) product involvement led to favorable attitudes toward the site.

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.

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.

A comparative modeling and molecular docking study on Mycobacterium tuberculosis targets involved in peptidoglycan biosynthesis.

PubMed

Fakhar, Zeynab; Naiker, Suhashni; Alves, Claudio N; Govender, Thavendran; Maguire, Glenn E M; Lameira, Jeronimo; Lamichhane, Gyanu; Kruger, Hendrik G; Honarparvar, Bahareh

2016-11-01

An alarming rise of multidrug-resistant Mycobacterium tuberculosis strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in M. tuberculosis are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 M. tuberculosis strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected M. tuberculosis targets involved in peptidoglycan biosynthesis.

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

An Efficient Estimator for Moving Target Localization Using Multi-Station Dual-Frequency Radars.

PubMed

Huang, Jiyan; Zhang, Ying; Luo, Shan

2017-12-15

Localization of a moving target in a dual-frequency radars system has now gained considerable attention. The noncoherent localization approach based on a least squares (LS) estimator has been addressed in the literature. Compared with the LS method, a novel localization method based on a two-step weighted least squares estimator is proposed to increase positioning accuracy for a multi-station dual-frequency radars system in this paper. The effects of signal noise ratio and the number of samples on the performance of range estimation are also analyzed in the paper. Furthermore, both the theoretical variance and Cramer-Rao lower bound (CRLB) are derived. The simulation results verified the proposed method.

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

S3 targets monitoring with an electron gun

NASA Astrophysics Data System (ADS)

Kallunkathariyil, J.; Stodel, Ch.; Marry, C.; Frémont, G.; Bastin, B.; Piot, J.; Clément, E.; Le Moal, S.; Morel, V.; Thomas, J.-C.; Kamalou, O.; Spitaëls, C.; Savajols, H.; Vostinar, M.; Pellemoine, F.; Mittig, W.

2018-05-01

The monitoring of targets under irradiation was investigated using a 20 keV electron beam. An integrated and automated electron beam deflection was developed allowing a monitoring over the whole surface of target materials. Thus, local defects could be identified on-line during an experiment performed at GANIL involving different materials irradiated with a focused krypton beam at 10.5 MeV/u. Performances of this target monitoring system are presented in this paper.

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

PubMed

Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R; Redmond, T Michael; Boye, Sanford L; Hauswirth, William W; Ding, Xi-Qin

2016-12-01

Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 -/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

An Efficient Estimator for Moving Target Localization Using Multi-Station Dual-Frequency Radars

PubMed Central

Zhang, Ying; Luo, Shan

2017-01-01

Localization of a moving target in a dual-frequency radars system has now gained considerable attention. The noncoherent localization approach based on a least squares (LS) estimator has been addressed in the literature. Compared with the LS method, a novel localization method based on a two-step weighted least squares estimator is proposed to increase positioning accuracy for a multi-station dual-frequency radars system in this paper. The effects of signal noise ratio and the number of samples on the performance of range estimation are also analyzed in the paper. Furthermore, both the theoretical variance and Cramer–Rao lower bound (CRLB) are derived. The simulation results verified the proposed method. PMID:29244727

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.

Observer efficiency in free-localization tasks with correlated noise.

PubMed

Abbey, Craig K; Eckstein, Miguel P

2014-01-01

The efficiency of visual tasks involving localization has traditionally been evaluated using forced choice experiments that capitalize on independence across locations to simplify the performance of the ideal observer. However, developments in ideal observer analysis have shown how an ideal observer can be defined for free-localization tasks, where a target can appear anywhere in a defined search region and subjects respond by localizing the target. Since these tasks are representative of many real-world search tasks, it is of interest to evaluate the efficiency of observer performance in them. The central question of this work is whether humans are able to effectively use the information in a free-localization task relative to a similar task where target location is fixed. We use a yes-no detection task at a cued location as the reference for this comparison. Each of the tasks is evaluated using a Gaussian target profile embedded in four different Gaussian noise backgrounds having power-law noise power spectra with exponents ranging from 0 to 3. The free localization task had a square 6.7° search region. We report on two follow-up studies investigating efficiency in a detect-and-localize task, and the effect of processing the white-noise backgrounds. In the fixed-location detection task, we find average observer efficiency ranges from 35 to 59% for the different noise backgrounds. Observer efficiency improves dramatically in the tasks involving localization, ranging from 63 to 82% in the forced localization tasks and from 78 to 92% in the detect-and- localize tasks. Performance in white noise, the lowest efficiency condition, was improved by filtering to give them a power-law exponent of 2. Classification images, used to examine spatial frequency weights for the tasks, show better tuning to ideal weights in the free-localization tasks. The high absolute levels of efficiency suggest that observers are well-adapted to free-localization tasks.

Observer efficiency in free-localization tasks with correlated noise

PubMed Central

Abbey, Craig K.; Eckstein, Miguel P.

2014-01-01

The efficiency of visual tasks involving localization has traditionally been evaluated using forced choice experiments that capitalize on independence across locations to simplify the performance of the ideal observer. However, developments in ideal observer analysis have shown how an ideal observer can be defined for free-localization tasks, where a target can appear anywhere in a defined search region and subjects respond by localizing the target. Since these tasks are representative of many real-world search tasks, it is of interest to evaluate the efficiency of observer performance in them. The central question of this work is whether humans are able to effectively use the information in a free-localization task relative to a similar task where target location is fixed. We use a yes-no detection task at a cued location as the reference for this comparison. Each of the tasks is evaluated using a Gaussian target profile embedded in four different Gaussian noise backgrounds having power-law noise power spectra with exponents ranging from 0 to 3. The free localization task had a square 6.7° search region. We report on two follow-up studies investigating efficiency in a detect-and-localize task, and the effect of processing the white-noise backgrounds. In the fixed-location detection task, we find average observer efficiency ranges from 35 to 59% for the different noise backgrounds. Observer efficiency improves dramatically in the tasks involving localization, ranging from 63 to 82% in the forced localization tasks and from 78 to 92% in the detect-and- localize tasks. Performance in white noise, the lowest efficiency condition, was improved by filtering to give them a power-law exponent of 2. Classification images, used to examine spatial frequency weights for the tasks, show better tuning to ideal weights in the free-localization tasks. The high absolute levels of efficiency suggest that observers are well-adapted to free-localization tasks. PMID:24817854

[Evaluation of the learning curve of residents in localizing a phantom target with ultrasonography].

PubMed

Dessieux, T; Estebe, J-P; Bloc, S; Mercadal, L; Ecoffey, C

2008-10-01

Few information are available regarding the learning curve in ultrasonography and even less for ultrasound-guided regional anesthesia. This study aimed to evaluate in a training program the learning curve on a phantom of 12 residents novice in ultrasonography. Twelve trainees inexperienced in ultrasonography were given introductory training consisting of didactic formation on the various components of the portable ultrasound machine (i.e. on/off button, gain, depth, resolution, and image storage). Then, students performed three trials, in two sets of increased difficulty, at executing these predefined tasks: adjustments of the machine, then localization of a small plastic piece introduced into roasting pork (3 cm below the surface). At the end of the evaluation, the residents were asked to insert a 22 G needle into an exact predetermined target (i.e. point of fascia intersection). The progression of the needle was continuously controlled by ultrasound visualization using injection of a small volume of water (needle perpendicular to the longitudinal plane of the ultrasound beam). Two groups of two different examiners evaluated for each three trials the skill of the residents (quality, time to perform the machine adjustments, to localize the plastic target, and to hydrolocalize, and volume used for hydrolocalization). After each trial, residents evaluated their performance using a difficulty scale (0: easy to 10: difficult). All residents performed the adjustments from the last trial of each set, with a learning curve observed in terms of duration. Localization of the plastic piece was achieved by all residents at the 6th trial, with a shorter duration of localization. Hydrolocalization was achieved after the 4th trial by all subjects. Difficulty scale was correlated to the number of trials. All these results were independent of the experience of residents in regional anesthesia. Four trials were necessary to adjust correctly the machine, to localize a target, and to

Commercial Complexity and Local and Global Involvement in Programs: Effects on Viewer Responses.

ERIC Educational Resources Information Center

Oberman, Heiko; Thorson, Esther

A study investigated the effects of local (momentary) and global (whole program) involvement in program context and the effects of message complexity on the retention of television commercials. Sixteen commercials, categorized as simple video/simple audio through complex video/complex audio were edited into two globally high- and two globally…

Localized increase of tissue oxygen tension by magnetic targeted drug delivery

NASA Astrophysics Data System (ADS)

Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

2014-07-01

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to

Attack Detection in Sensor Network Target Localization Systems With Quantized Data

NASA Astrophysics Data System (ADS)

Zhang, Jiangfan; Wang, Xiaodong; Blum, Rick S.; Kaplan, Lance M.

2018-04-01

We consider a sensor network focused on target localization, where sensors measure the signal strength emitted from the target. Each measurement is quantized to one bit and sent to the fusion center. A general attack is considered at some sensors that attempts to cause the fusion center to produce an inaccurate estimation of the target location with a large mean-square-error. The attack is a combination of man-in-the-middle, hacking, and spoofing attacks that can effectively change both signals going into and coming out of the sensor nodes in a realistic manner. We show that the essential effect of attacks is to alter the estimated distance between the target and each attacked sensor to a different extent, giving rise to a geometric inconsistency among the attacked and unattacked sensors. Hence, with the help of two secure sensors, a class of detectors are proposed to detect the attacked sensors by scrutinizing the existence of the geometric inconsistency. We show that the false alarm and miss probabilities of the proposed detectors decrease exponentially as the number of measurement samples increases, which implies that for sufficiently large number of samples, the proposed detectors can identify the attacked and unattacked sensors with any required accuracy.

Action Enhances Acoustic Cues for 3-D Target Localization by Echolocating Bats

PubMed Central

Wohlgemuth, Melville J.

2016-01-01

Under natural conditions, animals encounter a barrage of sensory information from which they must select and interpret biologically relevant signals. Active sensing can facilitate this process by engaging motor systems in the sampling of sensory information. The echolocating bat serves as an excellent model to investigate the coupling between action and sensing because it adaptively controls both the acoustic signals used to probe the environment and movements to receive echoes at the auditory periphery. We report here that the echolocating bat controls the features of its sonar vocalizations in tandem with the positioning of the outer ears to maximize acoustic cues for target detection and localization. The bat’s adaptive control of sonar vocalizations and ear positioning occurs on a millisecond timescale to capture spatial information from arriving echoes, as well as on a longer timescale to track target movement. Our results demonstrate that purposeful control over sonar sound production and reception can serve to improve acoustic cues for localization tasks. This finding also highlights the general importance of movement to sensory processing across animal species. Finally, our discoveries point to important parallels between spatial perception by echolocation and vision. PMID:27608186

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

Effect of Blast Injury on Auditory Localization in Military Service Members.

PubMed

Kubli, Lina R; Brungart, Douglas; Northern, Jerry

Among the many advantages of binaural hearing are the abilities to localize sounds in space and to attend to one sound in the presence of many sounds. Binaural hearing provides benefits for all listeners, but it may be especially critical for military personnel who must maintain situational awareness in complex tactical environments with multiple speech and noise sources. There is concern that Military Service Members who have been exposed to one or more high-intensity blasts during their tour of duty may have difficulty with binaural and spatial ability due to degradation in auditory and cognitive processes. The primary objective of this study was to assess the ability of blast-exposed Military Service Members to localize speech sounds in quiet and in multisource environments with one or two competing talkers. Participants were presented with one, two, or three topic-related (e.g., sports, food, travel) sentences under headphones and required to attend to, and then locate the source of, the sentence pertaining to a prespecified target topic within a virtual space. The listener's head position was monitored by a head-mounted tracking device that continuously updated the apparent spatial location of the target and competing speech sounds as the subject turned within the virtual space. Measurements of auditory localization ability included mean absolute error in locating the source of the target sentence, the time it took to locate the target sentence within 30 degrees, target/competitor confusion errors, response time, and cumulative head motion. Twenty-one blast-exposed Active-Duty or Veteran Military Service Members (blast-exposed group) and 33 non-blast-exposed Service Members and beneficiaries (control group) were evaluated. In general, the blast-exposed group performed as well as the control group if the task involved localizing the source of a single speech target. However, if the task involved two or three simultaneous talkers, localization ability was

'They don't just come for Machu Picchu': locals' views of tourist-local sexual relationships in Cuzco, Peru.

PubMed

Bauer, Irmgard

2008-08-01

Sexual and romantic relationships between local people and tourists have long taken place. Such encounters are not a modern phenomenon, but the potential of sexually transmitted infections (STIs), including HIV/AIDS, warrants greater research into the issue. This paper analyses local people's views of local-tourist relationships in Cuzco/Peru. Data were obtained through in-depth interviews, participant and non-participant observation and informal discussions. Attraction based on physical difference was reportedly the main trigger for such relationships. Emerging themes discussed include issues of self-esteem, strategies of approach, tourists' motives, emotional involvement and expectations from such encounters. Levels of unprotected sexual behaviour and lack of STI awareness are of sufficient concern to recommend urgent action. Suggestions for sexual health education are made with particular emphasis on targeting local people involved in the tourism and hospitality industries.

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

Infrared target recognition based on improved joint local ternary pattern

NASA Astrophysics Data System (ADS)

Sun, Junding; Wu, Xiaosheng

2016-05-01

This paper presents a simple, efficient, yet robust approach, named joint orthogonal combination of local ternary pattern, for automatic forward-looking infrared target recognition. It gives more advantages to describe the macroscopic textures and microscopic textures by fusing variety of scales than the traditional LBP-based methods. In addition, it can effectively reduce the feature dimensionality. Further, the rotation invariant and uniform scheme, the robust LTP, and soft concave-convex partition are introduced to enhance its discriminative power. Experimental results demonstrate that the proposed method can achieve competitive results compared with the state-of-the-art methods.

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

NASA Astrophysics Data System (ADS)

Neira, José L.; Bintz, Jennifer; Arruebo, María; Rizzuti, Bruno; Bonacci, Thomas; Vega, Sonia; Lanas, Angel; Velázquez-Campoy, Adrián; Iovanna, Juan L.; Abián, Olga

2017-01-01

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

PubMed Central

Neira, José L.; Bintz, Jennifer; Arruebo, María; Rizzuti, Bruno; Bonacci, Thomas; Vega, Sonia; Lanas, Angel; Velázquez-Campoy, Adrián; Iovanna, Juan L.; Abián, Olga

2017-01-01

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs. PMID:28054562

Turmeric (Curcuma longa): miRNAs and their regulating targets are involved in development and secondary metabolite pathways.

PubMed

Singh, Noopur; Sharma, Ashok

Turmeric has been used as a therapeutic herb over centuries in traditional medicinal systems due to the presence of several secondary metabolite compounds. microRNAs are known to regulate gene expression at the post-transcriptional level by transcriptional cleavage or translation repression. miRNAs have been demonstrated to play an active role in secondary metabolism regulation. The present work was focused on the identification of the miRNAs involved in the regulation of secondary metabolite and development process of turmeric. Eighteen miRNA families were identified for turmeric. Sixteen miRNA families were observed to regulate 238 target transcripts. LncRNAs targets of the putative miRNA candidates were also predicted. Our results indicated their role in binding, reproduction, stress, and other developmental processes. Gene annotation and pathway analysis illustrated the biological function of the targets regulated by the putative miRNAs. The miRNA-mediated gene regulatory network also revealed co-regulated targets that were regulated by two or more miRNA families. miR156 and miR5015 were observed to be involved in rhizome development. miR5021 showed regulation for terpenoid backbone biosynthesis and isoquinoline alkaloid biosynthesis pathways. The flavonoid biosynthesis pathway was observed to be regulated by miR2919. The analysis revealed the probable involvement of three miRNAs (miR1168.2, miR156b and miR1858) in curcumin biosynthesis. Other miRNAs were found to be involved in the growth and developmental process of turmeric. Phylogenetic analysis of selective miRNAs was also performed. Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Analytic Guided-Search Model of Human Performance Accuracy in Target- Localization Search Tasks

NASA Technical Reports Server (NTRS)

Eckstein, Miguel P.; Beutter, Brent R.; Stone, Leland S.

2000-01-01

Current models of human visual search have extended the traditional serial/parallel search dichotomy. Two successful models for predicting human visual search are the Guided Search model and the Signal Detection Theory model. Although these models are inherently different, it has been difficult to compare them because the Guided Search model is designed to predict response time, while Signal Detection Theory models are designed to predict performance accuracy. Moreover, current implementations of the Guided Search model require the use of Monte-Carlo simulations, a method that makes fitting the model's performance quantitatively to human data more computationally time consuming. We have extended the Guided Search model to predict human accuracy in target-localization search tasks. We have also developed analytic expressions that simplify simulation of the model to the evaluation of a small set of equations using only three free parameters. This new implementation and extension of the Guided Search model will enable direct quantitative comparisons with human performance in target-localization search experiments and with the predictions of Signal Detection Theory and other search accuracy models.

Target mimics: an embedded layer of microRNA-involved gene regulatory networks in plants.

PubMed

Meng, Yijun; Shao, Chaogang; Wang, Huizhong; Jin, Yongfeng

2012-05-21

MicroRNAs (miRNAs) play an essential role in gene regulation in plants. At the same time, the expression of miRNA genes is also tightly controlled. Recently, a novel mechanism called "target mimicry" was discovered, providing another layer for modulating miRNA activities. However, except for the artificial target mimics manipulated for functional studies on certain miRNA genes, only one example, IPS1 (Induced by Phosphate Starvation 1)-miR399 was experimentally confirmed in planta. To date, few analyses for comprehensive identification of natural target mimics have been performed in plants. Thus, limited evidences are available to provide detailed information for interrogating the questionable issue whether target mimicry was widespread in planta, and implicated in certain biological processes. In this study, genome-wide computational prediction of endogenous miRNA mimics was performed in Arabidopsis and rice, and dozens of target mimics were identified. In contrast to a recent report, the densities of target mimic sites were found to be much higher within the untranslated regions (UTRs) when compared to those within the coding sequences (CDSs) in both plants. Some novel sequence characteristics were observed for the miRNAs that were potentially regulated by the target mimics. GO (Gene Ontology) term enrichment analysis revealed some functional insights into the predicted mimics. After degradome sequencing data-based identification of miRNA targets, the regulatory networks constituted by target mimics, miRNAs and their downstream targets were constructed, and some intriguing subnetworks were further exploited. These results together suggest that target mimicry may be widely implicated in regulating miRNA activities in planta, and we hope this study could expand the current understanding of miRNA-involved regulatory networks.

Analysis and modeling of localized heat generation by tumor-targeted nanoparticles (Monte Carlo methods)

NASA Astrophysics Data System (ADS)

Sanattalab, Ehsan; SalmanOgli, Ahmad; Piskin, Erhan

2016-04-01

We investigated the tumor-targeted nanoparticles that influence heat generation. We suppose that all nanoparticles are fully functionalized and can find the target using active targeting methods. Unlike the commonly used methods, such as chemotherapy and radiotherapy, the treatment procedure proposed in this study is purely noninvasive, which is considered to be a significant merit. It is found that the localized heat generation due to targeted nanoparticles is significantly higher than other areas. By engineering the optical properties of nanoparticles, including scattering, absorption coefficients, and asymmetry factor (cosine scattering angle), the heat generated in the tumor's area reaches to such critical state that can burn the targeted tumor. The amount of heat generated by inserting smart agents, due to the surface Plasmon resonance, will be remarkably high. The light-matter interactions and trajectory of incident photon upon targeted tissues are simulated by MIE theory and Monte Carlo method, respectively. Monte Carlo method is a statistical one by which we can accurately probe the photon trajectories into a simulation area.

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.

A 20-Amino Acid Module of Protein Kinase Cϵ Involved in Translocation and Selective Targeting at Cell-Cell Contacts*

PubMed Central

Diouf, Barthélémy; Collazos, Alejandra; Labesse, Gilles; Macari, Françoise; Choquet, Armelle; Clair, Philippe; Gauthier-Rouvière, Cécile; Guérineau, Nathalie C.; Jay, Philippe; Hollande, Frédéric; Joubert, Dominique

2009-01-01

In the pituitary gland, activated protein kinase C (PKC) isoforms accumulate either selectively at the cell-cell contact (α and ϵ) or at the entire plasma membrane (β1 and δ). The molecular mechanisms underlying these various subcellular locations are not known. Here, we demonstrate the existence within PKCϵ of a cell-cell contact targeting sequence (3CTS) that, upon stimulation, is capable of targeting PKCδ, chimerin-α1, and the PKCϵ C1 domain to the cell-cell contact. We show that this selective targeting of PKCϵ is lost upon overexpression of 3CTS fused to a (R-Ahx-R)4 (where Ahx is 6-aminohexanoic acid) vectorization peptide, reflecting a dominant-negative effect of the overexpressed 3CTS on targeting selectivity. 3CTS contains a putative amphipathic α-helix, a 14-3-3-binding site, and the Glu-374 amino acid, involved in targeting selectivity. We show that the integrity of the α-helix is important for translocation but that 14-3-3 is not involved in targeting selectivity. However, PKCϵ translocation is increased when PKCϵ/14-3-3 interaction is abolished, suggesting that phorbol 12-myristate 13-acetate activation may initiate two sets of PKCϵ functions, those depending on 14-3-3 and those depending on translocation to cell-cell contacts. Thus, 3CTS is involved in the modulation of translocation via its 14-3-3-binding site, in cytoplasmic desequestration via the α-helix, and in selective PKCϵ targeting at the cell-cell contact via Glu-374. PMID:19429675

On the Impact of Localization and Density Control Algorithms in Target Tracking Applications for Wireless Sensor Networks

PubMed Central

Campos, Andre N.; Souza, Efren L.; Nakamura, Fabiola G.; Nakamura, Eduardo F.; Rodrigues, Joel J. P. C.

2012-01-01

Target tracking is an important application of wireless sensor networks. The networks' ability to locate and track an object is directed linked to the nodes' ability to locate themselves. Consequently, localization systems are essential for target tracking applications. In addition, sensor networks are often deployed in remote or hostile environments. Therefore, density control algorithms are used to increase network lifetime while maintaining its sensing capabilities. In this work, we analyze the impact of localization algorithms (RPE and DPE) and density control algorithms (GAF, A3 and OGDC) on target tracking applications. We adapt the density control algorithms to address the k-coverage problem. In addition, we analyze the impact of network density, residual integration with density control, and k-coverage on both target tracking accuracy and network lifetime. Our results show that DPE is a better choice for target tracking applications than RPE. Moreover, among the evaluated density control algorithms, OGDC is the best option among the three. Although the choice of the density control algorithm has little impact on the tracking precision, OGDC outperforms GAF and A3 in terms of tracking time. PMID:22969329

Tsunami Early Warning System in Italy and involvement of local communities

NASA Astrophysics Data System (ADS)

Tinti, Stefano; Armigliato, Alberto; Zaniboni, Filippo

2010-05-01

performance of the tsunami predictors. The role of the local communities in defining the strategies in case of uncertain data is essential: only involvement of such communities since the beginning of the planning and implementation phase of the TEWS as well as in the definition of a decision making matrix can ensure appropriate response in case of emergency, and most importantly, the acceptance of the system in the long run. The efforts to implement the Tsunami Warning System in Italy should take into proper account the above mentioned aspects. Involvement of local communities should be primarily realized through the involvement of the local components of the Civil Protection Agency that is responsible for the implementation of the system over the Italian territory. A pilot project is being conducted in cooperation between the Civil Protection Service of Sicily and the University of Bologna (UNIBO) that contemplates the empowering of the local sea-level monitoring system (TSUNET) and specific vulnerability and risk analyses, also exploiting results of national and European research projects (e.g. TRANSFER and SCHEMA) where UNIBO had a primary role.

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

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.

Engineering self-contained DNA circuit for proximity recognition and localized signal amplification of target biomolecules

PubMed Central

Ang, Yan Shan; Yung, Lin-Yue Lanry

2014-01-01

Biomolecular interactions have important cellular implications, however, a simple method for the sensing of such proximal events is lacking in the current molecular toolbox. We designed a dynamic DNA circuit capable of recognizing targets in close proximity to initiate a pre-programmed signal transduction process resulting in localized signal amplification. The entire circuit was engineered to be self-contained, i.e. it can self-assemble onto individual target molecules autonomously and form localized signal with minimal cross-talk. α-thrombin was used as a model protein to evaluate the performance of the individual modules and the overall circuit for proximity interaction under physiologically relevant buffer condition. The circuit achieved good selectivity in presence of non-specific protein and interfering serum matrix and successfully detected for physiologically relevant α-thrombin concentration (50 nM–5 μM) in a single mixing step without any further washing. The formation of localized signal at the interaction site can be enhanced kinetically through the control of temperature and probe concentration. This work provides a basic general framework from which other circuit modules can be adapted for the sensing of other biomolecular or cellular interaction of interest. PMID:25056307

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

Evaluation of kidney motion and target localization in abdominal SBRT patients

PubMed Central

Sonier, Marcus; Chu, William; Lalani, Nafisha; Erler, Darby; Cheung, Patrick

2016-01-01

The purpose of this study was to evaluate bilateral kidney and target translational/rotational intrafraction motion during stereotactic body radiation therapy treatment delivery of primary renal cell carcinoma and oligometastatic adrenal lesions for patients immobilized in the Elekta BodyFIX system. Bilateral kidney motion was assessed at midplane for 30 patients immobilized in a full‐body dual‐vacuum‐cushion system with two patients immobilized via abdominal compression. Intrafraction motion was assessed for 15 patients using kilovoltage cone‐beam computed tomography (kV‐CBCT) datasets (n=151) correlated to the planning CT. Patient positioning was corrected for translational and rotational misalignments using a robotic couch in six degrees of freedom if setup errors exceeded 1 mm and 1°. Absolute bilateral kidney motion between inhale and exhale 4D CT imaging phases for left–right (LR), superior–inferior (SI), and anterior–posterior (AP) directions was 1.51±1.00mm,8.10±4.33mm, and 3.08±2.11mm, respectively. Residual setup error determined across CBCT type (pretreatment, intrafraction, and post‐treatment) for x (LR), y (SI), and z (AP) translations was 0.63±0.74mm,1.08±1.38mm, and 0.70±1.00mm; while for x (pitch), y (roll), and z (yaw) rotations was 0.24±0.39°,0.19±0.34°, and 0.26±0.43°, respectively. Targets were localized to within 2.1 mm and 0.8° 95% of the time. The frequency of misalignments in the y direction was significant (p<0.05) when compared to the x and z directions with no significant difference in translations between IMRT and VMAT. This technique is robust using BodyFIX for patient immobilization and reproducible localization of kidney and adrenal targets and daily CBCT image guidance for correction of positional errors to maintain treatment accuracy. PACS number(s): 87.55.‐x, 87.56.‐v, 87.56.Da PMID:27929514

[Axillary pathologic response after neoadjuvant chemotherapy in locally advanced breast cancer with axillary involvement].

PubMed

Jiménez-Ballvé, A; Serrano-Palacio, A; García-Sáenz, J A; Ortega Candil, A; Salsidua-Arroyo, O; Román-Santamaría, J M; Pelayo Alarcón, A; Fuentes Ferrer, M E; Carreras-Delgado, J L

2015-01-01

To compare axillary involvement (N+) at initial staging in locally advanced breast cancer (LABC) with axillary lymphadenectomy histologic results after neoadjuvant chemotherapy treatment (NeoChemo). Retrospective study between November 2011 and September 2013 of LABC cases treated with neoadjuvant chemotherapy based on docetaxel (associated with trastuzumab in HER2 positive cases and carboplatin/adriamycin in HER2 negative cases). Those clinically or radiologically suspected cases of axillary involvement were histologically confirmed. When there was no suspicion of axillary involvement, sentinel lymph node radioguided biopsy (SLNRB) was performed using intradermal injection of (99m)Tc-nanocolloid albumin prior to neoadjuvant treatment. Axillary lymphadenectomy after NeoChemo was undertaken in all cases with positive axilla. Final pathologic response was classified as complete (pCR) when there was no evidence of tumoral disease and as non-pathologic complete response (no pCR) in the opposite case. A total of 346 patients treated with docetaxel were reviewed, identifying 105 LABC. Axillary involvement at initial staging was detected in 70 (67%) before starting NeoChemo. From these 70, 73% (n=51) were N+ (fine needle biopsy and/or biopsy) and the remaining 19 (27%) were occult N+ detected by SLNRB. Axillary lymphadenectomy detected pCR in 56% (39/70), increasing up to 84% pCR when initial N+ status was reached using SNLB. On the other hand, when N+ was detected using fine needle biopsy/lymph biopsy, pCR was only 45%. More than 50% of women affected by locally advanced breast cancer with tumoral axillary involvement at initial diagnosis present free metastatic axilla after therapeutic neoadjuvant chemotherapy effect. This increases up to almost 90% in case of occult metastatic axilla detected with sentinel node biopsy prior starting neoadjuvant chemotherapy. Copyright © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

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.

The role of the vestibular system in manual target localization

NASA Technical Reports Server (NTRS)

Barry, Susan R.; Mueller, S. Alyssa

1995-01-01

Astronauts experience perceptual and sensory-motor disturbances during spaceflight and immediately after return to the 1-g environment of Earth. During spaceflight, sensory information from the eyes, limbs and vestibular organs is reinterpreted by the central nervous system so that astronauts can produce appropriate body movements in microgravity. Alterations in sensory-motor function may affect eye-head-hand coordination and, thus, the crewmember's ability to manually locate objects in extrapersonal space. Previous reports have demonstrated that crewmembers have difficulty in estimating joint and limb position and in pointing to memorized target positions on orbit and immediately postflight. One set of internal cues that may assist in the manual localization of objects is information from the vestibular system. This system contributes to our sense of the body's position in space by providing information on head position and movement and the orientation of the body with respect to gravity. Research on the vestibular system has concentrated on its role in oculo-motor control. Little is known about the role that vestibular information plays in manual motor control, such as reaching and pointing movements. Since central interpretation of vestibular information is altered in microgravity, it is important to determine its role in this process. This summer, we determined the importance of vestibular information in a subject's ability to point accurately toward a target in extrapersonal space. Subjects were passively rotated across the earth-vertical axis and then asked to point back to a previously-seen target. In the first paradigm, the subjects used both visual and vestibular cues for the pointing response, while, in the second paradigm, subjects used only vestibular information. Subjects were able to point with 85 percent accuracy to a target using vestibular information alone. We infer from this result that vestibular input plays a role in the spatial programming of

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

Local involvement in measuring and governing carbon stocks in China, Vietnam, Indonesia and Laos

Treesearch

Michael Køie Poulsen

2013-01-01

An important element of MRV is to ensure accurate measurements of carbon stocks. Measuring trees on the ground may be needed for ground truthing of remote sensing results. It can also provide more accurate carbon stock monitoring than remote sensing alone. Local involvement in measuring trees for monitoring of carbon stocks may be advantageous in several ways....

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

PubMed

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

2018-03-01

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

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.

20 CFR 670.800 - How do Job Corps centers and service providers become involved in their local communities?

Code of Federal Regulations, 2010 CFR

2010-04-01

... INVESTMENT ACT Community Connections § 670.800 How do Job Corps centers and service providers become involved... Community Liaison designated by the director of the center to establish relationships with local and distant... businesses with employment opportunities in the local area and the areas to which students will return. (f...

20 CFR 670.800 - How do Job Corps centers and service providers become involved in their local communities?

Code of Federal Regulations, 2011 CFR

2011-04-01

... INVESTMENT ACT Community Connections § 670.800 How do Job Corps centers and service providers become involved... Community Liaison designated by the director of the center to establish relationships with local and distant... businesses with employment opportunities in the local area and the areas to which students will return. (f...

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

Multispectral photoacoustic decomposition with localized regularization for detecting targeted contrast agent

NASA Astrophysics Data System (ADS)

Tavakoli, Behnoosh; Chen, Ying; Guo, Xiaoyu; Kang, Hyun Jae; Pomper, Martin; Boctor, Emad M.

2015-03-01

Targeted contrast agents can improve the sensitivity of imaging systems for cancer detection and monitoring the treatment. In order to accurately detect contrast agent concentration from photoacoustic images, we developed a decomposition algorithm to separate photoacoustic absorption spectrum into components from individual absorbers. In this study, we evaluated novel prostate-specific membrane antigen (PSMA) targeted agents for imaging prostate cancer. Three agents were synthesized through conjugating PSMA-targeting urea with optical dyes ICG, IRDye800CW and ATTO740 respectively. In our preliminary PA study, dyes were injected in a thin wall plastic tube embedded in water tank. The tube was illuminated with pulsed laser light using a tunable Q-switch ND-YAG laser. PA signal along with the B-mode ultrasound images were detected with a diagnostic ultrasound probe in orthogonal mode. PA spectrums of each dye at 0.5 to 20 μM concentrations were estimated using the maximum PA signal extracted from images which are obtained at illumination wavelengths of 700nm-850nm. Subsequently, we developed nonnegative linear least square optimization method along with localized regularization to solve the spectral unmixing. The algorithm was tested by imaging mixture of those dyes. The concentration of each dye was estimated with about 20% error on average from almost all mixtures albeit the small separation between dyes spectrums.

Local area disadvantage and gambling involvement and disorder: Evidence for gene-environment correlation and interaction.

PubMed

Slutske, Wendy S; Deutsch, Arielle R; Statham, Dixie J; Martin, Nicholas G

2015-08-01

Previous research has demonstrated that local area characteristics (such as disadvantage and gambling outlet density) and genetic risk factors are associated with gambling involvement and disordered gambling. These 2 lines of research were brought together in the present study by examining the extent to which genetic contributions to individual differences in gambling involvement and disorder contributed to being exposed to, and were also accentuated by, local area disadvantage. Participants were members of the national community-based Australian Twin Registry who completed a telephone interview in which the past-year frequency of gambling and symptoms of disordered gambling were assessed. Indicators of local area disadvantage were based on census data matched to the participants' postal codes. Univariate biometric model-fitting revealed that exposure to area disadvantage was partially explained by genetic factors. Bivariate biometric model-fitting was conducted to examine the evidence for gene-environment interaction while accounting for gene-environment correlation. These analyses demonstrated that: (a) a small portion of the genetic propensity to gamble was explained by moving to or remaining in a disadvantaged area, and (b) the remaining genetic and unique environmental variation in the frequency of participating in electronic machine gambling (among men and women) and symptoms of disordered gambling (among women) was greater in more disadvantaged localities. As the gambling industry continues to grow, it will be important to take into account the multiple contexts in which problematic gambling behavior can emerge-from genes to geography-as well as the ways in which such contexts may interact with each other. (c) 2015 APA, all rights reserved).

Local Area Disadvantage and Gambling Involvement and Disorder: Evidence for Gene-Environment Correlation and Interaction

PubMed Central

Slutske, Wendy S.; Deutsch, Arielle R.; Statham, Dixie B.; Martin, Nicholas G.

2015-01-01

Previous research has demonstrated that local area characteristics (such as disadvantage and gambling outlet density) and genetic risk factors are associated with gambling involvement and disordered gambling. These two lines of research were brought together in the present study by examining the extent to which genetic contributions to individual differences in gambling involvement and disorder contributed to being exposed to, and were also accentuated by, local area disadvantage. Participants were members of the national community-based Australian Twin Registry who completed a telephone interview in which the past-year frequency of gambling and symptoms of disordered gambling were assessed. Indicators of local area disadvantage were based on census data matched to the participants' postal codes. Univariate biometric model-fitting revealed that exposure to area disadvantage was partially explained by genetic factors. Bivariate biometric model-fitting was conducted to examine the evidence for gene-environment interaction while accounting for gene-environment correlation. These analyses demonstrated that: (a) a small portion of the genetic propensity to gamble was explained by moving to or remaining in a disadvantaged area, and (b) the remaining genetic and unique environmental variation in the frequency of participating in electronic machine gambling (among men and women) and symptoms of disordered gambling (among women) was greater in more disadvantaged localities. As the gambling industry continues to grow, it will be important to take into account the multiple contexts in which problematic gambling behavior can emerge -- from genes to geography -- as well as the ways in which such contexts may interact with each other. PMID:26147321

WE-FG-BRA-06: Systematic Study of Target Localization for Bioluminescence Tomography Guided Radiation Therapy for Preclinical Research

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

Zhang, B; Reyes, J; Wong, J

Purpose: To overcome the limitation of CT/CBCT in guiding radiation for soft tissue targets, we developed a bioluminescence tomography(BLT) system for preclinical radiation research. We systematically assessed the system performance in target localization and the ability of resolving two sources in simulations, phantom and in vivo environments. Methods: Multispectral images acquired in single projection were used for the BLT reconstruction. Simulation studies were conducted for single spherical source radius from 0.5 to 3 mm at depth of 3 to 12 mm. The same configuration was also applied for the double sources simulation with source separations varying from 3 to 9more » mm. Experiments were performed in a standalone BLT/CBCT system. Two sources with 3 and 4.7 mm separations placed inside a tissue-mimicking phantom were chosen as the test cases. Live mice implanted with single source at 6 and 9 mm depth, 2 sources with 3 and 5 mm separation at depth of 5 mm or 3 sources in the abdomen were also used to illustrate the in vivo localization capability of the BLT system. Results: Simulation and phantom results illustrate that our BLT can provide 3D source localization with approximately 1 mm accuracy. The in vivo results are encouraging that 1 and 1.7 mm accuracy can be attained for the single source case at 6 and 9 mm depth, respectively. For the 2 sources study, both sources can be distinguished at 3 and 5 mm separations at approximately 1 mm accuracy using 3D BLT but not 2D bioluminescence image. Conclusion: Our BLT/CBCT system can be potentially applied to localize and resolve targets at a wide range of target sizes, depths and separations. The information provided in this study can be instructive to devise margins for BLT-guided irradiation and suggests that the BLT could guide radiation for multiple targets, such as metastasis. Drs. John W. Wong and Iulian I. Iordachita receive royalty payment from a licensing agreement between Xstrahl Ltd and Johns Hopkins

Time-Resolved Intrafraction Target Translations and Rotations During Stereotactic Liver Radiation Therapy: Implications for Marker-based Localization Accuracy

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

Bertholet, Jenny, E-mail: jennbe@rm.dk; Worm, Esben S.; Fledelius, Walther

Purpose: Image guided liver stereotactic body radiation therapy (SBRT) often relies on implanted fiducial markers. The target localization accuracy decreases with increased marker-target distance. This may occur partly because of liver rotations. The aim of this study was to examine time-resolved translations and rotations of liver marker constellations and investigate if time-resolved intrafraction rotational corrections can improve localization accuracy in liver SBRT. Methods and Materials: Twenty-nine patients with 3 implanted markers received SBRT in 3 to 6 fractions. The time-resolved trajectory of each marker was estimated from the projections of 1 to 3 daily cone beam computed tomography scans andmore » used to calculate the translation and rotation of the marker constellation. In all cone beam computed tomography projections, the time-resolved position of each marker was predicted from the position of another surrogate marker by assuming that the marker underwent either (1) the same translation as the surrogate marker; or (2) the same translation as the surrogate marker corrected by the rotation of the marker constellation. The localization accuracy was quantified as the root-mean-square error (RMSE) between the estimated and the actual marker position. For comparison, the RMSE was also calculated when the marker's position was estimated as its mean position for all the projections. Results: The mean translational and rotational range (2nd-98th percentile) was 2.0 mm/3.9° (right-left), 9.2 mm/2.9° (superior-inferior), 4.0 mm/4.0° (anterior-posterior), and 10.5 mm (3-dimensional). Rotational corrections decreased the mean 3-dimensional RMSE from 0.86 mm to 0.54 mm (P<.001) and halved the RMSE increase per millimeter increase in marker distance. Conclusions: Intrafraction rotations during liver SBRT reduce the accuracy of marker-guided target localization. Rotational correction can improve the localization accuracy with a factor of approximately 2

[Local fixation of antibiotics by fibrin spray : In bone defects with soft tissue involvement].

PubMed

Janko, Maren; Nau, Christoph; Marzi, Ingo; Frank, Johannes

2017-02-01

In acute and chronic bone infections with concomitant soft tissue involvement the current gold standard is radical surgical debridement including explantation of the infected prosthetic devices. This is followed by initiation of systemic antibiotic therapy appropriate for the antibiogram. Several revision operations are often necessary to achieve complete healing. Additional treatment with local antibiotics or antibiotic-containing substances is routinely used in bone surgery. Apart from the typical procedures with commercially available products, we have conducted a study with 21 patients by application of local antibiotic treatment in combination with the fibrin glue spray technique and evaluated the results. Out of nine wounds of the lower extremities with bone involvement, total healing could be achieved in eight cases. We were also successful in two out of three very complex pelvic wounds; however, as expected the implant infections were complicated. Out of the seven desolate cases we were only able to achieve complete long-term healing in two cases. In the meantime we routinely use the described method in such special disastrous infection situations; however, this is carried out only in combination with established surgical procedures in sepsis surgery and anti-infection management.

Planning paths to multiple targets: memory involvement and planning heuristics in spatial problem solving.

PubMed

Wiener, J M; Ehbauer, N N; Mallot, H A

2009-09-01

For large numbers of targets, path planning is a complex and computationally expensive task. Humans, however, usually solve such tasks quickly and efficiently. We present experiments studying human path planning performance and the cognitive processes and heuristics involved. Twenty-five places were arranged on a regular grid in a large room. Participants were repeatedly asked to solve traveling salesman problems (TSP), i.e., to find the shortest closed loop connecting a start location with multiple target locations. In Experiment 1, we tested whether humans employed the nearest neighbor (NN) strategy when solving the TSP. Results showed that subjects outperform the NN-strategy, suggesting that it is not sufficient to explain human route planning behavior. As a second possible strategy we tested a hierarchical planning heuristic in Experiment 2, demonstrating that participants first plan a coarse route on the region level that is refined during navigation. To test for the relevance of spatial working memory (SWM) and spatial long-term memory (LTM) for planning performance and the planning heuristics applied, we varied the memory demands between conditions in Experiment 2. In one condition the target locations were directly marked, such that no memory was required; a second condition required participants to memorize the target locations during path planning (SWM); in a third condition, additionally, the locations of targets had to retrieved from LTM (SWM and LTM). Results showed that navigation performance decreased with increasing memory demands while the dependence on the hierarchical planning heuristic increased.

Nuclear targeting of the maize R protein requires two nuclear localization sequences

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

Shieh, M.W.; Raikhel, N.V.; Wessler, S.R.

1993-02-01

Previous genetic and structural evidence indicates that the maize R gene encodes a nuclear transcriptional activating factor. In-frame carboxyl- and amino-terminal fusions of the R gene to the reporter gene encoding [beta]-glucuronidase (GUS) were sufficient to direct GUS to the nucleus of the transiently transformed onion (Allium cepa) epidermal cells. Further analysis of chimeric constructs containing regions of the R gene fused to the GUS cDNA revealed three specific nuclear localization sequences (NLSs) that were capable of redirecting the GUS protein to the nucleus. Amino-terminal NLS-A (amino acids 100-109, GDRRAAPARP) contained several arginine residues; a similar localization signal is foundmore » in only a few viral proteins. The medial NLS-M (amino acids 419-428, MSERKRREKL) is a simian virus 40 large T antigen-type NLS, and the carboxyl-terminal NLS-C (amino acids 598-610, MISESLRKAIGKR) is a mating type [alpha]2 type. NLSs M and C are independently sufficient to direct the GUS protein to the nucleus when it is fused at the amino terminus of GUS, whereas NLS-A fused to GUS partitioned between the nucleus and cytoplasm. Similar partitioning was observed when localization signals NLS-A and NLS-C were independently fused to the carboxy-terminal portion of GUS. A sequential deletion of the localization signals indicated that the amino-terminal and carboxyl-terminal fusions of R and GUS were redirected to the nucleus only when both NLS-A and -M, or NLS-C and -M, were present. These results indicate that multiple localization signals are necessary for nuclear targeting of this protein. The conservation of the localization signals within the alleles of R and similar proteins from other organisms is also discussed. 45 refs., 6 figs.« less

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

Heat localization for targeted tumor treatment with nanoscale near-infrared radiation absorbers

PubMed Central

Xie, Bin; Singh, Ravi; Torti, F. M.; Keblinski, Pawel; Torti, Suzy

2012-01-01

Focusing heat delivery while minimizing collateral damage to normal tissues is essential for successful nanoparticle-mediated laser-induced thermal cancer therapy. We present thermal maps obtained via magnetic resonance imaging (MRI) characterizing laser heating of a phantom tissue containing a multiwalled carbon nanotube inclusion. The data demonstrate that heating continuously over tens of seconds leads to poor localization (~ 0.5 cm) of the elevated temperature region. By contrast, for the same energy input, heat localization can be reduced to the millimeter rather than centimeter range by increasing the laser power and shortening the pulse duration. The experimental data can be well understood within a simple diffusive heat conduction model. Analysis of the model indicates that to achieve 1 mm or better resolution, heating pulses of ~ 2s or less need to be used with appropriately higher heating power. Modeling these data using a diffusive heat conduction analysis predicts parameters for optimal targeted delivery of heat for ablative therapy. PMID:22948207

7 CFR 799.7 - Early involvement in private and state and local activities requiring Federal approval.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 7 2014-01-01 2014-01-01 false Early involvement in private and state and local activities requiring Federal approval. 799.7 Section 799.7 Agriculture Regulations of the Department of Agriculture (Continued) FARM SERVICE AGENCY, DEPARTMENT OF AGRICULTURE ENVIRONMENTAL PROTECTION ENVIRONMENTAL...

Effects of Exposure to Environmental Groups on Student Awareness of Environmental Issues and Their Desire to Be Locally Involved

ERIC Educational Resources Information Center

Burke, Ann M.

2017-01-01

This study investigated changes in high school students' awareness of environmental issues and their intent to be involved with local environmental groups after attendance at an environmental fair that exposed them to local environmental groups. A comparison of prefair and postfair surveys given to students indicated a highly significant increase…

Localized Harmonic Motion Imaging for Focused Ultrasound Surgery Targeting

PubMed Central

Curiel, Laura; Hynynen, Kullervo

2011-01-01

Recently, an in vivo real-time ultrasound-based monitoring technique that uses localized harmonic motion (LHM) to detect changes in tissues during focused ultrasound surgery (FUS) has been proposed to control the exposure. This technique can potentially be used as well for targeting imaging. In the present study we evaluated the potential of using LHM to detect changes in stiffness and the feasibility of using it for imaging purposes in phantoms and in vivo tumor detection. A single-element FUS transducer (80 mm focal length, 100 mm diameter, 1.485 MHz) was used for inducing a localized harmonic motion and a separate ultrasound diagnostic transducer excited by a pulser/receiver (5 kHz PRF, 5 MHz) was used to track motion. The motion was estimated using cross-correlation techniques on the acquired RF signal. Silicon phantom studies were performed in order to determine the size of inclusion that was possible to detect using this technique. Inclusions were discerned from the surroundings as a reduction on LHM amplitude and it was possible to depict inclusions as small as 4 mm. The amplitude of the induced LHM was always lower at the inclusions as compared with the one obtained at the surroundings. Ten New Zealand rabbits had VX2 tumors implanted on their thighs and LHM was induced and measured at the tumor region. Tumors (as small as 10 mm in length and 4 mm in width) were discerned from the surroundings as a reduction on LHM amplitude. PMID:21683514

Transorbital target localization in the porcine model

NASA Astrophysics Data System (ADS)

DeLisi, Michael P.; Mawn, Louise A.; Galloway, Robert L.

2013-03-01

Current pharmacological therapies for the treatment of chronic optic neuropathies such as glaucoma are often inadequate due to their inability to directly affect the optic nerve and prevent neuron death. While drugs that target the neurons have been developed, existing methods of administration are not capable of delivering an effective dose of medication along the entire length of the nerve. We have developed an image-guided system that utilizes a magnetically tracked flexible endoscope to navigate to the back of the eye and administer therapy directly to the optic nerve. We demonstrate the capabilities of this system with a series of targeted surgical interventions in the orbits of live pigs. Target objects consisted of NMR microspherical bulbs with a volume of 18 μL filled with either water or diluted gadolinium-based contrast, and prepared with either the presence or absence of a visible coloring agent. A total of 6 pigs were placed under general anesthesia and two microspheres of differing color and contrast content were blindly implanted in the fat tissue of each orbit. The pigs were scanned with T1-weighted MRI, image volumes were registered, and the microsphere containing gadolinium contrast was designated as the target. The surgeon was required to navigate the flexible endoscope to the target and identify it by color. For the last three pigs, a 2D/3D registration was performed such that the target's coordinates in the image volume was noted and its location on the video stream was displayed with a crosshair to aid in navigation. The surgeon was able to correctly identify the target by color, with an average intervention time of 20 minutes for the first three pigs and 3 minutes for the last three.

Localization of genes involved in the metabolic syndrome using multivariate linkage analysis.

PubMed

Olswold, Curtis; de Andrade, Mariza

2003-12-31

There are no well accepted criteria for the diagnosis of the metabolic syndrome. However, the metabolic syndrome is identified clinically by the presence of three or more of these five variables: larger waist circumference, higher triglyceride levels, lower HDL-cholesterol concentrations, hypertension, and impaired fasting glucose. We use sets of two or three variables, which are available in the Framingham Heart Study data set, to localize genes responsible for this syndrome using multivariate quantitative linkage analysis. This analysis demonstrates the applicability of using multivariate linkage analysis and how its use increases the power to detect linkage when genes are involved in the same disease mechanism.

Targeting Resources for Local Growth.

ERIC Educational Resources Information Center

Casto, James E.

2001-01-01

Focusing state and federal dollars on targeted areas, the Kentucky Appalachian Community Development Initiative helps communities in eastern Kentucky fund their own strategies for economic growth. In Hindman, the project focuses on creating the Kentucky School of Crafts, to train master artisans; supporting the Kentucky Appalachian Artisan Center;…

The SPOR Domain, a Widely Conserved Peptidoglycan Binding Domain That Targets Proteins to the Site of Cell Division.

PubMed

Yahashiri, Atsushi; Jorgenson, Matthew A; Weiss, David S

2017-07-15

Sporulation-related repeat (SPOR) domains are small peptidoglycan (PG) binding domains found in thousands of bacterial proteins. The name "SPOR domain" stems from the fact that several early examples came from proteins involved in sporulation, but SPOR domain proteins are quite diverse and contribute to a variety of processes that involve remodeling of the PG sacculus, especially with respect to cell division. SPOR domains target proteins to the division site by binding to regions of PG devoid of stem peptides ("denuded" glycans), which in turn are enriched in septal PG by the intense, localized activity of cell wall amidases involved in daughter cell separation. This targeting mechanism sets SPOR domain proteins apart from most other septal ring proteins, which localize via protein-protein interactions. In addition to SPOR domains, bacteria contain several other PG-binding domains that can exploit features of the cell wall to target proteins to specific subcellular sites. Copyright © 2017 American Society for Microbiology.

A stochastic model for eye movements during fixation on a stationary target.

NASA Technical Reports Server (NTRS)

Vasudevan, R.; Phatak, A. V.; Smith, J. D.

1971-01-01

A stochastic model describing small eye movements occurring during steady fixation on a stationary target is presented. Based on eye movement data for steady gaze, the model has a hierarchical structure; the principal level represents the random motion of the image point within a local area of fixation, while the higher level mimics the jump processes involved in transitions from one local area to another. Target image motion within a local area is described by a Langevin-like stochastic differential equation taking into consideration the microsaccadic jumps pictured as being due to point processes and the high frequency muscle tremor, represented as a white noise. The transform of the probability density function for local area motion is obtained, leading to explicit expressions for their means and moments. Evaluation of these moments based on the model is comparable with experimental results.

Using local culture and gender roles to improve male involvement in maternal health in southern Nigeria.

PubMed

Adeleye, Omokhoa Adedayo; Aldoory, Linda; Parakoyi, Dauda Bayo

2011-11-01

Group health talks were conducted in Ekiadolor, Southern Nigeria, to improve male attitudes and practices regarding their involvement in prenatal care and family planning. Intervention planners highlight the importance of embedding local cultural norms along with co-opting gendered beliefs for purposes of planning and implementing the group talks. The authors facilitated 9 groups of adult males mostly from the traditional hierarchy of the community. Using gender theory as an analytical lens along with the application of local cultural beliefs and norms, a useful communication intervention was developed that increased the possibility of positive male engagement in maternal health in 1 Nigerian community.

MicroRNA-320 involves in the cardioprotective effect of insulin against myocardial ischemia by targeting survivin.

PubMed

Yang, Ni; Wu, Liuzhong; Zhao, Ying; Zou, Ning; Liu, Chunfeng

2018-04-01

It is generally accepted that insulin exerts an antiapoptotic effect against ischemia/reperfusion through the activation of PI3K/Akt/mTOR pathway. MicroRNAs involve in multiple cardiac pathophysiological processes, including ischemia/reperfusion-induced cardiac injury. However, the regulation of microRNAs in the cardioprotective effect of insulin is rarely discussed. In this study, using a cell model of ischemia through culturing H9C2 cardiac myocytes in serum-free medium with hypoxia, we demonstrated that pretreatment with insulin significantly inhibited cell apoptosis and downregulated microRNA-320 (miR-320) expression. Interestingly, miR-320 mimic impaired the cardioprotective effect of insulin against myocardial ischemia injury by targeting survivin, which is a member of the family of inhibitor of apoptosis proteins. Suppression miR-320 expression by miR-320 inhibitor in H9C2 cells with myocardial ischemia mimics the cardioprotective effect of insulin by maintaining survivin expression. Taken together, miR-320-mediated survivin expression involves in cardioprotective effect of insulin against myocardial ischemia injury. Myocardial ischemia/reperfusion (I/R) injury remains an important clinical problem with extremely deficient clinical therapies. Insulin exerts an antiapoptotic effect against I/R through the activation of PI3K/Akt/mTOR pathway. Here, we provided evidences to show that microRNA-320 involves in the cardioprotective effect of insulin by targeting survivin, which is an inhibitor of apoptosis protein and functions as a key regulator in cell apoptosis and involves in the tumour genesis and progression. Our findings may provide a new potential therapeutic strategy for I/R injury and ischemic heart disease. Copyright © 2018 John Wiley & Sons, Ltd.

ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung cancer.

PubMed

Nestle, Ursula; De Ruysscher, Dirk; Ricardi, Umberto; Geets, Xavier; Belderbos, Jose; Pöttgen, Christoph; Dziadiuszko, Rafal; Peeters, Stephanie; Lievens, Yolande; Hurkmans, Coen; Slotman, Ben; Ramella, Sara; Faivre-Finn, Corinne; McDonald, Fiona; Manapov, Farkhad; Putora, Paul Martin; LePéchoux, Cécile; Van Houtte, Paul

2018-04-01

Radiotherapy (RT) plays a major role in the curative treatment of locally advanced non-small cell lung cancer (NSCLC). Therefore, the ACROP committee was asked by the ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)radiotherapy (RT) and adjuvant RT for locally advanced NSCLC. The guidelines given here are a result of the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing procedure within the committee. Hence, we provide advice for methods and time-points of diagnostics and imaging before the start of treatment planning and for the mandatory and optional imaging to be used for planning itself. Concerning target volumes, recommendations are given for GTV delineation of primary tumour and lymph nodes followed by issues related to the delineation of CTVs for definitive and adjuvant radiotherapy. In the context of PTV delineation, recommendations about the management of geometric uncertainties and target motion are given. We further provide our opinions on normal tissue delineation and organisational and responsibility questions in the process of target volume delineation. This guideline intends to contribute to the standardisation and optimisation of the process of RT treatment planning for clinical practice and prospective studies. Copyright © 2018 Elsevier B.V. All rights reserved.

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

Sulfadiazine resistance in Toxoplasma gondii: no involvement of overexpression or polymorphisms in genes of therapeutic targets and ABC transporters

PubMed Central

Doliwa, Christelle; Escotte-Binet, Sandie; Aubert, Dominique; Sauvage, Virginie; Velard, Frédéric; Schmid, Aline; Villena, Isabelle

2013-01-01

Several treatment failures have been reported for the treatment of toxoplasmic encephalitis, chorioretinitis, and congenital toxoplasmosis. Recently we found three Toxoplasma gondii strains naturally resistant to sulfadiazine and we developed in vitro two sulfadiazine resistant strains, RH-RSDZ and ME-49-RSDZ, by gradual pressure. In Plasmodium, common mechanisms of drug resistance involve, among others, mutations and/or amplification within genes encoding the therapeutic targets dhps and dhfr and/or the ABC transporter genes family. To identify genotypic and/or phenotypic markers of resistance in T. gondii, we sequenced and analyzed the expression levels of therapeutic targets dhps and dhfr, three ABC genes, two Pgp, TgABC.B1 and TgABC.B2, and one MRP, TgABC.C1, on sensitive strains compared to sulfadiazine resistant strains. Neither polymorphism nor overexpression was identified. Contrary to Plasmodium, in which mutations and/or overexpression within gene targets and ABC transporters are involved in antimalarial resistance, T. gondii sulfadiazine resistance is not related to these toxoplasmic genes studied. PMID:23707894

Targeted predation of extrafloral nectaries by insects despite localized chemical defences

PubMed Central

Gish, Moshe; Mescher, Mark C.; De Moraes, Consuelo M.

2015-01-01

Extrafloral (EF) nectaries recruit carnivorous arthropods that protect plants from herbivory, but they can also be exploited by nectar thieves. We studied the opportunistic, targeted predation (and destruction) of EF nectaries by insects, and the localized chemical defences that plants presumably use to minimize this effect. In field and laboratory experiments, we identified insects that were possibly responsible for EF nectary predation in Vicia faba (fava bean) and determined the extent and accuracy of the feeding damage done to the EF nectaries by these insects. We also performed biochemical analyses of plant tissue samples in order to detect microscale distribution patterns of chemical defences in the area of the EF nectary. We observed selective, targeted feeding on EF nectaries by several insect species, including some that are otherwise not primarily herbivorous. Biochemical analyses revealed high concentrations of l-3,4-dihydroxyphenylalanine, a non-protein amino acid that is toxic to insects, near and within the EF nectaries. These results suggest that plants allocate defences to the protection of EF nectaries from predation, consistent with expectations of optimal defence theory, and that this may not be entirely effective, as insects limit their exposure to these defences by consuming only the secreting tissue of the nectary. PMID:26446809

PSMA, EpCAM, VEGF and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy.

PubMed

Rybalov, Maxim; Ananias, Hildo J K; Hoving, Hilde D; van der Poel, Henk G; Rosati, Stefano; de Jong, Igle J

2014-04-10

In this retrospective pilot study, the expression of the prostate-specific membrane antigen (PSMA), the epithelial cell adhesion molecule (EpCAM), the vascular endothelial growth factor (VEGF) and the gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated, and their adequacy for targeted imaging was analyzed. Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Immunohistochemistry was performed. A pathologist scored the immunoreactivity in prostate cancer and stroma. Staining for PSMA was seen in 100% (17/17), EpCAM in 82.3% (14/17), VEGF in 82.3% (14/17) and GRPR in 100% (17/17) of prostate cancer specimens. Staining for PSMA, EpCAM and VEGF was seen in 0% (0/17) and for GRPR in 100% (17/17) of the specimens' stromal compartments. In 11.8% (2/17) of cases, the GRPR staining intensity of prostate cancer was higher than stroma, while in 88.2% (15/17), the staining was equal. Based on the absence of stromal staining, PSMA, EpCAM and VEGF show high tumor distinctiveness. Therefore, PSMA, EpCAM and VEGF can be used as targets for the bioimaging of recurrent prostate cancer after EBRT to exclude metastatic disease and/or to plan local salvage therapy.

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

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.

The effect of tailoring a model HIV prevention program for local adolescent target audiences.

PubMed

Kennedy, M G; Mizuno, Y; Hoffman, R; Baume, C; Strand, J

2000-06-01

In five U.S. sites (Nashville, Tennessee; Newark, New Jersey; northern Virginia; Phoenix, Arizona; and Sacramento, California), HIV risk-reduction workshops were mounted as a part of the Prevention Marketing Initiative (PMI). In four of the five sites, the workshop curriculum was a version of Be Proud! Be Responsible! (Jemmott, Jemmott, & McCaffree, 1996) that had been tailored to fit the needs of local target audiences. This article describes the evaluation of the PMI workshops. Protective effects on several behavioral determinants and behavioral outcome measures were observed 1 month after the workshops. Based on the overall pattern of results, it was concluded that the PMI workshops reduced the likelihood of unprotected sex among participants. The intervention developed by Jemmott and colleagues appears to have retained its effectiveness after it was tailored to meet perceived local needs.

Multivariate analysis for the estimation of target localization errors in fiducial marker-based radiotherapy

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

Takamiya, Masanori; Nakamura, Mitsuhiro, E-mail: m-nkmr@kuhp.kyoto-u.ac.jp; Akimoto, Mami

Purpose: To assess the target localization error (TLE) in terms of the distance between the target and the localization point estimated from the surrogates (|TMD|), the average of respiratory motion for the surrogates and the target (|aRM|), and the number of fiducial markers used for estimating the target (n). Methods: This study enrolled 17 lung cancer patients who subsequently underwent four fractions of real-time tumor tracking irradiation. Four or five fiducial markers were implanted around the lung tumor. The three-dimensional (3D) distance between the tumor and markers was at maximum 58.7 mm. One of the markers was used as themore » target (P{sub t}), and those markers with a 3D |TMD{sub n}| ≤ 58.7 mm at end-exhalation were then selected. The estimated target position (P{sub e}) was calculated from a localization point consisting of one to three markers except P{sub t}. Respiratory motion for P{sub t} and P{sub e} was defined as the root mean square of each displacement, and |aRM| was calculated from the mean value. TLE was defined as the root mean square of each difference between P{sub t} and P{sub e} during the monitoring of each fraction. These procedures were performed repeatedly using the remaining markers. To provide the best guidance on the answer with n and |TMD|, fiducial markers with a 3D |aRM ≥ 10 mm were selected. Finally, a total of 205, 282, and 76 TLEs that fulfilled the 3D |TMD| and 3D |aRM| criteria were obtained for n = 1, 2, and 3, respectively. Multiple regression analysis (MRA) was used to evaluate TLE as a function of |TMD| and |aRM| in each n. Results: |TMD| for n = 1 was larger than that for n = 3. Moreover, |aRM| was almost constant for all n, indicating a similar scale for the marker’s motion near the lung tumor. MRA showed that |aRM| in the left–right direction was the major cause of TLE; however, the contribution made little difference to the 3D TLE because of the small amount of motion in the left–right direction

Putrescine-Dependent Re-Localization of TvCP39, a Cysteine Proteinase Involved in Trichomonas vaginalis Cytotoxicity

PubMed Central

Carvajal-Gamez, Bertha Isabel; Quintas-Granados, Laura Itzel; Arroyo, Rossana; Vázquez-Carrillo, Laura Isabel; Ramón-Luing, Lucero De los Angeles; Carrillo-Tapia, Eduardo; Alvarez-Sánchez, María Elizbeth

2014-01-01

Polyamines are involved in the regulation of some Trichomonas vaginalis virulence factors such as the transcript, proteolytic activity, and cytotoxicity of TvCP65, a cysteine proteinase (CP) involved in the trichomonal cytotoxicity. In this work, we reported the putrescine effect on TvCP39, other CP that also participate in the trichomonal cytotoxicity. Parasites treated with 1,4-diamino-2-butanone (DAB) (an inhibitor of putrescine biosynthesis), diminished the amount and proteolytic activity of TvCP39 as compared with untreated parasites. Inhibition of putrescine biosynthesis also reduced ∼80% the tvcp39 mRNA levels according to RT-PCR and qRT-PCR assays. Additionally, actinomycin D-treatment showed that the tvcp39 mRNA half-life decreased in the absence of putrescine. However, this reduction was restored by exogenous putrescine addition, suggesting that putrescine is necessary for tvcp39 mRNA stability. TvCP39 was localized in the cytoplasm but, in DAB treated parasites transferred into exogenous putrescine culture media, TvCP39 was re-localized to the nucleus and nuclear periphery of trichomonads. Interestingly, the amount and proteolytic activity of TvCP39 was recovered as well as the tvcp39 mRNA levels were restored when putrescine exogenous was added to the DAB-treated parasites. In conclusion, our data show that putrescine regulate the TvCP39 expression, protein amount, proteolytic activity, and cellular localization. PMID:25251406

INCENP Centromere and Spindle Targeting: Identification of Essential Conserved Motifs and Involvement of Heterochromatin Protein HP1

PubMed Central

Ainsztein, Alexandra M.; Kandels-Lewis, Stefanie E.; Mackay, Alastair M.; Earnshaw, William C.

1998-01-01

The inner centromere protein (INCENP) has a modular organization, with domains required for chromosomal and cytoskeletal functions concentrated near the amino and carboxyl termini, respectively. In this study we have identified an autonomous centromere- and midbody-targeting module in the amino-terminal 68 amino acids of INCENP. Within this module, we have identified two evolutionarily conserved amino acid sequence motifs: a 13–amino acid motif that is required for targeting to centromeres and transfer to the spindle, and an 11–amino acid motif that is required for transfer to the spindle by molecules that have targeted previously to the centromere. To begin to understand the mechanisms of INCENP function in mitosis, we have performed a yeast two-hybrid screen for interacting proteins. These and subsequent in vitro binding experiments identify a physical interaction between INCENP and heterochromatin protein HP1Hsα. Surprisingly, this interaction does not appear to be involved in targeting INCENP to the centromeric heterochromatin, but may instead have a role in its transfer from the chromosomes to the anaphase spindle. PMID:9864353

Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism.

PubMed

Liao, Wenjuan; Liu, Hongbing; Zhang, Yiwei; Jung, Ji Hoon; Chen, Jiaxiang; Su, Xiaohua; Kim, Yeong C; Flores, Elsa R; Wang, San Ming; Czarny-Ratajczak, Malwina; Li, Wen; Zeng, Shelya X; Lu, Hua

2017-08-21

TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.

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.

Molecular basis of Williams-Beuren syndrome: TFII-I regulated targets involved in craniofacial development.

PubMed

Makeyev, Aleksandr V; Bayarsaihan, Dashzeveg

2011-01-01

The aim of this study is to identify gene targets of TFII-I transcription factors involved in craniofacial development. Recent findings in individuals with Williams-Beuren syndrome who show facial dysmorphism and cognitive defects have pointed to TFII-I genes (GTF2I and GTF2IRD1) as the prime candidates responsible for these clinical features. However, TFII-I proteins are multifunctional transcriptional factors regulating a number of genes during development, and how their haploinsufficiency leads to the Williams-Beuren syndrome phenotype is currently unknown. Here we report the identification of three genes with a well-established relevance to craniofacial development as direct TFII-I targets. These genes, craniofacial development protein 1 (Cfdp1), Sec23 homolog A (Sec23a), and nuclear receptor binding SET domain protein 1 (Nsd1), contain consensus TFII-I binding sites in their proximal promoters; the chromatin immunoprecipitation analysis showed that TFII-I transcription factors are recruited to these sites in vivo. The results suggest that transcriptional regulation of these genes by TFII-I proteins could provide a possible genotype-phenotype link in Williams-Beuren syndrome.

The prelude on novel receptor and ligand targets involved in the treatment of diabetes mellitus.

PubMed

Jonnalagadda, Venu Gopal; Ram Raju, Allam Venkata Sita; Pittala, Srinivas; Shaik, Afsar; Selkar, Nilakash Annaji

2014-01-01

Metabolic disorders are a group of disorders, due to the disruption of the normal metabolic process at a cellular level. Diabetes Mellitus and Tyrosinaemia are the majorly reported metabolic disorders. Among them, Diabetes Mellitus is a one of the leading metabolic syndrome, affecting 5 to 7 % of the population worldwide and mainly characterised by elevated levels of glucose and is associated with two types of physiological event disturbances such as impaired insulin secretion and insulin resistance. Up to now, various treatment strategies are like insulin, alphaglucosidase inhibitors, biguanides, incretins were being followed. Concurrently, various novel therapeutic strategies are required to advance the therapy of Diabetes mellitus. For the last few decades, there has been an extensive research in understanding the metabolic pathways involved in Diabetes Mellitus at the cellular level and having the profound knowledge on cell-growth, cell-cycle, and apoptosis at a molecular level provides new targets for the treatment of Diabetes Mellitus. Receptor signalling has been involved in these mechanisms, to translate the information coming from outside. To understand the various receptors involved in these pathways, we must have a sound knowledge on receptors and ligands involved in it. This review mainly summarises the receptors and ligands which are involved the Diabetes Mellitus. Finally, researchers have to develop the alternative chemical moieties that retain their affinity to receptors and efficacy. Diabetes Mellitus being a metabolic disorder due to the glucose surfeit, demands the need for regular exercise along with dietary changes.

40 CFR 310.9 - If more than one local agency or government is involved, can each receive up to $25,000?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 27 2010-07-01 2010-07-01 false If more than one local agency or... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SUPERFUND, EMERGENCY PLANNING, AND COMMUNITY RIGHT-TO-KNOW PROGRAMS... Reimbursed? § 310.9 If more than one local agency or government is involved, can each receive up to $25,000...

SU-F-J-13: Choosing An IMRT Technique in the Treatment of Head and Neck Cancer with Daily Localization Uncertainties

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

Lin, T; Wang, L; Galloway, T

Purpose: Head and Neck cancer treatment with IMRT/VMAT has two choices: split-filed IMRT(SFI), in which the LAN is treated with a separate anterior field and the extended whole-field IMRT(WFI) in which LAN is included with the IMRT/VMAT field. This study shows that under the same dose limit criteria, choosing the technique becomes a critical issue if daily localization and immobilization altered the dose distribution. Methods: Nine common head-and-neck cancer cases were chosen to illustrate how the daily localization and immobilization uncertainties affect to choose between SFI and WFI. Both SFI and WFI at upper target coverage were generated with VMAT.more » For each case, the same planning criteria were applied to the target and critical structures; therefore, similar target coverage and dose falloff can be observed in both techniques. Thirty days of kV cone beam CT(CBCT) images on each case were also delineated with contralateral and ipsilateral target as well as larynx as critical structure. About 300 CBCT images with daily delivered doses were analyzed and compared in a form of dose-volume histograms. Results: While both plans for SFI and WFI with VMAT planning utilized and meet the criteria of D95>prescription dose and for not-involved larynx with mean dose <35Gy and V55<10%, the daily localization and immobilization has a great contribution to the resulted dose delivery. With WFI, the better daily contralateral and ipsilateral neck target coverage can reflect a simpler or shorter localization; however, a much superior avoidance (WFI: mean dose a 42.5Gy; SFI: mean dose a 18.9Gy) of the non-involved larynx from the SFI is preferred. Conclusion: Dosimetrically, SFI and WFI are equally well for head and Neck cancer treatment with VMAT technique; however, if considering the contribution of daily localization(CBCT) method uncertainties, SFI is better with sparing non-involved larynx and WFI has better target coverage.« less

Subcellular Localization Screening of Colletotrichum higginsianum Effector Candidates Identifies Fungal Proteins Targeted to Plant Peroxisomes, Golgi Bodies, and Microtubules.

PubMed

Robin, Guillaume P; Kleemann, Jochen; Neumann, Ulla; Cabre, Lisa; Dallery, Jean-Félix; Lapalu, Nicolas; O'Connell, Richard J

2018-01-01

The genome of the hemibiotrophic anthracnose fungus, Colletotrichum higginsianum , encodes a large inventory of putative secreted effector proteins that are sequentially expressed at different stages of plant infection, namely appressorium-mediated penetration, biotrophy and necrotrophy. However, the destinations to which these proteins are addressed inside plant cells are unknown. In the present study, we selected 61 putative effector genes that are highly induced in appressoria and/or biotrophic hyphae. We then used Agrobacterium -mediated transformation to transiently express them as N -terminal fusions with fluorescent proteins in cells of Nicotiana benthamiana for imaging by confocal microscopy. Plant compartments labeled by the fusion proteins in N. benthamiana were validated by co-localization with specific organelle markers, by transient expression of the proteins in the true host plant, Arabidopsis thaliana , and by transmission electron microscopy-immunogold labeling. Among those proteins for which specific subcellular localizations could be verified, nine were imported into plant nuclei, three were imported into the matrix of peroxisomes, three decorated cortical microtubule arrays and one labeled Golgi stacks. Two peroxisome-targeted proteins harbored canonical C -terminal tripeptide signals for peroxisome import via the PTS1 (peroxisomal targeting signal 1) pathway, and we showed that these signals are essential for their peroxisome localization. Our findings provide valuable information about which host processes are potentially manipulated by this pathogen, and also reveal plant peroxisomes, microtubules, and Golgi as novel targets for fungal effectors.

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.

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

An open label trial of folate receptor-targeted intraoperative molecular imaging to localize pulmonary squamous cell carcinomas

PubMed Central

Predina, Jarrod D.; Newton, Andrew D.; Xia, Leilei; Corbett, Christopher; Connolly, Courtney; Shin, Michael; Sulyok, Lydia Frezel; Litzky, Leslie; Deshpande, Charuhas; Nie, Shuming; Kularatne, Sumith A.; Low, Philip S.; Singhal, Sunil

2018-01-01

Background Clinical applicability of folate receptor-targeted intraoperative molecular imaging (FR-IMI) has been established for surgically resectable pulmonary adenocarcinoma. A role for FR-IMI in other lung cancer histologies has not been studied. In this study, we evaluate feasibility of FR-IMI in patients undergoing pulmonary resection for squamous cell carcinomas (SCCs). Methods In a human clinical trial (NCT02602119), twelve subjects with pulmonary SCCs underwent FR-IMI with a near-infrared contrast agent that targets the folate receptor-α (FRα), OTL38. Near-infrared signal from tumors and benign lung was quantified to calculate tumor-to-background ratios (TBR). Folate receptor-alpha expression was characterized, and histopathologic correlative analyses were performed to evaluate patterns of OTL38 accumulation. An exploratory analysis was performed to determine patient and histopathologic variables that predict tumor fluorescence. Results 9 of 13 SCCs (in 9 of 12 of subjects) displayed intraoperative fluorescence upon NIR evaluation (median TBR, 3.9). OTL38 accumulated within SCCs in a FRα-dependent manner. FR-IMI was reliable in localizing nodules as small as 1.1 cm, and prevented conversion to thoracotomy for nodule localization in three subjects. Upon evaluation of patient and histopathologic variables, in situ fluorescence was associated with distance from the pleural surface, and was independent of alternative variables including tumor size and metabolic activity. Conclusions This work demonstrates that FR-IMI is potentially feasible in 70% of SCC patients, and that molecular imaging can improve localization during minimally invasive pulmonary resection. These findings complement previous data demonstrating that ∼98% of pulmonary adenocarcinomas are localized during FR-IMI and suggest broad applicability for NSCLC patients undergoing resection. PMID:29568374

Planning Target Margin Calculations for Prostate Radiotherapy Based on Intrafraction and Interfraction Motion Using Four Localization Methods

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

Beltran, Chris; Herman, Michael G.; Davis, Brian J.

2008-01-01

Purpose: To determine planning target volume (PTV) margins for prostate radiotherapy based on the internal margin (IM) (intrafractional motion) and the setup margin (SM) (interfractional motion) for four daily localization methods: skin marks (tattoo), pelvic bony anatomy (bone), intraprostatic gold seeds using a 5-mm action threshold, and using no threshold. Methods and Materials: Forty prostate cancer patients were treated with external radiotherapy according to an online localization protocol using four intraprostatic gold seeds and electronic portal images (EPIs). Daily localization and treatment EPIs were obtained. These data allowed inter- and intrafractional analysis of prostate motion. The SM for the fourmore » daily localization methods and the IM were determined. Results: A total of 1532 fractions were analyzed. Tattoo localization requires a SM of 6.8 mm left-right (LR), 7.2 mm inferior-superior (IS), and 9.8 mm anterior-posterior (AP). Bone localization requires 3.1, 8.9, and 10.7 mm, respectively. The 5-mm threshold localization requires 4.0, 3.9, and 3.7 mm. No threshold localization requires 3.4, 3.2, and 3.2 mm. The intrafractional prostate motion requires an IM of 2.4 mm LR, 3.4 mm IS and AP. The PTV margin using the 5-mm threshold, including interobserver uncertainty, IM, and SM, is 4.8 mm LR, 5.4 mm IS, and 5.2 mm AP. Conclusions: Localization based on EPI with implanted gold seeds allows a large PTV margin reduction when compared with tattoo localization. Except for the LR direction, bony anatomy localization does not decrease the margins compared with tattoo localization. Intrafractional prostate motion is a limiting factor on margin reduction.« less

Hindsight regulates photoreceptor axon targeting through transcriptional control of jitterbug/Filamin and multiple genes involved in axon guidance in Drosophila.

PubMed

Oliva, Carlos; Molina-Fernandez, Claudia; Maureira, Miguel; Candia, Noemi; López, Estefanía; Hassan, Bassem; Aerts, Stein; Cánovas, José; Olguín, Patricio; Sierralta, Jimena

2015-09-01

During axon targeting, a stereotyped pattern of connectivity is achieved by the integration of intrinsic genetic programs and the response to extrinsic long and short-range directional cues. How this coordination occurs is the subject of intense study. Transcription factors play a central role due to their ability to regulate the expression of multiple genes required to sense and respond to these cues during development. Here we show that the transcription factor HNT regulates layer-specific photoreceptor axon targeting in Drosophila through transcriptional control of jbug/Filamin and multiple genes involved in axon guidance and cytoskeleton organization.Using a microarray analysis we identified 235 genes whose expression levels were changed by HNT overexpression in the eye primordia. We analyzed nine candidate genes involved in cytoskeleton regulation and axon guidance, six of which displayed significantly altered gene expression levels in hnt mutant retinas. Functional analysis confirmed the role of OTK/PTK7 in photoreceptor axon targeting and uncovered Tiggrin, an integrin ligand, and Jbug/Filamin, a conserved actin- binding protein, as new factors that participate of photoreceptor axon targeting. Moreover, we provided in silico and molecular evidence that supports jbug/Filamin as a direct transcriptional target of HNT and that HNT acts partially through Jbug/Filamin in vivo to regulate axon guidance. Our work broadens the understanding of how HNT regulates the coordinated expression of a group of genes to achieve the correct connectivity pattern in the Drosophila visual system. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1018-1032, 2015. © 2015 Wiley Periodicals, Inc.

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

Histopathology of prostate tissue after vascular-targeted photodynamic therapy for localized prostate cancer.

PubMed

Eymerit-Morin, Caroline; Zidane, Merzouka; Lebdai, Souhil; Triau, Stéphane; Azzouzi, Abdel Rahmene; Rousselet, Marie-Christine

2013-10-01

Low-risk prostate adenocarcinoma is classically managed either with active surveillance or radical therapy (such as external radiotherapy or radical prostatectomy), but both have significant side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy proposed as an alternative approach for localized, low-volume, and low-Gleason score (≤6) carcinomas. We report histological modifications observed in prostate biopsies of 56 patients, performed 6 months after VTP using the photosensitizer TOOKAD® Soluble (WST11) and low-energy laser administered in the tumor area transperineally by optic fibers. In 53 patients, we observed sharply demarcated hyaline fibrotic scars, with or without rare atrophic glands, sometimes reduced to corpora amylacea surrounded by giant multinuclear macrophages. Mild chronic inflammation, hemosiderin, and coagulative necrosis were also observed. When residual cancer was present in a treated lobe (17 patients), it was always located outside the scar, most often close to the prostate capsule, and it showed no therapy-related modification. Histopathological interpretation of post-WST11 VTP prostate biopsies was straightforward, in contrast with that of prostate biopsies after radio or hormonal therapy, which introduces lesions difficult to interpret. VTP resulted in complete ablation of cancer in the targeted area.

Evidence of locally enhanced target heating due to instabilities of counter-streaming fast electron beams

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

Koester, Petra; Cecchetti, Carlo A.; Booth, Nicola

2015-02-15

The high-current fast electron beams generated in high-intensity laser-solid interactions require the onset of a balancing return current in order to propagate in the target material. Such a system of counter-streaming electron currents is unstable to a variety of instabilities such as the current-filamentation instability and the two-stream instability. An experimental study aimed at investigating the role of instabilities in a system of symmetrical counter-propagating fast electron beams is presented here for the first time. The fast electron beams are generated by double-sided laser-irradiation of a layered target foil at laser intensities above 10{sup 19 }W/cm{sup 2}. High-resolution X-ray spectroscopy ofmore » the emission from the central Ti layer shows that locally enhanced energy deposition is indeed achieved in the case of counter-propagating fast electron beams.« less

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

Targeting of Drosophila Rhodopsin Requires Helix 8 but Not the Distal C-Terminus

PubMed Central

Kock, Ines; Bulgakova, Natalia A.; Knust, Elisabeth; Sinning, Irmgard; Panneels, Valérie

2009-01-01

Background The fundamental role of the light receptor rhodopsin in visual function and photoreceptor cell development has been widely studied. Proper trafficking of rhodopsin to the photoreceptor membrane is of great importance. In human, mutations in rhodopsin involving its intracellular mislocalization, are the most frequent cause of autosomal dominant Retinitis Pigmentosa, a degenerative retinal pathology characterized by progressive blindness. Drosophila is widely used as an animal model in visual and retinal degeneration research. So far, little is known about the requirements for proper rhodopsin targeting in Drosophila. Methodology/Principal Findings Different truncated fly-rhodopsin Rh1 variants were expressed in the eyes of Drosophila and their localization was analyzed in vivo or by immunofluorescence. A mutant lacking the last 23 amino acids was found to properly localize in the rhabdomeres, the light-sensing organelle of the photoreceptor cells. This constitutes a major difference to trafficking in vertebrates, which involves a conserved QVxPA motif at the very C-terminus. Further truncations of Rh1 indicated that proper localization requires the last amino acid residues of a region called helix 8 following directly the last transmembrane domain. Interestingly, the very C-terminus of invertebrate visual rhodopsins is extremely variable but helix 8 shows conserved amino acid residues that are not conserved in vertebrate homologs. Conclusions/Significance Despite impressive similarities in the folding and photoactivation of vertebrate and invertebrate visual rhodopsins, a striking difference exists between mammalian and fly rhodopsins in their requirements for proper targeting. Most importantly, the distal part of helix 8 plays a central role in invertebrates. Since the last amino acid residues of helix 8 are dispensable for rhodopsin folding and function, we propose that this domain participates in the recognition of targeting factors involved in

The role of visual context in manual target localization

NASA Technical Reports Server (NTRS)

Barry, Susan R.

1993-01-01

During space flight and immediately after return to the 1-g environment of earth, astronauts experience perceptual and sensory-motor disturbances. These changes result from adaptation of the astronaut to the microgravity environment of space. During space flight, sensory information from the eyes, limbs, and vestibular organs is reinterpreted by the central nervous system in order to produce appropriate body movements in the microgravity. This adaptation takes several days to develop. Upon return to earth, the changes in the sensory-motor system are no longer appropriate to a 1-g environment. Over several days, the astronaut must re-adapt to the terrestrial environment. Alterations in sensory-motor function may affect eye-head-hand coordination and, thus, the crewmember's ability to manually locate objects in extrapersonal space. Previous reports have demonstrated that crewmembers have difficulty in estimating joint and limb position and in pointing to memorized target positions on orbit and immediately postflight. The ability to point at or reach toward an object or perform other manual tasks is essential for safe Shuttle operation and may be compromised particularly during re-entry and landing sequences and during possible emergency egress from the Shuttle. An understanding of eye-head-hand coordination and the changes produced during space flight is necessary to develop effective countermeasures. This summer's project formed part of the study of the sensory cues use in the manual localization of objects.

Complete resection of locally advanced ovarian carcinoma fixed to the pelvic sidewall and involving external and internal iliac vessels.

PubMed

Nishikimi, Kyoko; Tate, Shinichi; Matsuoka, Ayumu; Shozu, Makio

2017-08-01

Locally advanced ovarian carcinomas may be fixed to the pelvic sidewall, and although these often involve the internal iliac vessels, they rarely involve the external iliac vessels. Such tumors are mostly considered inoperable. We present a surgical technique for complete resection of locally advanced ovarian carcinoma fixed to the pelvic sidewall and involving external and internal iliac vessels. A 69-year-old woman presented with ovarian carcinoma fixed to the right pelvic sidewall, which involved the right external and internal iliac arteries and veins and the right lower ureter, rectum, and vagina. We cut the external iliac artery and vein at the bifurcation and at the inguinal ligament to resect the external artery and vein. Then, we reconstructed the arterial and venous supplies of the right external artery and vein with grafts. After creating a wide space immediately inside of the sacral plexus to allow the tumor fixed to pelvic sidewall with the internal iliac vessels to move medially, we performed total internal iliac vessel resection. We achieved complete en bloc tumor resection with the right external and internal artery and vein, right ureter, vagina, and rectum adhering to the tumor. There were no intra- or postoperative complications, such as bleeding, graft occlusion, infection, or limb edema. Exfoliation from the sacral plexus and total resection with external and internal iliac vessels enables complete resection of the tumor fixed to the pelvic sidewall. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Two MATE Transporters with Different Subcellular Localization are Involved in Al Tolerance in Buckwheat.

PubMed

Lei, Gui Jie; Yokosho, Kengo; Yamaji, Naoki; Ma, Jian Feng

2017-12-01

Buckwheat (Fagopyrum esculentum) shows high tolerance to aluminum (Al) toxicity, but the molecular mechanisms responsible for this high Al tolerance are still poorly understood. Here, we investigated the involvement of two MATE (multi-drug and toxic compound extrusion) genes in Al tolerance. Both FeMATE1 and FeMATE2 showed efflux transport activity for citrate, but not for oxalate when expressed in Xenopus oocytes. A transient assay with buckwheat leaf protoplasts using green fluorescent protein (GFP) fusion showed that FeMATE1 was mainly localized to the plasma membrane, whereas FeMATE2 was localized to the trans-Golgi and Golgi. The expression of FeMATE1 was induced by Al only in the roots, but that of FeMATE2 was up-regulated in both the roots and leaves. Furthermore, the expression of both genes only responded to Al toxicity, but not to other stresses including low pH, cadmium (Cd) and lanthanum (La). Heterologous expression of FeMATE1 or FeMATE2 in the Arabidopsis mutant atmate partially rescued its Al tolerance. Expression of FeMATE1 also partially recovered the Al-induced secretion of citrate in the transgenic lines, whereas expression of FeMATE2 did not complement the citrate secretion. Further physiological analysis showed that buckwheat roots also secreted citrate in addition to oxalate in response to Al in a dose-responsive manner. Taken together, our results indicate that FeMATE1 is involved in the Al-activated citrate secretion in the roots, while FeMATE2 is probably responsible for transporting citrate into the Golgi system for the internal detoxification of Al in the roots and leaves of buckwheat. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

WE-AB-BRA-09: Registration of Preoperative MRI to Intraoperative Radiographs for Automatic Vertebral Target Localization

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

De Silva, T; Uneri, A; Ketcha, M

Purpose: Accurate localization of target vertebrae is essential to safe, effective spine surgery, but wrong-level surgery occurs with surprisingly high frequency. Recent research yielded the “LevelCheck” method for 3D-2D registration of preoperative CT to intraoperative radiographs, providing decision support for level localization. We report a new method (MR-LevelCheck) to perform 3D-2D registration based on preoperative MRI, presenting a solution for the increasingly common scenario in which MRI (not CT) is used for preoperative planning. Methods: Direct extension of LevelCheck is confounded by large mismatch in image intensity between MRI and radiographs. The proposed method overcomes such challenges with a simplemore » vertebrae segmentation. Using seed points at centroids, vertebrae are segmented using continuous max-flow method and dilated by 1.8 mm to include surrounding cortical bone (inconspicuous in T2w-MRI). MRI projections are computed (analogous to DRR) using segmentation and registered to intraoperative radiographs. The method was tested in a retrospective IRB-approved study involving 11 patients undergoing cervical, thoracic, or lumbar spine surgery following preoperative MRI. Registration accuracy was evaluated in terms of projection-distance-error (PDE) between the true and estimated location of vertebrae in each radiograph. 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. Segmentation achieved Dice coefficient = 89.2 ± 2.3 and mean-absolute-distance (MAD) = 1.5 ± 0.3 mm. Registration demonstrated robust performance under realistic patient variations, with PDE = 4.0 ± 1.9 mm (median ± iqr) and converged with run-time = 23.3 ± 1.7 s. Conclusion: The MR-LevelCheck algorithm provides an important extension to a previously validated decision support tool in spine surgery by extending its

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.

Inter-kingdom prediction certainty evaluation of protein subcellular localization tools: microbial pathogenesis approach for deciphering host microbe interaction.

PubMed

Khan, Abdul Arif; Khan, Zakir; Kalam, Mohd Abul; Khan, Azmat Ali

2018-01-01

Microbial pathogenesis involves several aspects of host-pathogen interactions, including microbial proteins targeting host subcellular compartments and subsequent effects on host physiology. Such studies are supported by experimental data, but recent detection of bacterial proteins localization through computational eukaryotic subcellular protein targeting prediction tools has also come into practice. We evaluated inter-kingdom prediction certainty of these tools. The bacterial proteins experimentally known to target host subcellular compartments were predicted with eukaryotic subcellular targeting prediction tools, and prediction certainty was assessed. The results indicate that these tools alone are not sufficient for inter-kingdom protein targeting prediction. The correct prediction of pathogen's protein subcellular targeting depends on several factors, including presence of localization signal, transmembrane domain and molecular weight, etc., in addition to approach for subcellular targeting prediction. The detection of protein targeting in endomembrane system is comparatively difficult, as the proteins in this location are channelized to different compartments. In addition, the high specificity of training data set also creates low inter-kingdom prediction accuracy. Current data can help to suggest strategy for correct prediction of bacterial protein's subcellular localization in host cell. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Human target acquisition performance

NASA Astrophysics Data System (ADS)

Teaney, Brian P.; Du Bosq, Todd W.; Reynolds, Joseph P.; Thompson, Roger; Aghera, Sameer; Moyer, Steven K.; Flug, Eric; Espinola, Richard; Hixson, Jonathan

2012-06-01

The battlefield has shifted from armored vehicles to armed insurgents. Target acquisition (identification, recognition, and detection) range performance involving humans as targets is vital for modern warfare. The acquisition and neutralization of armed insurgents while at the same time minimizing fratricide and civilian casualties is a mounting concern. U.S. Army RDECOM CERDEC NVESD has conducted many experiments involving human targets for infrared and reflective band sensors. The target sets include human activities, hand-held objects, uniforms & armament, and other tactically relevant targets. This paper will define a set of standard task difficulty values for identification and recognition associated with human target acquisition performance.

Intracellular localization of gold nanoparticles with targeted delivery in MT-4 lymphocytes

NASA Astrophysics Data System (ADS)

Singh, Lavanya; Parboosing, Raveen; Kruger, Hendrik G.; Maguire, Glenn E. M.; Govender, Thavendran

2016-12-01

The clinical utility of important therapeutic agents is often limited by the poor permeability of biological membranes. Cell penetrating peptides are usually employed to circumvent this challenge. This approach, coupled with gold nanoparticles, are a promising vehicle for drug delivery due to its good biocompatibility profile, negligable toxicity and possibility for multi-functionalization. Here we report the functionalization and intracellular tracking of gold nanoparticles decorated with a TAT cell penetrating peptide and a fluorescein tag in a simple, two step process. Fluorescence microscopy has confirmed the localization of the functionalized nanoparticles to be inside the cells, specifically within, or in close proximity to the nuclei of MT-4 lymphocytes; a HIV-relevant cell line in which this has not been previously demonstrated. The results of this study demonstrate that TAT has been efficiently conjugated to gold nanoparticles to facilitate both cellular and targeted nuclear entry.

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.

[Hodgkin's disease with esophageal involvement].

PubMed

Njeh, M; Yengui, N; Tahri, N; Kchaou, M; Sellami, A; Jlidi, R; Krichen, M S

2000-10-01

Esophageal involvement in Hodgkin's disease, commonly known as a belated localization of the advanced forms, has been seldom reported (3 to 5% in post-mortem series and 0.7% in clinical series). We report the case of a 61-year-old man who had an esophagus localization revealing Hodgkin's disease stage IV EBb of Ann Arbor classification. The originality of this case was represented by: the revelation mode of the esophageal involvement such as dysphagia and upper gastrointestinal bleeding; the localization at the distal third of the esophagus with contiguous involvement of the gastric fundus; the absence of mediastinal nodes showing the primitive character of the esophageal injury. This observation incites us to consider Hodgkin's disease in the list of differential diagnoses of tumoral dysphagia, even if there was no ganglionic and/or visceral localization of the disease.

Light localization with low-contrast targets in a patient implanted with a suprachoroidal-transretinal stimulation retinal prosthesis.

PubMed

Endo, Takao; Fujikado, Takashi; Hirota, Masakazu; Kanda, Hiroyuki; Morimoto, Takeshi; Nishida, Kohji

2018-04-20

To evaluate the improvement in targeted reaching movements toward targets of various contrasts in a patient implanted with a suprachoroidal-transretinal stimulation (STS) retinal prosthesis. An STS retinal prosthesis was implanted in the right eye of a 42-year-old man with advanced Stargardt disease (visual acuity: right eye, light perception; left eye, hand motion). In localization tests during the 1-year follow-up period, the patient attempted to touch the center of a white square target (visual angle, 10°; contrast, 96, 85, or 74%) displayed at a random position on a monitor. The distance between the touched point and the center of the target (the absolute deviation) was averaged over 20 trials with the STS system on or off. With the left eye occluded, the absolute deviation was not consistently lower with the system on than off for high-contrast (96%) targets, but was consistently lower with the system on for low-contrast (74%) targets. With both eyes open, the absolute deviation was consistently lower with the system on than off for 85%-contrast targets. With the system on and 96%-contrast targets, we detected a shorter response time while covering the right eye, which was being implanted with the STS, compared to covering the left eye (2.41 ± 2.52 vs 8.45 ± 3.78 s, p < 0.01). Performance of a reaching movement improved in a patient with an STS retinal prosthesis implanted in an eye with residual natural vision. Patients with a retinal prosthesis may be able to improve their visual performance by using both artificial vision and their residual natural vision. Beginning date of the trial: Feb. 20, 2014 Date of registration: Jan. 4, 2014 Trial registration number: UMIN000012754 Registration site: UMIN Clinical Trials Registry (UMIN-CTR) http://www.umin.ac.jp/ctr/index.htm.

Mechanistic Insights into Molecular Targeting and Combined Modality Therapy for Aggressive, Localized Prostate Cancer

PubMed Central

Dal Pra, Alan; Locke, Jennifer A.; Borst, Gerben; Supiot, Stephane; Bristow, Robert G.

2016-01-01

Radiation therapy (RT) is one of the mainstay treatments for prostate cancer (PCa). The potentially curative approaches can provide satisfactory results for many patients with non-metastatic PCa; however, a considerable number of individuals may present disease recurrence and die from the disease. Exploiting the rich molecular biology of PCa will provide insights into how the most resistant tumor cells can be eradicated to improve treatment outcomes. Important for this biology-driven individualized treatment is a robust selection procedure. The development of predictive biomarkers for RT efficacy is therefore of utmost importance for a clinically exploitable strategy to achieve tumor-specific radiosensitization. This review highlights the current status and possible opportunities in the modulation of four key processes to enhance radiation response in PCa by targeting the: (1) androgen signaling pathway; (2) hypoxic tumor cells and regions; (3) DNA damage response (DDR) pathway; and (4) abnormal extra-/intracell signaling pathways. In addition, we discuss how and which patients should be selected for biomarker-based clinical trials exploiting and validating these targeted treatment strategies with precision RT to improve cure rates in non-indolent, localized PCa. PMID:26909338

Reprint of: Reaction measurements with the Jet Experiments in Nuclear Structure and Astrophysics (JENSA) gas jet target

NASA Astrophysics Data System (ADS)

Chipps, K. A.

2018-01-01

Explosive stellar environments are sometimes driven by nuclear reactions on short-lived, radioactive nuclei. These reactions often drive the stellar explosion, alter the observable light curves produced, and dictate the final abundances of the isotopes created. Unfortunately, many reaction rates at stellar temperatures cannot be directly measured in the laboratory, due to the physical limitations of ultra-low cross sections and high background rates. An additional complication arises because many of the important reactions involve radioactive nuclei which have lifetimes too short to be made into a target. As such, direct reactions require very intense and pure beams of exotic nuclei. Indirect approaches with both stable and radioactive beams can, however, provide crucial information on the nuclei involved in these astrophysical reactions. A major development toward both direct and indirect studies of nuclear reactions rates is the commissioning of the Jet Experiments in Nuclear Structure and Astrophysics (JENSA) supersonic gas jet target. The JENSA system provides a pure, homogeneous, highly localized, dense, and robust gaseous target for radioactive ion beam studies. Charged-particle reactions measurements made with gas jet targets can be cleaner and display better resolution than with traditional targets. With the availability of pure and localized gas jet targets in combination with developments in exotic radioactive ion beams and next-generation detector systems, the range of reaction studies that are experimentally possible is vastly expanded. Various representative cases will be discussed.

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

Axotomy-induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in ALS transgenic mice

PubMed Central

Haulcomb, Melissa M.; Mesnard, Nichole A.; Batka, Richard J.; Alexander, Thomas D.; Sanders, Virginia M.; Jones, Kathryn J.

2014-01-01

The target disconnection theory of amyotrophic lateral sclerosis (ALS) pathogenesis suggests disease onset is initiated by a peripheral pathological event resulting in neuromuscular junction loss and motoneuron (MN) degeneration. Pre-symptomatic mSOD1G93A mouse facial MN (FMN) are more susceptible to axotomy-induced cell death than wild-type (WT) FMN, which suggests additional CNS pathology. We have previously determined that the mSOD1 molecular response to facial nerve axotomy is phenotypically regenerative and indistinguishable from WT, whereas the surrounding microenvironment shows significant dysregulation in the mSOD1 facial nucleus. To elucidate the mechanisms underlying the enhanced mSOD1 FMN loss after axotomy, we superimposed the facial nerve axotomy model on pre-symptomatic mSOD1 mice and investigated gene expression for death receptor pathways after target disconnection by axotomy vs. disease progression. We determined that the TNFR1 death receptor pathway is involved in axotomy-induced FMN death in WT, and partially responsible for the mSOD1 FMN death. In contrast, an inherent mSOD1 CNS pathology resulted in a suppressed glial reaction and an upregulation in the Fas death pathway after target disconnection. We propose that the dysregulated mSOD1 glia fail to provide support to injured MN, leading to Fas-induced FMN death. Finally, we demonstrated that during disease progression, the mSOD1 facial nucleus displays target disconnection-induced gene expression changes that mirror those induced by axotomy. This validates the use of axotomy as an investigative tool in understanding the role of peripheral target disconnection in the pathogenesis of ALS. PMID:24424947

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

User and stakeholder involvement for relevant, reliable and robust local-scale climate projections in Norway

NASA Astrophysics Data System (ADS)

Neby, Simon; Sobolowski, Stefan

2017-04-01

How can users and stakeholders be actively involved with providing input to and using output from local-scale climate projections? How can the scientific community better understand the needs of local actors? And how should communication and cooperation efforts be organized? These are critical questions we aim to answer in a climate services project funded by the Norwegian Research Council (R3: Relevant, Reliable and Robust local-scale climate projections for Norway). The project takes into consideration not only the scientific issues in establishing useful local-scale climate projections, but also addresses the "usability gap" between climate information and decision-making. The lack of effective communication between scientists and user communities often result in outputs and products that are not matched with decision-relevant climate information. In the R3 project, the scientific participants actively engage with a range of users that have quite different information needs: municipalities, infrastructure developers, agriculture, energy producers, insurance companies, and more. In this particular presentation, we present our experiences concerning three specific issues that relate to the stakeholder-science interface: 1) Preferences are not clear-cut and pre-defined. In practice, this means that stakeholders often do not have precise information about their needs, nor precise information about how, where and whether their needs can be voiced. Similarly, science communities tend to presuppose that stakeholders are interested and have well-articulated needs, which is hardly the case. Collectively, that means that there is a need for an approach that guides the articulation and prioritization of preferences in a manner that integrates both scientific and stakeholder perspectives and takes the integrity of both perspectives seriously. 2) Technologies are unclear. Although information may be produced and used, past experiences, trial and error processes and pragmatic

Why social science matters in river management: involvement of local stakeholders in monitoring the effects of room for the river measures in the Netherlands

NASA Astrophysics Data System (ADS)

Verbrugge, Laura; van den Born, Riyan

2015-04-01

The Netherlands is a densely populated delta region with a long tradition in flood protection and river management. In response to climate change, adaptive measures are implemented to create more room for the river (and thus increasing water discharge capacity) while at the same time maintaining the multifunctional use of the river system. These functions include for example navigation, water supply, housing and spatial quality, nature development and recreation. The incorporation of social aspects in water management is vital for the development and implementation of sustainable solutions in environmental planning. Active stakeholder involvement has major benefits in terms of trust, public support, social learning and creative decision making. In practice, however, stakeholder involvement is often confined to one-way communication (e.g. information on websites and public hearings) instead of establishing a dialogue with the relevant local stakeholders. Moreover, stakeholders are often involved too late. Our study focusses on stakeholder perceptions and the opportunities for stakeholder participation and collaboration in river management. One way to actively involve stakeholders and invest in a dialogue is through participatory monitoring, i.e. to involve local stakeholders in collecting, analyzing and evaluating monitoring data. Currently, a pilot engineering intervention (2013-2015) is carried out in the Waal river, i.e. the main Rhine branch in The Netherlands. This intervention comprises the substitution of traditional groynes by a 10 km longitudinal dam and will change the appearance of the fluvial landscape dramatically. An interdisciplinary team of scientists, government representatives and other public and private parties is involved in monitoring the hydrological, ecological and socio-economic effects of the longitudinal dam with the aim to develop and improve models, guidelines and tools for integrative river management. This also provides unique

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

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

Localized Hyperthermia for Enhanced Targeted Delivery of Polymer Therapeutics

NASA Astrophysics Data System (ADS)

Frazier, Nicholas

It is estimated that in 2016, more than 848,000 new cases of cancer will be diagnosed in men with more than a quarter being prostate cancer and more than 26,000 deaths attributed to this disease. Prostate cancer poses a limited risk when detected at an early stage and treatment of stages II-III has a 5-year survival rate of almost 100%. However, these early-stage cancers can eventually progress and develop into stage IV, dramatically dropping the 5-year survival rate to 28%. Thus, development of a new therapy is needed to fully eliminate these tumors. Combination of heat and chemotherapy improves therapeutic efficacy while allowing for reduced dosing of drugs and limiting side effects. Localized hyperthermia has been used to enhance the delivery of polymer therapeutics to prostate tumors through increased blood flow, vascular permeability, and incorporation of heat shock targeting. This strategy has been shown to increase the delivery and retention of polymer-drug conjugates leading to enhanced efficacy. Although much work has been done using this strategy, the effects of different thermal dosing on polymer accumulation are unknown. The first aim of this research is to examine how altering heating parameters influences polymer tumor accumulation. The hypothesis for this aim is that there is an optimal thermal treatment that leads to the maximal amount of polymer accumulation in the tumors. Additionally, the previously used heating method of plasmonic photothermal therapy (PPTT) can result in long-term accumulation of gold nanoparticles in healthy organs, potentially limiting clinical applicability. The second aim of this proposal will be focused on investigating the alternative method of high intensity focused ultrasound (HIFU) for selective heating of tumors and enhancing macromolecular delivery. HIFU has shown the capability for precise, noninvasive heating of specific regions within the prostate through magnetic resonance imaging (MRI) guidance. The hypothesis

[C-terminal lysosome targeting domain of CD63 modifies cellular localization of rabies virus glycoprotein].

PubMed

Starodubova, E S; Kuzmenko, Y V; Latanova, A A; Preobrazhenskaya, O V; Karpov, V L

2017-01-01

The glycoprotein of rabies virus is the central antigen elicited the immune response to infection; therefore, the majority of developing anti-rabies vaccines are based on this protein. In order to increase the efficacy of DNA immunogen encoding rabies virus glycoprotein, the construction of chimeric protein with the CD63 domain has been proposed. The CD63 is a transmembrane protein localized on the cell surface and in lysosomes. The lysosome targeting motif GYEVM is located at its C-terminus. We used the domain that bears this motif (c-CD63) to generate chimeric glycoprotein in order to relocalize it into lysosomes. Here, it was shown that, in cells transfected with plasmid that encodes glycoprotein with c-CD63 motif at the C-terminus, the chimeric protein was predominantly observed in lysosomes and at the cell membrane where the unmodified glycoprotein is localized in the endoplasmic reticulum and at the cell surface. We suppose that current modification of the glycoprotein may improve the immunogenicity of anti-rabies DNA vaccines due to more efficient antibody production.

Targeted polypeptide degradation

DOEpatents

Church, George M [Brookline, MA; Janse, Daniel M [Brookline, MA

2008-05-13

This invention pertains to compositions, methods, cells and organisms useful for selectively localizing polypeptides to the proteasome for degradation. Therapeutic methods and pharmaceutical compositions for treating disorders associated with the expression and/or activity of a polypeptide by targeting these polypeptides for degradation, as well as methods for targeting therapeutic polypeptides for degradation and/or activating therapeutic polypeptides by degradation are provided. The invention provides methods for identifying compounds that mediate proteasome localization and/or polypeptide degradation. The invention also provides research tools for the study of protein function.

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

microRNAs and Their Targets in Apple (Malus domestica cv. "Fuji") Involved in Response to Infection of Pathogen Valsa mali.

PubMed

Feng, Hao; Xu, Ming; Zheng, Xiang; Zhu, Tongyi; Gao, Xiaoning; Huang, Lili

2017-01-01

miRNAs are important regulators involving in plant-pathogen interactions. However, their roles in apple tree response to Valsa canker pathogen ( Valsa mali, Vm ) infection were poorly understood. In this study, we constructed two miRNA libraries using the twig bark tissues of apple tree ( Malus domestica Borkh. cv. "Fuji") inoculated with Vm (IVm) and PDA medium (control, BMd). Among all detected miRNAs, 23 miRNAs were specifically isolated from BMd and 39 miRNAs were specifically isolated from IVm. Meanwhile, the expression of 294 miRNAs decreased; and another 172 miRNAs showed an increased expression trend in IVm compared with that in BMd. Furthermore, two degradome sequencing libraries were also constructed to identify the target genes of these miRNAs. In total, 353 differentially expressed miRNAs between IVm and BMd were detected to be able to target 1,077 unigenes with 2,251 cleavage sites. Based on GO and KEGG analysis, these genes were found to be mainly related to transcription regulation and signal transduction. In addition, we selected 17 miRNAs and 22 corresponding target genes to screen the expression profiles when apple twigs were infected by Vm . The expression trends of most miRNAs/target genes were consist with the results of deep sequencing. Many of them may involve in the apple twig- Vm interaction by inducing/reducing their expression. What's more, miRNAs and their target genes regulate the apple twig- Vm interaction by forming many complicated regulation networks rather than one to one model. It is worth that a conserved miRNAs mdm-miR482b, which was down regulated in IVm compared with BMd, has 14 potential target genes, most of which are disease resistance related genes. This indicates that mdm-miR482b may play important roles in apple twig response to Vm . More important, the feedback regulation of sRNA pathway in apple twig is also very complex, and play critical role in the interaction between apple twig and Vm based on the results of

Bringing the Community into the Process: Issues and Promising Practices for Involving Parents & Business in Local Smart Start Partnerships. UNC Smart Start Evaluation Report.

ERIC Educational Resources Information Center

Cornish, Mary; Noblit, George

Smart Start is North Carolina's partnership between state government and local leaders, service providers, and families to better serve children under age 6 and their families. The aim of the program is ensuring that all children enter school healthy and ready to learn. This study examined parent and business involvement in local Smart Start…

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

The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle.

PubMed

Warnatz, Hans-Jörg; Schmidt, Dominic; Manke, Thomas; Piccini, Ilaria; Sultan, Marc; Borodina, Tatiana; Balzereit, Daniela; Wruck, Wasco; Soldatov, Alexey; Vingron, Martin; Lehrach, Hans; Yaspo, Marie-Laure

2011-07-01

The regulation of gene expression in response to environmental signals and metabolic imbalances is a key step in maintaining cellular homeostasis. BTB and CNC homology 1 (BACH1) is a heme-binding transcription factor repressing the transcription from a subset of MAF recognition elements at low intracellular heme levels. Upon heme binding, BACH1 is released from the MAF recognition elements, resulting in increased expression of antioxidant response genes. To systematically address the gene regulatory networks involving BACH1, we combined chromatin immunoprecipitation sequencing analysis of BACH1 target genes in HEK 293 cells with knockdown of BACH1 using three independent types of small interfering RNAs followed by transcriptome profiling using microarrays. The 59 BACH1 target genes identified by chromatin immunoprecipitation sequencing were found highly enriched in genes showing expression changes after BACH1 knockdown, demonstrating the impact of BACH1 repression on transcription. In addition to known and new BACH1 targets involved in heme degradation (HMOX1, FTL, FTH1, ME1, and SLC48A1) and redox regulation (GCLC, GCLM, and SLC7A11), we also discovered BACH1 target genes affecting cell cycle and apoptosis pathways (ITPR2, CALM1, SQSTM1, TFE3, EWSR1, CDK6, BCL2L11, and MAFG) as well as subcellular transport processes (CLSTN1, PSAP, MAPT, and vault RNA). The newly identified impact of BACH1 on genes involved in neurodegenerative processes and proliferation provides an interesting basis for future dissection of BACH1-mediated gene repression in neurodegeneration and virus-induced cancerogenesis.

The mechanisms involved in miR-9 regulated apoptosis in cervical cancer by targeting FOXO3.

PubMed

Zhang, Haiyan; Zhang, Zhen; Wang, Surong; Zhang, Shiqian; Bi, Junying

2018-06-01

As a seriously global health problem, cervical cancer is a great risk to women which threatens their lives. Approximately 30% patients who received definitive treatment may fail to recover from this disease. Accordingly, there is an imperatively need to explore alternative therapeutic approaches for this disease. Several studies have revealed that miR-9 was a critical regulator during cervical cancer growth. Here, we reported that the miR-9 was overexpressed in cervical tumor tissue and exerted a promoting effect on human cervical cancer cell (SiHa) growth. Both in vitro and in vivo experiments confirmed that miR-9 could stimulate the proliferation and migration of SiHa cells. In contrast, inhibition of miR-9 induced apoptosis in SiHa cells. In addition, dual luciferase reporter system assay verified that there was a strong target relationship between miR-9 and FOXO3. Result of western blot assay showed that the inhibition of miR-9 increased the expression of FOXO3. Moreover, miR-9 regulated FOXO3 downstream proteins Bax, Bcl-2 and p-Akt expressions, which suggesting that miR-9 was involved in the SiHa cells apoptosis. In conclusion, our results suggest that the inhibition of miR-9 could induce apoptosis in cervical cancer by targeting FOXO3 and presented a potential molecular target for the treatment of cervical cancer patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Inclusion of populations at risk of advanced melanoma in an opportunistic targeted screening project involving general practitioners

PubMed Central

Rat, Cédric; Quereux, Gaelle; Grimault, Charlotte; Fernandez, Jérémy; Poiraud, Mickael; Gaultier, Aurélie; Chaslerie, Anicet; Pivette, Jacques; Khammari, Amir; Dreno, Brigitte; Nguyen, Jean-Michel

2016-01-01

Objective The study objective was to measure the rates of inclusion of populations at risk of advanced melanoma in a pilot targeted screening project involving general practitioners. Design This cross-sectional database study compared the inclusion rates of patients who signed inclusion in a targeted screening project with those of patients who did not, during a period in which both groups of patients consulted investigators. Setting Data were extracted from the national healthcare insurance records in western France from 11 April to 30 October 2011. Patients Patients, older than 18, considered for the data extraction had consulted one of the 78 participating GPs during the study period, and were affiliated with the national healthcare insurance. Main outcome measures Inclusion in the screening was the main outcome measure. Patients at risk of advanced melanoma were characterized by male gender, age over 50, low income, rural residence, farmer, and presence of chronic disease. Results A total of 57,279 patients consulted GPs during the inclusion period and 2711 (4.73%) were included in the targeted screening. Populations at risk of advanced melanoma were less included: men (OR = 0.67; 95%CI [0.61–0.73]; p < 0.001), older than 50 (OR = 0.67; 95%CI [0.60–0.74]; p < 0.001), low income (OR = 0.65; 95%CI [0.55–0.77]; p < 0.001), farmer (OR = 0.23; 95%CI [0.17–0.30]; p < 0.001) and presence of a chronic disease (OR = 0.87; 95%CI [0.77–0.98]; p < 0.028). Conclusion This study demonstrated inequalities in the inclusion of patients in a melanoma screening. Patients at risk of advanced cancer were screened less often. Further studies should focus on GPs ability to identify and screen these patients. Key Points Advanced melanoma is more frequently diagnosed in men, older patients and socioeconomically disadvantaged populations, which leads to survival inequalities.• Despite the involvement of general practitioners, the

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.

Learning from Software Localization.

ERIC Educational Resources Information Center

Guo, She-Sen

2003-01-01

Localization is the process of adapting a product to meet the language, cultural and other requirements of a specific target environment or market. This article describes ways in which software localization impacts upon curriculum, and discusses what students will learn from software localization. (AEF)

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.

Genomic Target Database (GTD): A database of potential targets in human pathogenic bacteria

PubMed Central

Barh, Debmalya; Kumar, Anil; Misra, Amarendra Narayana

2009-01-01

A Genomic Target Database (GTD) has been developed having putative genomic drug targets for human bacterial pathogens. The selected pathogens are either drug resistant or vaccines are yet to be developed against them. The drug targets have been identified using subtractive genomics approaches and these are subsequently classified into Drug targets in pathogen specific unique metabolic pathways,Drug targets in host-pathogen common metabolic pathways, andMembrane localized drug targets. HTML code is used to link each target to its various properties and other available public resources. Essential resources and tools for subtractive genomic analysis, sub-cellular localization, vaccine and drug designing are also mentioned. To the best of authors knowledge, no such database (DB) is presently available that has listed metabolic pathways and membrane specific genomic drug targets based on subtractive genomics. Listed targets in GTD are readily available resource in developing drug and vaccine against the respective pathogen, its subtypes, and other family members. Currently GTD contains 58 drug targets for four pathogens. Shortly, drug targets for six more pathogens will be listed. Availability GTD is available at IIOAB website http://www.iioab.webs.com/GTD.htm. It can also be accessed at http://www.iioabdgd.webs.com.GTD is free for academic research and non-commercial use only. Commercial use is strictly prohibited without prior permission from IIOAB. PMID:20011153

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 .

Subcellular localization based comparative study on radioresistant bacteria: A novel approach to mine proteins involve in radioresistance.

PubMed

Vishambra, Divya; Srivastava, Malay; Dev, Kamal; Jaiswal, Varun

2017-08-01

Radioresistant bacteria (RRB) are among the most radioresistant organisms and has a unique role in evolution. Along with the evolutionary role, radioresistant organisms play important role in paper industries, bioremediation, vaccine development and possibility in anti-aging and anti-cancer treatment. The study of radiation resistance in RRB was mainly focused on cytosolic mechanisms such as DNA repair mechanism, cell cleansing activity and high antioxidant activity. Although it was known that protein localized on outer areas of cell play role in resistance towards extreme condition but the mechanisms/proteins localized on the outer area of cells are not studied for radioresistance. Considering the fact that outer part of cell is more exposed to radiations and proteins present in outer area of the cell may have role in radioresistance. Localization based comparative study of proteome from RRB and non-radio resistant bacteria was carried out. In RRB 20 unique proteins have been identified. Further domain, structural, and pathway analysis of selected proteins were carried out. Out of 20 proteins, 8 proteins were direct involvement in radioresistance and literature study strengthens this, however, 1 proteins had assumed relation in radioresistance. Selected radioresistant proteins may be helpful for optimal use of RRB in industry and health care. Copyright © 2017 Elsevier Ltd. 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.

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

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.

Timing matters: sonar call groups facilitate target localization in bats.

PubMed

Kothari, Ninad B; Wohlgemuth, Melville J; Hulgard, Katrine; Surlykke, Annemarie; Moss, Cynthia F

2014-01-01

To successfully negotiate a cluttered environment, an echolocating bat must control the timing of motor behaviors in response to dynamic sensory information. Here we detail the big brown bat's adaptive temporal control over sonar call production for tracking prey, moving predictably or unpredictably, under different experimental conditions. We studied the adaptive control of vocal-motor behaviors in free-flying big brown bats, Eptesicus fuscus, as they captured tethered and free-flying insects, in open and cluttered environments. We also studied adaptive sonar behavior in bats trained to track moving targets from a resting position. In each of these experiments, bats adjusted the features of their calls to separate target and clutter. Under many task conditions, flying bats produced prominent sonar sound groups identified as clusters of echolocation pulses with relatively stable intervals, surrounded by longer pulse intervals. In experiments where bats tracked approaching targets from a resting position, bats also produced sonar sound groups, and the prevalence of these sonar sound groups increased when motion of the target was unpredictable. We hypothesize that sonar sound groups produced during flight, and the sonar call doublets produced by a bat tracking a target from a resting position, help the animal resolve dynamic target location and represent the echo scene in greater detail. Collectively, our data reveal adaptive temporal control over sonar call production that allows the bat to negotiate a complex and dynamic environment.

Timing matters: sonar call groups facilitate target localization in bats

PubMed Central

Kothari, Ninad B.; Wohlgemuth, Melville J.; Hulgard, Katrine; Surlykke, Annemarie; Moss, Cynthia F.

2014-01-01

To successfully negotiate a cluttered environment, an echolocating bat must control the timing of motor behaviors in response to dynamic sensory information. Here we detail the big brown bat's adaptive temporal control over sonar call production for tracking prey, moving predictably or unpredictably, under different experimental conditions. We studied the adaptive control of vocal-motor behaviors in free-flying big brown bats, Eptesicus fuscus, as they captured tethered and free-flying insects, in open and cluttered environments. We also studied adaptive sonar behavior in bats trained to track moving targets from a resting position. In each of these experiments, bats adjusted the features of their calls to separate target and clutter. Under many task conditions, flying bats produced prominent sonar sound groups identified as clusters of echolocation pulses with relatively stable intervals, surrounded by longer pulse intervals. In experiments where bats tracked approaching targets from a resting position, bats also produced sonar sound groups, and the prevalence of these sonar sound groups increased when motion of the target was unpredictable. We hypothesize that sonar sound groups produced during flight, and the sonar call doublets produced by a bat tracking a target from a resting position, help the animal resolve dynamic target location and represent the echo scene in greater detail. Collectively, our data reveal adaptive temporal control over sonar call production that allows the bat to negotiate a complex and dynamic environment. PMID:24860509

microRNAs and Their Targets in Apple (Malus domestica cv. “Fuji”) Involved in Response to Infection of Pathogen Valsa mali

PubMed Central

Feng, Hao; Xu, Ming; Zheng, Xiang; Zhu, Tongyi; Gao, Xiaoning; Huang, Lili

2017-01-01

miRNAs are important regulators involving in plant-pathogen interactions. However, their roles in apple tree response to Valsa canker pathogen (Valsa mali, Vm) infection were poorly understood. In this study, we constructed two miRNA libraries using the twig bark tissues of apple tree (Malus domestica Borkh. cv. “Fuji”) inoculated with Vm (IVm) and PDA medium (control, BMd). Among all detected miRNAs, 23 miRNAs were specifically isolated from BMd and 39 miRNAs were specifically isolated from IVm. Meanwhile, the expression of 294 miRNAs decreased; and another 172 miRNAs showed an increased expression trend in IVm compared with that in BMd. Furthermore, two degradome sequencing libraries were also constructed to identify the target genes of these miRNAs. In total, 353 differentially expressed miRNAs between IVm and BMd were detected to be able to target 1,077 unigenes with 2,251 cleavage sites. Based on GO and KEGG analysis, these genes were found to be mainly related to transcription regulation and signal transduction. In addition, we selected 17 miRNAs and 22 corresponding target genes to screen the expression profiles when apple twigs were infected by Vm. The expression trends of most miRNAs/target genes were consist with the results of deep sequencing. Many of them may involve in the apple twig-Vm interaction by inducing/reducing their expression. What's more, miRNAs and their target genes regulate the apple twig-Vm interaction by forming many complicated regulation networks rather than one to one model. It is worth that a conserved miRNAs mdm-miR482b, which was down regulated in IVm compared with BMd, has 14 potential target genes, most of which are disease resistance related genes. This indicates that mdm-miR482b may play important roles in apple twig response to Vm. More important, the feedback regulation of sRNA pathway in apple twig is also very complex, and play critical role in the interaction between apple twig and Vm based on the results of

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

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

Development of a dendritic cell-targeting lipopeptide as an immunoadjuvant that inhibits tumor growth without inducing local inflammation.

PubMed

Akazawa, Takashi; Ohashi, Toshimitsu; Nakajima, Hiroko; Nishizawa, Yasuko; Kodama, Ken; Sugiura, Kikuya; Inaba, Toshio; Inoue, Norimitsu

2014-12-15

Materials used for the past 30 years as immunoadjuvants induce suboptimal antitumor immune responses and often cause undesirable local inflammation. Some bacterial lipopeptides that act as Toll-like receptor (TLR) 2 ligands activate immune cells as immunoadjuvants and induce antitumor effects. Here, we developed a new dendritic cell (DC)-targeting lipopeptide, h11c (P2C-ATPEDNGRSFS), which uses the CD11c-binding sequence of intracellular adhesion molecule-1 to selectively and efficiently activate DCs but not other immune cells. Although the h11c lipopeptide activated DCs similarly to an artificial lipopeptide, P2C-SKKKK (P2CSK4), via TLR2 in vitro, h11c induced more effective tumor inhibition than P2CSK4 at low doses in vivo with tumor antigens. Even without tumor antigens, h11c lipopeptide significantly inhibited tumor growth and induced tumor-specific cytotoxic T cells. P2CSK4 was retained subcutaneously at the vaccination site and induced severe local inflammation in in vivo experiments. In contrast, h11c was not retained at the vaccination site and was transported into the tumor within 24 hr. The recruitment of DCs into the tumor was induced by h11c more effectively, while P2CSK4 induced the accumulation of neutrophils leading to severe inflammation at the vaccination site. Because CD11b+ cells, but not CD11c+ cells, produced neutrophil chemotactic factors such as macrophage inflammatory protein (MIP)-2 in response to stimulation with TLR2 ligands, the DC-targeting lipopeptide h11c induced less MIP-2 production by splenocytes than P2CSK4. In this study, we succeeded in developing a novel immunoadjuvant, h11c, which effectively induces antitumor activity without adverse effects such as local inflammation via the selective activation of DCs. © 2014 UICC.

SU-G-JeP3-01: A Method to Quantify Lung SBRT Target Localization Accuracy Based On Digitally Reconstructed Fluoroscopy

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

Lafata, K; Ren, L; Cai, J

2016-06-15

Purpose: To develop a methodology based on digitally-reconstructed-fluoroscopy (DRF) to quantitatively assess target localization accuracy of lung SBRT, and to evaluate using both a dynamic digital phantom and a patient dataset. Methods: For each treatment field, a 10-phase DRF is generated based on the planning 4DCT. Each frame is pre-processed with a morphological top-hat filter, and corresponding beam apertures are projected to each detector plane. A template-matching algorithm based on cross-correlation is used to detect the tumor location in each frame. Tumor motion relative beam aperture is extracted in the superior-inferior direction based on each frame’s impulse response to themore » template, and the mean tumor position (MTP) is calculated as the average tumor displacement. The DRF template coordinates are then transferred to the corresponding MV-cine dataset, which is retrospectively filtered as above. The treatment MTP is calculated within each field’s projection space, relative to the DRF-defined template. The field’s localization error is defined as the difference between the DRF-derived-MTP (planning) and the MV-cine-derived-MTP (delivery). A dynamic digital phantom was used to assess the algorithm’s ability to detect intra-fractional changes in patient alignment, by simulating different spatial variations in the MV-cine and calculating the corresponding change in MTP. Inter-and-intra-fractional variation, IGRT accuracy, and filtering effects were investigated on a patient dataset. Results: Phantom results demonstrated a high accuracy in detecting both translational and rotational variation. The lowest localization error of the patient dataset was achieved at each fraction’s first field (mean=0.38mm), with Fx3 demonstrating a particularly strong correlation between intra-fractional motion-caused localization error and treatment progress. Filtering significantly improved tracking visibility in both the DRF and MV-cine images. Conclusion: We

A beam based method for target localization: inspiration from bats' directivity and binaural reception for ultrasonic sonar.

PubMed

Guarato, Francesco; Windmill, James; Gachagan, Anthony

2013-06-01

The process of echolocation is accomplished by bats partly using the beam profiles associated with their ear shapes that allow for discrimination between different echo directions. Indeed, knowledge of the emitted signal characteristic and measurement of the echo travel time from a target make it possible to compensate for attenuation due to distance, and to focus on filtering through the receivers' beam profiles by comparing received echoes to the original signal at all frequencies in the spectrum of interest. From this basis, a beam profile method to localize a target in three-dimensional space for an ultrasonic sensor system equipped with an emitter and two receivers is presented. Simulations were conducted with different noise levels, and only the contribution of the receivers' beam profiles was considered to estimate the orientation of the target with respect to the receivers. The beam pattern of the Phyllostomus discolor's ear was adopted as that of a receiver. Analyses of beam resolution and frequency ranges were conducted to enhance the accuracy of orientation estimates. The choice of appropriate resolution and frequency ranges guarantee that error mean values for most of the orientations are within [0.5°, 1.5°], even in noisy situations: Signal-to-noise ratio values considered in this work are 35 and 50 dB.

Optimization of prostate biopsy: the role of magnetic resonance imaging targeted biopsy in detection, localization and risk assessment.

PubMed

Bjurlin, Marc A; Meng, Xiaosong; Le Nobin, Julien; Wysock, James S; Lepor, Herbert; Rosenkrantz, Andrew B; Taneja, Samir S

2014-09-01

Optimization of prostate biopsy requires addressing the shortcomings of standard systematic transrectal ultrasound guided biopsy, including false-negative rates, incorrect risk stratification, detection of clinically insignificant disease and the need for repeat biopsy. Magnetic resonance imaging is an evolving noninvasive imaging modality that increases the accurate localization of prostate cancer at the time of biopsy, and thereby enhances clinical risk assessment and improves the ability to appropriately counsel patients regarding therapy. In this review we 1) summarize the various sequences that comprise a prostate multiparametric magnetic resonance imaging examination along with its performance characteristics in cancer detection, localization and reporting standards; 2) evaluate potential applications of magnetic resonance imaging targeting in prostate biopsy among men with no previous biopsy, a negative previous biopsy and those with low stage cancer; and 3) describe the techniques of magnetic resonance imaging targeted biopsy and comparative study outcomes. A bibliographic search covering the period up to October 2013 was conducted using MEDLINE®/PubMed®. Articles were reviewed and categorized based on which of the 3 objectives of this review was addressed. Data were extracted, analyzed and summarized. Multiparametric magnetic resonance imaging consists of anatomical T2-weighted imaging coupled with at least 2 functional imaging techniques. It has demonstrated improved prostate cancer detection sensitivity up to 80% in the peripheral zone and 81% in the transition zone. A prostate cancer magnetic resonance imaging suspicion score has been developed, and is depicted using the Likert or PI-RADS (Prostate Imaging Reporting and Data System) scale for better standardization of magnetic resonance imaging interpretation and reporting. Among men with no previous biopsy, magnetic resonance imaging increases the frequency of significant cancer detection to 50

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.

Fe-S cluster coordination of the chromokinesin KIF4A alters its sub-cellular localization during mitosis.

PubMed

Ben-Shimon, Lilach; Paul, Viktoria D; David-Kadoch, Galit; Volpe, Marina; Stümpfig, Martin; Bill, Eckhard; Mühlenhoff, Ulrich; Lill, Roland; Ben-Aroya, Shay

2018-05-30

Fe-S clusters act as co-factors of proteins with diverse functions, e.g. in DNA repair. Down-regulation of the cytosolic iron-sulfur protein assembly (CIA) machinery promotes genomic instability by the inactivation of multiple DNA repair pathways. Furthermore, CIA deficiencies are associated with so far unexplained mitotic defects. Here, we show that CIA2B and MMS19, constituents of the CIA targeting complex involved in facilitating Fe-S cluster insertion into cytosolic and nuclear target proteins, co-localize with components of the mitotic machinery. Down-regulation of CIA2B and MMS19 impairs the mitotic cycle. We identify the chromokinesin KIF4A as a mitotic component involved in these effects. KIF4A binds a Fe-S cluster in vitro through its conserved cysteine-rich domain. We demonstrate in vivo that this domain is required for the mitosis-related KIF4A localization and for the mitotic defects associated with KIF4A knockout. KIF4A is the first identified mitotic component carrying such a post-translational modification. These findings suggest that the lack of Fe-S clusters in KIF4A upon down-regulation of the CIA targeting complex contributes to the mitotic defects. © 2018. Published by The Company of Biologists Ltd.

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...

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

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

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.

MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes.

PubMed

Horie, Takahiro; Ono, Koh; Nishi, Hitoo; Iwanaga, Yoshitaka; Nagao, Kazuya; Kinoshita, Minako; Kuwabara, Yasuhide; Takanabe, Rieko; Hasegawa, Koji; Kita, Toru; Kimura, Takeshi

2009-11-13

GLUT4 shows decreased levels in failing human adult hearts. We speculated that GLUT4 expression in cardiac muscle may be fine-tuned by microRNAs. Forced expression of miR-133 decreased GLUT4 expression and reduced insulin-mediated glucose uptake in cardiomyocytes. A computational miRNA target prediction algorithm showed that KLF15 is one of the targets of miR-133. It was confirmed that over-expression of miR-133 reduced the protein level of KLF15, which reduced the level of the downstream target GLUT4. Cardiac myocytes infected with lenti-decoy, in which the 3'UTR with tandem sequences complementary to miR-133 was linked to the luciferase reporter gene, had decreased miR-133 levels and increased levels of GLUT4. The expression levels of KLF15 and GLUT4 were decreased at the left ventricular hypertrophy and congestive heart failure stage in a rat model. The present results indicated that miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.

Neutral Beam Source and Target Plasma for Development of a Local Electric Field Fluctuation Diagnostic

NASA Astrophysics Data System (ADS)

Bakken, M. R.; Burke, M. G.; Fonck, R. J.; Lewicki, B. T.; Rhodes, A. T.; Winz, G. R.

2016-10-01

A new diagnostic measuring local E-> (r , t) fluctuations is being developed for plasma turbulence studies in tokamaks. This is accomplished by measuring fluctuations in the separation of the π components in the Hα motional Stark spectrum. Fluctuations in this separation are expected to be Ẽ / ẼEMSE 10-3EMSE 10-3 . In addition to a high throughput, high speed spectrometer, the project requires a low divergence (Ω 0 .5°) , 80 keV, 2.5 A H0 beam and a target plasma test stand. The beam employs a washer-stack arc ion source to achieve a high species fraction at full energy. Laboratory tests of the ion source demonstrate repeatable plasmas with Te 10 eV and ne 1.6 ×1017 m-3, sufficient for the beam ion optics requirements. Te and ne scalings of the ion source plasma are presented with respect to operational parameters. A novel three-phase resonant converter power supply will provide 6 mA/cm2 of 80 keV H0 at the focal plane for pulse lengths up to 15 ms, with low ripple δV / 80 keV 0.05 % at 280 kHz. Diagnostic development and validation tests will be performed on a magnetized plasma test stand with 0.5 T field. The test chamber will utilize a washer-stack arc source to produce a target plasma comparable to edge tokamak plasmas. A bias-plate with programmable power supply will be used to impose Ẽ within the target plasma. Work supported by US DOE Grant DE-FG02-89ER53296.

Lmx1b-targeted cis-regulatory modules involved in limb dorsalization.

PubMed

Haro, Endika; Watson, Billy A; Feenstra, Jennifer M; Tegeler, Luke; Pira, Charmaine U; Mohan, Subburaman; Oberg, Kerby C

2017-06-01

Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct gene targets in the limb have been confirmed. To determine direct targets, we performed a chromatin immunoprecipitation against Lmx1b in mouse limbs at embryonic day 12.5 followed by next-generation sequencing (ChIP-seq). Nearly 84% ( n =617) of the Lmx1b-bound genomic intervals (LBIs) identified overlap with chromatin regulatory marks indicative of potential cis -regulatory modules (PCRMs). In addition, 73 LBIs mapped to CRMs that are known to be active during limb development. We compared Lmx1b-bound PCRMs with genes regulated by Lmx1b and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontological analysis suggests that Lmx1b targets extracellular matrix production, bone/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of a PCRM associated with joint-related Gdf5 that provides a mechanism for Lmx1b-mediated joint modification and a PCRM associated with Lmx1b that suggests a role in autoregulation. This is the first report to describe genome-wide Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization. © 2017. Published by The Company of Biologists Ltd.

Time reversal optical tomography and decomposition methods for detection and localization of targets in highly scattering turbid media

NASA Astrophysics Data System (ADS)

Wu, Binlin

New near-infrared (NIR) diffuse optical tomography (DOT) approaches were developed to detect, locate, and image small targets embedded in highly scattering turbid media. The first approach, referred to as time reversal optical tomography (TROT), is based on time reversal (TR) imaging and multiple signal classification (MUSIC). The second approach uses decomposition methods of non-negative matrix factorization (NMF) and principal component analysis (PCA) commonly used in blind source separation (BSS) problems, and compare the outcomes with that of optical imaging using independent component analysis (OPTICA). The goal is to develop a safe, affordable, noninvasive imaging modality for detection and characterization of breast tumors in early growth stages when those are more amenable to treatment. The efficacy of the approaches was tested using simulated data, and experiments involving model media and absorptive, scattering, and fluorescent targets, as well as, "realistic human breast model" composed of ex vivo breast tissues with embedded tumors. The experimental arrangements realized continuous wave (CW) multi-source probing of samples and multi-detector acquisition of diffusely transmitted signal in rectangular slab geometry. A data matrix was generated using the perturbation in the transmitted light intensity distribution due to the presence of absorptive or scattering targets. For fluorescent targets the data matrix was generated using the diffusely transmitted fluorescence signal distribution from the targets. The data matrix was analyzed using different approaches to detect and characterize the targets. The salient features of the approaches include ability to: (a) detect small targets; (b) provide three-dimensional location of the targets with high accuracy (~within a millimeter or 2); and (c) assess optical strength of the targets. The approaches are less computation intensive and consequently are faster than other inverse image reconstruction methods that

Human T-cell leukemia virus-I tax oncoprotein functionally targets a subnuclear complex involved in cellular DNA damage-response.

PubMed

Haoudi, Abdelali; Daniels, Rodney C; Wong, Eric; Kupfer, Gary; Semmes, O John

2003-09-26

The virally encoded oncoprotein Tax has been implicated in HTLV-1-mediated cellular transformation. The exact mechanism by which this protein contributes to the oncogenic process is not known. However, it has been hypothesized that Tax induces genomic instability via repression of cellular DNA repair. We examined the effect of de novo Tax expression upon the cell cycle, because appropriate activation of cell cycle checkpoints is essential to a robust damage-repair response. Upon induction of tax expression, Jurkat T-cells displayed a pronounced accumulation in G2/M that was reversible by caffeine. We examined the G2-specific checkpoint signaling response in these cells and found activation of the ATM/chk2-mediated pathway, whereas the ATR/chk1-mediated response was unaffected. Immunoprecipitation with anti-chk2 antibody results in co-precipitation of Tax demonstrating a direct interaction of Tax with a chk2-containing complex. We also show that Tax targets a discrete nuclear site and co-localizes with chk2 and not chk1. This nuclear site, previously identified as Tax Speckled Structures (TSS), also contains the early damage response factor 53BP1. The recruitment of 53BP1 to TSS is dependent upon ATM signaling and requires expression of Tax. Specifically, Tax expression induces redistribution of diffuse nuclear 53BP1 to the TSS foci. Taken together these data suggest that the TSS describe a unique nuclear site involved in DNA damage recognition, repair response, and cell cycle checkpoint activation. We suggest that association of Tax with this multifunctional subnuclear site results in disruption of a subset of the site-specific activities and contributes to cellular genomic instability.

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.

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.

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.

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.

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

Global and Targeted Pathway Impact of Gliomas on White Matter Integrity Based on Lobar Localization.

PubMed

Ormond, David R; D'Souza, Shawn; Thompson, John A

2017-09-07

Primary brain tumors comprise 28% of all tumors and 80% of malignant tumors. Pathophysiology of high-grade gliomas includes significant distortion of white matter architecture, necrosis, the breakdown of the blood brain barrier, and increased intracranial pressure. Diffusion tensor imaging (DTI), a diffusion weighted imaging technique, can be used to assess white matter architecture. Use of DTI as a non-invasive pathophysiological tool to analyze glioma impact on white matter microstructure has yet to be fully explored. Preliminary assessment of DTI tractography was done as a measure of intracranial tumor impact on white matter architecture. Specifically, we addressed three questions: 1) whether glioma differentially affects local white matter structure compared to metastasis, 2) whether glioma affects tract integrity of major white matter bundles, 3) whether glioma lobe localization affects tract integrity of different white matter bundles. In this study, we retrospectively investigated preoperative DTI scans from 24 patients undergoing tumor resection. Fiber tractography was estimated using a deterministic fiber tracking algorithm in DSI (diffusion spectrum imaging) Studio. The automatic anatomical labeling (AAL) atlas was used to define the left and right (L/R)   hemisphere regions of interest (ROI). In addition, the John Hopkins University (JHU) White Matter Atlas was used to auto-segment major white matter bundle ROIs. For all tracts derived from ROI seed targets, we computed the following parameters: tract number, tract length, fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD). The DTI tractography analysis revealed that white matter integrity in the hemisphere ipsilateral to intracranial tumor was significantly compromised compared to the control contralateral hemisphere. No differences were observed between high vs low-grade gliomas, however, gliomas induced significantly greater white matter

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.

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

Leveraging The Affordable Care Act To Enroll Justice-Involved Populations In Medicaid: State And Local Efforts

PubMed Central

Bandara, Sachini N.; Huskamp, Haiden A.; Riedel, Lauren E.; McGinty, Emma E.; Webster, Daniel; Toone, Robert E.; Barry, Colleen L.

2016-01-01

The Affordable Care Act provides an unprecedented opportunity to enroll criminal justice–involved populations in health insurance, particularly Medicaid. As a result, many state and county corrections departments have launched programs that incorporate Medicaid enrollment in discharge planning. Our study characterizes the national landscape of programs enrolling criminal justice–involved populations in Medicaid as of January 2015. We provide an overview of sixty-four programs operating in jails, prisons, or community probation and parole systems that enroll individuals during detention, incarceration, and the release process. We describe the variation among the programs in terms of settings, personnel, timing of eligibility screening, and target populations. Seventy-seven percent of the programs are located in jails, and 56 percent use personnel from public health or social service agencies. We describe four practices that have facilitated the Medicaid enrollment process: suspending instead of terminating Medicaid benefits upon incarceration, presuming that an individual is eligible for Medicaid before the process is completed, allowing enrollment during incarceration, and accepting alternative forms of identification for enrollment. The criminal justice system is a complex one that requires a variety of approaches to enroll individuals in Medicaid. Future research should examine how these approaches influence health and criminal justice outcomes. PMID:26643624

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

A Universal Stress Protein Involved in Oxidative Stress Is a Phosphorylation Target for Protein Kinase CIPK61

PubMed Central

2017-01-01

Calcineurin B-like interacting protein kinases (CIPKs) decode calcium signals upon interaction with the calcium sensors calcineurin B like proteins into phosphorylation events that result into adaptation to environmental stresses. Few phosphorylation targets of CIPKs are known and therefore the molecular mechanisms underlying their downstream output responses are not fully understood. Tomato (Solanum lycopersicum) Cipk6 regulates immune and susceptible Programmed cell death in immunity transforming Ca2+ signals into reactive oxygen species (ROS) signaling. To investigate SlCipk6-induced molecular mechanisms and identify putative substrates, a yeast two-hybrid approach was carried on and a protein was identified that contained a Universal stress protein (Usp) domain present in bacteria, protozoa and plants, which we named “SlRd2”. SlRd2 was an ATP-binding protein that formed homodimers in planta. SlCipk6 and SlRd2 interacted using coimmunoprecipitation and bimolecular fluorescence complementation (BiFC) assays in Nicotiana benthamiana leaves and the complex localized in the cytosol. SlCipk6 phosphorylated SlRd2 in vitro, thus defining, to our knowledge, a novel target for CIPKs. Heterologous SlRd2 overexpression in yeast conferred resistance to highly toxic LiCl, whereas SlRd2 expression in Escherichia coli UspA mutant restored bacterial viability in response to H2O2 treatment. Finally, transient expression of SlCipk6 in transgenic N. benthamiana SlRd2 overexpressors resulted in reduced ROS accumulation as compared to wild-type plants. Taken together, our results establish that SlRd2, a tomato UspA, is, to our knowledge, a novel interactor and phosphorylation target of a member of the CIPK family, SlCipk6, and functionally regulates SlCipk6-mediated ROS generation. PMID:27899535

A Universal Stress Protein Involved in Oxidative Stress Is a Phosphorylation Target for Protein Kinase CIPK6.

PubMed

Gutiérrez-Beltrán, Emilio; Personat, José María; de la Torre, Fernando; Del Pozo, Olga

2017-01-01

Calcineurin B-like interacting protein kinases (CIPKs) decode calcium signals upon interaction with the calcium sensors calcineurin B like proteins into phosphorylation events that result into adaptation to environmental stresses. Few phosphorylation targets of CIPKs are known and therefore the molecular mechanisms underlying their downstream output responses are not fully understood. Tomato (Solanum lycopersicum) Cipk6 regulates immune and susceptible Programmed cell death in immunity transforming Ca 2+ signals into reactive oxygen species (ROS) signaling. To investigate SlCipk6-induced molecular mechanisms and identify putative substrates, a yeast two-hybrid approach was carried on and a protein was identified that contained a Universal stress protein (Usp) domain present in bacteria, protozoa and plants, which we named "SlRd2". SlRd2 was an ATP-binding protein that formed homodimers in planta. SlCipk6 and SlRd2 interacted using coimmunoprecipitation and bimolecular fluorescence complementation (BiFC) assays in Nicotiana benthamiana leaves and the complex localized in the cytosol. SlCipk6 phosphorylated SlRd2 in vitro, thus defining, to our knowledge, a novel target for CIPKs. Heterologous SlRd2 overexpression in yeast conferred resistance to highly toxic LiCl, whereas SlRd2 expression in Escherichia coli UspA mutant restored bacterial viability in response to H 2 O 2 treatment. Finally, transient expression of SlCipk6 in transgenic N benthamiana SlRd2 overexpressors resulted in reduced ROS accumulation as compared to wild-type plants. Taken together, our results establish that SlRd2, a tomato UspA, is, to our knowledge, a novel interactor and phosphorylation target of a member of the CIPK family, SlCipk6, and functionally regulates SlCipk6-mediated ROS generation. © 2017 American Society of Plant Biologists. All Rights Reserved.

eHealth Literacy and Partner Involvement in Treatment Decision Making for Men With Newly Diagnosed Localized Prostate Cancer.

PubMed

Song, Lixin; Tatum, Kimberly; Greene, Giselle; Chen, Ronald C

2017-03-01

To examine how the eHealth literacy of partners of patients with newly diagnosed prostate cancer affects their involvement in decision making, and to identify the factors that influence their eHealth literacy.
. Cross-sectional exploratory study.
. North Carolina.
. 142 partners of men with newly diagnosed localized prostate cancer. 
. A telephone survey and descriptive and multiple linear regression analyses were used.
. The partners' eHealth literacy, involvement in treatment decision making, and demographics, and the health statuses of the patients and their partners. 
. Higher levels of eHealth literacy among partners were significantly associated with their involvement in getting a second opinion, their awareness of treatment options, and the size of the social network they relied on for additional information and support for treatment decision making for prostate cancer. The factor influencing eHealth literacy was the partners' access to the Internet for personal use, which explained some of the variance in eHealth literacy.
. This study described how partners' eHealth literacy influenced their involvement in treatment decision making for prostate cancer and highlighted the influencing factors (i.e., partners' access to the Internet for personal use).
. When helping men with prostate cancer and their partners with treatment decision making, nurses need to assess eHealth literacy levels to determine whether nonelectronically based education materials are needed and to provide clear instructions on how to use eHealth resources.

A novel local anti-colorectal cancer drug delivery system: negative lipidoid nanoparticles with a passive target via a size-dependent pattern

NASA Astrophysics Data System (ADS)

Ding, Weifeng; Wang, Feng; Zhang, Jianfeng; Guo, Yibing; Ju, Shaoqing; Wang, Huimin

2013-09-01

The nontoxic, targeted and effective delivery of nucleic acid drugs remains an important challenge for clinical development. Here, we describe a novel negative lipidoid nanoparticle delivery system, providing entrapment-based transfection agents for local delivery of siRNA to the colorectal cancer focus. The delivery system was synthesized with lipidoid material 98N12-5(1), mPEG2000-C12/C14 glyceride and cholesterol at a desired molar ratio to realize the anionic surface charge of particles, which could alleviate to a larger degree the inflammatory response and immune stimulation of the organism, embodying dramatic biocompatibility. In particular, mPEG2000-C12/C14 glyceride was selected to ameliorate the stability of the delivery system and protection of nucleic acids by extending the tail length of the carbons, crucial also to neutralize the positive charge of 98N12-5(1) to form a resultant anionic particle. In vivo experiments revealed that a particle size of 90 nm perfectly realized a passive target in a size-dependent manner and did not affect the function of the liver and kidneys by a local delivery method, enema. We clarified that the uptake of negative lipidoid nanoparticles internalized through a lipid raft endocytotic pathway with low cytotoxicity, strong biocompatibility and high efficacy. This study suggests that negative lipidoid nanoparticles with enema delivery costitute, uniquely and appropriately, a local anti-colorectal cancer nucleic acid drug delivery platform, and the application of similar modes may be feasible in other therapeutic settings.

Prediction of novel target genes and pathways involved in bevacizumab-resistant colorectal cancer

PubMed Central

Makondi, Precious Takondwa; Lee, Chia-Hwa; Huang, Chien-Yu; Chu, Chi-Ming; Chang, Yu-Jia

2018-01-01

Bevacizumab combined with cytotoxic chemotherapy is the backbone of metastatic colorectal cancer (mCRC) therapy; however, its treatment efficacy is hampered by therapeutic resistance. Therefore, understanding the mechanisms underlying bevacizumab resistance is crucial to increasing the therapeutic efficacy of bevacizumab. The Gene Expression Omnibus (GEO) database (dataset, GSE86525) was used to identify the key genes and pathways involved in bevacizumab-resistant mCRC. The GEO2R web tool was used to identify differentially expressed genes (DEGs). Functional and pathway enrichment analyses of the DEGs were performed using the Database for Annotation, Visualization, and Integrated Discovery(DAVID). Protein–protein interaction (PPI) networks were established using the Search Tool for the Retrieval of Interacting Genes/Proteins database(STRING) and visualized using Cytoscape software. A total of 124 DEGs were obtained, 57 of which upregulated and 67 were downregulated. PPI network analysis showed that seven upregulated genes and nine downregulated genes exhibited high PPI degrees. In the functional enrichment, the DEGs were mainly enriched in negative regulation of phosphate metabolic process and positive regulation of cell cycle process gene ontologies (GOs); the enriched pathways were the phosphoinositide 3-kinase-serine/threonine kinase signaling pathway, bladder cancer, and microRNAs in cancer. Cyclin-dependent kinase inhibitor 1A(CDKN1A), toll-like receptor 4 (TLR4), CD19 molecule (CD19), breast cancer 1, early onset (BRCA1), platelet-derived growth factor subunit A (PDGFA), and matrix metallopeptidase 1 (MMP1) were the DEGs involved in the pathways and the PPIs. The clinical validation of the DEGs in mCRC (TNM clinical stages 3 and 4) revealed that high PDGFA expression levels were associated with poor overall survival, whereas high BRCA1 and MMP1 expression levels were associated with favorable progress free survival(PFS). The identified genes and pathways

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.

Synthesis and characterization of theranostic poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymer targeting tumor angiogenesis: tumor localization visualized by positron emission tomography.

PubMed

Yuan, Jianchao; Zhang, Haiyuan; Kaur, Harpreet; Oupicky, David; Peng, Fangyu

2013-05-01

Poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers were synthesized and characterized for tumor localization in vivo as a theranostic scaffold for cancer imaging and anticancer drug delivery targeting tumor angiogenesis. Tumor localization of the poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers was visualized in mice bearing human prostate cancer xenografts by positron emission tomography (PET) using a microPET scanner. PET quantitative analysis demonstrated that tumor 64Cu radioactivity (2.75 ± 0.34 %ID/g) in tumor-bearing mice 3 hours following intravenous injection of the poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers was significantly higher than the tumor 64Cu radioactivity (1.29 ± 0.26 %ID/g) in tumor-bearing mice injected with the nontargeted poly(HPMA)-DOTA-64Cu copolymers (p = .004). The poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers hold potential as a theranostic scaffold for cancer imaging and radiochemotherapy of prostate cancer targeting tumor angiogenesis by noninvasive tracking with PET.

Involving local health departments in community health partnerships: evaluation results from the partnership for the public's health initiative.

PubMed

Cheadle, Allen; Hsu, Clarissa; Schwartz, Pamela M; Pearson, David; Greenwald, Howard P; Beery, William L; Flores, George; Casey, Maria Campbell

2008-03-01

Improving community health "from the ground up" entails a comprehensive ecological approach, deep involvement of community-based entities, and addressing social determinants of population health status. Although the Centers for Disease Control and Prevention, the Office of the Surgeon General, and other authorities have called for public health to be an "inter-sector" enterprise, few models have surfaced that feature local health departments as a key part of the collaborative model for effecting community-level change. This paper presents evaluation findings and lessons learned from the Partnership for the Public's Health (PPH), a comprehensive community initiative that featured a central role for local health departments with their community partners. Funded by The California Endowment, PPH provided technical and financial resources to 39 community partnerships in 14 local health department jurisdictions in California to promote community and health department capacity building and community-level policy and systems change designed to produce long-term improvements in population health. The evaluation used multiple data sources to create progress ratings for each partnership in five goal areas related to capacity building, community health improvement programs, and policy and systems change. Overall results were generally positive; in particular, of the 37 partnerships funded continuously throughout the 5 years of the initiative, between 25% and 40% were able to make a high level of progress in each of the Initiative's five goal areas. Factors associated with partnership success were also identified by local evaluators. These results showed that health departments able to work effectively with community groups had strong, committed leaders who used creative financing mechanisms, inclusive planning processes, organizational changes, and open communication to promote collaboration with the communities they served.

Synthesis and characterization of Her2-NLP peptide conjugates targeting circulating breast cancer cells: cellular uptake and localization by fluorescent microscopic imaging.

PubMed

Cai, Huawei; Singh, Ajay N; Sun, Xiankai; Peng, Fangyu

2015-01-01

To synthesize a fluorescent Her2-NLP peptide conjugate consisting of Her2/neu targeting peptide and nuclear localization sequence peptide (NLP) and assess its cellular uptake and intracellular localization for radionuclide cancer therapy targeting Her2/neu-positive circulating breast cancer cells (CBCC). Fluorescent Cy5.5 Her2-NLP peptide conjugate was synthesized by coupling a bivalent peptide sequence, which consisted of a Her2-binding peptide (NH2-GSGKCCYSL) and an NLP peptide (CGYGPKKKRKVGG) linked by a polyethylene glycol (PEG) chain with 6 repeating units, with an activated Cy5.5 ester. The conjugate was separated and purified by HPLC and then characterized by Maldi-MS. The intracellular localization of fluorescent Cy5.5 Her2-NLP peptide conjugate was assessed by fluorescent microscopic imaging using a confocal microscope after incubation of Cy5.5-Her2-NLP with Her2/neu positive breast cancer cells and Her2/neu negative control breast cancer cells, respectively. Fluorescent signals were detected in cytoplasm of Her2/neu positive breast cancer cells (SKBR-3 and BT474 cell lines), but not or little in cytoplasm of Her2/neu negative breast cancer cells (MDA-MB-231), after incubation of the breast cancer cells with Cy5.5-Her2-NLP conjugates in vitro. No fluorescent signals were detected within the nuclei of Her2/neu positive SKBR-3 and BT474 breast cancer cells, neither Her2/neu negative MDA-MB-231 cells, incubated with the Cy5.5-Her2-NLP peptide conjugates, suggesting poor nuclear localization of the Cy5.5-Her2-NLP conjugates localized within the cytoplasm after their cellular uptake and internalization by the Her2/neu positive breast cancer cells. Her2-binding peptide (KCCYSL) is a promising agent for radionuclide therapy of Her2/neu positive breast cancer using a β(-) or α emitting radionuclide, but poor nuclear localization of the Her2-NLP peptide conjugates may limit its use for eradication of Her2/neu-positive CBCC using I-125 or other Auger electron

Chitosan Nanoparticles for Nuclear Targeting: The Effect of Nanoparticle Size and Nuclear Localization Sequence Density.

PubMed

Tammam, Salma N; Azzazy, Hassan M E; Breitinger, Hans G; Lamprecht, Alf

2015-12-07

Many recently discovered therapeutic proteins exert their main function in the nucleus, thus requiring both efficient uptake and correct intracellular targeting. Chitosan nanoparticles (NPs) have attracted interest as protein delivery vehicles due to their biocompatibility and ability to escape the endosomes offering high potential for nuclear delivery. Molecular entry into the nucleus occurs through the nuclear pore complexes, the efficiency of which is dependent on NP size and the presence of nuclear localization sequence (NLS). Chitosan nanoparticles of different sizes (S-NPs ≈ 25 nm; L-NP ≈ 150 nm) were formulated, and they were modified with different densities of the octapeptide NLS CPKKKRKV (S-NPs, 0.25, 0.5, 2.0 NLS/nm(2); L-NPs, 0.6, 0.9, 2 NLS/nm(2)). Unmodified and NLS-tagged NPs were evaluated for their protein loading capacity, extent of cell association, cell uptake, cell surface binding, and finally nuclear delivery efficiency in L929 fibroblasts. To avoid errors generated with cell fractionation and nuclear isolation protocols, nuclear delivery was assessed in intact cells utilizing Förster resonance energy transfer (FRET) fluorometry and microscopy. Although L-NPs showed ≈10-fold increase in protein loading per NP when compared to S-NPs, due to higher cell association and uptake S-NPs showed superior protein delivery. NLS exerts a size and density dependent effect on nanoparticle uptake and surface binding, with a general reduction in NP cell surface binding and an increase in cell uptake with the increase in NLS density (up to 8.4-fold increase in uptake of High-NLS-L-NPs (2 NLS/nm(2)) compared to unmodified L-NPs). However, for nuclear delivery, unmodified S-NPs show higher nuclear localization rates when compared to NLS modified NPs (up to 5-fold by FRET microscopy). For L-NPs an intermediate NLS density (0.9 NLS/nm(2)) seems to provide highest nuclear localization (3.7-fold increase in nuclear delivery compared to High

Infants' Visual Localization of Visual and Auditory Targets.

ERIC Educational Resources Information Center

Bechtold, A. Gordon; And Others

This study is an investigation of 2-month-old infants' abilities to visually localize visual and auditory peripheral stimuli. Each subject (N=40) was presented with 50 trials; 25 of these visual and 25 auditory. The infant was placed in a semi-upright infant seat positioned 122 cm from the center speaker of an arc formed by five loudspeakers. At…

Who wants to be involved in health care decisions? Comparing preferences for individual and collective involvement in England and Sweden.

PubMed

Fredriksson, Mio; Eriksson, Max; Tritter, Jonathan

2017-07-14

Patient and public involvement (PPI) is framed as positive for individuals, the health system, public health, as well as for communities and society as a whole. We investigated whether preferences for PPI differed between two countries with Beveridge type health systems-Sweden and England. We measured willingness to be involved in individual treatment decisions and in decisions about the organization and provision of local health and social care services. This was a comparative cross-sectional study of the general population's preferences. Together, the two samples included 3125 respondents; 1625 in England and 1500 in Sweden. Country differences were analysed in a multinomial regression model controlling for gender, age and educational attainment. Overall, 68% of respondents wanted a passive patient role and 44% wanted to be involved in local decisions about organization and provision of services. In comparison with in Sweden, they were in England less likely to want a health professional such as a GP or consultant to make decisions about their treatment and also more likely to want to make their own decisions. They were also less likely to want to be involved in local service development decisions. An increased likelihood of wanting to be involved in organizational decision-making was associated with individuals wanting to make their own treatment decisions. Women were less likely to want health professionals to make decisions and more likely to want to be involved in organizational decisions. An effective health system that ensures public health must integrate an effective approach to PPI both in individual treatment decisions and shaping local health and social care priorities. To be effective, involvement activities must take in to account the variation in the desire for involvement and the implications that this has for equity. More work is needed to understand the relationship between the desire to be involved and actually being involved, but both appear

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

MicroRNA-320 is Involved in the Regulation of Cardiac Ischemia/Reperfusion Injury by Targeting Hsp20

PubMed Central

Ren, Xiao-Ping; Wang, Xiaohong; Sartor, Maureen A.; Jones, Keith; Qian, Jiang; Nicolaou, Persoulla; Pritchard, Tracy J.; Fan, Guo-Chang

2009-01-01

Background Recent studies have identified critical roles for microRNAs (miRNAs) in a variety of cellular processes, including regulation of cardiomyocyte death. However, the signature of miRNA expression and possible roles of miRNA in the ischemic heart have been less well-studied. Methods and Results Here we performed miRNA arrays to detect the expression pattern of miRNAs in murine hearts subjected to ischemia/reperfusion (I/R) in vivo and ex vivo. Surprisingly, we found that only miR-320 expression was significantly decreased in the hearts upon I/R in vivo and ex vivo. This was further confirmed by Taqman RT-PCR. Gain-of-function and loss-of-function approaches were employed in cultured adult rat cardiomyocytes to investigate the functional roles of miR-320. Overexpression of miR-320 enhanced cardiomyocyte death and apoptosis, while knock-down was cytoprotective, upon simulated I/R. Furthermore, transgenic mice with cardiac-specific overexpression of miR-320 revealed an increased extent of apoptosis and infarction size in the hearts upon I/R in vivo and ex vivo, relative to the WT controls. Conversely, in vivo treatment with antagomir-320 reduced the infarction size, relative to the administration of mutant antagomir-320 and saline controls. Using Target-Scan software and proteomic analysis, we identified Hsp20, a known cardioprotective protein, as an important candidate target for miR-320. This was validated experimentally by utilizing a luciferase/GFP reporter activity assay and examining the expression of Hsp20 upon miR-320 overexpression and knockdown in cardiomyocytes. Conclusions Our data demonstrate that miR-320 is involved in the regulation of I/R-induced cardiac injury and dysfunction via antithetical regulation of Hsp20. Thus, miR-320 may constitute a new therapeutic target for ischemic heart diseases. PMID:19380620

Duplicate Maize Wrinkled1 Transcription Factors Activate Target Genes Involved in Seed Oil Biosynthesis1[C][W

PubMed Central

Pouvreau, Benjamin; Baud, Sébastien; Vernoud, Vanessa; Morin, Valérie; Py, Cyrille; Gendrot, Ghislaine; Pichon, Jean-Philippe; Rouster, Jacques; Paul, Wyatt; Rogowsky, Peter M.

2011-01-01

WRINKLED1 (WRI1), a key regulator of seed oil biosynthesis in Arabidopsis (Arabidopsis thaliana), was duplicated during the genome amplification of the cereal ancestor genome 90 million years ago. Both maize (Zea mays) coorthologs ZmWri1a and ZmWri1b show a strong transcriptional induction during the early filling stage of the embryo and complement the reduced fatty acid content of Arabidopsis wri1-4 seeds, suggesting conservation of molecular function. Overexpression of ZmWri1a not only increases the fatty acid content of the mature maize grain but also the content of certain amino acids, of several compounds involved in amino acid biosynthesis, and of two intermediates of the tricarboxylic acid cycle. Transcriptomic experiments identified 18 putative target genes of this transcription factor, 12 of which contain in their upstream regions an AW box, the cis-element bound by AtWRI1. In addition to functions related to late glycolysis and fatty acid biosynthesis in plastids, the target genes also have functions related to coenzyme A biosynthesis in mitochondria and the production of glycerol backbones for triacylglycerol biosynthesis in the cytoplasm. Interestingly, the higher seed oil content in ZmWri1a overexpression lines is not accompanied by a reduction in starch, thus opening possibilities for the use of the transgenic maize lines in breeding programs. PMID:21474435

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

MicroRNA-Target Network Inference and Local Network Enrichment Analysis Identify Two microRNA Clusters with Distinct Functions in Head and Neck Squamous Cell Carcinoma

PubMed Central

Sass, Steffen; Pitea, Adriana; Unger, Kristian; Hess, Julia; Mueller, Nikola S.; Theis, Fabian J.

2015-01-01

MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and functional annotation of target gene sets. We here present a novel method “miRlastic”, which infers miRNA-target interactions using transcriptomic data as well as prior knowledge and performs functional annotation of target genes by exploiting the local structure of the inferred network. For the network inference, we applied linear regression modeling with elastic net regularization on matched microRNA and messenger RNA expression profiling data to perform feature selection on prior knowledge from sequence-based target prediction resources. The novelty of miRlastic inference originates in predicting data-driven intra-transcriptome regulatory relationships through feature selection. With synthetic data, we showed that miRlastic outperformed commonly used methods and was suitable even for low sample sizes. To gain insight into the functional role of miRNAs and to determine joint functional properties of miRNA clusters, we introduced a local enrichment analysis procedure. The principle of this procedure lies in identifying regions of high functional similarity by evaluating the shortest paths between genes in the network. We can finally assign functional roles to the miRNAs by taking their regulatory relationships into account. We thoroughly evaluated miRlastic on a cohort of head and neck cancer (HNSCC) patients provided by The Cancer Genome Atlas. We inferred an mi-/mRNA regulatory network for human papilloma virus (HPV)-associated miRNAs in HNSCC. The resulting network best enriched for experimentally validated miRNA-target interaction, when compared to common methods. Finally, the local enrichment step identified two functional clusters of mi

MicroRNA-Target Network Inference and Local Network Enrichment Analysis Identify Two microRNA Clusters with Distinct Functions in Head and Neck Squamous Cell Carcinoma.

PubMed

Sass, Steffen; Pitea, Adriana; Unger, Kristian; Hess, Julia; Mueller, Nikola S; Theis, Fabian J

2015-12-18

MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and functional annotation of target gene sets. We here present a novel method "miRlastic", which infers miRNA-target interactions using transcriptomic data as well as prior knowledge and performs functional annotation of target genes by exploiting the local structure of the inferred network. For the network inference, we applied linear regression modeling with elastic net regularization on matched microRNA and messenger RNA expression profiling data to perform feature selection on prior knowledge from sequence-based target prediction resources. The novelty of miRlastic inference originates in predicting data-driven intra-transcriptome regulatory relationships through feature selection. With synthetic data, we showed that miRlastic outperformed commonly used methods and was suitable even for low sample sizes. To gain insight into the functional role of miRNAs and to determine joint functional properties of miRNA clusters, we introduced a local enrichment analysis procedure. The principle of this procedure lies in identifying regions of high functional similarity by evaluating the shortest paths between genes in the network. We can finally assign functional roles to the miRNAs by taking their regulatory relationships into account. We thoroughly evaluated miRlastic on a cohort of head and neck cancer (HNSCC) patients provided by The Cancer Genome Atlas. We inferred an mi-/mRNA regulatory network for human papilloma virus (HPV)-associated miRNAs in HNSCC. The resulting network best enriched for experimentally validated miRNA-target interaction, when compared to common methods. Finally, the local enrichment step identified two functional clusters of miRNAs that

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.

Space based lidar shot pattern targeting strategies for small targets such as streams

NASA Technical Reports Server (NTRS)

Spiers, Gary D.

2001-01-01

An analysis of the effectiveness of four different types of lidar shot distribution is conducted to determine which is best for concentrating shots in a given location. A simple preemptive targeting strategy is found to work as adequately as a more involved dynamic strategy for most target sizes considered.

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

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

In Vivo Optical Imaging for Targeted Drug Kinetics and Localization for Oral Surgery and Super-Resolution, Facilitated by Printed Phantoms

NASA Astrophysics Data System (ADS)

Bentz, Brian Z.

Many human cancer cell types over-express folate receptors, and this provides an opportunity to develop targeted anti-cancer drugs. For these drugs to be effective, their kinetics must be well understood in vivo and in deep tissue where tumors occur. We demonstrate a method for imaging these parameters by incorporating a kinetic compartment model and fluorescence into optical diffusion tomography (ODT). The kinetics were imaged in a live mouse, and found to be in agreement with previous in vitro studies, demonstrating the validity of the method and its feasibility as an effective tool in preclinical drug development studies. Progress in developing optical imaging for biomedical applications requires customizable and often complex objects known as "phantoms" for testing and evaluation. We present new optical phantoms fabricated using inexpensive 3D printing methods with multiple materials, allowing for the placement of complex inhomogeneities in heterogeneous or anatomically realistic geometries, as opposed to previous phantoms which were limited to simple shapes formed by molds or machining. Furthermore, we show that Mie theory can be used to design the optical properties to match a target tissue. The phantom fabrication methods are versatile, can be applied to optical imaging methods besides diffusive imaging, and can be used in the calibration of live animal imaging data. Applications of diffuse optical imaging in the operating theater have been limited in part due to computational burden. We present an approach for the fast localization of arteries in the roof of the mouth that has the potential to reduce complications. Furthermore, we use the extracted position information to fabricate a custom surgical guide using 3D printing that could protect the arteries during surgery. The resolution of ODT is severely limited by the attenuation of high spatial frequencies. We present a super-resolution method achieved through the point localization of fluorescent

The Cretaceous-Tertiary extinction: A lethal mechanism involving anhydrite target rocks

USGS Publications Warehouse

Brett, R.

1992-01-01

The Chicxulub Crater, Yucatan, Mexico, is a leading contender as the site for the impact event that caused the Cretaceous-Tertiary (K-T) extinctions. A considerable thickness of anhydrite (CaSO4) forms part of the target rock. High temperatures resulting from impact would drive SO2 off from the anhydrite. Hundreds of billions of tonnes of sulfuric acid aerosol would thus enter the stratosphere and cause considerable cooling of the Earth's surface, decrease photosynthesis by orders of magnitude, deplete the ozone layer, and permit increased UV radiation to reach the Earth's surface. Finally, the aerosol would fall back to Earth as acid rain and devastate land and some lacustrine biota and near-surface marine creatures. The presence of anhydrite in the Chicxulub target rock may thus help explain the many extinctions observed at the K-T boundary. ?? 1992.

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.

A Theory of Eye Movements during Target Acquisition

ERIC Educational Resources Information Center

Zelinsky, Gregory J.

2008-01-01

The gaze movements accompanying target localization were examined via human observers and a computational model (target acquisition model [TAM]). Search contexts ranged from fully realistic scenes to toys in a crib to Os and Qs, and manipulations included set size, target eccentricity, and target-distractor similarity. Observers and the model…

Construction of an Overhauser magnetic gradiometer and the applications in geomagnetic observation and ferromagnetic target localization

NASA Astrophysics Data System (ADS)

Liu, H.; Dong, H.; Liu, Z.; Ge, J.; Bai, B.; Zhang, C.

2017-10-01

The proton precession magnetometer with single sensor is commonly used in geomagnetic observation and magnetic anomaly detection. Due to technological limitations, the measurement accuracy is restricted by several factors such as the sensor performance, frequency measurement precision, instability of polarization module, etc. Aimed to improve the anti-interference ability, an Overhauser magnetic gradiometer with dual sensor structure was designed. An alternative design of a geomagnetic sensor with differential dual-coil structure was presented. A multi-channel frequency measurement algorithm was proposed to increase the measurement accuracy. A silicon oscillator was adopted to resolve the instability of polarization system. This paper briefly discusses the design and development of the gradiometer and compares the data recorded by this instrument with a commonly used commercially Overhauser magnetometer in the world market. The proposed gradiometer records the earth magnetic field in 24 hours with measurement accuracy of ± 0.3 nT and a sampling rate of 3 seconds per sample. The quality of data recorded is excellent and consistent with the commercial instrument. In addition, experiments of ferromagnetic target localization were conducted. This gradiometer shows a strong ability in magnetic anomaly detection and localization. To sum up, it has the advantages of convenient operation, high precision, strong anti-interference, etc., which proves the effectiveness of the dual sensor structure Overhauser magnetic gradiometer.

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.

Analysis of Genes Involved in Body Weight Regulation by Targeted Re-Sequencing.

PubMed

Volckmar, Anna-Lena; Han, Chung Ting; Pütter, Carolin; Haas, Stefan; Vogel, Carla I G; Knoll, Nadja; Struve, Christoph; Göbel, Maria; Haas, Katharina; Herrfurth, Nikolas; Jarick, Ivonne; Grallert, Harald; Schürmann, Annette; Al-Hasani, Hadi; Hebebrand, Johannes; Sauer, Sascha; Hinney, Anke

2016-01-01

Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing. We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) ≥ 99th percentile and 176 lean adults (BMI ≤ 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults. We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (pTDT = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.

A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs

PubMed Central

McKinsey, EL; Parrish, JK; Irwin, AE; Niemeyer, BF; Kern, HB; Birks, DK; Jedlicka, P

2015-01-01

MicroRNAs (miRs) are a novel class of cellular bioactive molecules with critical functions in the regulation of gene expression in normal biology and disease. MiRs are frequently misexpressed in cancer, with potent biological consequences. However, relatively little is known about miRs in pediatric cancers, including sarcomas. Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood. Ewing sarcoma is an aggressive pediatric malignancy driven by EWS/Ets fusion oncoproteins, which are gain-of-function transcriptional regulators. We employed stable silencing of EWS/Fli1, the most common of the oncogenic fusions, and global miR profiling to identify EWS/Fli1-regulated miRs with oncogenesis-modifying roles in Ewing sarcoma. In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1. Strikingly, all of these miRs have predicted targets in the insulin-like growth factor (IGF) signaling pathway, a pivotal driver of Ewing sarcoma oncogenesis. We demonstrate that miRs in this group negatively regulate the expression of multiple pro-oncogenic components of the IGF pathway, namely IGF-1, IGF-1 receptor, mammalian/mechanistic target of rapamycin and ribosomal protein S6 kinase A1. Consistent with tumor-suppressive functions, these miRs manifest growth inhibitory properties in Ewing sarcoma cells. Our studies thus uncover a novel oncogenic mechanism in Ewing sarcoma, involving post-transcriptional derepression of IGF signaling by the EWS/Fli1 fusion oncoprotein via miRs. This novel pathway may be amenable to innovative therapeutic targeting in Ewing sarcoma and other malignancies with activated IGF signaling. PMID:21643012

A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs.

PubMed

McKinsey, E L; Parrish, J K; Irwin, A E; Niemeyer, B F; Kern, H B; Birks, D K; Jedlicka, P

2011-12-08

MicroRNAs (miRs) are a novel class of cellular bioactive molecules with critical functions in the regulation of gene expression in normal biology and disease. MiRs are frequently misexpressed in cancer, with potent biological consequences. However, relatively little is known about miRs in pediatric cancers, including sarcomas. Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood. Ewing sarcoma is an aggressive pediatric malignancy driven by EWS/Ets fusion oncoproteins, which are gain-of-function transcriptional regulators. We employed stable silencing of EWS/Fli1, the most common of the oncogenic fusions, and global miR profiling to identify EWS/Fli1-regulated miRs with oncogenesis-modifying roles in Ewing sarcoma. In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1. Strikingly, all of these miRs have predicted targets in the insulin-like growth factor (IGF) signaling pathway, a pivotal driver of Ewing sarcoma oncogenesis. We demonstrate that miRs in this group negatively regulate the expression of multiple pro-oncogenic components of the IGF pathway, namely IGF-1, IGF-1 receptor, mammalian/mechanistic target of rapamycin and ribosomal protein S6 kinase A1. Consistent with tumor-suppressive functions, these miRs manifest growth inhibitory properties in Ewing sarcoma cells. Our studies thus uncover a novel oncogenic mechanism in Ewing sarcoma, involving post-transcriptional derepression of IGF signaling by the EWS/Fli1 fusion oncoprotein via miRs. This novel pathway may be amenable to innovative therapeutic targeting in Ewing sarcoma and other malignancies with activated IGF signaling.

Effects of local infusions of apomorphine on the extracellular citrulline level in the striatum: Involvement of D1 and D2 dopamine receptors.

PubMed

Savel'ev, S A

2006-11-01

Studies using vital microdialysis and high-performance liquid chromatography showed that local infusion of the NO synthase inhibitor N-nitro-L-arginine (1 mM) into the striatum decreased, while infusion of the dopamine receptor agonist apomorphine (100 microM) increased the level of citrulline (a side product of nitric oxide synthesis) in the intercellular space of this structure in Sprague-Dawley rats. The increase in the citrulline level induced by infusions of apomorphine was completely prevented by local infusions of N-nitro-L-arginine (1 mM) and raclopride (10 microm), a dopamine D2 receptor blocker, but not by infusion of SCH-23390 (50 microm), a dopamine D1 receptor blocker. These data suggest that the increase in extracellular citrulline in the striatum induced by dopaminergic stimulation results from local increases in NO synthase activity and that this effect involves D2, but not D1 dopamine receptors.

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.

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.

Camera calibration: active versus passive targets

NASA Astrophysics Data System (ADS)

Schmalz, Christoph; Forster, Frank; Angelopoulou, Elli

2011-11-01

Traditionally, most camera calibrations rely on a planar target with well-known marks. However, the localization error of the marks in the image is a source of inaccuracy. We propose the use of high-resolution digital displays as active calibration targets to obtain more accurate calibration results for all types of cameras. The display shows a series of coded patterns to generate correspondences between world points and image points. This has several advantages. No special calibration hardware is necessary because suitable displays are practically ubiquitious. The method is fully automatic, and no identification of marks is necessary. For a coding scheme based on phase shifting, the localization accuracy is approximately independent of the camera's focus settings. Most importantly, higher accuracy can be achieved compared to passive targets, such as printed checkerboards. A rigorous evaluation is performed to substantiate this claim. Our active target method is compared to standard calibrations using a checkerboard target. We perform camera, calibrations with different combinations of displays, cameras, and lenses, as well as with simulated images and find markedly lower reprojection errors when using active targets. For example, in a stereo reconstruction task, the accuracy of a system calibrated with an active target is five times better.

Assessment of esophageal involvement in systemic sclerosis and morphea (localized scleroderma) by clinical, endoscopic, manometric and pH metric features: a prospective comparative hospital based study.

PubMed

Arif, Tasleem; Masood, Qazi; Singh, Jaswinder; Hassan, Iffat

2015-02-15

Systemic sclerosis (SSc) is a generalized disorder of unknown etiology affecting the connective tissue of the body. It affects the skin and various internal organs. Gastrointestinal tract involvement is seen in almost 90% of the patients. Esophagus is the most frequently affected part of the gastrointestinal tract. Esophageal motility disturbance classically manifests as a reduced lower esophageal sphincter pressure (LESP) and loss of distal esophageal body peristalsis. Consequently, SSc patients may be complicated by erosive esophagitis and eventually by Barrett's esophagus and esophageal adenocarcinoma. Morphea, also known as localized scleroderma, is characterized by predominant skin involvement, with occasional involvement of subjacent muscles and usually sparing the internal organs. The involvement of esophagus in morphea has been studied very scarcely. The proposed study will investigate the esophageal involvement in the two forms of scleroderma (systemic and localized), compare the same and address any need of upper gastrointestinal evaluation in morphea (localized scleroderma) patients. 56 and 31 newly and already diagnosed cases of SSc and morphea respectively were taken up for the study. All the patients were inquired about the dyspeptic symptoms (heartburn and/or acid regurgitation and/or dysphagia). Upper gastrointestinal endoscopy, esophageal manometry and 24-hour pH monitoring were done in 52, 47 and 41 patients of SSc; and 28, 25 and 20 patients of morphea respectively. Esophageal symptoms were present in 39 cases (69.6%) of SSc which were mild in 22 (39.3%), moderate in 14 (25%), severe in three (5.3%); while only four cases (7.1%) of morphea had esophageal symptoms all of which were mild in severity. Reflux esophagitis was seen in 17 cases (32.7%) of SSc and only two cases (7.14%) of morphea. Manometric abnormalities were seen in 32 cases (68.1%) of SSc and none in morphea. Ambulatory 24-hour esophageal pH monitoring documented abnormal reflux in

Tele-Autonomous control involving contact. Final Report Thesis; [object localization

NASA Technical Reports Server (NTRS)

Shao, Lejun; Volz, Richard A.; Conway, Lynn; Walker, Michael W.

1990-01-01

Object localization and its application in tele-autonomous systems are studied. Two object localization algorithms are presented together with the methods of extracting several important types of object features. The first algorithm is based on line-segment to line-segment matching. Line range sensors are used to extract line-segment features from an object. The extracted features are matched to corresponding model features to compute the location of the object. The inputs of the second algorithm are not limited only to the line features. Featured points (point to point matching) and featured unit direction vectors (vector to vector matching) can also be used as the inputs of the algorithm, and there is no upper limit on the number of the features inputed. The algorithm will allow the use of redundant features to find a better solution. The algorithm uses dual number quaternions to represent the position and orientation of an object and uses the least squares optimization method to find an optimal solution for the object's location. The advantage of using this representation is that the method solves for the location estimation by minimizing a single cost function associated with the sum of the orientation and position errors and thus has a better performance on the estimation, both in accuracy and speed, than that of other similar algorithms. The difficulties when the operator is controlling a remote robot to perform manipulation tasks are also discussed. The main problems facing the operator are time delays on the signal transmission and the uncertainties of the remote environment. How object localization techniques can be used together with other techniques such as predictor display and time desynchronization to help to overcome these difficulties are then discussed.

Trans-Golgi network localized small GTPase RabA1d is involved in cell plate formation and oscillatory root hair growth.

PubMed

Berson, Tobias; von Wangenheim, Daniel; Takáč, Tomáš; Šamajová, Olga; Rosero, Amparo; Ovečka, Miroslav; Komis, George; Stelzer, Ernst H K; Šamaj, Jozef

2014-09-27

Small Rab GTPases are important regulators of vesicular trafficking in plants. AtRabA1d, a member of the RabA1 subfamily of small GTPases, was previously found in the vesicle-rich apical dome of growing root hairs suggesting a role during tip growth; however, its specific intracellular localization and role in plants has not been well described. The transient expression of 35S::GFP:RabA1d construct in Allium porrum and Nicotiana benthamiana revealed vesicular structures, which were further corroborated in stable transformed Arabidopsis thaliana plants. GFP-RabA1d colocalized with the trans-Golgi network marker mCherry-VTI12 and with early FM4-64-labeled endosomal compartments. Late endosomes and endoplasmic reticulum labeled with FYVE-DsRed and ER-DsRed, respectively, were devoid of GFP-RabA1d. The accumulation of GFP-RabA1d in the core of brefeldin A (BFA)-induced-compartments and the quantitative upregulation of RabA1d protein levels after BFA treatment confirmed the association of RabA1d with early endosomes/TGN and its role in vesicle trafficking. Light-sheet microscopy revealed involvement of RabA1d in root development. In root cells, GFP-RabA1d followed cell plate expansion consistently with cytokinesis-related vesicular trafficking and membrane recycling. GFP-RabA1d accumulated in disc-like structures of nascent cell plates, which progressively evolved to marginal ring-like structures of the growing cell plates. During root hair growth and development, GFP-RabA1d was enriched at root hair bulges and at the apical dome of vigorously elongating root hairs. Importantly, GFP-RabA1d signal intensity exhibited an oscillatory behavior in-phase with tip growth. Progressively, this tip localization dissapeared in mature root hairs suggesting a link between tip localization of RabA1d and root hair elongation. Our results support a RabA1d role in events that require vigorous membrane trafficking. RabA1d is located in early endosomes/TGN and is involved in vesicle

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

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

Structural and sequencing analysis of local target DNA recognition by MLV integrase.

PubMed

Aiyer, Sriram; Rossi, Paolo; Malani, Nirav; Schneider, William M; Chandar, Ashwin; Bushman, Frederic D; Montelione, Gaetano T; Roth, Monica J

2015-06-23

Target-site selection by retroviral integrase (IN) proteins profoundly affects viral pathogenesis. We describe the solution nuclear magnetic resonance structure of the Moloney murine leukemia virus IN (M-MLV) C-terminal domain (CTD) and a structural homology model of the catalytic core domain (CCD). In solution, the isolated MLV IN CTD adopts an SH3 domain fold flanked by a C-terminal unstructured tail. We generated a concordant MLV IN CCD structural model using SWISS-MODEL, MMM-tree and I-TASSER. Using the X-ray crystal structure of the prototype foamy virus IN target capture complex together with our MLV domain structures, residues within the CCD α2 helical region and the CTD β1-β2 loop were predicted to bind target DNA. The role of these residues was analyzed in vivo through point mutants and motif interchanges. Viable viruses with substitutions at the IN CCD α2 helical region and the CTD β1-β2 loop were tested for effects on integration target site selection. Next-generation sequencing and analysis of integration target sequences indicate that the CCD α2 helical region, in particular P187, interacts with the sequences distal to the scissile bonds whereas the CTD β1-β2 loop binds to residues proximal to it. These findings validate our structural model and disclose IN-DNA interactions relevant to target site selection. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

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

A novel protein involved in heart development in Ambystoma mexicanum is localized in endoplasmic reticulum.

PubMed

Jia, P; Zhang, C; Huang, X P; Poda, M; Akbas, F; Lemanski, S L; Erginel-Unaltuna, N; Lemanski, L F

2008-11-01

The discovery of the naturally occurring cardiac non-function (c) animal strain in Ambystoma mexicanum (axolotl) provides a valuable animal model to study cardiomyocyte differentiation. In homozygous mutant animals (c/c), rhythmic contractions of the embryonic heart are absent due to a lack of organized myofibrils. We have previously cloned a partial sequence of a peptide cDNA (N1) from an anterior-endoderm-conditioned-medium RNA library that had been shown to be able to rescue the mutant phenotype. In the current studies we have fully cloned the N1 full length cDNA sequence from the library. N1 protein has been detected in both adult heart and skeletal muscle but not in any other adult tissues. GFP-tagged expression of the N1 protein has revealed localization of the N1 protein in the endoplasmic reticulum (ER). Results from in situ hybridization experiments have confirmed the dramatic decrease of expression of N1 mRNA in mutant (c/c) embryos indicating that the N1 gene is involved in heart development.

Immunodetection of 11 beta-hydroxysteroid dehydrogenase type 2 in human mineralocorticoid target tissues: evidence for nuclear localization.

PubMed

Shimojo, M; Ricketts, M L; Petrelli, M D; Moradi, P; Johnson, G D; Bradwell, A R; Hewison, M; Howie, A J; Stewart, P M

1997-03-01

11 beta-Hydroxysteroid dehydrogenase (11 beta HSI) is an enzyme complex responsible for the conversion of hormonally active cortisol to inactive cortisone; two isoforms of the enzyme have been cloned and characterized. Clinical observations from patients with the hypertensive syndrome apparent mineralocorticoid excess, recently explained on the basis of mutations in the human 11 beta HSD2 gene, suggest that it is the 11 beta HSD2 isoform that serves a vital role in dictating specificity upon the mineralocorticoid receptor (MR). We have raised a novel antibody in sheep against human 11 beta HSD2 using synthetic multiantigenic peptides and have examined the localization and subcellular distribution of 11 beta HSD2 in mineralocorticoid target tissues. The immunopurified antibody recognized a single band of approximately 44 kDa in placenta, trophoblast, and distal colon. In kidney tissue, two bands of approximately 44 and 48 kDa were consistently observed. No signal was seen in decidua, adrenal, or liver. Immunoperoxidase studies on the mineralocorticoid target tissues, kidney, colon, and parotid gland indicated positive staining in epithelial cells known to express the MR: respectively, renal collecting ducts, surface and crypt colonic epithelial cells, and parotid duct epithelial cells. No staining was seen in these tissues in other sites. The intracellular localization of 11 beta HSD2 in kidney and colon epithelial cells was addressed using confocal laser microscopy. Parallel measurements of 11 beta HSD2 and nuclear propidium iodide fluorescence on sections scanned through an optical section of approximately 0.1 micron indicated significant 11 beta HSD2 immunofluorescence in the nucleus. In human kidney, colon, and salivary gland, 11 beta HSD2 protects the MR from glucocorticoid excess in an autocrine fashion. Furthermore, within these tissues, 11 beta HSD2, which had been considered to be a microsomal enzyme, is also found in the nucleus, suggesting that the

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

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.

Localization, Localization, Localization

NASA Technical Reports Server (NTRS)

Parker, T.; Malin, M.; Golombek, M.; Duxbury, T.; Johnson, A.; Guinn, J.; McElrath, T.; Kirk, R.; Archinal, B.; Soderblom, L.

2004-01-01

Localization of the two Mars Exploration Rovers involved three independent approaches to place the landers with respect to the surface of Mars and to refine the location of those points on the surface with the Mars control net: 1) Track the spacecraft through entry, descent, and landing, then refine the final roll stop position by radio tracking and comparison to images taken during descent; 2) Locate features on the horizon imaged by the two rovers and compare them to the MOC and THEMIS VIS images, and the DIMES images on the two MER landers; and 3) 'Check' and refine locations by acquisition of MOC 1.5 meter and 50 cm/pixel images.

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

The GARP Complex Is Involved in Intracellular Cholesterol Transport via Targeting NPC2 to Lysosomes.

PubMed

Wei, Jian; Zhang, Ying-Yu; Luo, Jie; Wang, Ju-Qiong; Zhou, Yu-Xia; Miao, Hong-Hua; Shi, Xiong-Jie; Qu, Yu-Xiu; Xu, Jie; Li, Bo-Liang; Song, Bao-Liang

2017-06-27

Proper intracellular cholesterol trafficking is critical for cellular function. Two lysosome-resident proteins, NPC1 and NPC2, mediate the egress of low-density lipoprotein-derived cholesterol from lysosomes. However, other proteins involved in this process remain largely unknown. Through amphotericin B-based selection, we isolated two cholesterol transport-defective cell lines. Subsequent whole-transcriptome-sequencing analysis revealed two cell lines bearing the same mutation in the vacuolar protein sorting 53 (Vps53) gene. Depletion of VPS53 or other subunits of the Golgi-associated retrograde protein (GARP) complex impaired NPC2 sorting to lysosomes and caused cholesterol accumulation. GARP deficiency blocked the retrieval of the cation-independent mannose 6-phosphate receptor (CI-MPR) to the trans-Golgi network. Further, Vps54 mutant mice displayed reduced cellular NPC2 protein levels and increased cholesterol accumulation, underscoring the physiological role of the GARP complex in cholesterol transport. We conclude that the GARP complex contributes to intracellular cholesterol transport by targeting NPC2 to lysosomes in a CI-MPR-dependent manner. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

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

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.

Surface targeting of the dopamine transporter involves discrete epitopes in the distal C terminus but does not require canonical PDZ domain interactions.

PubMed

Bjerggaard, Christian; Fog, Jacob U; Hastrup, Hanne; Madsen, Kenneth; Loland, Claus J; Javitch, Jonathan A; Gether, Ulrik

2004-08-04

The human dopamine transporter (hDAT) contains a C-terminal type 2 PDZ (postsynaptic density 95/Discs large/zona occludens 1) domain-binding motif (LKV) known to interact with PDZ domain proteins such as PICK1 (protein interacting with C-kinase 1). As reported previously, we found that, after deletion of this motif, hDAT was retained in the endoplasmic reticulum (ER) of human embryonic kidney (HEK) 293 and Neuro2A cells, suggesting that PDZ domain interactions might be critical for hDAT targeting. Nonetheless, substitution of LKV with SLL, the type 1 PDZ-binding sequence from the beta2-adrenergic receptor, did not disrupt plasma membrane targeting. Moreover, the addition of an alanine to the hDAT C terminus (+Ala), resulting in an LKVA termination sequence, or substitution of LKV with alanines (3xAla_618-620) prevented neither plasma membrane targeting nor targeting into sprouting neurites of differentiated N2A cells. The inability of +Ala and 3xAla_618-620 to bind PDZ domains was confirmed by lack of colocalization with PICK1 in cotransfected HEK293 cells and by the inability of corresponding C-terminal fusion proteins to pull down purified PICK1. Thus, although residues in the hDAT C terminus are indispensable for proper targeting, PDZ domain interactions are not required. By progressive substitutions with beta2-adrenergic receptor sequence, and by triple-alanine substitutions in the hDAT C terminus, we examined the importance of epitopes preceding the LKV motif. Substitution of RHW(615-617) with alanines caused retention of the transporter in the ER despite preserved ability of this mutant to bind PICK1. We propose dual roles of the hDAT C terminus: a role independent of PDZ interactions for ER export and surface targeting, and a not fully clarified role involving PDZ interactions with proteins such as PICK1.

Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex

PubMed Central

De-May, C.L.; Ali, A.B.

2013-01-01

To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings – combined with biocytin labelling – were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II–V of rat (postnatal days 17–22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appeared to coincide with the interneuron subclass; upon depolarisation, EPSPs received by multipolar non-adapting interneurons either decreased in amplitude or appeared insensitive, multipolar adapting interneuron EPSP amplitudes increased or appeared insensitive, whereas bitufted interneuron EPSP amplitudes increased or decreased. Connections were challenged with the NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid (d-AP5) (50 μM) revealing NMDA receptors to contribute to EPSPs received by all cell types, this also abolished the non-conventional voltage dependency. Reciprocal connections were frequent between pyramidal cells and multipolar interneurons, and inhibitory postsynaptic potentials (IPSPs) elicited in pyramidal cells by both multipolar adapting and multipolar non-adapting interneurons were sensitive to a significant reduction in amplitude by d-AP5. The involvement of presynaptic NMDA receptors was indicated by coefficient of variation analysis and an increase in the failures of transmission. Furthermore, by loading MK-801 into the pre- or postsynaptic neurons, we observed that a reduction in inhibition requires presynaptic and not postsynaptic NMDA receptors. These results suggest that NMDA receptors possess pre- and postsynaptic roles at selective neocortical synapses that are probably important in governing spike-timing and information flow. PMID:23079623

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…

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.

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction.

PubMed

Zhang, Li; Sun, Zhenxing; Ren, Pingping; You, Manjie; Zhang, Jing; Fang, Lingyun; Wang, Jing; Chen, Yihan; Yan, Fei; Zheng, Hairong; Xie, Mingxing

2017-01-01

Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 10 8 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm 2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial sh

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

PubMed Central

Zhang, Li; Sun, Zhenxing; Ren, Pingping; You, Manjie; Zhang, Jing; Fang, Lingyun; Wang, Jing; Chen, Yihan; Yan, Fei; Zheng, Hairong; Xie, Mingxing

2017-01-01

Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 108 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial sh

DUBbing Cancer: Deubiquitylating Enzymes Involved in Epigenetics, DNA Damage and the Cell Cycle As Therapeutic Targets.

PubMed

Pinto-Fernandez, Adan; Kessler, Benedikt M

2016-01-01

Controlling cell proliferation is one of the hallmarks of cancer. A number of critical checkpoints ascertain progression through the different stages of the cell cycle, which can be aborted when perturbed, for instance by errors in DNA replication and repair. These molecular checkpoints are regulated by a number of proteins that need to be present at the right time and quantity. The ubiquitin system has emerged as a central player controlling the fate and function of such molecules such as cyclins, oncogenes and components of the DNA repair machinery. In particular, proteases that cleave ubiquitin chains, referred to as deubiquitylating enzymes (DUBs), have attracted recent attention due to their accessibility to modulation by small molecules. In this review, we describe recent evidence of the critical role of DUBs in aspects of cell cycle checkpoint control, associated DNA repair mechanisms and regulation of transcription, representing pathways altered in cancer. Therefore, DUBs involved in these processes emerge as potentially critical targets for the treatment of not only hematological, but potentially also solid tumors.

DUBbing Cancer: Deubiquitylating Enzymes Involved in Epigenetics, DNA Damage and the Cell Cycle As Therapeutic Targets

PubMed Central

Pinto-Fernandez, Adan; Kessler, Benedikt M.

2016-01-01

Controlling cell proliferation is one of the hallmarks of cancer. A number of critical checkpoints ascertain progression through the different stages of the cell cycle, which can be aborted when perturbed, for instance by errors in DNA replication and repair. These molecular checkpoints are regulated by a number of proteins that need to be present at the right time and quantity. The ubiquitin system has emerged as a central player controlling the fate and function of such molecules such as cyclins, oncogenes and components of the DNA repair machinery. In particular, proteases that cleave ubiquitin chains, referred to as deubiquitylating enzymes (DUBs), have attracted recent attention due to their accessibility to modulation by small molecules. In this review, we describe recent evidence of the critical role of DUBs in aspects of cell cycle checkpoint control, associated DNA repair mechanisms and regulation of transcription, representing pathways altered in cancer. Therefore, DUBs involved in these processes emerge as potentially critical targets for the treatment of not only hematological, but potentially also solid tumors. PMID:27516771

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

Intramuscular Therapeutic Vaccination Targeting HPV16 Induces T Cell Responses That Localize in Mucosal Lesions

PubMed Central

Jotova, Iveta; Wu, T. C.; Wang, Chenguang; Desmarais, Cindy; Boyer, Jean D.; Tycko, Benjamin; Robins, Harlan S.; Clark, Rachael A.; Trimble, Cornelia L.

2014-01-01

About 25% of high-grade cervical intraepithelial neoplasias (CIN2/3) caused by human papillomavirus serotype 16 (HPV16) undergo complete spontaneous regression. However, to date, therapeutic vaccination strategies for HPV disease have yielded limited success when measured by their ability to induce robust peripheral blood T cell responses to vaccine antigen. We report marked immunologic changes in the target lesion microenvironment after intramuscular therapeutic vaccination targeting HPV16 E6/E7 antigens, in subjects with CIN2/3 who had modest detectable responses in circulating T lymphocytes. Histologic and molecular changes, including markedly (average threefold) increased intensity of CD8+ T cell infiltrates in both the stromal and epithelial compartments, suggest an effector response to vaccination. Postvaccination cervical tissue immune infiltrates included organized tertiary lymphoid-like structures in the stroma subjacent to residual intraepithelial lesions and, unlike infiltrates in unvaccinated lesions, showed evidence of proliferation induced by recognition of cognate antigen. At a molecular level, these histologic changes in the stroma were characterized by increased expression of genes associated with immune activation (CXCR3) and effector function (Tbet and IFNβ), and were also associated with an immunologic signature in the overlying dysplastic epithelium. High-throughput T cell receptor sequencing of unmanipulated specimens identified clonal expansions in the tissue that were not readily detectable in peripheral blood. Together, these findings indicate that peripheral therapeutic vaccination to HPV antigens can induce a robust tissue-localized effector immune response, and that analyses of immune responses at sites of antigen are likely to be much more informative than analyses of cells that remain in the circulation. PMID:24477000

New TFII-I family target genes involved in embryonic development.

PubMed

Makeyev, Aleksandr V; Bayarsaihan, Dashzeveg

2009-09-04

Two members of the TFII-I family transcription factor genes, GTF2I and GTF2IRD1, are the prime candidates responsible for the craniofacial and cognitive abnormalities of Williams syndrome patients. We have previously generated mouse lines with targeted disruption of Gtf2i and Gtf2ird1. Microarray analysis revealed significant changes in the expression profile of mutant embryos. Here we described three unknown genes that were dramatically down-regulated in mutants. The 2410018M08Rik/Scand3 gene encodes a protein of unknown function with CHCH and hATC domains. Scand3 is down-regulated during mouse embryonic stem cell (ES) differentiation. 4933436H12Rik is a testis-specific gene, which encodes a protein with no known domains. It is expressed in mouse ES cells. 1110008P08Rik/Kbtbd7 encodes an adapter protein with BTB/POZ, BACK, and Kelch motifs, previously shown to recruit substrates to the enzymatic complexes of the histone modifying or E3 ubiquitin ligase activities. Based on its expression pattern Kbtbd7 may have a specific role in brain development and function. All three genes possess well-conserved TFII-I-binding consensus sites within proximal promoters. Therefore our analysis suggests that these genes can be direct targets of TFII-I proteins and their impaired expression, as a result of the GTF2I and GTF2IRD1 haploinsufficiency, could contribute to the etiology of Williams syndrome.

Research on the application of satellite remote sensing to local, state, regional and national programs involved with resource management and environmental quality

NASA Technical Reports Server (NTRS)

Barr, B. G.

1974-01-01

A program designed to involve state, regional and local agency personnel in the application of remote sensing is reported. During this period fifteen applications projects were initiated in support of twenty-five separate state, county and municipal agencies or entities. Eight of the projects were completed with positive results which aided the agencies involved. These results included information which contributed to decisions on: (1) selection of a route for a scenic parkway, (2) policy development on open land use, (3) policy related to urban development, (4) a major reservoir project by a governor's staff, (5) control tactics and damage assessment during flooding conditions on the Kansas and Missouri rivers, and (6) initiating a program of habitat inventory by remote sensing by the Kansas Forestry, Fish and Game Commission.

Towards large scale multi-target tracking

NASA Astrophysics Data System (ADS)

Vo, Ba-Ngu; Vo, Ba-Tuong; Reuter, Stephan; Lam, Quang; Dietmayer, Klaus

2014-06-01

Multi-target tracking is intrinsically an NP-hard problem and the complexity of multi-target tracking solutions usually do not scale gracefully with problem size. Multi-target tracking for on-line applications involving a large number of targets is extremely challenging. This article demonstrates the capability of the random finite set approach to provide large scale multi-target tracking algorithms. In particular it is shown that an approximate filter known as the labeled multi-Bernoulli filter can simultaneously track one thousand five hundred targets in clutter on a standard laptop computer.

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)

Community empowerment and involvement of female sex workers in targeted sexual and reproductive health interventions in Africa: a systematic review.

PubMed

Moore, Lizzie; Chersich, Matthew F; Steen, Richard; Reza-Paul, Sushena; Dhana, Ashar; Vuylsteke, Bea; Lafort, Yves; Scorgie, Fiona

2014-06-10

Female sex workers (FSWs) experience high levels of sexual and reproductive health (SRH) morbidity, violence and discrimination. Successful SRH interventions for FSWs in India and elsewhere have long prioritised community mobilisation and structural interventions, yet little is known about similar approaches in African settings. We systematically reviewed community empowerment processes within FSW SRH projects in Africa, and assessed them using a framework developed by Ashodaya, an Indian sex worker organisation. In November 2012 we searched Medline and Web of Science for studies of FSW health services in Africa, and consulted experts and websites of international organisations. Titles and abstracts were screened to identify studies describing relevant services, using a broad definition of empowerment. Data were extracted on service-delivery models and degree of FSW involvement, and analysed with reference to a four-stage framework developed by Ashodaya. This conceptualises community empowerment as progressing from (1) initial engagement with the sex worker community, to (2) community involvement in targeted activities, to (3) ownership, and finally, (4) sustainability of action beyond the community. Of 5413 articles screened, 129 were included, describing 42 projects. Targeted services in FSW 'hotspots' were generally isolated and limited in coverage and scope, mostly offering only free condoms and STI treatment. Many services were provided as part of research activities and offered via a clinic with associated community outreach. Empowerment processes were usually limited to peer-education (stage 2 of framework). Community mobilisation as an activity in its own right was rarely documented and while most projects successfully engaged communities, few progressed to involvement, community ownership or sustainability. Only a few interventions had evolved to facilitate collective action through formal democratic structures (stage 3). These reported improved sexual

Community empowerment and involvement of female sex workers in targeted sexual and reproductive health interventions in Africa: a systematic review

PubMed Central

2014-01-01

Background Female sex workers (FSWs) experience high levels of sexual and reproductive health (SRH) morbidity, violence and discrimination. Successful SRH interventions for FSWs in India and elsewhere have long prioritised community mobilisation and structural interventions, yet little is known about similar approaches in African settings. We systematically reviewed community empowerment processes within FSW SRH projects in Africa, and assessed them using a framework developed by Ashodaya, an Indian sex worker organisation. Methods In November 2012 we searched Medline and Web of Science for studies of FSW health services in Africa, and consulted experts and websites of international organisations. Titles and abstracts were screened to identify studies describing relevant services, using a broad definition of empowerment. Data were extracted on service-delivery models and degree of FSW involvement, and analysed with reference to a four-stage framework developed by Ashodaya. This conceptualises community empowerment as progressing from (1) initial engagement with the sex worker community, to (2) community involvement in targeted activities, to (3) ownership, and finally, (4) sustainability of action beyond the community. Results Of 5413 articles screened, 129 were included, describing 42 projects. Targeted services in FSW ‘hotspots’ were generally isolated and limited in coverage and scope, mostly offering only free condoms and STI treatment. Many services were provided as part of research activities and offered via a clinic with associated community outreach. Empowerment processes were usually limited to peer-education (stage 2 of framework). Community mobilisation as an activity in its own right was rarely documented and while most projects successfully engaged communities, few progressed to involvement, community ownership or sustainability. Only a few interventions had evolved to facilitate collective action through formal democratic structures (stage 3

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.

Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells.

PubMed

Kamata, Shigeyuki; Kishimoto, Takashi; Kobayashi, Soichi; Miyazaki, Masaru; Ishikura, Hiroshi

2007-07-01

AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97 and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.

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

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.

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.

Nuclear localization signal targeting to macronucleus and micronucleus in binucleated ciliate Tetrahymena thermophila.

PubMed

Iwamoto, Masaaki; Mori, Chie; Osakada, Hiroko; Koujin, Takako; Hiraoka, Yasushi; Haraguchi, Tokuko

2018-06-08

Ciliated protozoa possess two morphologically and functionally distinct nuclei: a macronucleus (MAC) and a micronucleus (MIC). The MAC is transcriptionally active and functions in all cellular events. The MIC is transcriptionally inactive during cell growth, but functions in meiotic events to produce progeny nuclei. Thus, these two nuclei must be distinguished by the nuclear proteins required for their distinct functions during cellular events such as cell proliferation and meiosis. To understand the mechanism of the nuclear transport specific to either MAC or MIC, we identified specific nuclear localization signals (NLSs) in two MAC- and MIC-specific nuclear proteins, macronuclear histone H1 and micronuclear linker histone-like protein (Mlh1), respectively. By expressing GFP-fused fragments of these proteins in Tetrahymena thermophila cells, two distinct regions in macronuclear histone H1 protein were assigned as independent MAC-specific NLSs and two distinct regions in Mlh1 protein were assigned as independent MIC-specific NLSs. These NLSs contain several essential lysine residues responsible for the MAC- and MIC-specific nuclear transport, but neither contains any consensus sequence with known monopartite or bipartite NLSs in other model organisms. Our findings contribute to understanding how specific nuclear targeting is achieved to perform distinct nuclear functions in binucleated ciliates. © 2018 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Localized scleroderma: clinical spectrum and therapeutic update*

PubMed Central

Careta, Mariana Figueiroa; Romiti, Ricardo

2015-01-01

Scleroderma is a rare connective tissue disease that is manifested by cutaneous sclerosis and variable systemic involvement. Two categories of scleroderma are known: systemic sclerosis, characterized by cutaneous sclerosis and visceral involvement, and localized scleroderma or morphea which classically presents benign and self-limited evolution and is confined to the skin and/or underlying tissues. Localized scleroderma is a rare disease of unknown etiology. Recent studies show that the localized form may affect internal organs and have variable morbidity. Treatment should be started very early, before complications occur due to the high morbidity of localized scleroderma. In this review, we report the most important aspects and particularities in the treatment of patients diagnosed with localized scleroderma. PMID:25672301

Localized scleroderma: clinical spectrum and therapeutic update.

PubMed

Careta, Mariana Figueiroa; Romiti, Ricardo

2015-01-01

Scleroderma is a rare connective tissue disease that is manifested by cutaneous sclerosis and variable systemic involvement. Two categories of scleroderma are known: systemic sclerosis, characterized by cutaneous sclerosis and visceral involvement, and localized scleroderma or morphea which classically presents benign and self-limited evolution and is confined to the skin and/or underlying tissues. Localized scleroderma is a rare disease of unknown etiology. Recent studies show that the localized form may affect internal organs and have variable morbidity. Treatment should be started very early, before complications occur due to the high morbidity of localized scleroderma. In this review, we report the most important aspects and particularities in the treatment of patients diagnosed with localized scleroderma.

The role of PET in target localization for radiotherapy treatment planning.

PubMed

Rembielak, Agata; Price, Pat

2008-02-01

Positron emission tomography (PET) is currently accepted as an important tool in oncology, mostly for diagnosis, staging and restaging purposes. It provides a new type of information in radiotherapy, functional rather than anatomical. PET imaging can also be used for target volume definition in radiotherapy treatment planning. The need for very precise target volume delineation has arisen with the increasing use of sophisticated three-dimensional conformal radiotherapy techniques and intensity modulated radiation therapy. It is expected that better delineation of the target volume may lead to a significant reduction in the irradiated volume, thus lowering the risk of treatment complications (smaller safety margins). Better tumour visualisation also allows a higher dose of radiation to be applied to the tumour, which may lead to better tumour control. The aim of this article is to review the possible use of PET imaging in the radiotherapy of various cancers. We focus mainly on non-small cell lung cancer, lymphoma and oesophageal cancer, but also include current opinion on the use of PET-based planning in other tumours including brain, uterine cervix, rectum and prostate.

Birth control vaccine targeting leukemia inhibitory factor.

PubMed

Lemons, Angela R; Naz, Rajesh K

2012-02-01

The population explosion and unintended pregnancies resulting in elective abortions continue to impose major public health issues. This calls for a better method of contraception. Immunocontraception has been proposed as a valuable alternative that can fulfill most, if not all, of the properties of an ideal contraceptive. There are several targets that are being explored for contraceptive vaccine development. Leukemia inhibitory factor (LIF), a member of interleukin-6 family, is required for embryo development and successful blastocyst implantation in several mammalian species. The present study was conducted to examine if LIF can be a target for the development of a birth control vaccine. Three sequences from LIF and two sequences from LIF-receptor (LIF-R) that span the regions involved in ligand-receptor binding were delineated, and peptides were synthesized based upon these sequences. Antibodies raised against these five peptides reduced LIF bioactivity in an in vitro culture assay using BA/F3 mLIF-R-mpg130 cells. Vaccines were prepared by conjugating these peptides to various carrier proteins. Immunization of female mice with these peptide vaccines induced a long-lasting, circulating as well as local antibody response in various parts of the genital tract, and resulted in a significant (P ≤ 0.05) inhibition in fertility in all the three trials; the LIF-R peptide vaccines proved to be a better vaccine target. The data indicate that LIF/LIF-R is an excellent target for the development of a birth control vaccine. This is the first study, to our knowledge, that examined LIF/LIF-R as a target for immunocontraception. The findings of this study can be easily translated to humans since LIF/LIF-R is also important for implantation and pregnancy in women. Copyright © 2011 Wiley Periodicals, Inc.

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.

Targeted therapies: a nursing perspective.

PubMed

Kay, Polly

2006-02-01

To review the development of targeted therapies and the biology of relevant therapeutic targets. To analyze the relevance of targeted agents as part of current clinical practice. Research articles. Several targeted agents are now available for clinical use. Their mechanisms of action are more specific against tumor cells than traditional cytotoxics. Monotherapy regimens based on targeted agents tend to be better tolerated than chemotherapy, and most combination regimens with targeted agents have proven feasible. Their availability has greatly expanded cancer treatment options, especially for chemorefractory patients. Nurses involved in the care of patients with cancer can benefit from an increased understanding of targeted therapies, including their mechanisms of action, their efficacy profile, as well as prophylaxis and management of adverse events and administration procedures.

Involvement of the ventral premotor cortex in controlling image motion of the hand during performance of a target-capturing task.

PubMed

Ochiai, Tetsuji; Mushiake, Hajime; Tanji, Jun

2005-07-01

The ventral premotor cortex (PMv) has been implicated in the visual guidance of movement. To examine whether neuronal activity in the PMv is involved in controlling the direction of motion of a visual image of the hand or the actual movement of the hand, we trained a monkey to capture a target that was presented on a video display using the same side of its hand as was displayed on the video display. We found that PMv neurons predominantly exhibited premovement activity that reflected the image motion to be controlled, rather than the physical motion of the hand. We also found that the activity of half of such direction-selective PMv neurons depended on which side (left versus right) of the video image of the hand was used to capture the target. Furthermore, this selectivity for a portion of the hand was not affected by changing the starting position of the hand movement. These findings suggest that PMv neurons play a crucial role in determining which part of the body moves in which direction, at least under conditions in which a visual image of a limb is used to guide limb movements.

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

Adaptive non-local means on local principle neighborhood for noise/artifacts reduction in low-dose CT images.

PubMed

Zhang, Yuanke; Lu, Hongbing; Rong, Junyan; Meng, Jing; Shang, Junliang; Ren, Pinghong; Zhang, Junying

2017-09-01

Low-dose CT (LDCT) technique can reduce the x-ray radiation exposure to patients at the cost of degraded images with severe noise and artifacts. Non-local means (NLM) filtering has shown its potential in improving LDCT image quality. However, currently most NLM-based approaches employ a weighted average operation directly on all neighbor pixels with a fixed filtering parameter throughout the NLM filtering process, ignoring the non-stationary noise nature of LDCT images. In this paper, an adaptive NLM filtering scheme on local principle neighborhoods (PC-NLM) is proposed for structure-preserving noise/artifacts reduction in LDCT images. Instead of using neighboring patches directly, in the PC-NLM scheme, the principle component analysis (PCA) is first applied on local neighboring patches of the target patch to decompose the local patches into uncorrelated principle components (PCs), then a NLM filtering is used to regularize each PC of the target patch and finally the regularized components is transformed to get the target patch in image domain. Especially, in the NLM scheme, the filtering parameter is estimated adaptively from local noise level of the neighborhood as well as the signal-to-noise ratio (SNR) of the corresponding PC, which guarantees a "weaker" NLM filtering on PCs with higher SNR and a "stronger" filtering on PCs with lower SNR. The PC-NLM procedure is iteratively performed several times for better removal of the noise and artifacts, and an adaptive iteration strategy is developed to reduce the computational load by determining whether a patch should be processed or not in next round of the PC-NLM filtering. The effectiveness of the presented PC-NLM algorithm is validated by experimental phantom studies and clinical studies. The results show that it can achieve promising gain over some state-of-the-art methods in terms of artifact suppression and structure preservation. With the use of PCA on local neighborhoods to extract principal structural

Patient and public involvement: what next for the NHS?

PubMed

Hogg, Christine N L

2007-06-01

Patient and public involvement is the cornerstone of the 'patient-led' National Health Service (NHS). Though the UK has had state sponsored arrangements for patient and public involvement since 1974, they have become fragmented and unstable. Patients' forums and the Commission for Patient and Public Involvement in Health replaced community health councils (CHCs) and their national association in England in 2003, but now will be replaced by local involvement networks (LINks) and the Commission will be abolished in 2007. This study provides an overview of research on the effectiveness of arrangements for patient and public involvement and reviews the debates about accountability, independence, ensuring consistency of performance, representation and how arrangements for the NHS fit within the wider agenda of citizenship and renewal of democracy. It explores key themes and areas for learning to inform the debate about how LINks might work effectively to improve the health of local people, in particular addressing issues of equity, representation and citizen engagement. The proposed LINks provide the opportunity to integrate patient and public involvement into wider initiatives for local democracy and citizen engagement. But debates and key issues about user and public involvement in the 1970s remain current and unresolved. If the new LINks are to succeed where forums and CHCs are considered to have failed, the strengths and weakness of both need to be understood and addressed.

Feature long axis size and local luminance contrast determine ship target acquisition performance: strong evidence for the TOD case

NASA Astrophysics Data System (ADS)

Bijl, Piet; Toet, Alexander; Kooi, Frank L.

2016-10-01

Visual images of a civilian target ship on a sea background were produced using a CAD model. The total set consisted of 264 images and included 3 different color schemes, 2 ship viewing aspects, 5 sun illumination conditions, 2 sea reflection values, 2 ship positions with respect to the horizon and 3 values of atmospheric contrast reduction. In a perception experiment, the images were presented on a display in a long darkened corridor. Observers were asked to indicate the range at which they were able to detect the ship and classify the following 5 ship elements: accommodation, funnel, hull, mast, and hat above the bridge. This resulted in a total of 1584 Target Acquisition (TA) range estimates for two observers. Next, the ship contour, ship elements and corresponding TA ranges were analyzed applying several feature size and contrast measures. Most data coincide on a contrast versus angular size plot using (1) the long axis as characteristic ship/ship feature size and (2) local Weber contrast as characteristic ship/ship feature contrast. Finally, the data were compared with a variety of visual performance functions assumed to be representative for Target Acquisition: the TOD (Triangle Orientation Discrimination), MRC (Minimum Resolvable Contrast), CTF (Contrast Threshold Function), TTP (Targeting Task Performance) metric and circular disc detection data for the unaided eye (Blackwell). The results provide strong evidence for the TOD case: both position and slope of the TOD curve match the ship detection and classification data without any free parameter. In contrast, the MRC and CTF are too steep, the TTP and disc detection curves are too shallow and all these curves need an overall scaling factor in order to coincide with the ship and ship feature recognition data.

Rapid and Localized Mechanical Stimulation and Adhesion Assay: TRPM7 Involvement in Calcium Signaling and Cell Adhesion

PubMed Central

Nishitani, Wagner Shin; Alencar, Adriano Mesquita; Wang, Yingxiao

2015-01-01

A cell mechanical stimulation equipment, based on cell substrate deformation, and a more sensitive method for measuring adhesion of cells were developed. A probe, precisely positioned close to the cell, was capable of a vertical localized mechanical stimulation with a temporal frequency of 207 Hz, and strain magnitude of 50%. This setup was characterized and used to probe the response of Human Umbilical Endothelial Vein Cells (HUVECs) in terms of calcium signaling. The intracellular calcium ion concentration was measured by the genetically encoded Cameleon biosensor, with the Transient Receptor Potential cation channel, subfamily M, member 7 (TRPM7) expression inhibited. As TRPM7 expression also regulates adhesion, a relatively simple method for measuring adhesion of cells was also developed, tested and used to study the effect of adhesion alone. Three adhesion conditions of HUVECs on polyacrylamide gel dishes were compared. In the first condition, the substrate is fully treated with Sulfo-SANPAH crosslinking and fibronectin. The other two conditions had increasingly reduced adhesion: partially treated (only coated with fibronectin, with no use of Sulfo-SANPAH, at 5% of the normal amount) and non-treated polyacrylamide gels. The cells showed adhesion and calcium response to the mechanical stimulation correlated to the degree of gel treatment: highest for fully treated gels and lowest for non-treated ones. TRPM7 inhibition by siRNA on HUVECs caused an increase in adhesion relative to control (no siRNA treatment) and non-targeting siRNA, but a decrease to 80% of calcium response relative to non-targeting siRNA which confirms the important role of TRPM7 in mechanotransduction despite the increase in adhesion. PMID:25946314

Central Localization of Plasticity Involved in Appetitive Conditioning in "Lymnaea"

ERIC Educational Resources Information Center

Straub, Volko A.; Styles, Benjamin J.; Ireland, Julie S.; O'Shea, Michael; Benjamin, Paul R.

2004-01-01

Learning to associate a conditioned (CS) and unconditioned stimulus (US) results in changes in the processing of CS information. Here, we address directly the question whether chemical appetitive conditioning of "Lymnaea" feeding behavior involves changes in the peripheral and/or central processing of the CS by using extracellular recording…

Genomic signatures of fine-scale local selection in Atlantic salmon suggest involvement of sexual maturation, energy homeostasis and immune defence-related genes.

PubMed

Pritchard, Victoria L; Mäkinen, Hannu; Vähä, Juha-Pekka; Erkinaro, Jaakko; Orell, Panu; Primmer, Craig R

2018-06-01

Elucidating the genetic basis of adaptation to the local environment can improve our understanding of how the diversity of life has evolved. In this study, we used a dense SNP array to identify candidate loci potentially underlying fine-scale local adaptation within a large Atlantic salmon (Salmo salar) population. By combining outlier, gene-environment association and haplotype homozygosity analyses, we identified multiple regions of the genome with strong evidence for diversifying selection. Several of these candidate regions had previously been identified in other studies, demonstrating that the same loci could be adaptively important in Atlantic salmon at subdrainage, regional and continental scales. Notably, we identified signals consistent with local selection around genes associated with variation in sexual maturation, energy homeostasis and immune defence. These included the large-effect age-at-maturity gene vgll3, the known obesity gene mc4r, and major histocompatibility complex II. Most strikingly, we confirmed a genomic region on Ssa09 that was extremely differentiated among subpopulations and that is also a candidate for local selection over the global range of Atlantic salmon. This region colocalized with a haplotype strongly associated with spawning ecotype in sockeye salmon (Oncorhynchus nerka), with circumstantial evidence that the same gene (six6) may be the selective target in both cases. The phenotypic effect of this region in Atlantic salmon remains cryptic, although allelic variation is related to upstream catchment area and covaries with timing of the return spawning migration. Our results further inform management of Atlantic salmon and open multiple avenues for future research. © 2018 John Wiley & Sons Ltd.

Neurologic involvement in scleroderma: a systematic review.

PubMed

Amaral, Tiago Nardi; Peres, Fernando Augusto; Lapa, Aline Tamires; Marques-Neto, João Francisco; Appenzeller, Simone

2013-12-01

To perform a systematic review of neurologic involvement in Systemic sclerosis (SSc) and Localized Scleroderma (LS), describing clinical features, neuroimaging, and treatment. We performed a literature search in PubMed using the following MeSH terms, scleroderma, systemic sclerosis, localized scleroderma, localized scleroderma "en coup de sabre", Parry-Romberg syndrome, cognitive impairment, memory, seizures, epilepsy, headache, depression, anxiety, mood disorders, Center for Epidemiologic Studies Depression (CES-D), SF-36, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Patient Health Questionnaire-9 (PHQ-9), neuropsychiatric, psychosis, neurologic involvement, neuropathy, peripheral nerves, cranial nerves, carpal tunnel syndrome, ulnar entrapment, tarsal tunnel syndrome, mononeuropathy, polyneuropathy, radiculopathy, myelopathy, autonomic nervous system, nervous system, electroencephalography (EEG), electromyography (EMG), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA). Patients with other connective tissue disease knowingly responsible for nervous system involvement were excluded from the analyses. A total of 182 case reports/studies addressing SSc and 50 referring to LS were identified. SSc patients totalized 9506, while data on 224 LS patients were available. In LS, seizures (41.58%) and headache (18.81%) predominated. Nonetheless, descriptions of varied cranial nerve involvement and hemiparesis were made. Central nervous system involvement in SSc was characterized by headache (23.73%), seizures (13.56%) and cognitive impairment (8.47%). Depression and anxiety were frequently observed (73.15% and 23.95%, respectively). Myopathy (51.8%), trigeminal neuropathy (16.52%), peripheral sensorimotor polyneuropathy (14.25%), and carpal tunnel syndrome (6.56%) were the most frequent peripheral nervous system involvement in SSc. Autonomic neuropathy involving cardiovascular and gastrointestinal systems was regularly described

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

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

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.

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

Dendritic cells are early cellular targets of Listeria monocytogenes after intestinal delivery and are involved in bacterial spread in the host.

PubMed

Pron, B; Boumaila, C; Jaubert, F; Berche, P; Milon, G; Geissmann, F; Gaillard, J L

2001-05-01

We studied the sequence of cellular events leading to the dissemination of Listeria monocytogenes from the gut to draining mesenteric lymph nodes (MLNs) by confocal microscopy of immunostained tissue sections from a rat ligated ileal loop system. OX-62-positive cells beneath the epithelial lining of Peyer's patches (PPs) were the first Listeria targets identified after intestinal inoculation. These cells had other features typical of dendritic cells (DCs): they were large, pleiomorphic and major histocompatibility complex class II(hi). Listeria were detected by microscopy in draining MLNs as early as 6 h after inoculation. Some 80-90% of bacteria were located in the deep paracortical regions, and 100% of the bacteria were present in OX-62-positive cells. Most infected cells contained more than five bacteria each, suggesting that they had arrived already loaded with bacteria. At later stages, the bacteria in these areas were mostly present in ED1-positive mononuclear phagocytes. These cells were also infected by an actA mutant defective in cell-to-cell spreading. This suggests that Listeria are transported by DCs from PPs to the deep paracortical regions of draining MLNs and are then transmitted to other cell populations by mechanisms independent of ActA. Another pathway of dissemination to MLNs was identified, probably involving free Listeria and leading to the infection of ED3-positive mononuclear phagocytes in the subcapsular sinus and adjacent paracortical areas. This study provides evidence that DCs are major cellular targets of L. monocytogenes in PPs and that DCs may be involved in the early dissemination of this pathogen. DCs were not sites of active bacterial replication, making these cells ideal vectors of infection.

Factors Perceived as Influencing Local Health Department Involvement in Mental Health.

PubMed

Purtle, Jonathan; Peters, Rachel; Kolker, Jennifer; Klassen, Ann C

2017-01-01

Local health departments (LHDs) are potentially well positioned to implement population-based approaches to mental health promotion, but research indicates that most LHDs are not substantively engaged in activities to address mental health. Little is known about factors that influence if and how LHDs address population mental health. The objectives of this qualitative study were to (1) understand how LHD officials perceive population mental health; (2) identify factors that influence these perceptions and LHD activities to address population mental health; and (3) develop an empirically derived conceptual framework of LHD engagement in population mental health. Twenty-one semi-structured interviews were conducted with a purposive sample of LHD officials and analyzed using thematic content analysis in 2014-2015. Transcripts were double coded, inter-rater reliability statistics were calculated, and categories with κ ≥0.60 were retained. Respondents perceived mental health as a public health issue and expressed that it has emerged as a priority through community health needs assessment processes, such as those conducted for health department accreditation. However, most LHDs were not substantively engaged in population mental health activities because of limited resources, knowledge, data, and hesitancy to infringe upon the territory of local behavioral health agencies. LHDs and local behavioral health agencies had difficulty communicating and collaborating because of divergent perspectives and financing arrangements. LHD officials are eager to embrace population mental health, but resources, training and education, and systems-level changes are needed. Contemporary reforms to the structure and financing of the U.S. health system offer opportunities to address these challenges. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach.

PubMed

Marsollier, Anne-Charlotte; Ciszewski, Lukasz; Mariot, Virginie; Popplewell, Linda; Voit, Thomas; Dickson, George; Dumonceaux, Julie

2016-04-15

Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double homeobox 4 (DUX4) transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. Here, we demonstrate that targeting either the mRNA polyadenylation signal and/or cleavage site is an efficient strategy to down-regulate DUX4 expression and to decrease the abnormally high-pathological expression of genes downstream of DUX4. We conclude that targeting key functional 3' end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

An Arabidopsis mitochondria-localized RRL protein mediates abscisic acid signal transduction through mitochondrial retrograde regulation involving ABI4.

PubMed

Yao, Xuan; Li, Juanjuan; Liu, Jianping; Liu, Kede

2015-10-01

The molecular mechanisms of abscisic acid (ABA) signalling have been studied for many years; however, how mitochondria-localized proteins play roles in ABA signalling remains unclear. Here an Arabidopsis mitochondria-localized protein RRL (RETARDED ROOT GROWTH-LIKE) was shown to function in ABA signalling. A previous study had revealed that the Arabidopsis mitochondria-localized protein RRG (RETARDED ROOT GROWTH) is required for cell division in the root meristem. RRL shares 54% and 57% identity at the nucleotide and amino acid sequences, respectively, with RRG; nevertheless, RRL shows a different function in Arabidopsis. In this study, disruption of RRL decreased ABA sensitivity whereas overexpression of RRL increased ABA sensitivity during seed germination and seedling growth. High expression levels of RRL were found in germinating seeds and developing seedlings, as revealed by β-glucuronidase (GUS) staining of ProRRL-GUS transgenic lines. The analyses of the structure and function of mitochondria in the knockout rrl mutant showed that the disruption of RRL causes extensively internally vacuolated mitochondria and reduced ABA-stimulated reactive oxygen species (ROS) production. Previous studies have revealed that the expression of alternative oxidase (AOX) in the alternative respiratory pathway is increased by mitochondrial retrograde regulation to regain ROS levels when the mitochondrial electron transport chain is impaired. The APETALA2 (AP2)-type transcription factor ABI4 is a regulator of ALTERNATIVE OXIDASE1a (AOX1a) in mitochondrial retrograde signalling. This study showed that ABA-induced AOX1a and ABI4 expression was inhibited in the rrl mutant, suggesting that RRL is probably involved in ABI4-mediated mitochondrial retrograde signalling. Furthermore, the results revealed that ABI4 is a downstream regulatory factor in RRL-mediated ABA signalling in seed germination and seedling growth. © The Author 2015. Published by Oxford University Press on behalf of

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus.

PubMed

Elmwall, Jonas; Kwiecinski, Jakub; Na, Manli; Ali, Abukar Ahmed; Osla, Veronica; Shaw, Lindsey N; Wang, Wanzhong; Sävman, Karin; Josefsson, Elisabet; Bylund, Johan; Jin, Tao; Welin, Amanda; Karlsson, Anna

2017-07-01

Staphylococcus aureus is a major cause of skin and soft tissue infection. The bacterium expresses four major proteases that are emerging as virulence factors: aureolysin (Aur), V8 protease (SspA), staphopain A (ScpA), and staphopain B (SspB). We hypothesized that human galectin-3, a β-galactoside-binding lectin involved in immune regulation and antimicrobial defense, is a target for these proteases and that proteolysis of galectin-3 is a novel immune evasion mechanism. Indeed, supernatants from laboratory strains and clinical isolates of S. aureus caused galectin-3 degradation. Similar proteolytic capacities were found in Staphylococcus epidermidis isolates but not in Staphylococcus saprophyticus Galectin-3-induced activation of the neutrophil NADPH oxidase was abrogated by bacterium-derived proteolysis of galectin-3, and SspB was identified as the major protease responsible. The impact of galectin-3 and protease expression on S. aureus virulence was studied in a murine skin infection model. In galectin-3 +/+ mice, SspB-expressing S. aureus caused larger lesions and resulted in higher bacterial loads than protease-lacking bacteria. No such difference in bacterial load or lesion size was detected in galectin-3 -/- mice, which overall showed smaller lesion sizes than the galectin-3 +/+ animals. In conclusion, the staphylococcal protease SspB inactivates galectin-3, abrogating its stimulation of oxygen radical production in human neutrophils and increasing tissue damage during skin infection. Copyright © 2017 American Society for Microbiology.

Accumulation of cynaropicrin in globe artichoke and localization of enzymes involved in its biosynthesis.

PubMed

Eljounaidi, K; Comino, C; Moglia, A; Cankar, K; Genre, A; Hehn, A; Bourgaud, F; Beekwilder, J; Lanteri, S

2015-10-01

Globe artichoke (Cynara cardunculus var. scolymus) belongs to the Asteraceae family, in which one of the most biologically significant class of secondary metabolites are sesquiterpene lactones (STLs). In globe artichoke the principal STL is the cynaropicrin, which contributes to approximately 80% of its characteristic bitter taste. Cynaropicrin content was assessed in globe artichoke tissues and was observed to accumulate in leaves of different developmental stages. In the receptacle, a progressive decrease was observed during inflorescence development, while the STL could not be detected in the inflorescence bracts. Almost undetectable amounts were found in the roots and inflorescence stems at the commercial stage. Cynaropicrin content was found to correlate with expression of genes encoding CcGAS, CcGAO and CcCOS, which are involved in the STL biosynthesis. A more detailed study of leaf material revealed that cynaropicrin predominantly accumulates in the trichomes, and not in the apoplastic cavity fluids. Analysis of the promoter regions of CcGAO and CcCOS revealed the presence of L1-box motifs, which confers trichome-specific expression in Arabidopsis, suggesting that cynaropicrin is not only stored but also synthesized in trichomes. A transient expression of GFP fusion proteins was performed in Nicotiana benthamiana plants: the CcGAS fluorescence signal was located in the cytoplasm while the CcGAO and CcCOS localized to the endoplasmatic reticulum. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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.

Perception of shapes targeting local and global processes in autism spectrum disorders.

PubMed

Grinter, Emma J; Maybery, Murray T; Pellicano, Elizabeth; Badcock, Johanna C; Badcock, David R

2010-06-01

Several researchers have found evidence for impaired global processing in the dorsal visual stream in individuals with autism spectrum disorders (ASDs). However, support for a similar pattern of visual processing in the ventral visual stream is less consistent. Critical to resolving the inconsistency is the assessment of local and global form processing ability. Within the visual domain, radial frequency (RF) patterns - shapes formed by sinusoidally varying the radius of a circle to add 'bumps' of a certain number to a circle - can be used to examine local and global form perception. Typically developing children and children with an ASD discriminated between circles and RF patterns that are processed either locally (RF24) or globally (RF3). Children with an ASD required greater shape deformation to identify RF3 shapes compared to typically developing children, consistent with difficulty in global processing in the ventral stream. No group difference was observed for RF24 shapes, suggesting intact local ventral-stream processing. These outcomes support the position that a deficit in global visual processing is present in ASDs, consistent with the notion of Weak Central Coherence.

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

Localized scleroderma and systemic sclerosis: is there a connection?

PubMed

Gupta, Rajnish A; Fiorentino, David

2007-12-01

Excess fibrosis of the skin is a clinical hallmark of both localized scleroderma and systemic sclerosis. Localized scleroderma is generally thought to be a skin-limited disease whereas systemic sclerosis can have a wide range of internal organ involvement. Recent data suggest that a subset of patients with juvenile localized scleroderma can go on to develop systemic involvement of their disease. This raises the question of what the connection is, if any, between localized scleroderma and systemic sclerosis.

Effects of stakeholder involvement in river management

NASA Astrophysics Data System (ADS)

Buchecker, M.; Menzel, S.

2012-04-01

In the last decades, in many parts of Europe involving local stakeholders or the local public in river management has become a standard procedure. For many decision makers, the purpose of involving other interest groups is limited to achieving a sufficient local acceptance of the project, and accordingly they adopt minimal forms of involvement. Theoretical literature and first empirical studies, however, suggest that stakeholder involvement can have, if done in appropriate quality, have much more far-reaching benefits for a sustainable river management such as a better consensus, social learning and social capital building. But there is so far only little reliable evidence that and under which conditions such benefits or effects in fact result from stakeholder involvement processes. The reason for this is that such involvement processes represent very complex social interventions, and all"affordable"effect measurement methods have their weaknesses. In our project we wanted to find out which were the really robust social effects of stakeholder involvement in river management. We therefore evaluated a number of real Swiss case studies of participatory river management using three different approaches of effect measurements: a quasi-experimental approach using repeated standardized measurement of stakeholders' attitudes, a qualitative long-term ex-post measurement approach based on interviews with stakeholders of five participatory river projects, and a comparative analysis approach based on data of residents effect assessments of participatory river planning gathered in a Swiss national survey. The analysis of all three evaluation studies confirmed that stakeholder involvement in river management projects have substantive social effects. The comparison of the results of the three measurement approaches revealed that social learning and acceptance building were the most robust effects of stakeholder involvement, as they were confirmed by all the three measurement

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

Aldosterone Target NGAL (Neutrophil Gelatinase-Associated Lipocalin) Is Involved in Cardiac Remodeling After Myocardial Infarction Through NFκB Pathway.

PubMed

Martínez-Martínez, Ernesto; Buonafine, Mathieu; Boukhalfa, Ines; Ibarrola, Jaime; Fernández-Celis, Amaya; Kolkhof, Peter; Rossignol, Patrick; Girerd, Nicolas; Mulder, Paul; López-Andrés, Natalia; Ouvrard-Pascaud, Antoine; Jaisser, Frédéric

2017-12-01

Myocardial infarction (MI) is accompanied by cardiac fibrosis, which contributes to cardiac dysfunction. Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with left ventricular (LV) dysfunction after MI. We herein investigated the role of the MR target NGAL (neutrophil gelatinase-associated lipocalin) in post-MI cardiac damages. Both higher baseline NGAL and a greater increase in serum NGAL levels during follow-up were significantly associated with lower 6-month LV ejection fraction recovery in a cohort of 119 post-MI patients, as assessed by cardiac magnetic resonance imaging. NGAL protein levels increased in the LV at 7 days post-MI in wild-type mice with MI. This effect was prevented by treatment with the nonsteroidal MR antagonist finerenone (1 mg/kg per day). NGAL knockout mice with MI had lower LV interstitial fibrosis and inflammation, better LV contractility and compliance, and greater stroke volume and cardiac output than wild-type mice with MI at 3 months post-MI. Aldosterone (10 -8 mol/L) increased NGAL expression in cultured human cardiac fibroblasts. Cells treated with aldosterone or NGAL (500 ng/mL) showed increased production of collagen type I. The effects of aldosterone were abolished by finerenone (10 -6 mol/L) or NGAL knockdown. This NGAL-mediated activity relied on NFκB (nuclear factor-κB) activation, confirmed by the use of the NFκB-specific inhibitor BAY11-7082, which prevented the effect of both aldosterone and NGAL on collagen type I production. In conclusion, NGAL, a downstream MR activation target, is a key mediator of post-MI cardiac damage. NGAL may be a potential therapeutic target in cardiovascular pathological situations in which MR is involved. © 2017 American Heart Association, Inc.

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

Localization of the enzymes involved in the photoevolution of H sub 2 from acetate in Chlamydomonas reinhardtii

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

Willeford, K.O.; Gibbs, M.

1989-07-01

The localization of a series of enzymes involved in the anaerobic photodissimilation of acetate in Chlamydomonas reinhardtii F-60 adapted to a hydrogen metabolism was determined through the enzymatic analyses of the chloroplastic, cytoplasmic, and mitochondrial fractions obtained with a cellular fractionation procedure that incorporated cell wall removal by treatment with autolysine, digestion of the plasmalemma with the detergent digitonin, and fractionation by differential centrifugation on a Percoll step gradient. The sequence of events leading to the photoevolution of H{sub 2} from acetate includes the conversion of acetate into succinate via the extraplastidic glyoxylate cycle, the oxidation of succinate to fumaratemore » by chloroplastic succinate dehydrogenase, and the oxidation of malate to oxaloacetate in the chloroplast by NAD dependent malate dehydrogenase. The level of potential activity for the enzymes assayed were sufficient to accommodate the observed rate of the photoanaerobic dissimilation of acetate and the photoevolution of H{sub 2}.« less

Subcellular localization of rice acyl-CoA-binding proteins (ACBPs) indicates that OsACBP6::GFP is targeted to the peroxisomes.

PubMed

Meng, Wei; Hsiao, An-Shan; Gao, Caiji; Jiang, Liwen; Chye, Mee-Len

2014-07-01

Acyl-CoA-binding proteins (ACBPs) show conservation at the acyl-CoA-binding (ACB) domain which facilitates binding to acyl-CoA esters. In Arabidopsis thaliana, six ACBPs participate in development and stress responses. Rice (Oryza sativa) also contains six genes encoding ACBPs. We investigated differences in subcellular localization between monocot rice and eudicot A. thaliana ACBPs. The subcellular localization of the six OsACBPs was achieved via transient expression of green fluorescence protein (GFP) fusions in tobacco (Nicotiana tabacum) epidermal cells, and stable transformation of A. thaliana. As plant ACBPs had not been reported in the peroxisomes, OsACBP6::GFP localization was confirmed by transient expression in rice sheath cells. The function of OsACBP6 was investigated by overexpressing 35S::OsACBP6 in the peroxisomal abc transporter1 (pxa1) mutant defective in peroxisomal fatty acid β-oxidation. As predicted, OsACBP1::GFP and OsACBP2::GFP were localized to the cytosol, and OsACBP4::GFP and OsACBP5::GFP to the endoplasmic reticulum (ER). However, OsACBP3::GFP displayed subcellular multi-localization while OsACBP6::GFP was localized to the peroxisomes. 35S::OsACBP6-OE/pxa1 lines showed recovery in indole-3-butyric acid (IBA) peroxisomal β-oxidation, wound-induced VEGETATIVE STORAGE PROTEIN1 (VSP1) expression and jasmonic acid (JA) accumulation. These findings indicate a role for OsACBP6 in peroxisomal β-oxidation, and suggest that rice ACBPs are involved in lipid degradation in addition to lipid biosynthesis. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

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.

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.

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.

Antibodies Specifically Targeting a Locally Misfolded Region of Tumor Associated EGFR

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

Garrett, T.; Burgess, A; Gan, H

2009-01-01

Epidermal Growth Factor Receptor (EGFR) is involved in stimulating the growth of many human tumors, but the success of therapeutic agents has been limited in part by interference from the EGFR on normal tissues. Previously, we reported an antibody (mab806) against a truncated form of EGFR found commonly in gliomas. Remarkably, it also recognizes full-length EGFR on tumor cells but not on normal cells. However, the mechanism for this activity was unclear. Crystallographic structures for Fab:EGFR{sub 287-302} complexes of mAb806 (and a second, related antibody, mAb175) show that this peptide epitope adopts conformations similar to those found in the wtEGFR.more » However, in both conformations observed for wtEGFR, tethered and untethered, antibody binding would be prohibited by significant steric clashes with the CR1 domain. Thus, these antibodies must recognize a cryptic epitope in EGFR. Structurally, it appeared that breaking the disulfide bond preceding the epitope might allow the CR1 domain to open up sufficiently for antibody binding. The EGFR{sub C271A/C283A} mutant not only binds mAb806, but binds with 1:1 stoichiometry, which is significantly greater than wtEGFR binding. Although mAb806 and mAb175 decrease tumor growth in xenografts displaying mutant, overexpressed, or autocrine stimulated EGFR, neither antibody inhibits the in vitro growth of cells expressing wtEGFR. In contrast, mAb806 completely inhibits the ligand-associated stimulation of cells expressing EGFR{sub C271A/C283A}. Clearly, the binding of mAb806 and mAb175 to the wtEGFR requires the epitope to be exposed either during receptor activation, mutation, or overexpression. This mechanism suggests the possibility of generating antibodies to target other wild-type receptors on tumor cells.« less

Evidence for the involvement of lung-specific γδ T cell subsets in local responses to Streptococcus pneumoniae infection

PubMed Central

Kirby, Alun C; Newton, Darren J; Carding, Simon R; Kaye, Paul M

2007-01-01

Although γδ T cells are involved in the response to many pathogens, the dynamics and heterogeneity of the local γδ T cell response remains poorly defined. We recently identified γδ T cells as regulators of macrophages and dendritic cells during the resolution of Streptococcus pneumoniae-mediated lung inflammation. Here, using PCR, spectratype analysis and flow cytometry, we show that multiple γδ T cell subsets, including those bearing Vγ1, Vγ4 and Vγ6 TCR, increase in number in the lungs of infected mice, but not in associated lymphoid tissue. These γδ T cells displayed signs of activation, as defined by CD69 and CD25 expression. In vivo BrdU incorporation suggested that local expansion, rather than recruitment, was the principal mechanism underlying this increase in γδ T cells. This conclusion was supported by the finding that pulmonary γδ T cells, but not αβ T cells, isolated from mice that had resolved infection exhibited lung-homing capacity in both naive and infected recipients. Together, these data provide novel insights into the origins of the heterogeneous γδ T cell response that accompanies lung infection, and the first evidence that inflammation-associated γδ T cells may exhibit distinct tissue-homing potential. PMID:18022862

WE-AB-BRA-01: 3D-2D Image Registration for Target Localization in Spine Surgery: Comparison of Similarity Metrics Against Robustness to Content Mismatch

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

De Silva, T; Ketcha, M; Siewerdsen, J H

Purpose: In image-guided spine surgery, mapping 3D preoperative images to 2D intraoperative images via 3D-2D registration can provide valuable assistance in target localization. However, the presence of surgical instrumentation, hardware implants, and soft-tissue resection/displacement causes mismatches in image content, confounding existing registration methods. Manual/semi-automatic methods to mask such extraneous content is time consuming, user-dependent, error prone, and disruptive to clinical workflow. We developed and evaluated 2 novel similarity metrics within a robust registration framework to overcome such challenges in target localization. Methods: An IRB-approved retrospective study in 19 spine surgery patients included 19 preoperative 3D CT images and 50 intraoperativemore » mobile radiographs in cervical, thoracic, and lumbar spine regions. A neuroradiologist provided truth definition of vertebral positions in CT and radiography. 3D-2D registration was performed using the CMA-ES optimizer with 4 gradient-based image similarity metrics: (1) gradient information (GI); (2) gradient correlation (GC); (3) a novel variant referred to as gradient orientation (GO); and (4) a second variant referred to as truncated gradient correlation (TGC). Registration accuracy was evaluated in terms of the projection distance error (PDE) of the vertebral levels. Results: Conventional similarity metrics were susceptible to gross registration error and failure modes associated with the presence of surgical instrumentation: for GI, the median PDE and interquartile range was 33.0±43.6 mm; similarly for GC, PDE = 23.0±92.6 mm respectively. The robust metrics GO and TGC, on the other hand, demonstrated major improvement in PDE (7.6 ±9.4 mm and 8.1± 18.1 mm, respectively) and elimination of gross failure modes. Conclusion: The proposed GO and TGC similarity measures improve registration accuracy and robustness to gross failure in the presence of strong image content mismatch

Tuberculosis therapeutics: Engineering of nanomedicinal systems for local delivery of targeted drug cocktails

NASA Astrophysics Data System (ADS)

D'Addio, Suzanne M.

In this thesis, a multifunctional nanocarrier drug delivery system was investigated and optimized to improve tuberculosis therapy by promoting the intracellular delivery of high payloads of antibiotics. To meet the needs of a patient population which continues to grow by close to 10 million people a year, innovative therapeutics must be formulated by robust and scalable processes. We use Flash NanoPrecipitation for the continuous precipitation of nanocarriers by block copolymer directed assembly, which enables the development of nanocarriers with tunable properties. Stable nanocarriers of Rifampicin and a hydrophobic Rifampicin prodrug have efficacy against tuberculosis in vitro that is equivalent to the soluble Rifampicin. To overcome poor in vivo efficacy of the recently discovered antitubercular drug SQ641, we co-encapsulate SQ641 and Cyclosporine A in a stable aqueous nanocarrier suspension, which enables drug administration and also enhances intracellular accumulation and antitubercular efficacy relative to SQ641 in solution. Since the mannose receptor is involved in the phagocytosis of tuberculosis bacilli, we modify the surface of nanocarriers with mannoside residues to target specific intracellular accumulation in macrophages. The surface density of mannoside terminated polyethylene glycol chains was controlled between 0 and 75% and in vitro cellular association reveals a 9% surface density is optimal for internalization mediated by the mannose receptor. We explore the preparation of large, porous aerosol carrier particles of with tunable deposition characteristics by spray freeze drying with ultrasonic atomization for direct dosing to the lungs. Nanocarriers are loaded at 3 - 50 wt% in mannitol particles with constant size, limited nanocarrier aggregation, and 63% dose delivered to the lungs, as determined by in vitro cascade impaction. There has been a lag in the development of new technologies to facilitate development and commercialization of

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

EARP, a multisubunit tethering complex involved in endocytic recycling

PubMed Central

Schindler, Christina; Chen, Yu; Pu, Jing; Guo, Xiaoli; Bonifacino, Juan S.

2015-01-01

Recycling of endocytic receptors to the cell surface involves passage through a series of membrane-bound compartments by mechanisms that are poorly understood. In particular, it is unknown if endocytic recycling requires the function of multisubunit tethering complexes, as is the case for other intracellular trafficking pathways. Herein we describe a tethering complex named Endosome-Associated Recycling Protein (EARP) that is structurally related to the previously described Golgi-Associated Retrograde Protein (GARP) complex. Both complexes share the Ang2, Vps52 and Vps53 subunits, but EARP comprises an uncharacterized protein, Syndetin, in place of the Vps54 subunit of GARP. This change determines differential localization of EARP to recycling endosomes and GARP to the Golgi complex. EARP interacts with the target-SNARE Syntaxin 6 and various cognate SNAREs. Depletion of Syndetin or Syntaxin 6 delays recycling of internalized transferrin to the cell surface. These findings implicate EARP in canonical membrane-fusion events in the process of endocytic recycling. PMID:25799061

Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

NASA Astrophysics Data System (ADS)

Guest, Will; Cashman, Neil; Plotkin, Steven

2009-05-01

Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

Breast cancer stem cells, EMT and therapeutic targets

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

Kotiyal, Srishti; Bhattacharya, Susinjan, E-mail: s.bhattacharya@jiit.ac.in

Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they aremore » also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.« less

Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas

PubMed Central

Pea, Antonio; Yu, Jun; Rezaee, Neda; Luchini, Claudio; He, Jin; Molin, Marco Dal; Griffin, James F.; Fedor, Helen; Fesharakizadeh, Shahriar; Salvia, Roberto; Weiss, Matthew J.; Bassi, Claudio; Cameron, John L.; Zheng, Lei; Scarpa, Aldo; Hruban, Ralph H.; Lennon, Anne Marie; Goggins, Michael

2016-01-01

Objective The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS). Background Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm. Methods Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression. Results We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas. Conclusions Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas. PMID:27433916

Cooperative tumour cell membrane targeted phototherapy

NASA Astrophysics Data System (ADS)

Kim, Heegon; Lee, Junsung; Oh, Chanhee; Park, Ji-Ho

2017-06-01

The targeted delivery of therapeutics using antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumours have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. Here, we construct a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumour cell membrane-selective localization of synthetic receptor-lipid conjugates (SR-lipids) to amplify the subsequent targeting of therapeutics. The SR-lipids are first delivered selectively to tumour cell membranes in the perivascular region using fusogenic liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the SR-lipids are transferred to neighbouring cells and further spread throughout the tumour tissues where the molecular targets are limited. We show that this tumour cell membrane-targeted delivery of SR-lipids leads to uniform distribution and enhanced phototherapeutic efficacy of the targeted photosensitizer.

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

Key Ingredients-Target Groups, Methods and Messages, and Evaluation-of Local-Level, Public Interventions to Counter Stigma and Discrimination: A Lived Experience Informed Selective Narrative Literature Review.

PubMed

Ashton, Laura J; Gordon, Sarah E; Reeves, Racheal A

2018-04-01

A proliferation of recent literature provides substantial direction as to the key ingredients-target groups, messages and methods, and evaluation-of local-level, public interventions to counter stigma and discrimination. This paper provides a selective narrative review of that literature from the perspective or standpoint of anti-stigma experts with lived experience of mental distress, the key findings of which have been synthesised and presented in diagrammatic overviews (infographics). These are intended to guide providers in planning, delivering and evaluating lived experience-directed local-level, public interventions to counter stigma and discrimination in accord with current best practice.

MiR-9 is involved in TGF-β1-induced lung cancer cell invasion and adhesion by targeting SOX7.

PubMed

Han, Lichun; Wang, Wei; Ding, Wei; Zhang, Lijian

2017-09-01

MicroRNA (miR)-9 plays different roles in different cancer types. Here, we investigated the role of miR-9 in non-small-cell lung cancer (NSCLC) cell invasion and adhesion in vitro and explored whether miR-9 was involved in transforming growth factor-beta 1 (TGF-β1)-induced NSCLC cell invasion and adhesion by targeting SOX7. The expression of miR-9 and SOX7 in human NSCLC tissues and cell lines was examined by reverse transcription-quantitative polymerase chain reaction. Gain-of-function and loss-of-function experiments were performed on A549 and HCC827 cells to investigate the effect of miR-9 and SOX7 on NSCLC cell invasion and adhesion in the presence or absence of TGF-β1. Transwell-Matrigel assay and cell adhesion assay were used to examine cell invasion and adhesion abilities. Luciferase reporter assay was performed to determine whether SOX7 was a direct target of miR-9. We found miR-9 was up-regulated and SOX7 was down-regulated in human NSCLC tissues and cell lines. Moreover, SOX7 expression was negatively correlated with miR-9 expression. miR-9 knockdown or SOX7 overexpression could suppress TGF-β1-induced NSCLC cell invasion and adhesion. miR-9 directly targets the 3' untranslated region of SOX7, and SOX7 protein expression was down-regulated by miR-9. TGF-β1 induced miR-9 expression in NSCLC cells. miR-9 up-regulation led to enhanced NSCLC cell invasion and adhesion; however, these effects could be attenuated by SOX7 overexpression. We concluded that miR-9 expression was negatively correlated with SOX7 expression in human NSCLC. miR-9 was up-regulated by TGF-β1 and contributed to TGF-β1-induced NSCLC cell invasion and adhesion by directly targeting SOX7. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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.

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.

Local Drug Delivery to Prevent Restenosis

PubMed Central

Seedial, Stephen M.; Ghosh, Soumojit; Saunders, R. Scott; Suwanabol, Pasithorn A.; Shi, Xudong; Liu, Bo; Kent, K. Craig

2013-01-01

Introduction Despite significant advances in vascular biology, bioengineering and pharmacology, restenosis remains a limitation to the overall efficacy of vascular reconstructions, both percutaneous and open. Although the pathophysiology of intimal hyperplasia is complex, a number of drugs and/or molecular tools have been identified that can prevent restenosis. Moreover, the focal nature of this process lends itself to treatment with local drug administration. In this article we provide a broad overview of current and future techniques for local drug delivery that have been developed to prevent restenosis following vascular intervention. Methods A systematic electronic literature search using PubMed was performed for all accessible published articles through September 2012. In an effort to remain current, additional searches were performed for abstracts presented at relevant societal meetings, filed patents, clinical trials and funded NIH awards. Results The efficacy of local drug delivery has been demonstrated in the coronary circulation with the current clinical use of drug-eluting stents (DES). Until recently, however, DES were not found to be efficacious in the peripheral circulation. Further pursuit of intraluminal devices has led to the development of balloon-based technologies with a recent surge in trials involving drug-eluting balloons. Early data appears encouraging, particularly for treatment of lesions in the superficial femoral artery, with several devices having recently received the CE mark in Europe. Investigators have also explored periadventitial application of biomaterials containing anti-restenotic drugs, an approach that could be particularly useful for surgical bypass or endarterectomy. In the past systemic drug delivery has been unsuccessful, however, there has been recent exploration of intravenous delivery of drugs designed specifically to target injured or reconstructed arteries. Our review revealed a multitude of additional interesting

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.

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

CD163-Macrophages Are Involved in Rhabdomyolysis-Induced Kidney Injury and May Be Detected by MRI with Targeted Gold-Coated Iron Oxide Nanoparticles.

PubMed

Rubio-Navarro, Alfonso; Carril, Mónica; Padro, Daniel; Guerrero-Hue, Melanie; Tarín, Carlos; Samaniego, Rafael; Cannata, Pablo; Cano, Ainhoa; Villalobos, Juan Manuel Amaro; Sevillano, Ángel Manuel; Yuste, Claudia; Gutiérrez, Eduardo; Praga, Manuel; Egido, Jesús; Moreno, Juan Antonio

2016-01-01

Macrophages play an important role in rhabdomyolysis-acute kidney injury (AKI), although the molecular mechanisms involved in macrophage differentiation are poorly understood. We analyzed the expression and regulation of CD163, a membrane receptor mainly expressed by anti-inflammatory M2 macrophages, in rhabdomyolysis-AKI and developed targeted probes for its specific detection in vivo by MRI. Intramuscular injection of glycerol in mice promoted an early inflammatory response, with elevated proportion of M1 macrophages, and partial differentiation towards a M2 phenotype in later stages, where increased CD163 expression was observed. Immunohistological studies confirmed the presence of CD163-macrophages in human rhabdomyolysis-AKI. In cultured macrophages, myoglobin upregulated CD163 expression via HO-1/IL-10 axis. Moreover, we developed gold-coated iron oxide nanoparticles vectorized with an anti-CD163 antibody that specifically targeted CD163 in kidneys from glycerol-injected mice, as determined by MRI studies, and confirmed by electron microscopy and immunological analysis. Our findings are the first to demonstrate that CD163 is present in both human and experimental rhabdomyolysis-induced AKI, suggesting an important role of this molecule in this pathological condition. Therefore, the use of probes targeting CD163-macrophages by MRI may provide important information about the cellular composition of renal lesion in rhabdomyolysis.

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.

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.

(Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy.

PubMed

Kanda, Atsuhiro; Ishida, Susumu

2018-03-25

The renin-angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)-A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal-regulated kinase); namely, the (P)RR-induced dual pathogenic bioactivity referred to as the receptor-associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor-associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal-regulated kinase and VEGF-A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF-A-driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS-independent role of (P)RR in glucose-induced oxidative stress. Recently, we developed an innovative single-strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes-induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis. © 2018 The Authors

5 CFR 9901.332 - Standard and targeted local market supplements.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) Standard local market supplements are not applicable to physicians and dentists (in occupational series... dentists paid under 38 U.S.C. chapter 74 and since their adjusted salary rates apply on a worldwide basis...) Except for physicians and dentists (in occupational series 0602 and 0680, respectively) or as otherwise...

5 CFR 9901.332 - Standard and targeted local market supplements.

Code of Federal Regulations, 2011 CFR

2011-01-01

...) Standard local market supplements are not applicable to physicians and dentists (in occupational series... dentists paid under 38 U.S.C. chapter 74 and since their adjusted salary rates apply on a worldwide basis...) Except for physicians and dentists (in occupational series 0602 and 0680, respectively) or as otherwise...

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.

Interventions that involve parents to improve children's weight-related nutrition intake and activity patterns - what nutrition and activity targets and behaviour change techniques are associated with intervention effectiveness?

PubMed

Golley, R K; Hendrie, G A; Slater, A; Corsini, N

2011-02-01

Parent involvement is an important component of obesity prevention interventions. However, the best way to support parents remains unclear. This review identifies interventions targeting parents to improve children's weight status, dietary and/or activity patterns, examines whether intervention content and behaviour change techniques employed are associated with effectiveness. Seventeen studies, in English, 1998-2008, were included. Studies were evaluated by two reviewers for study quality, nutrition/activity content and behaviour change techniques using a validated quality assessment tool and behaviour change technique taxonomy. Study findings favoured intervention effectiveness in 11 of 17 studies. Interventions that were considered effective had similar features: better study quality, parents responsible for participation and implementation, greater parental involvement and inclusion of prompt barrier identification, restructure the home environment, prompt self-monitoring, prompt specific goal setting behaviour change techniques. Energy intake/density and food choices were more likely to be targeted in effective interventions. The number of lifestyle behaviours targeted did not appear to be associated with effectiveness. Intervention effectiveness was favoured when behaviour change techniques spanned the spectrum of behaviour change process. The review provides guidance for researchers to make informed decisions on how best to utilize resources in interventions to support and engage parents, and highlights a need for improvement in intervention content reporting practices. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.

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.

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.

Contribution of the residue at position 4 within classical nuclear localization signals to modulating interaction with importins and nuclear targeting.

PubMed

Smith, Kate M; Di Antonio, Veronica; Bellucci, Luca; Thomas, David R; Caporuscio, Fabiana; Ciccarese, Francesco; Ghassabian, Hanieh; Wagstaff, Kylie M; Forwood, Jade K; Jans, David A; Palù, Giorgio; Alvisi, Gualtiero

2018-08-01

Nuclear import involves the recognition by importin (IMP) superfamily members of nuclear localization signals (NLSs) within protein cargoes destined for the nucleus, the best understood being recognition of classical NLSs (cNLSs) by the IMPα/β1 heterodimer. Although the cNLS consensus [K-(K/R)-X-(K/R) for positions P2-P5] is generally accepted, recent studies indicated that the contribution made by different residues at the P4 position can vary. Here, we apply a combination of microscopy, molecular dynamics, crystallography, in vitro binding, and bioinformatics approaches to show that the nature of residues at P4 indeed modulates cNLS function in the context of a prototypical Simian Virus 40 large tumor antigen-derived cNLS (KKRK, P2-5). Indeed, all hydrophobic substitutions in place of R impaired binding to IMPα and nuclear targeting, with the largest effect exerted by a G residue at P4. Substitution of R with neutral hydrophobic residues caused the loss of electrostatic and van der Waals interactions between the P4 residue side chains and IMPα. Detailed bioinformatics analysis confirmed the importance of the P4 residue for cNLS function across the human proteome, with specific residues such as G being associated with low activity. Furthermore, we validate our findings for two additional cNLSs from human cytomegalovirus (HCMV) DNA polymerase catalytic subunit UL54 and processivity factor UL44, where a G residue at P4 results in a 2-3-fold decrease in NLS activity. Our results thus showed that the P4 residue makes a hitherto poorly appreciated contribution to nuclear import efficiency, which is essential to determining the precise nuclear levels of cargoes. Copyright © 2018 Elsevier B.V. All rights reserved.

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.

PubMed

Regad, Leslie; Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

2017-01-01

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight

PubMed Central

Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

2017-01-01

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http

A radiographic and tomographic imaging system integrated into a medical linear accelerator for localization of bone and soft-tissue targets.

PubMed

Jaffray, D A; Drake, D G; Moreau, M; Martinez, A A; Wong, J W

1999-10-01

Dose escalation in conformal radiation therapy requires accurate field placement. Electronic portal imaging devices are used to verify field placement but are limited by the low subject contrast of bony anatomy at megavoltage (MV) energies, the large imaging dose, and the small size of the radiation fields. In this article, we describe the in-house modification of a medical linear accelerator to provide radiographic and tomographic localization of bone and soft-tissue targets in the reference frame of the accelerator. This system separates the verification of beam delivery (machine settings, field shaping) from patient and target localization. A kilovoltage (kV) x-ray source is mounted on the drum assembly of an Elekta SL-20 medical linear accelerator, maintaining the same isocenter as the treatment beam with the central axis at 90 degrees to the treatment beam axis. The x-ray tube is powered by a high-frequency generator and can be retracted to the drum-face. Two CCD-based fluoroscopic imaging systems are mounted on the accelerator to collect MV and kV radiographic images. The system is also capable of cone-beam tomographic imaging at both MV and kV energies. The gain stages of the two imaging systems have been modeled to assess imaging performance. The contrast-resolution of the kV and MV systems was measured using a contrast-detail (C-D) phantom. The dosimetric advantage of using the kV imaging system over the MV system for the detection of bone-like objects is quantified for a specific imaging geometry using a C-D phantom. Accurate guidance of the treatment beam requires registration of the imaging and treatment coordinate systems. The mechanical characteristics of the treatment and imaging gantries are examined to determine a localizing precision assuming an unambiguous object. MV and kV radiographs of patients receiving radiation therapy are acquired to demonstrate the radiographic performance of the system. The tomographic performance is demonstrated on

Involving Communities in the Targeting of Cash Transfer Programs for Vulnerable Children: Opportunities and Challenges☆

PubMed Central

Robertson, Laura; Mushati, Phyllis; Skovdal, Morten; Eaton, Jeffrey W.; Makoni, Jeremiah C.; Crea, Tom; Mavise, Gideon; Dumba, Lovemore; Schumacher, Christina; Sherr, Lorraine; Nyamukapa, Constance; Gregson, Simon

2014-01-01

Summary We used baseline data, collected in July–September 2009, from a randomized controlled trial of a cash transfer program for vulnerable children in eastern Zimbabwe to investigate the effectiveness, coverage, and efficiency of census- and community-based targeting methods for reaching vulnerable children. Focus group discussions and in-depth interviews with beneficiaries and other stakeholders were used to explore community perspectives on targeting. Community members reported that their participation improved ownership and reduced conflict and jealousy. However, all the methods failed to target a large proportion of vulnerable children and there was poor agreement between the community- and census-based methods. PMID:24748713

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.

Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately.

PubMed

Shi, Yan; Shu, Bin; Yang, Ronghua; Xu, Yingbin; Xing, Bangrong; Liu, Jian; Chen, Lei; Qi, Shaohai; Liu, Xusheng; Wang, Peng; Tang, Jinming; Xie, Julin

2015-06-16

Wnt and Notch signaling pathways are critically involved in relative cell fate decisions within the development of cutaneous tissues. Moreover, several studies identified the above two pathways as having a significant role during wound healing. However, their biological effects during cutaneous tissues repair are unclear. We employed a self-controlled model (Sprague-Dawley rats with full-thickness skin wounds) to observe the action and effect of Wnt/β-catenin and Notch signalings in vivo. The quality of wound repair relevant to the gain/loss-of-function Wnt/β-catenin and Notch activation was estimated by hematoxylin-and-eosin and Masson staining. Immunofluorescence analysis and Western blot analysis were used to elucidate the underlying mechanism of the regulation of Wnt and Notch signaling pathways in wound healing. Meanwhile, epidermal stem cells (ESCs) were cultured in keratinocyte serum-free medium with Jaggedl or in DAPT (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl) to investigate whether the interruption of Notch signaling contributes to the expression of Wnt/β-catenin signaling. The results showed that in vivo the gain-of-function Wnt/β-catenin and Notch activation extended the ability to promote wound closure. We further determined that activation or inhibition of Wnt signaling and Notch signaling can affect the proliferation of ESCs, the differentiation and migration of keratinocytes, and follicle regeneration by targeting c-Myc and Hes1, which ultimately lead to enhanced or delayed wound healing. Furthermore, Western blot analysis suggested that the two pathways might interact in vivo and in vitro. These results suggest that Wnt and Notch signalings play important roles in cutaneous repair by targeting c-Myc and Hes1 separately. What's more, interaction between the above two pathways might act as a vital role in regulation of wound healing.

Biodegradable polymers for targeted delivery of anti-cancer drugs.

PubMed

Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

2016-06-01

Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells.

PubMed

Orecchioni, Stefania; Reggiani, Francesca; Talarico, Giovanna; Mancuso, Patrizia; Calleri, Angelica; Gregato, Giuliana; Labanca, Valentina; Noonan, Douglas M; Dallaglio, Katiuscia; Albini, Adriana; Bertolini, Francesco

2015-03-15

The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo. We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro, biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. In coculture, biguanides inhibited the production of several angiogenic proteins. In vivo, biguanides inhibited local and metastatic growth of triple negative and HER2+ BC in immune-competent and immune-deficient mice orthotopically injected with BC. Biguanides inhibited local and metastatic BC growth in a genetically engineered murine model model of HER2+ BC. In vivo, biguanides increased pimonidazole binding (but not HIF-1 expression) of WAT progenitors, reduced tumor microvessel density and altered the vascular pericyte/endothelial cell ratio, so that cancer vessels displayed a dysplastic phenotype. Phe was significantly more active than Met both in vitro and in vivo. Considering their safety profile, biguanides deserve to be further investigated for BC prevention in high-risk subjects, in combination with chemo and/or targeted therapy and/or as post-therapy consolidation or maintenance therapy for the prevention of BC recurrence. © 2014 UICC.

RNA-Targeted Therapeutics.

PubMed

Crooke, Stanley T; Witztum, Joseph L; Bennett, C Frank; Baker, Brenda F

2018-04-03

RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform. Copyright © 2018 Elsevier Inc. All rights reserved.

Eye-Target Synchrony and Attention

NASA Astrophysics Data System (ADS)

Contreras, R.; Kolster, R.; Basu, S.; Voss, H. U.; Ghajar, J.; Suh, M.; Bahar, S.

2007-03-01

Eye-target synchrony is critical during smooth pursuit. We apply stochastic phase synchronization to human pursuit of a moving target, in both normal and mild traumatic brain injured (TBI) subjects. Smooth pursuit utilizes the same neural networks used by attention. To test whether smooth pursuit is modulated by attention, subjects tracked a target while loaded with tasks involving working memory. Preliminary results suggest that additional cognitive load increases normal subjects' performance, while the effect is reversed in TBI patients. We correlate these results with eye-target synchrony. Additionally, we correlate eye-target synchrony with frequency of target motion, and discuss how the range of frequencies for optimal synchrony depends on the shift from attentional to automatic-response time scales. Synchrony deficits in TBI patients can be correlated with specific regions of brain damage imaged with diffusion tensor imaging (DTI).

Vesicle Docking Is a Key Target of Local PI(4,5)P2 Metabolism in the Secretory Pathway of INS-1 Cells.

PubMed

Ji, Chen; Fan, Fan; Lou, Xuelin

2017-08-08

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) signaling is transient and spatially confined in live cells. How this pattern of signaling regulates transmitter release and hormone secretion has not been addressed. We devised an optogenetic approach to control PI(4,5)P 2 levels in time and space in insulin-secreting cells. Combining this approach with total internal reflection fluorescence microscopy, we examined individual vesicle-trafficking steps. Unlike long-term PI(4,5)P 2 perturbations, rapid and cell-wide PI(4,5)P 2 reduction in the plasma membrane (PM) strongly inhibits secretion and intracellular Ca 2+ concentration ([Ca 2+ ] i ) responses, but not sytaxin1a clustering. Interestingly, local PI(4,5)P 2 reduction selectively at vesicle docking sites causes remarkable vesicle undocking from the PM without affecting [Ca 2+ ] i . These results highlight a key role of local PI(4,5)P 2 in vesicle tethering and docking, coordinated with its role in priming and fusion. Thus, different spatiotemporal PI(4,5)P 2 signaling regulates distinct steps of vesicle trafficking, and vesicle docking may be a key target of local PI(4,5)P 2 signaling in vivo. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Guidelines for Parent Involvement in Chapter 1 Programs.

ERIC Educational Resources Information Center

Weckstein, Paul

Chapter 1 is the largest federal education program in existence. It provides extra services to help low-achieving students and is targeted primarily at areas where low-income families reside. Parent involvement in designing and implementing the program is an essential part of Chapter 1. However, the parent involvement component is often not as…

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.

Enzymes involved in plastid-targeted phosphatidic acid synthesis are essential for Plasmodium yoelii liver stage development

PubMed Central

Lindner, Scott E.; Sartain, Mark J.; Hayes, Kiera; Harupa, Anke; Moritz, Robert L.; Kappe, Stefan H. I.; Vaughan, Ashley M.

2014-01-01

SUMMARY Malaria parasites scavenge nutrients from their host but also harbor enzymatic pathways for de novo macromolecule synthesis. One such pathway is apicoplast-targeted type II fatty acid synthesis, which is essential for late liver stage development in rodent malaria. It is likely that fatty acids synthesized in the apicoplast are ultimately incorporated into membrane phospholipids necessary for exoerythrocytic merozoite formation. We hypothesized that these synthesized fatty acids are being utilized for apicoplast-targeted phosphatidic acid synthesis, the phospholipid precursor. Phosphatidic acid is typically synthesized in a three-step reaction utilizing three enzymes: glycerol 3-phosphate dehydrogenase, glycerol 3-phosphate acyltransferase and lysophosphatidic acid acyltransferase. The Plasmodium genome is predicted to harbor genes for both apicoplast- and cytosol/endoplasmic reticulum-targeted phosphatidic synthesis. Our research shows that apicoplast-targeted P. yoelii glycerol 3-phosphate dehydrogenase and glycerol 3-phosphate acyltransferase are expressed only during liver stage development and deletion of the encoding genes resulted in late liver stage growth arrest and lack of merozoite differentiation. However, the predicted apicoplast-targeted lysophosphatidic acid acyltransferase gene was refractory to deletion and was expressed solely in the endoplasmic reticulum throughout the parasite lifecycle. Our results suggest that P. yoelii has an incomplete apicoplast-targeted phosphatidic acid synthesis pathway that is essential for liver stage maturation. PMID:24330260

Treatment outcomes in locally advanced colorectal carcinoma

PubMed Central

Harish, K; Narayanaswamy, YV; Nirmala, S

2004-01-01

Background Locally advanced colorectal cancers form a distinct subgroup where contiguous organs could be involved without distant metastases and so may be amenable to curative surgical resection. It was our objective to report our experience in treating six such patients with operable locally advanced colorectal carcinomas. Methods We retrospectively reviewed the case notes of 47 patients who were diagnosed with colorectal cancers at M S Ramaiah Medical Teaching Hospital between the years 1996 – 2001. Six patients were identified with T4 lesions, adjacent organ involvement and with no nodal involvement. The treatments and outcomes for these patients were then reviewed. Results Two of three patients with rectal malignancies who underwent pelvic exenteration succumbed to disease recurrence within the first 18 months. One of the three patients with colonic cancers died of non malignant causes. The other two are disease free till date. Conclusions Aggressive multivisceral resections for locally advanced colonic cancers might be appropriate. Rectal cancers when locally advanced may be considered for pelvic exenteration, but a more guarded prognosis may apply. PMID:15527504

Emergence and robustness of target waves in a neuronal network

NASA Astrophysics Data System (ADS)

Xu, Ying; Jin, Wuyin; Ma, Jun

2015-08-01

Target waves in excitable media such as neuronal network can regulate the spatial distribution and orderliness as a continuous pacemaker. Three different schemes are used to develop stable target wave in the network, and the potential mechanism for emergence of target waves in the excitable media is investigated. For example, a local pacing driven by external periodical forcing can generate stable target wave in the excitable media, furthermore, heterogeneity and local feedback under self-feedback coupling are also effective to generate continuous target wave as well. To discern the difference of these target waves, a statistical synchronization factor is defined by using mean field theory and artificial defects are introduced into the network to block the target wave, thus the robustness of these target waves could be detected. However, these target waves developed from the above mentioned schemes show different robustness to the blocking from artificial defects. A regular network of Hindmarsh-Rose neurons is designed in a two-dimensional square array, target waves are induced by using three different ways, and then some artificial defects, which are associated with anatomical defects, are set in the network to detect the effect of defects blocking on the travelling waves. It confirms that the robustness of target waves to defects blocking depends on the intrinsic properties (ways to generate target wave) of target waves.

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.

RNA Transport and Local Control of Translation

PubMed Central

Kindler, Stefan; Wang, Huidong; Richter, Dietmar; Tiedge, Henri

2007-01-01

In eukaryotes, the entwined pathways of RNA transport and local translational regulation are key determinants in the spatio-temporal articulation of gene expression. One of the main advantages of this mechanism over transcriptional control in the nucleus lies in the fact that it endows local sites with independent decision-making authority, a consideration that is of particular relevance in cells with complex cellular architecture such as neurons. Localized RNAs typically contain codes, expressed within cis-acting elements, that specify subcellular targeting. Such codes are recognized by trans-acting factors, adaptors that mediate translocation along cytoskeletal elements by molecular motors. Most transported mRNAs are assumed translationally dormant while en route. In some cell types, especially in neurons, it is considered crucial that translation remains repressed after arrival at the destination site (e.g., a postsynaptic microdomain) until an appropriate activation signal is received. Several candidate mechanisms have been suggested to participate in the local implementation of translational repression and activation, and such mechanisms may target translation at the level of initiation and/or elongation. Recent data indicate that untranslated RNAs may play important roles in the local control of translation. PMID:16212494

Parental Involvement and the Theory of Planned Behavior

ERIC Educational Resources Information Center

Bracke, Deborah; Corts, Daniel

2012-01-01

The "Theory of Planned Behavior" provided a specific theoretical framework to evaluate the impact of attitudes, norms, and controls on parental involvement in a local school district. The "new knowledge" that resulted from the measurement of these constructs affirmed that regardless of the perceived level of parental involvement, virtually all…

Exploring Parental Involvement in Early Years Education in China: Development and Validation of the Chinese Early Parental Involvement Scale (CEPIS)

ERIC Educational Resources Information Center

Lau, Eva Yi Hung; Li, Hui; Rao, Nirmala

2012-01-01

This study developed and validated an instrument, the Chinese Early Parental Involvement Scale (CEPIS), that can be widely used in both local and international contexts to assess Chinese parental involvement in early childhood education. The study was carried out in two stages: (1) focus group interviews were conducted with 41 teachers and 35…

Musculoskeletal MRI findings of juvenile localized scleroderma.

PubMed

Eutsler, Eric P; Horton, Daniel B; Epelman, Monica; Finkel, Terri; Averill, Lauren W

2017-04-01

Juvenile localized scleroderma comprises a group of autoimmune conditions often characterized clinically by an area of skin hardening. In addition to superficial changes in the skin and subcutaneous tissues, juvenile localized scleroderma may involve the deep soft tissues, bones and joints, possibly resulting in functional impairment and pain in addition to cosmetic changes. There is literature documenting the spectrum of findings for deep involvement of localized scleroderma (fascia, muscles, tendons, bones and joints) in adults, but there is limited literature for the condition in children. We aimed to document the spectrum of musculoskeletal magnetic resonance imaging (MRI) findings of both superficial and deep juvenile localized scleroderma involvement in children and to evaluate the utility of various MRI sequences for detecting those findings. Two radiologists retrospectively evaluated 20 MRI studies of the extremities in 14 children with juvenile localized scleroderma. Each imaging sequence was also given a subjective score of 0 (not useful), 1 (somewhat useful) or 2 (most useful for detecting the findings). Deep tissue involvement was detected in 65% of the imaged extremities. Fascial thickening and enhancement were seen in 50% of imaged extremities. Axial T1, axial T1 fat-suppressed (FS) contrast-enhanced and axial fluid-sensitive sequences were rated most useful. Fascial thickening and enhancement were the most commonly encountered deep tissue findings in extremity MRIs of children with juvenile localized scleroderma. Because abnormalities of the skin, subcutaneous tissues and fascia tend to run longitudinally in an affected limb, axial T1, axial fluid-sensitive and axial T1-FS contrast-enhanced sequences should be included in the imaging protocol.

Expansion moments for the local field distribution that involve the three-particle distribution function

NASA Astrophysics Data System (ADS)

Attard, Phil

The second moment of the Lennard-Jones local field distribution in a hard-sphere fluid is evaluated using the PY3 three-particle distribution function. An approximation due to Lado that avoids the explicit calculation of the latter is shown to be accurate. Partial results are also given for certain cavity-hard-sphere radial distribution functions that occur in a closest particle expansion for the local field.

School Integration Efforts Three Years after "Parents Involved"

ERIC Educational Resources Information Center

Tefera, Adai; Siegel-Hawley, Genevieve; Frankenberg, Erica

2010-01-01

This report synthesizes major themes in local policymaking during the last year, as local school districts continue to grapple with legal and economic constraints on policies that are aimed at creating diverse schools. The report last year on the second anniversary of "Parents Involved" began to uncover some of the consequences of the difficult…

Targeted Nanoparticle Thermometry: A Method to Measure Local Temperature at the Nanoscale Point Where Water Vapor Nucleation Occurs.

PubMed

Alaulamie, Arwa A; Baral, Susil; Johnson, Samuel C; Richardson, Hugh H

2017-01-01

An optical nanothermometer technique based on laser trapping, moving and targeted attaching an erbium oxide nanoparticle cluster is developed to measure the local temperature. The authors apply this new nanoscale temperature measuring technique (limited by the size of the nanoparticles) to measure the temperature of vapor nucleation in water. Vapor nucleation is observed after superheating water above the boiling point for degassed and nondegassed water. The average nucleation temperature for water without gas is 560 K but this temperature is lowered by 100 K when gas is introduced into the water. The authors are able to measure the temperature inside the bubble during bubble formation and find that the temperature inside the bubble spikes to over 1000 K because the heat source (optically-heated nanorods) is no longer connected to liquid water and heat dissipation is greatly reduced. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Technologies for Controlled, Local Delivery of siRNA

PubMed Central

Sarett, Samantha M.; Nelson, Christopher E.; Duvall, Craig L.

2015-01-01

The discovery of RNAi in the late 1990s unlocked a new realm of therapeutic possibilities by enabling potent and specific silencing of theoretically any desired genetic target. Better elucidation of the mechanism of action, the impact of chemical modifications that stabilize and reduce nonspecific effects of siRNA molecules, and the key design considerations for effective delivery systems has spurred progress toward developing clinically-successful siRNA therapies. A logical aim for initial siRNA translation is local therapies, as delivering siRNA directly to its site of action helps to ensure that a sufficient dose reaches the target tissue, lessens the potential for off-target side effects, and circumvents the substantial systemic delivery barriers. While topical siRNA delivery has progressed into numerous clinical trials, an enormous opportunity also exists to develop sustained-release, local delivery systems that enable both spatial and temporal control of gene silencing. This review focuses on material platforms that establish both localized and controlled gene silencing, with emphasis on the systems that show most promise for clinical translation. PMID:26476177

Enzymes involved in plastid-targeted phosphatidic acid synthesis are essential for Plasmodium yoelii liver-stage development.

PubMed

Lindner, Scott E; Sartain, Mark J; Hayes, Kiera; Harupa, Anke; Moritz, Robert L; Kappe, Stefan H I; Vaughan, Ashley M

2014-02-01

Malaria parasites scavenge nutrients from their host but also harbour enzymatic pathways for de novo macromolecule synthesis. One such pathway is apicoplast-targeted type II fatty acid synthesis, which is essential for late liver-stage development in rodent malaria. It is likely that fatty acids synthesized in the apicoplast are ultimately incorporated into membrane phospholipids necessary for exoerythrocytic merozoite formation. We hypothesized that these synthesized fatty acids are being utilized for apicoplast-targeted phosphatidic acid synthesis, the phospholipid precursor. Phosphatidic acid is typically synthesized in a three-step reaction utilizing three enzymes: glycerol 3-phosphate dehydrogenase, glycerol 3-phosphate acyltransferase and lysophosphatidic acid acyltransferase. The Plasmodium genome is predicted to harbour genes for both apicoplast- and cytosol/endoplasmic reticulum-targeted phosphatidic acid synthesis. Our research shows that apicoplast-targeted Plasmodium yoelii glycerol 3-phosphate dehydrogenase and glycerol 3-phosphate acyltransferase are expressed only during liver-stage development and deletion of the encoding genes resulted in late liver-stage growth arrest and lack of merozoite differentiation. However, the predicted apicoplast-targeted lysophosphatidic acid acyltransferase gene was refractory to deletion and was expressed solely in the endoplasmic reticulum throughout the parasite life cycle. Our results suggest that P. yoelii has an incomplete apicoplast-targeted phosphatidic acid synthesis pathway that is essential for liver-stage maturation. © 2013 John Wiley & Sons Ltd.

Locally targeted delivery of a micron-size radiation therapy source using temperature-sensitive hydrogel.

PubMed

Kim, Yusung; Seol, Dong Rim; Mohapatra, Sucheta; Sunderland, John J; Schultz, Michael K; Domann, Frederick E; Lim, Tae-Hong

2014-04-01

To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection with a minimal accumulation of In-111 to the kidneys. Preliminary data of RT-GEL as a delivery modality of

Biochemical localization of a protein involved in Gluconacetobacter hansenii cellulose synthesis

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

Iyer, Prashanti R; Catchmark, Jeffrey M; Brown, Nicole Robitaille

2011-02-08

Using subcellular fractionation and Western blot methods, we have shown that AcsD, one of the proteins encoded by the Acetobacter cellulose synthase (acs) operon, is localized in the periplasmic region of the cell. AcsD protein was heterologously expressed in Escherichia coli and purified using histidine tag affinity methods. The purified protein was used to obtain rabbit polyclonal antibodies. The purity of the subcellular fractions was assessed by marker enzyme assays.

5 CFR 9901.333 - Setting and adjusting local market supplements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... factors. The Secretary may determine the effective date of newly set or adjusted targeted local market... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Setting and adjusting local market... DEFENSE NATIONAL SECURITY PERSONNEL SYSTEM (NSPS) Pay and Pay Administration Local Market Supplements...

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.