36 CFR 230.32 - National program administration.

Code of Federal Regulations, 2011 CFR

2011-07-01

... environmental, economic, and social values and public benefits are derived from the program. (c) The Chief shall... accomplishments. (k) FLEP funds may not be used by States for capital investments or capital improvements unless specifically authorized in a funding document and must be limited to $5,000. The limitation on capital...

48 CFR 3046.791-2 - Tailoring warranty terms and conditions (USCG).

Code of Federal Regulations, 2010 CFR

2010-10-01

... appropriately tailor the warranty on a case-by-case basis, including remedies, exclusions, limitations and durations, provided the tailoring is consistent with the specific requirements of this subpart and (FAR) 48... the terms of the warranty (limitations), as appropriate, if necessary to derive a cost-effective...

Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism

USDA-ARS?s Scientific Manuscript database

Probiotics are health-promoting bacteria which may protect the intestines from injury and inflammatory diseases but our understanding of the mechanisms for probiotic action are limited. In this study, we hypothesized that a protein, known as p40, which is derived from the probiotic bacteria, Lactoba...

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

PubMed

Bercu, J P; Galloway, S M; Parris, P; Teasdale, A; Masuda-Herrera, M; Dobo, K; Heard, P; Kenyon, M; Nicolette, J; Vock, E; Ku, W; Harvey, J; White, A; Glowienke, S; Martin, E A; Custer, L; Jolly, R A; Thybaud, V

2018-04-01

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication. Copyright © 2018. Published by Elsevier Inc.

MPC and ALI: their basis and their comparison

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

Kennedy, W.E. Jr.; Watson, E.C.

Radiation protection regulations in the United States have evolved from the recommendations of the International Commission on Radiological Protection (ICRP) and the National Council on Radiation Protection and Measurements (NCRP). In 1959, the ICRP issued Publication 2 which contained specific recommendations on dose rate limits, permissible body burdens, metabolic data for radionuclides, and maximum permissible concentrations (MPC) in air or water. Over the next 20 years, new information became available concerning the effects of radiation, the uptake and retention of radionuclides, and the radioactive decay schemes of parent radionuclides. To include this newer information, the ICRP issued Publication 30 inmore » 1978 to supersede Publication 2. One of the secondary limits defined in Publication 30 is the annual limit of intake (ALI). Radionuclide specific ALI values are intended to replace MPC values in determining whether or not ambient air and water concentrations are sufficiently low to maintain the dose to workers within accepted dose rate limits. In this paper, we discuss the derivation of MPC and ALI values, compare inhalation committed dose equivalent factors derived from ICRP Publications 2 and 30, and discuss the practical implications of using either MPC or ALI in determining compliance with occupational exposure limits. 6 references.« less

Antigen-Specific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells

PubMed Central

Chmielewski, Markus; Hombach, Andreas A.; Abken, Hinrich

2013-01-01

Adoptive T-cell therapy has recently shown promise in initiating a lasting anti-tumor response with spectacular therapeutic success in some cases. Specific T-cell therapy, however, is limited since a number of cancer cells are not recognized by T cells due to various mechanisms including the limited availability of tumor-specific T cells and deficiencies in antigen processing or major histocompatibility complex (MHC) expression of cancer cells. To make adoptive cell therapy applicable for the broad variety of cancer entities, patient’s T cells are engineered ex vivo with pre-defined specificity by a recombinant chimeric antigen receptor (CAR) which consists in the extracellular part of an antibody-derived domain for binding with a “tumor-associated antigen” and in the intracellular part of a T-cell receptor (TCR)-derived signaling moiety for T-cell activation. The specificity of CAR-mediated T-cell recognition is defined by the antibody domain, is independent of MHC presentation and can be extended to any target for which an antibody is available. We discuss the advantages and limitations of MHC-independent T-cell targeting by an engineered CAR in comparison to TCR modified T cells and the impact of the CAR activation threshold on redirected T-cell activation. Finally we review most significant progress recently made in early stage clinical trials to treat cancer. PMID:24273543

Antigen-Specific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells.

PubMed

Chmielewski, Markus; Hombach, Andreas A; Abken, Hinrich

2013-01-01

Adoptive T-cell therapy has recently shown promise in initiating a lasting anti-tumor response with spectacular therapeutic success in some cases. Specific T-cell therapy, however, is limited since a number of cancer cells are not recognized by T cells due to various mechanisms including the limited availability of tumor-specific T cells and deficiencies in antigen processing or major histocompatibility complex (MHC) expression of cancer cells. To make adoptive cell therapy applicable for the broad variety of cancer entities, patient's T cells are engineered ex vivo with pre-defined specificity by a recombinant chimeric antigen receptor (CAR) which consists in the extracellular part of an antibody-derived domain for binding with a "tumor-associated antigen" and in the intracellular part of a T-cell receptor (TCR)-derived signaling moiety for T-cell activation. The specificity of CAR-mediated T-cell recognition is defined by the antibody domain, is independent of MHC presentation and can be extended to any target for which an antibody is available. We discuss the advantages and limitations of MHC-independent T-cell targeting by an engineered CAR in comparison to TCR modified T cells and the impact of the CAR activation threshold on redirected T-cell activation. Finally we review most significant progress recently made in early stage clinical trials to treat cancer.

PCR technology for screening and quantification of genetically modified organisms (GMOs).

PubMed

Holst-Jensen, Arne; Rønning, Sissel B; Løvseth, Astrid; Berdal, Knut G

2003-04-01

Although PCR technology has obvious limitations, the potentially high degree of sensitivity and specificity explains why it has been the first choice of most analytical laboratories interested in detection of genetically modified (GM) organisms (GMOs) and derived materials. Because the products that laboratories receive for analysis are often processed and refined, the quality and quantity of target analyte (e.g. protein or DNA) frequently challenges the sensitivity of any detection method. Among the currently available methods, PCR methods are generally accepted as the most sensitive and reliable methods for detection of GM-derived material in routine applications. The choice of target sequence motif is the single most important factor controlling the specificity of the PCR method. The target sequence is normally a part of the modified gene construct, for example a promoter, a terminator, a gene, or a junction between two of these elements. However, the elements may originate from wildtype organisms, they may be present in more than one GMO, and their copy number may also vary from one GMO to another. They may even be combined in a similar way in more than one GMO. Thus, the choice of method should fit the purpose. Recent developments include event-specific methods, particularly useful for identification and quantification of GM content. Thresholds for labelling are now in place in many countries including those in the European Union. The success of the labelling schemes is dependent upon the efficiency with which GM-derived material can be detected. We will present an overview of currently available PCR methods for screening and quantification of GM-derived DNA, and discuss their applicability and limitations. In addition, we will discuss some of the major challenges related to determination of the limits of detection (LOD) and quantification (LOQ), and to validation of methods.

Intercept Centering and Time Coding in Latent Difference Score Models

ERIC Educational Resources Information Center

Grimm, Kevin J.

2012-01-01

Latent difference score (LDS) models combine benefits derived from autoregressive and latent growth curve models allowing for time-dependent influences and systematic change. The specification and descriptions of LDS models include an initial level of ability or trait plus an accumulation of changes. A limitation of this specification is that the…

Porosity control in nanoporous carbide-derived carbon by oxidation in air and carbon dioxide

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

Osswald, S.; Portet, C.; Gogotsi, Y., E-mail: gogotsi@drexel.ed

2009-07-15

Carbide-derived carbons (CDC) allow a precise control over the pore size through the selection of the carbide precursor and varying of the synthesis conditions. However, their pore volume is limited by the carbide stoichiometry. While activation of carbons derived from various organic precursors has been widely studied, this process may similarly be able to increase the pore volume and specific surface area of CDC. Oxidation of carbide-derived carbon in air and CO{sub 2} at different temperatures and times allows for significant increase in pore volume and specific surface area as well as control over average pore size with subnanometer accuracy.more » The effect of activation and associated changes in the pore volume and surface area on the hydrogen uptake are also discussed. - Graphical abstract: Carbide-derived carbons (CDC) provide great potential for sorption of toxicants and gas storage applications. Activation of CDC in air and CO{sub 2} at different temperatures and times is applied in order to maximize pore volume and specific surface area, and control the average pore size with subnanometer accuracy.« less

Controversies in Cardiovascular Research: Induced pluripotent stem cell-derived cardiomyocytes – boutique science or valuable arrhythmia model?

PubMed Central

Knollmann, Björn C

2013-01-01

As part of the series on Controversies in Cardiovascular Research, the article reviews the strengths and limitations of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) as models of cardiac arrhythmias. Specifically, the article attempts to answer the following questions: Which clinical arrhythmias can be modeled by iPSC-CM? How well can iPSC-CM model adult ventricular myocytes? What are the strengths and limitations of published iPSC-CM arrhythmia models? What new mechanistic insight has been gained? What is the evidence that would support using iPSC-CM to personalize anti-arrhythmic drug therapy? The review also discusses the pros and cons of using the iPSC-CM technology for modeling specific genetic arrhythmia disorders such as long QT syndrome, Brugada Syndrome or Catecholaminergic Polymorphic Ventricular Tachycardia. PMID:23569106

The Scientific Basis of Uncertainty Factors Used in Setting Occupational Exposure Limits.

PubMed

Dankovic, D A; Naumann, B D; Maier, A; Dourson, M L; Levy, L S

2015-01-01

The uncertainty factor concept is integrated into health risk assessments for all aspects of public health practice, including by most organizations that derive occupational exposure limits. The use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups. There are differences in the application of the uncertainty factor approach among groups that conduct occupational assessments; however, there are common areas of uncertainty which are considered by all or nearly all occupational exposure limit-setting organizations. Five key uncertainties that are often examined include interspecies variability in response when extrapolating from animal studies to humans, response variability in humans, uncertainty in estimating a no-effect level from a dose where effects were observed, extrapolation from shorter duration studies to a full life-time exposure, and other insufficiencies in the overall health effects database indicating that the most sensitive adverse effect may not have been evaluated. In addition, a modifying factor is used by some organizations to account for other remaining uncertainties-typically related to exposure scenarios or accounting for the interplay among the five areas noted above. Consideration of uncertainties in occupational exposure limit derivation is a systematic process whereby the factors applied are not arbitrary, although they are mathematically imprecise. As the scientific basis for uncertainty factor application has improved, default uncertainty factors are now used only in the absence of chemical-specific data, and the trend is to replace them with chemical-specific adjustment factors whenever possible. The increased application of scientific data in the development of uncertainty factors for individual chemicals also has the benefit of increasing the transparency of occupational exposure limit derivation. Improved characterization of the scientific basis for uncertainty factors has led to increasing rigor and transparency in their application as part of the overall occupational exposure limit derivation process.

Incorporating Allee effects into the potential biological removal level

USGS Publications Warehouse

Hadier, Humza; Oldfield, Sarah; Tu, Tiffany; Moreno, Rosa; Diffendorfer, Jay E.; Eager, Eric A.; Erickson, Richard A.

2017-01-01

Potential biological removal (PBR) is an approach used to calculate sustainable harvest and “take” limits for populations. PBR was originally derived assuming logistic growth while ignoring the effects of small population size (i.e., an Allee effect). We derived a version of PBR that includes an Allee effect (i.e., small population size or densities limiting population growth rates). We found that PBR becomes less conservative when it fails to consider an Allee effect. Specifically, sustainable harvest and take levels based upon PBR with an Allee effect were between approximately 51% and 66% of levels based upon PBR without an Allee effect. Managers and biologists using PBR may need to consider the limitations if an Allee effect may be present in the species being modeled.

Potential roles of cell-derived microparticles in ischemic brain disease.

PubMed

Horstman, Lawrence L; Jy, Wenche; Bidot, Carlos J; Nordberg, Mary L; Minagar, Alireza; Alexander, J Steven; Kelley, Roger E; Ahn, Yeon S

2009-10-01

The objective of this study is to review the role of cell-derived microparticles in ischemic cerebrovascular diseases. An extensive PubMed search of literature pertaining to this study was performed in April 2009 using specific keyword search terms related to cell-derived microparticles and ischemic stroke. Some references are not cited here as it is not possible to be all inclusive or due to space limitation. Cell-derived microparticles are small membranous vesicles released from the plasma membranes of platelets, leukocytes, red cells and endothelial cells in response to diverse biochemical agents or mechanical stresses. They are the main carriers of circulating tissue factor, the principal initiator of intravascular thrombosis, and are implicated in a variety of thrombotic and inflammatory disorders. This review outlines evidence suggesting that cell-derived microparticles are involved predominantly with microvascular, as opposed to macrovascular, thrombosis. More specifically, cell-derived microparticles may substantially contribute to ischemic brain disease in several settings, as well as to neuroinflammatory conditions. If further work confirms this hypothesis, novel therapeutic strategies for minimizing cell-derived microparticles-mediated ischemia are available or can be developed, as discussed.

Derivation of gender and age-specific reference intervals from fully normal Japanese individuals and the implications for health screening.

PubMed

Yamakado, Minoru; Ichihara, Kiyoshi; Matsumoto, Yoshiyuki; Ishikawa, Yoshiki; Kato, Kiminori; Komatsubara, Yusuke; Takaya, Norihide; Tomita, Shohken; Kawano, Reo; Takada, Keisuke; Watanabe, Kiyoaki

2015-07-20

With nationwide standardization of laboratory tests among institutions for health screening in Japan, common reference intervals (RIs) were derived from records of 1,500,000 health check attendees. Targets were 20 basic laboratory tests including body mass index (BMI) and systolic and diastolic blood pressures (SBP, DBP). Individuals fulfilling the following strict criteria were chosen: SBP<130, DBP<85mmHg, BMI<25kg/m(2), non-smoking, ethanol consumption<20g/day and under no mediation with no remarkable current/past illnesses. The latent abnormal values exclusion (LAVE) method was applied to ensure fully normal results. RIs were derived by parametric method using modified Box-Cox power transformation. Among all attendees, 23% fulfilled the criteria. Application of the LAVE method further reduced the dataset by 40%-50%. Age-related charts of test results differed greatly between genders in almost all tests. Comparison of derived RIs with clinical decision limits (CDLs) revealed that the upper limits of RIs differed from CDLs according to gender and age. Implementation of gender and age-specific RIs derived from individuals with fully normal health attributes will (1) enable appropriate interpretation of test results in health screening and (2) promote judicious application of CDLs for therapeutic intervention, taking into account gender, age and other health attributes. Copyright © 2015 Elsevier B.V. All rights reserved.

Limits of detection and decision. Part 4

NASA Astrophysics Data System (ADS)

Voigtman, E.

2008-02-01

Probability density functions (PDFs) have been derived for a number of commonly used limit of detection definitions, including several variants of the Relative Standard Deviation of the Background-Background Equivalent Concentration (RSDB-BEC) method, for a simple linear chemical measurement system (CMS) having homoscedastic, Gaussian measurement noise and using ordinary least squares (OLS) processing. All of these detection limit definitions serve as both decision and detection limits, thereby implicitly resulting in 50% rates of Type 2 errors. It has been demonstrated that these are closely related to Currie decision limits, if the coverage factor, k, is properly defined, and that all of the PDFs are scaled reciprocals of noncentral t variates. All of the detection limits have well-defined upper and lower limits, thereby resulting in finite moments and confidence limits, and the problem of estimating the noncentrality parameter has been addressed. As in Parts 1-3, extensive Monte Carlo simulations were performed and all the simulation results were found to be in excellent agreement with the derived theoretical expressions. Specific recommendations for harmonization of detection limit methodology have also been made.

Adoptive transfer of CD8+ T cells generated from induced pluripotent stem cells triggers regressions of large tumors along with immunological memory

PubMed Central

Saito, Hidehito; Okita, Keisuke; Chang, Alfred E.; Ito, Fumito

2016-01-01

Current approaches to adoptive T cell therapy are limited by the difficulty of obtaining sufficient numbers of T cells against targeted antigens with useful in vivo characteristics. Theoretically, this limitation could be overcome by using induced pluripotent stem cells (iPSCs) that could provide an unlimited source of autologous T cells. However, the therapeutic efficacy of iPSC-derived regenerated T cells remains to be demonstrated. Here we report the first successful reprogramming of T-cell receptor (TCR) transgenic CD8+ T cells into pluripotency. As part of the work, we established a syngeneic mouse model for evaluating in vitro and in vivo antitumor reactivity of regenerated T cells from iPSCs bearing a rearranged TCR of known antigen specificity. Stably TCR retained T cell-derived iPSCs differentiated into CD4+CD8+ T cells that expressed CD3 and the desired TCR in vitro. Stimulation of iPSC-derived CD4+CD8+ T cells with the cognate antigen in the presence of IL-7 and IL-15 followed by expansion with IL-2, IL-7 and IL-15 generated large numbers of less-differentiated CD8+ T cells with antigen-specific potent cytokine production and cytolytic capacity. Furthermore, adoptively transferred iPSC-derived CD8+ T cells escaped immune rejection, mediated effective regression of large tumors, improved survival, and established antigen-specific immunological memory. Our findings illustrate the translational potential of iPSCs to provide an unlimited number of phenotypically defined, functional, and expandable autologous antigen-specific T cells with the characteristics needed to enable in vivo effectiveness. PMID:27197199

Concise Review: Criteria for Chamber‐Specific Categorization of Human Cardiac Myocytes Derived from Pluripotent Stem Cells

PubMed Central

Kane, Christopher

2017-01-01

Abstract Human pluripotent stem cell‐derived cardiomyocytes (PSC‐CMs) have great potential application in almost all areas of cardiovascular research. A current major goal of the field is to build on the past success of differentiation strategies to produce CMs with the properties of those originating from the different chambers of the adult human heart. With no anatomical origin or developmental pathway to draw on, the question of how to judge the success of such approaches and assess the chamber specificity of PSC‐CMs has become increasingly important; commonly used methods have substantial limitations and are based on limited evidence to form such an assessment. In this article, we discuss the need for chamber‐specific PSC‐CMs in a number of areas as well as current approaches used to assess these cells on their likeness to those from different chambers of the heart. Furthermore, describing in detail the structural and functional features that distinguish the different chamber‐specific human adult cardiac myocytes, we propose an evidence‐based tool to aid investigators in the phenotypic characterization of differentiated PSC‐CMs. Stem Cells 2017;35:1881–1897 PMID:28577296

Derivation of site-specific surface water quality criteria for the protection of aquatic ecosystems near a Korean military training facility.

PubMed

Jeong, Seung-Woo; An, Youn-Joo

2014-01-01

This study suggested the first Korean site-specific ecological surface water quality criteria for the protection of ecosystems near an artillery range at a Korean military training facility. Surface water quality (SWQ) criteria in Korea address human health protection but do not encompass ecological criteria such as limits for metals and explosives. The first objective of this study was to derive site-specific SWQ criteria for the protection of aquatic ecosystems in Hantan River, Korea. The second objective was to establish discharge criteria for the artillery range to protect the aquatic ecosystems of Hantan River. In this study, we first identified aquatic organisms living in the Hantan River, including fishes, reptiles, invertebrates, phytoplankton, zooplankton, and amphibians. Second, we collected ecotoxicity data for these aquatic organisms and constructed an ecotoxicity database for Cd, Cu, Zn, TNT, and RDX. This study determined the ecological maximum permissible concentrations for metals and explosives based on the ecotoxicity database and suggested ecological surface water quality criteria for the Hantan River by considering analytical detection limits. Discharge limit criteria for the shooting range were determined based on the ecological surface water quality criteria suggested for Hantan River with further consideration of the dilution of the contaminants discharged into the river.

Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor

PubMed Central

Perretti, Mauro; Chiang, Nan; La, Mylinh; Fierro, Iolanda M.; Marullo, Stefano; Getting, Stephen J; Solito, Egle; Serhan, Charles N.

2009-01-01

Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A4 receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci. PMID:12368905

Patient-specific cardiovascular progenitor cells derived from integration-free induced pluripotent stem cells for vascular tissue regeneration.

PubMed

Hu, Jiang; Wang, Yongyu; Jiao, Jiao; Liu, Zhongning; Zhao, Chao; Zhou, Zhou; Zhang, Zhanpeng; Forde, Kaitlynn; Wang, Lunchang; Wang, Jiangang; Baylink, David J; Zhang, Xiao-Bing; Gao, Shaorong; Yang, Bo; Chen, Y Eugene; Ma, Peter X

2015-12-01

Tissue-engineered blood vessels (TEBVs) are promising in regenerating a live vascular replacement. However, the vascular cell source is limited, and it is crucial to develop a scaffold that accommodates new type of vascular progenitor cells and facilitates in vivo lineage specification of the cells into functional vascular smooth muscle cells (VSMCs) to regenerate vascular tissue. In the present study, integration-free human induced pluripotent stem cells (hiPSCs) were established from patient peripheral blood mononuclear cells through episomal vector nucleofection of reprogramming factors. The established hiPSCs were then induced into mesoderm-originated cardiovascular progenitor cells (CVPCs) with a highly efficient directed lineage specification method. The derived CVPCs were demonstrated to be able to differentiate into functional VSMCs. Subcutaneous implantation of CVPCs seeded on macroporous nanofibrous poly(l-lactide) scaffolds led to in vivo VSMC lineage specification and matrix deposition inside the scaffolds. In summary, we established integration-free patient-specific hiPSCs from peripheral blood mononuclear cells, derived CVPCs through directed lineage specification, and developed an advanced scaffold for these progenitor cells to further differentiate in vivo into VSMCs and regenerate vascular tissue in a subcutaneous implantation model. This study has established an efficient patient-specific approach towards in vivo regeneration of vascular tissue. Copyright © 2015 Elsevier Ltd. All rights reserved.

Emerging biological roles for erythropoietin in the nervous system.

PubMed

Brines, Michael; Cerami, Anthony

2005-06-01

Erythropoietin mediates an evolutionarily conserved, ancient immune response that limits damage to the heart, the nervous system and other tissues following injury. New evidence indicates that erythropoietin specifically prevents the destruction of viable tissue surrounding the site of an injury by signalling through a non-haematopoietic receptor. Engineered derivatives of erythropoietin that have a high affinity for this receptor have been developed, and these show robust tissue-protective effects in diverse preclinical models without stimulating erythropoiesis. A recent successful proof-of-concept clinical trial that used erythropoietin to treat human patients who had suffered a stroke encourages the evaluation of both this cytokine and non-erythropoietic derivatives as therapeutic agents to limit tissue injury.

Reaction rates for mesoscopic reaction-diffusion kinetics

DOE PAGES

Hellander, Stefan; Hellander, Andreas; Petzold, Linda

2015-02-23

The mesoscopic reaction-diffusion master equation (RDME) is a popular modeling framework frequently applied to stochastic reaction-diffusion kinetics in systems biology. The RDME is derived from assumptions about the underlying physical properties of the system, and it may produce unphysical results for models where those assumptions fail. In that case, other more comprehensive models are better suited, such as hard-sphere Brownian dynamics (BD). Although the RDME is a model in its own right, and not inferred from any specific microscale model, it proves useful to attempt to approximate a microscale model by a specific choice of mesoscopic reaction rates. In thismore » paper we derive mesoscopic scale-dependent reaction rates by matching certain statistics of the RDME solution to statistics of the solution of a widely used microscopic BD model: the Smoluchowski model with a Robin boundary condition at the reaction radius of two molecules. We also establish fundamental limits on the range of mesh resolutions for which this approach yields accurate results and show both theoretically and in numerical examples that as we approach the lower fundamental limit, the mesoscopic dynamics approach the microscopic dynamics. Finally, we show that for mesh sizes below the fundamental lower limit, results are less accurate. Thus, the lower limit determines the mesh size for which we obtain the most accurate results.« less

Reaction rates for mesoscopic reaction-diffusion kinetics

PubMed Central

Hellander, Stefan; Hellander, Andreas; Petzold, Linda

2016-01-01

The mesoscopic reaction-diffusion master equation (RDME) is a popular modeling framework frequently applied to stochastic reaction-diffusion kinetics in systems biology. The RDME is derived from assumptions about the underlying physical properties of the system, and it may produce unphysical results for models where those assumptions fail. In that case, other more comprehensive models are better suited, such as hard-sphere Brownian dynamics (BD). Although the RDME is a model in its own right, and not inferred from any specific microscale model, it proves useful to attempt to approximate a microscale model by a specific choice of mesoscopic reaction rates. In this paper we derive mesoscopic scale-dependent reaction rates by matching certain statistics of the RDME solution to statistics of the solution of a widely used microscopic BD model: the Smoluchowski model with a Robin boundary condition at the reaction radius of two molecules. We also establish fundamental limits on the range of mesh resolutions for which this approach yields accurate results and show both theoretically and in numerical examples that as we approach the lower fundamental limit, the mesoscopic dynamics approach the microscopic dynamics. We show that for mesh sizes below the fundamental lower limit, results are less accurate. Thus, the lower limit determines the mesh size for which we obtain the most accurate results. PMID:25768640

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

Klima, Matej; Kucharik, MIlan; Shashkov, Mikhail Jurievich

We analyze several new and existing approaches for limiting tensor quantities in the context of deviatoric stress remapping in an ALE numerical simulation of elastic flow. Remapping and limiting of the tensor component-by-component is shown to violate radial symmetry of derived variables such as elastic energy or force. Therefore, we have extended the symmetry-preserving Vector Image Polygon algorithm, originally designed for limiting vector variables. This limiter constrains the vector (in our case a vector of independent tensor components) within the convex hull formed by the vectors from surrounding cells – an equivalent of the discrete maximum principle in scalar variables.more » We compare this method with a limiter designed specifically for deviatoric stress limiting which aims to constrain the J 2 invariant that is proportional to the specific elastic energy and scale the tensor accordingly. We also propose a method which involves remapping and limiting the J 2 invariant independently using known scalar techniques. The deviatoric stress tensor is then scaled to match this remapped invariant, which guarantees conservation in terms of elastic energy.« less

Augmenting Species Diversity in Water Quality Criteria Derivation using Interspecies Correlation Models

EPA Science Inventory

The specific requirements for taxa diversity of the 1985 guidelines have limited the number of ambient water quality criteria (AWQC) developed for aquatic life protection. The EPA developed the Web-based Interspecies Correlation Estimation (Web-ICE) tool to allow extrapolation of...

Development of a pavement warranty contract and performance specification for a hot-mix asphalt resurfacing project.

DOT National Transportation Integrated Search

2005-01-01

As the primary focus of the Virginia Department of Transportation (VDOT) changes from highway construction to transportation maintenance, there is an increased need to extend the value derived from limited funding resources by increasing the service ...

Lessons Learned about Neurodegeneration from Microglia and Monocyte Depletion Studies

PubMed Central

Lund, Harald; Pieber, Melanie; Harris, Robert A.

2017-01-01

While bone marrow-derived Ly6Chi monocytes can infiltrate the central nervous system (CNS) they are developmentally and functionally distinct from resident microglia. Our understanding of the relative importance of these two populations in the distinct processes of pathogenesis and resolution of inflammation during neurodegenerative disorders was limited by a lack of tools to specifically manipulate each cell type. During recent years, the development of experimental cell-specific depletion models has enabled this issue to be addressed. Herein we compare and contrast the different depletion approaches that have been used, focusing on the respective functionalities of microglia and monocyte-derived macrophages in a range of neurodegenerative disease states, and discuss their prospects for immunotherapy. PMID:28804456

Macroscopic relationship in primal-dual portfolio optimization problem

NASA Astrophysics Data System (ADS)

Shinzato, Takashi

2018-02-01

In the present paper, using a replica analysis, we examine the portfolio optimization problem handled in previous work and discuss the minimization of investment risk under constraints of budget and expected return for the case that the distribution of the hyperparameters of the mean and variance of the return rate of each asset are not limited to a specific probability family. Findings derived using our proposed method are compared with those in previous work to verify the effectiveness of our proposed method. Further, we derive a Pythagorean theorem of the Sharpe ratio and macroscopic relations of opportunity loss. Using numerical experiments, the effectiveness of our proposed method is demonstrated for a specific situation.

Recombinant PrPSc shares structural features with brain-derived PrPSc: Insights from limited proteolysis.

PubMed

Sevillano, Alejandro M; Fernández-Borges, Natalia; Younas, Neelam; Wang, Fei; R Elezgarai, Saioa; Bravo, Susana; Vázquez-Fernández, Ester; Rosa, Isaac; Eraña, Hasier; Gil, David; Veiga, Sonia; Vidal, Enric; Erickson-Beltran, Melissa L; Guitián, Esteban; Silva, Christopher J; Nonno, Romolo; Ma, Jiyan; Castilla, Joaquín; R Requena, Jesús

2018-01-01

Very solid evidence suggests that the core of full length PrPSc is a 4-rung β-solenoid, and that individual PrPSc subunits stack to form amyloid fibers. We recently used limited proteolysis to map the β-strands and connecting loops that make up the PrPSc solenoid. Using high resolution SDS-PAGE followed by epitope analysis, and mass spectrometry, we identified positions ~116/118, 133-134, 141, 152-153, 162, 169 and 179 (murine numbering) as Proteinase K (PK) cleavage sites in PrPSc. Such sites likely define loops and/or borders of β-strands, helping us to predict the threading of the β-solenoid. We have now extended this approach to recombinant PrPSc (recPrPSc). The term recPrPSc refers to bona fide recombinant prions prepared by PMCA, exhibiting infectivity with attack rates of ~100%. Limited proteolysis of mouse and bank vole recPrPSc species yielded N-terminally truncated PK-resistant fragments similar to those seen in brain-derived PrPSc, albeit with varying relative yields. Along with these fragments, doubly N- and C-terminally truncated fragments, in particular ~89/97-152, were detected in some recPrPSc preparations; similar fragments are characteristic of atypical strains of brain-derived PrPSc. Our results suggest a shared architecture of recPrPSc and brain PrPSc prions. The observed differences, in particular the distinct yields of specific PK-resistant fragments, are likely due to differences in threading which result in the specific biochemical characteristics of recPrPSc. Furthermore, recombinant PrPSc offers exciting opportunities for structural studies unachievable with brain-derived PrPSc.

Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

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

Ma, Hai-Ying, E-mail: cmu4h-mhy@126.com; Sun, Dong-Xue; Cao, Yun-Feng

2014-05-15

Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (K{sub i}) were determined for themore » compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (K{sub i}) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7. - Highlights: • Specific inhibition of andrographolide derivatives towards UGT2B7. • Herb-drug interaction related withAndrographis paniculata. • Guidance for design of UGT2B7 specific inhibitors.« less

Cell-Specific Production and Antimicrobial Activity of Naphthoquinones in Roots of Lithospermum erythrorhizon1

PubMed Central

Brigham, Lindy A.; Michaels, Paula J.; Flores, Hector E.

1999-01-01

Pigmented naphthoquinone derivatives of shikonin are produced at specific times and in specific cells of Lithospermum erythrorhizon roots. Normal pigment development is limited to root hairs and root border cells in hairy roots grown on “noninducing” medium, whereas induction of additional pigment production by abiotic (CuSO4) or biotic (fungal elicitor) factors increases the amount of total pigment, changes the ratios of derivatives produced, and initiates production of pigment de novo in epidermal cells. When the biological activity of these compounds was tested against soil-borne bacteria and fungi, a wide range of sensitivity was recorded. Acetyl-shikonin and β-hydroxyisovaleryl-shikonin, the two most abundant derivatives in both Agrobacterium rhizogenes-transformed “hairy-root” cultures and greenhouse-grown plant roots, were the most biologically active of the seven compounds tested. Hyphae of the pathogenic fungi Rhizoctonia solani, Pythium aphanidermatum, and Nectria hematococca induced localized pigment production upon contact with the roots. Challenge by R. solani crude elicitor increased shikonin derivative production 30-fold. We have studied the regulation of this suite of related, differentially produced, differentially active compounds to understand their role(s) in plant defense at the cellular level in the rhizosphere. PMID:9952436

Human embryonic stem cell-derived NK cells acquire functional receptors and cytolytic activity.

PubMed

Woll, Petter S; Martin, Colin H; Miller, Jeffrey S; Kaufman, Dan S

2005-10-15

Human embryonic stem cells (hESCs) provide a unique resource to analyze early stages of human hematopoiesis. However, little is known about the ability to use hESCs to evaluate lymphocyte development. In the present study, we use a two-step culture method to demonstrate efficient generation of functional NK cells from hESCs. The CD56(+)CD45(+) hESC-derived lymphocytes express inhibitory and activating receptors typical of mature NK cells, including killer cell Ig-like receptors, natural cytotoxicity receptors, and CD16. Limiting dilution analysis suggests that these cells can be produced from hESC-derived hemopoietic progenitors at a clonal frequency similar to CD34(+) cells isolated from cord blood. The hESC-derived NK cells acquire the ability to lyse human tumor cells by both direct cell-mediated cytotoxicity and Ab-dependent cellular cytotoxicity. Additionally, activated hESC-derived NK cells up-regulate cytokine production. hESC-derived lymphoid progenitors provide a novel means to characterize specific cellular and molecular mechanisms that lead to development of specific human lymphocyte populations. These cells may also provide a source for innovative cellular immune therapies.

Using default methodologies to derive an acceptable daily exposure (ADE).

PubMed

Faria, Ellen C; Bercu, Joel P; Dolan, David G; Morinello, Eric J; Pecquet, Alison M; Seaman, Christopher; Sehner, Claudia; Weideman, Patricia A

2016-08-01

This manuscript discusses the different historical and more recent default approaches that have been used to derive an acceptable daily exposure (ADE). While it is preferable to derive a health-based ADE based on a complete nonclinical and clinical data package, this is not always possible. For instance, for drug candidates in early development there may be no or limited nonclinical or clinical trial data. Alternative approaches that can support decision making with less complete data packages represent a variety of methods that rely on default assumptions or data inputs where chemical-specific data on health effects are lacking. A variety of default approaches are used including those based on certain toxicity estimates, a fraction of the therapeutic dose, cleaning-based limits, the threshold of toxicological concern (TTC), and application of hazard banding tools such as occupational exposure banding (OEB). Each of these default approaches is discussed in this manuscript, including their derivation, application, strengths, and limitations. In order to ensure patient safety when faced with toxicological and clinical data-gaps, default ADE methods should be purposefully as or more protective than ADEs derived from full data packages. Reliance on the subset of default approaches (e.g., TTC or OEB) that are based on toxicological data is preferred over other methods for establishing ADEs in early development while toxicology and clinical data are still being collected. Copyright © 2016. Published by Elsevier Inc.

Identification of anti-SF3B1 autoantibody as a diagnostic marker in patients with hepatocellular carcinoma.

PubMed

Hwang, Hai-Min; Heo, Chang-Kyu; Lee, Hye Jung; Kwak, Sang-Seob; Lim, Won-Hee; Yoo, Jong-Shin; Yu, Dae-Yuel; Lim, Kook Jin; Kim, Jeong-Yoon; Cho, Eun-Wie

2018-06-28

Tumor-associated (TA) autoantibodies, which are generated by the immune system upon the recognition of abnormal TA antigens, are promising biomarkers for the early detection of tumors. In order to detect autoantibody biomarkers effectively, antibody-specific epitopes in the diagnostic test should maintain the specific conformations that are as close as possible to those presenting in the body. However, when using patients' serum as a source of TA autoantibodies the characterization of the autoantibody-specific epitope is not easy due to the limited amount of patient-derived serum. To overcome these limits, we constructed a B cell hybridoma pool derived from a hepatocellular carcinoma (HCC) model HBx-transgenic mouse and characterized autoantibodies derived from them as tumor biomarkers. Their target antigens were identified by mass spectrometry and the correlations with HCC were examined. With the assumption that TA autoantibodies generated in the tumor mouse model are induced in human cancer patients, the enzyme-linked immunosorbent assays (ELISA) based on the characteristics of mouse TA autoantibodies were developed for the detection of autoantibody biomarkers in human serum. To mimic natural antigenic structures, the specific epitopes against autoantibodies were screened from the phage display cyclic random heptapeptide library, and the streptavidin antigens fused with the specific epitopes were used as coating antigens. In this study, one of HCC-associated autoantibodies derived from HBx-transgenic mouse, XC24, was characterized. Its target antigen was identified as splicing factor 3b subunit 1 (SF3B1) and the high expression of SF3B1 was confirmed in HCC tissues. The specific peptide epitopes against XC24 were selected and, among them, XC24p11 cyclic peptide (-CDATPPRLC-) was used as an epitope of anti-SF3B1 autoantibody ELISA. With this epitope, we could effectively distinguish between serum samples from HCC patients (n = 102) and healthy subjects (n = 85) with 73.53% sensitivity and 91.76% specificity (AUC = 0.8731). Moreover, the simultaneous detection of anti-XC24p11 epitope autoantibody and AFP enhanced the efficiency of HCC diagnosis with 87.25% sensitivity and 90.59% specificity (AUC = 0.9081). ELISA using XC24p11 peptide epitope that reacts against anti-SF3B1 autoantibody can be used as a novel test to enhance the diagnostic efficiency of HCC.

Excitation anisotropy in laser-induced-fluorescence spectroscopy: Broad-line excitation case

NASA Astrophysics Data System (ADS)

Hirabayashi, A.; Nambu, Y.; Fujimoto, T.

1986-01-01

Treatment of excitation anisotropy for Laser-Induced-Fluorescence Spectroscopy (LIFS) is extended to the intense excitation case. The depolarization coefficient is derived for intense excitation limit (linearly-polarized or unpolarized light excitation), and the result is presented in tables. For the region of intermediate intensity between the weak and intense excitation limits, the master equation is solved for specific example of transitions and its result is compared with experiment.

State-of-Science Approaches to Determine Sensitive Taxa for Water Quality Criteria Derivation

EPA Science Inventory

Current Ambient Water Quality Criteria (AWQC) guidelines specify pre-defined taxa diversity requirements, which has limited chemical-specific criteria development in the U.S. to less than 100 chemicals. A priori knowledge of sensitive taxa to toxicologically similar groups of che...

[Reference Intervals of Standard Test Items in Ningen Dock Examination].

PubMed

Yamakado, Minoru

2016-03-01

Reference intervals (RIs) were derived from records of 1,499,288 individuals who underwent ningen dock examination in 188 institutes which belong to Japan Society of Ningen Dock in 2012. Targets were 27 basic laboratory tests, including the body mass index (BMI) and systolic and diastolic blood pressures (SBP, DBP). Individuals fulfilling strict criteria were chosen: SBP < 130, DBP < 85 mmHg, BMI < 25 Kg/m2, non-smoking, ethanol consumption < 20 g/day, under no medication, with no remarkable current/past illness. The latent abnormal values exclusion (LAVE) method was applied to ensure normal results. RLs were derived using a parametric method with modified Box-Cox power transformation. Among all attendees, 23% fulfilled the criteria. Application of the LAVE method further reduced the dataset by 40-50%. RIs without distinction of the sex and age were SBP, DBP, TP, TB, MCV, WBC, and Plt. Sex-specific RIs were BMI, CRE, UA, TG, HDL-C, ALT, GGT, Glu, RBC, Hb, and Ht. Age-specific RIs in either sex were Alb, AST, HbA1c, TC, LDL-C, FW-LDL-C, nonHDL-C, and ALP. An age-specific RI without distinction of the sex was eGFR. Comparison of derived RIs with clinical decision limits (CDLs) revealed that the upper limits of RIs differed from CDLs according to the sex and age. Implementation of sex- and age-related RIs derived from individuals with fully normal ningen dock results will enable the appropriate interpretation of test results in health screening, and promote the effective application of CDLs for therapeutic intervention, taking into account the sex, age, and other health attributes.

Benefits and Limitations of Protein Hydrolysates as Components of Serum-Free Media for Animal Cell Culture Applications

NASA Astrophysics Data System (ADS)

Lobo-Alfonso, Juliet; Price, Paul; Jayme, David

Increased understanding of influential factors for the cultivation of animal cells, combined with heightened regulatory concern over potential transmission of adventitious contaminants associated with serum and other animal-derived components, has elevated interest in using protein hydrolysates as serum replacements or nutrient supplements. This paper reviews the chemistry and biology of various hydrolysates derived from animal, plant and microbial sources. It provides specific examples of a beneficial selection of plant and yeast hydrolysates as ingredients of serum-free nutrient formulations for bioproduction applications of cultured mammalian and insect cells. Strategies for customizing and optimizing nutrients for specialized applications and general benefits and limitations of protein hydrolysates for biopharmaceutical production are also discussed.

Gene Expression of Tissue-Specific Molecules in Ex vivo Dermacentor variabilis (Acari: Ixodidae) During Rickettsial Exposure

PubMed Central

SUNYAKUMTHORN, PIYANATE; PETCHAMPAI, NATTHIDA; GRASPERGE, BRITTON J.; KEARNEY, MICHAEL T.; SONENSHINE, DANIEL E.; MACALUSO, KEVIN R.

2014-01-01

Ticks serve as both vectors and the reservoir hosts capable of transmitting spotted fever group Rickettsia by horizontal and vertical transmission. Persistent maintenance of Rickettsia species in tick populations is dependent on the specificity of the tick and Rickettsia relationship that limits vertical transmission of particular Rickettsia species, suggesting host-derived mechanisms of control. Tick-derived molecules are differentially expressed in a tissue-specific manner in response to rickettsial infection; however, little is known about tick response to specific rickettsial species. To test the hypothesis that tissue-specific tick-derived molecules are uniquely responsive to rickettsial infection, a bioassay to characterize the tick tissue-specific response to different rickettsial species was used. Whole organs of Dermacentor variabilis (Say) were exposed to either Rickettsia montanensis or Rickettsia amblyommii, two Rickettsia species common, or absent, in field-collected D. variabilis, respectively, for 1 and 12 h and harvested for quantitative real time-polymerase chain reaction assays of putative immune-like tick-derived factors. The results indicated that tick genes are differently expressed in a temporal and tissue-specific manner. Genes encoding glutathione S-transferase 1 (dvgst1) and Kunitz protease inhibitor (dvkpi) were highly expressed in midgut, and rickettsial exposure downregulated the expression of both genes. Two other genes encoding glutathione S-transferase 2 (dvgst2) and β-thymosin (dvβ-thy) were highly expressed in ovary, with dvβ-thy expression significantly downregulated in ovaries exposed to R. montanensis, but not R. amblyommii, at 12-h postexposure, suggesting a selective response. Deciphering the tissue-specific molecular interactions between tick and Rickettsia will enhance our understanding of the key mechanisms that mediate rickettsial infection in ticks. PMID:24180114

Simultaneous determination of dextromethorphan HBr and bromhexine HCl in tablets by first-derivative spectrophotometry.

PubMed

Tantishaiyakul, V; Poeaknapo, C; Sribun, P; Sirisuppanon, K

1998-06-01

A rapid, simple and direct assay procedure based on first-derivative spectrophotometry, using a zero-crossing and peak-to-base measurement at 234 and 324 nm, respectively, has been developed for the specific determination of dextromethorphan HBr and bromhexine HCl in tablets. Calibration graphs were linear with the correlation coefficients of 0.9999 for both analytes. The limit of detections were 0.033 and 0.103 microgram ml-1 for dextromethorphan HBr and bromhexine HCl, respectively. A HPLC method has been developed as the reference method. The results obtained by the first-derivative spectrophotometry were in good agreement with those found by the HPLC method.

21 CFR 172.755 - Stearyl monoglyceridyl citrate.

Code of Federal Regulations, 2014 CFR

2014-04-01

... controlled chemical reaction of the following: Reactant Limitations Citric acid Monoglycerides of fatty acids Prepared by the glycerolysis of edible fats and oils or derived from fatty acids conforming with § 172.860... (a) of this section, meets the following specifications: Acid number 40 to 52. Total citric acid 15...

Ladder Safety Live #12985

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

Chochoms, Michael

2017-02-23

This course presents information for working safely with portable ladders: specifically, stepladders, extensions ladders, and their derivations. Additionally, this course provides limited information on the safe use of stepstools and fixed ladders. The skills, techniques, and good practices needed for selecting, inspecting, setting up and securing, and using ladders are presented in this course.

Paper-Based MicroRNA Expression Profiling from Plasma and Circulating Tumor Cells.

PubMed

Leong, Sai Mun; Tan, Karen Mei-Ling; Chua, Hui Wen; Huang, Mo-Chao; Cheong, Wai Chye; Li, Mo-Huang; Tucker, Steven; Koay, Evelyn Siew-Chuan

2017-03-01

Molecular characterization of circulating tumor cells (CTCs) holds great promise for monitoring metastatic progression and characterizing metastatic disease. However, leukocyte and red blood cell contamination of routinely isolated CTCs makes CTC-specific molecular characterization extremely challenging. Here we report the use of a paper-based medium for efficient extraction of microRNAs (miRNAs) from limited amounts of biological samples such as rare CTCs harvested from cancer patient blood. Specifically, we devised a workflow involving the use of Flinders Technology Associates (FTA) ® Elute Card with a digital PCR-inspired "partitioning" method to extract and purify miRNAs from plasma and CTCs. We demonstrated the sensitivity of this method to detect miRNA expression from as few as 3 cancer cells spiked into human blood. Using this method, background miRNA expression was excluded from contaminating blood cells, and CTC-specific miRNA expression profiles were derived from breast and colorectal cancer patients. Plasma separated out during purification of CTCs could likewise be processed using the same paper-based method for miRNA detection, thereby maximizing the amount of patient-specific information that can be derived from a single blood draw. Overall, this paper-based extraction method enables an efficient, cost-effective workflow for maximized recovery of small RNAs from limited biological samples for downstream molecular analyses. © 2016 American Association for Clinical Chemistry.

Are context-specific measures of parental-reported physical activity and sedentary behaviour associated with accelerometer data in 2-9-year-old European children?

PubMed

Verbestel, Vera; De Henauw, Stefaan; Bammann, Karin; Barba, Gianvincenzo; Hadjigeorgiou, Charalambos; Eiben, Gabriele; Konstabel, Kenn; Kovács, Eva; Pitsiladis, Yannis; Reisch, Lucia; Santaliestra-Pasías, Alba M; Maes, Lea; De Bourdeaudhuij, Ilse

2015-04-01

The aim of the present study was to investigate if context-specific measures of parental-reported physical activity and sedentary behaviour are associated with objectively measured physical activity and sedentary time in children. Cross-sectional study. Seven European countries taking part in the IDEFICS (Identification and Prevention of Dietary- and Lifestyle-induced Health Effects in Children and Infants) study. Data were analysed from 2-9-year-old children (n 5982) who provided both parental-reported and accelerometer-derived physical activity/sedentary behaviour measures. Parents reported their children's daily screen-time, weekly sports participation and daily outdoor playtime by means of the Outdoor Playtime Checklist (OPC) and Outdoor Playtime Recall Questions (OPRQ). Sports participation, OPC- and OPRQ-derived outdoor play were positively associated with accelerometer-derived physical activity. Television viewing and computer use were positively associated with accelerometer-derived sedentary time. All parental-reported measures that were significantly associated with accelerometer outcomes explained only a minor part of the variance in accelerometer-derived physical activity or sedentary time. Parental-reported measures of physical activity and sedentary behaviour are not useful as a proxy for 2-9-year-old children's physical activity and sedentary time. Findings do not preclude the use of context-specific measures but imply that conclusions should be limited to the context-specific behaviours that are actually measured. Depending on the aim of the study, future research should carefully consider the choice of measurements, including the use of subjective or objective measures of the behaviour of interest or a combination of both.

Dose Modeling Evaluations and Technical Support Document For the Authorized Limits Request for the DOE-Owned Property Outside the Limited Area, Paducah Gaseous Diffusion Plant Paducah, Kentucky

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

Boerner, A. J.; Maldonado, D. G.; Hansen, Tom

2012-09-01

Environmental assessments and remediation activities are being conducted by the U.S. Department of Energy (DOE) at the Paducah Gaseous Diffusion Plant (PGDP), Paducah, Kentucky. The Oak Ridge Institute for Science and Education (ORISE), a DOE prime contractor, was contracted by the DOE Portsmouth/Paducah Project Office (DOE-PPPO) to conduct radiation dose modeling analyses and derive single radionuclide soil guidelines (soil guidelines) in support of the derivation of Authorized Limits (ALs) for 'DOE-Owned Property Outside the Limited Area' ('Property') at the PGDP. The ORISE evaluation specifically included the area identified by DOE restricted area postings (public use access restrictions) and areas licensedmore » by DOE to the West Kentucky Wildlife Management Area (WKWMA). The licensed areas are available without restriction to the general public for a variety of (primarily) recreational uses. Relevant receptors impacting current and reasonably anticipated future use activities were evaluated. In support of soil guideline derivation, a Conceptual Site Model (CSM) was developed. The CSM listed radiation and contamination sources, release mechanisms, transport media, representative exposure pathways from residual radioactivity, and a total of three receptors (under present and future use scenarios). Plausible receptors included a Resident Farmer, Recreational User, and Wildlife Worker. single radionuclide soil guidelines (outputs specified by the software modeling code) were generated for three receptors and thirteen targeted radionuclides. These soil guidelines were based on satisfying the project dose constraints. For comparison, soil guidelines applicable to the basic radiation public dose limit of 100 mrem/yr were generated. Single radionuclide soil guidelines from the most limiting (restrictive) receptor based on a target dose constraint of 25 mrem/yr were then rounded and identified as the derived soil guidelines. An additional evaluation using the derived soil guidelines as inputs into the code was also performed to determine the maximum (peak) dose for all receptors. This report contains the technical basis in support of the DOE?s derivation of ALs for the 'Property.' A complete description of the methodology, including an assessment of the input parameters, model inputs, and results is provided in this report. This report also provides initial recommendations on applying the derived soil guidelines.« less

PROCEDURES FOR THE DERIVATION OF EQUILIBRIUM ...

EPA Pesticide Factsheets

This equilibrium partitioning sediment benchmark (ESB) document describes procedures to derive concentrations for 32 nonionic organic chemicals in sediment which are protective of the presence of freshwater and marine benthic organisms. The equilibrium partitioning (EqP) approach was chosen because it accounts for the varying biological availability of chemicals in different sediments and allows for the incorporation of the appropriate biological effects concentration. This provides for the derivation of benchmarks that are causally linked to the specific chemical, applicable across sediments, and appropriately protective of benthic organisms. EqP can be used to calculate ESBs for any toxicity endpoint for which there are water-only toxicity data; it is not limited to any single effect endpoint. For the purposes of this document, ESBs for 32 nonionic organic chemicals, including several low molecular weight aliphatic and aromatic compounds, pesticides, and phthalates, were derived using Final Chronic Values (FCV) from Water Quality Criteria (WQC) or Secondary Chronic Values (SCV) derived from existing toxicological data using the Great Lakes Water Quality Initiative (GLI) or narcosis theory approaches. These values are intended to be the concentration of each chemical in water that is protective of the presence of aquatic life. For nonionic organic chemicals demonstrating a narcotic mode of action, ESBs derived using the GLI approach specifically for fres

Universality class of non-Fermi-liquid behavior in mixed-valence systems

NASA Astrophysics Data System (ADS)

Zhang, Guang-Ming; Su, Zhao-Bin; Yu, Lu

1996-01-01

A generalized Anderson single-impurity model with off-site Coulomb interactions is derived from the extended three-band Hubbard model, originally proposed to describe the physics of the copper oxides. Using the Abelian bosonization technique and canonical transformations, an effective Hamiltonian is derived in the strong-coupling limit, which is essentially analogous to the Toulouse limit of the ordinary Kondo problem. In this limit, the effective Hamiltonian can be exactly solved, with a mixed-valence quantum critical point separating two different Fermi-liquid phases, i.e., the Kondo phase and the empty orbital phase. In the mixed-valence quantum critical regime, the local moment is only partially quenched and x-ray edge singularities are generated. Around the quantum critical point, a type of non-Fermi-liquid behavior is predicted with an extra specific heat Cimp~T1/4 and a singular spin susceptibility χimp~T-3/4. At the same time, the effective Hamiltonian under single occupancy is transformed into a resonant-level model, from which the correct Kondo physical properties (specific heat, spin susceptibility, and an enhanced Wilson ratio) are easily rederived. Finally, a brief discussion is given to relate these theoretical results to observations in UPdxCu5-x (x=1,1.5) alloys, which show single-impurity critical behavior consistent with our predictions.

Performance of a cavity-method-based algorithm for the prize-collecting Steiner tree problem on graphs

NASA Astrophysics Data System (ADS)

Biazzo, Indaco; Braunstein, Alfredo; Zecchina, Riccardo

2012-08-01

We study the behavior of an algorithm derived from the cavity method for the prize-collecting steiner tree (PCST) problem on graphs. The algorithm is based on the zero temperature limit of the cavity equations and as such is formally simple (a fixed point equation resolved by iteration) and distributed (parallelizable). We provide a detailed comparison with state-of-the-art algorithms on a wide range of existing benchmarks, networks, and random graphs. Specifically, we consider an enhanced derivative of the Goemans-Williamson heuristics and the dhea solver, a branch and cut integer linear programming based approach. The comparison shows that the cavity algorithm outperforms the two algorithms in most large instances both in running time and quality of the solution. Finally we prove a few optimality properties of the solutions provided by our algorithm, including optimality under the two postprocessing procedures defined in the Goemans-Williamson derivative and global optimality in some limit cases.

iPSCs to the rescue in Alzheimer's research.

PubMed

Choi, Se Hoon; Tanzi, Rudolph E

2012-03-02

A crucial limitation to our understanding of Alzheimer's disease has been the inability to test hypotheses on live, patient-specific neurons. A recent study in Nature by Israel et al. (2012) reports that iPSC-derived neurons from AD patients recapitulate multiple aspects of disease pathology. Copyright © 2012 Elsevier Inc. All rights reserved.

Incoherent transport for phases that spontaneously break translations

NASA Astrophysics Data System (ADS)

Donos, Aristomenis; Gauntlett, Jerome P.; Griffin, Tom; Ziogas, Vaios

2018-04-01

We consider phases of matter at finite charge density which spontaneously break spatial translations. Without taking a hydrodynamic limit we identify a boost invariant incoherent current operator. We also derive expressions for the small frequency behaviour of the thermoelectric conductivities generalising those that have been derived in a translationally invariant context. Within holographic constructions we show that the DC conductivity for the incoherent current can be obtained from a solution to a Stokes flow for an auxiliary fluid on the black hole horizon combined with specific thermodynamic quantities associated with the equilibrium black hole solutions.

Tissue Extracellular Matrix Nanoparticle Presentation in Electrospun Nanofibers

PubMed Central

Gibson, Matt; Mao, Hai-Quan; Elisseeff, Jennifer

2014-01-01

Biomaterials derived from the decellularization of mature tissues retain biological and architectural features that profoundly influence cellular activity. However, the clinical utility of such materials remains limited as the shape and physical properties are difficult to control. In contrast, scaffolds based on synthetic polymers can be engineered to exhibit specific physical properties, yet often suffer from limited biological functionality. This study characterizes composite materials that present decellularized extracellular matrix (DECM) particles in combination with synthetic nanofibers and examines the ability of these materials to influence stem cell differentiation. Mechanical processing of decellularized tissues yielded particles with diameters ranging from 71 to 334 nm. Nanofiber scaffolds containing up to 10% DECM particles (wt/wt) derived from six different tissues were engineered and evaluated to confirm DECM particle incorporation and to measure bioactivity. Scaffolds containing bone, cartilage, and fat promoted osteogenesis at 1 and 3 weeks compared to controls. In contrast, spleen and lung DECM significantly reduced osteogenic outcomes compared to controls. These findings highlight the potential to incorporate appropriate source DECM nanoparticles within nanofiber composites to design a scaffold with bioactivity targeted to specific applications. PMID:24971329

Design of mitochondria-targeted colorimetric and ratiometric fluorescent probes for rapid detection of SO2 derivatives in living cells

NASA Astrophysics Data System (ADS)

Yang, Yutao; Zhou, Tingting; Bai, Bozan; Yin, Caixia; Xu, Wenzhi; Li, Wei

2018-05-01

Two mitochondria-targeted colorimetric and ratiometric fluorescent probes for SO2 derivatives were constructed based on the SO2 derivatives-triggered Michael addition reaction. The probes exhibit high specificity toward HSO3-/SO32- by interrupting their conjugation system resulting in a large ratiometric blue shift of 46-121 nm in their emission spectrum. The two well-resolved emission bands can ensure accurate detection of HSO3-. The detection limits were calculated to be 1.09 and 1.35 μM. Importantly, probe 1 and probe 2 were successfully used to fluorescence ratiometric imaging of endogenous HSO3- in BT-474 cells.

Human induced pluripotent stem cells and their use in drug discovery for toxicity testing.

PubMed

Scott, Clay W; Peters, Matthew F; Dragan, Yvonne P

2013-05-10

Predicting human safety risks of novel xenobiotics remains a major challenge, partly due to the limited availability of human cells to evaluate tissue-specific toxicity. Recent progress in the production of human induced pluripotent stem cells (hiPSCs) may fill this gap. hiPSCs can be continuously expanded in culture in an undifferentiated state and then differentiated to form most cell types. Thus, it is becoming technically feasible to generate large quantities of human cell types and, in combination with relatively new detection methods, to develop higher-throughput in vitro assays that quantify tissue-specific biological properties. Indeed, the first wave of large scale hiSC-differentiated cell types including patient-derived hiPSCS are now commercially available. However, significant improvements in hiPSC production and differentiation processes are required before cell-based toxicity assays that accurately reflect mature tissue phenotypes can be delivered and implemented in a cost-effective manner. In this review, we discuss the promising alignment of hiPSCs and recently emerging technologies to quantify tissue-specific functions. We emphasize liver, cardiovascular, and CNS safety risks and highlight limitations that must be overcome before routine screening for toxicity pathways in hiSC-derived cells can be established. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Ag85A-specific CD4+ T cell lines derived after boosting BCG-vaccinated cattle with Ad5-85A possess both mycobacterial growth inhibition and anti-inflammatory properties.

PubMed

Metcalfe, Hannah J; Biffar, Lucia; Steinbach, Sabine; Guzman, Efrain; Connelley, Tim; Morrison, Ivan; Vordermeier, H Martin; Villarreal-Ramos, Bernardo

2018-05-11

There is a need to improve the efficacy of the BCG vaccine against human and bovine tuberculosis. Previous data showed that boosting bacilli Calmette-Guerin (BCG)-vaccinated cattle with a recombinant attenuated human type 5 adenovirally vectored subunit vaccine (Ad5-85A) increased BCG protection and was associated with increased frequency of Ag85A-specific CD4 + T cells post-boosting. Here, the capacity of Ag85A-specific CD4 + T cell lines - derived before and after viral boosting - to interact with BCG-infected macrophages was evaluated. No difference before and after boosting was found in the capacity of these Ag85A-specific CD4 + T cell lines to restrict mycobacterial growth, but the secretion of IL-10 in vitro post-boost increased significantly. Furthermore, cell lines derived post-boost had no statistically significant difference in the secretion of pro-inflammatory cytokines (IL-1β, IL-12, IFNγ or TNFα) compared to pre-boost lines. In conclusion, the protection associated with the increased number of Ag85A-specific CD4 + T cells restricting mycobacterial growth may be associated with anti-inflammatory properties to limit immune-pathology. Copyright © 2018 Department for Environment Food and Rural Affairs. Published by Elsevier Ltd.. All rights reserved.

Application of parameter estimation to aircraft stability and control: The output-error approach

NASA Technical Reports Server (NTRS)

Maine, Richard E.; Iliff, Kenneth W.

1986-01-01

The practical application of parameter estimation methodology to the problem of estimating aircraft stability and control derivatives from flight test data is examined. The primary purpose of the document is to present a comprehensive and unified picture of the entire parameter estimation process and its integration into a flight test program. The document concentrates on the output-error method to provide a focus for detailed examination and to allow us to give specific examples of situations that have arisen. The document first derives the aircraft equations of motion in a form suitable for application to estimation of stability and control derivatives. It then discusses the issues that arise in adapting the equations to the limitations of analysis programs, using a specific program for an example. The roles and issues relating to mass distribution data, preflight predictions, maneuver design, flight scheduling, instrumentation sensors, data acquisition systems, and data processing are then addressed. Finally, the document discusses evaluation and the use of the analysis results.

Cell-type–restricted anti-cytokine therapy: TNF inhibition from one pathogenic source

PubMed Central

Efimov, Grigory A.; Kruglov, Andrei A.; Khlopchatnikova, Zoya V.; Rozov, Fedor N.; Mokhonov, Vladislav V.; Rose-John, Stefan; Scheller, Jürgen; Gordon, Siamon; Stacey, Martin; Drutskaya, Marina S.; Tillib, Sergei V.; Nedospasov, Sergei A.

2016-01-01

Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type–restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)—a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine–induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF. PMID:26936954

New glycoside derivatives of carnosine and analogs resistant to carnosinase hydrolysis: synthesis and characterization of their copper(II) complexes.

PubMed

Lanza, Valeria; Bellia, Francesco; D'Agata, Roberta; Grasso, Giuseppe; Rizzarelli, Enrico; Vecchio, Graziella

2011-02-01

Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely and abundantly distributed in muscle and nervous tissues of several animal species. Many functions have been proposed for this compound, such as antioxidant and metal ion-chelator properties. However, the main limitation on therapeutic use of carnosine on pathologies related to increased oxidative stress and/or metal ion dishomeostasis is associated with the hydrolysis by the specific dipeptidase carnosinase. Several attempts have been made to overcome this limitation. On this basis, we functionalized carnosine and its amide derivative with small sugars such as glucose and lactose. The resistance of these derivatives to the carnosinase hydrolysis was tested and compared with that of carnosine. We found that the glycoconjugation protects the dipeptide moiety from carnosinase hydrolysis, thus potentially improving the availability of carnosine. The copper(II) binding properties of all the new synthesized compounds were investigated by spectroscopic (UV-Visible and circular dichroism) and ESI-MS studies. Particularly, the new family of amide derivatives that are not significantly hydrolyzed by carnosinase is a very promising class of carnosine derivatives. The sugar moiety can act as a recognition element. These new derivatives are potentially able to act as chelating agents in the development of clinical approaches for the regulation of metal homeostasis in the field of medicinal inorganic chemistry. Copyright © 2010 Elsevier Inc. All rights reserved.

Force Limited Vibration Testing

NASA Technical Reports Server (NTRS)

Scharton, Terry; Chang, Kurng Y.

2005-01-01

This slide presentation reviews the concept and applications of Force Limited Vibration Testing. The goal of vibration testing of aerospace hardware is to identify problems that would result in flight failures. The commonly used aerospace vibration tests uses artificially high shaker forces and responses at the resonance frequencies of the test item. It has become common to limit the acceleration responses in the test to those predicted for the flight. This requires an analysis of the acceleration response, and requires placing accelerometers on the test item. With the advent of piezoelectric gages it has become possible to improve vibration testing. The basic equations have are reviewed. Force limits are analogous and complementary to the acceleration specifications used in conventional vibration testing. Just as the acceleration specification is the frequency spectrum envelope of the in-flight acceleration at the interface between the test item and flight mounting structure, the force limit is the envelope of the in-flight force at the interface . In force limited vibration tests, both the acceleration and force specifications are needed, and the force specification is generally based on and proportional to the acceleration specification. Therefore, force limiting does not compensate for errors in the development of the acceleration specification, e.g., too much conservatism or the lack thereof. These errors will carry over into the force specification. Since in-flight vibratory force data are scarce, force limits are often derived from coupled system analyses and impedance information obtained from measurements or finite element models (FEM). Fortunately, data on the interface forces between systems and components are now available from system acoustic and vibration tests of development test models and from a few flight experiments. Semi-empirical methods of predicting force limits are currently being developed on the basis of the limited flight and system test data. A simple two degree of freedom system is shown and the governing equations for basic force limiting results for this system are reviewed. The design and results of the shuttle vibration forces (SVF) experiments are reviewed. The Advanced Composition Explorer (ACE) also was used to validate force limiting. Test instrumentation and supporting equipment are reviewed including piezo-electric force transducers, signal processing and conditioning systems, test fixtures, and vibration controller systems. Several examples of force limited vibration testing are presented with some results.

Guided Cardiopoiesis Enhances Therapeutic Benefit of Bone Marrow Human Mesenchymal Stem Cells in Chronic Myocardial Infarction

PubMed Central

Behfar, Atta; Yamada, Satsuki; Crespo-Diaz, Ruben; Nesbitt, Jonathan J.; Rowe, Lois A.; Perez-Terzic, Carmen; Gaussin, Vinciane; Homsy, Christian; Bartunek, Jozef; Terzic, Andre

2010-01-01

Objective The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSC) into a cardiac progenitor phenotype, and assess therapeutic benefit in chronic myocardial infarction. Background Adult stem cells, delivered in their naïve state, demonstrate a limited benefit in patients with ischemic heart disease. Preemptive lineage pre-specification may optimize therapeutic outcome. Methods hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of TGFβ1, BMP-4, Activin-A, retinoic acid, IGF-1, FGF-2, α-thrombin and IL-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model, and followed over 1-year for functional and structural end-points. Results While the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of Nkx2.5, Tbx5, Mesp-1 and Mef2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared to unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric and gap junction content along with induction of myocardial cell cycle activity. Conclusions Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived human mesenchymal stem cells in chronic ischemic cardiomyopathy. PMID:20723802

21 CFR 528.1070 - Bc6 recombinant deoxyribonucleic acid construct.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 155-92 site in a specific hemizygous diploid line of dairy breeds of domestic goats (Capra aegagrus... of humans) in the mammary gland of goats derived from lineage progenitor 155-92. (b) Sponsor. See No. 042976 in § 510.600 of this chapter. (c) Limitations. Food or feed from GTC-155-92 goats is not permitted...

21 CFR 528.1070 - Bc6 recombinant deoxyribonucleic acid construct.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 155-92 site in a specific hemizygous diploid line of dairy breeds of domestic goats (Capra aegagrus... of humans) in the mammary gland of goats derived from lineage progenitor 155-92. (b) Sponsor. See No. 042976 in § 510.600 of this chapter. (c) Limitations. Food or feed from GTC-155-92 goats is not permitted...

Sex-specific lean body mass predictive equations are accurate in the obese paediatric population

PubMed Central

Jackson, Lanier B.; Henshaw, Melissa H.; Carter, Janet; Chowdhury, Shahryar M.

2015-01-01

Background The clinical assessment of lean body mass (LBM) is challenging in obese children. A sex-specific predictive equation for LBM derived from anthropometric data was recently validated in children. Aim The purpose of this study was to independently validate these predictive equations in the obese paediatric population. Subjects and methods Obese subjects aged 4–21 were analysed retrospectively. Predicted LBM (LBMp) was calculated using equations previously developed in children. Measured LBM (LBMm) was derived from dual-energy x-ray absorptiometry. Agreement was expressed as [(LBMm-LBMp)/LBMm] with 95% limits of agreement. Results Of 310 enrolled patients, 195 (63%) were females. The mean age was 11.8 ± 3.4 years and mean BMI Z-score was 2.3 ± 0.4. The average difference between LBMm and LBMp was −0.6% (−17.0%, 15.8%). Pearson’s correlation revealed a strong linear relationship between LBMm and LBMp (r=0.97, p<0.01). Conclusion This study validates the use of these clinically-derived sex-specific LBM predictive equations in the obese paediatric population. Future studies should use these equations to improve the ability to accurately classify LBM in obese children. PMID:26287383

Lane-changing behavior and its effect on energy dissipation using full velocity difference model

NASA Astrophysics Data System (ADS)

Wang, Jian; Ding, Jian-Xun; Shi, Qin; Kühne, Reinhart D.

2016-07-01

In real urban traffic, roadways are usually multilane with lane-specific velocity limits. Most previous researches are derived from single-lane car-following theory which in the past years has been extensively investigated and applied. In this paper, we extend the continuous single-lane car-following model (full velocity difference model) to simulate the three-lane-changing behavior on an urban roadway which consists of three lanes. To meet incentive and security requirements, a comprehensive lane-changing rule set is constructed, taking safety distance and velocity difference into consideration and setting lane-specific speed restriction for each lane. We also investigate the effect of lane-changing behavior on distribution of cars, velocity, headway, fundamental diagram of traffic and energy dissipation. Simulation results have demonstrated asymmetric lane-changing “attraction” on changeable lane-specific speed-limited roadway, which leads to dramatically increasing energy dissipation.

Electrocardiographic Criteria for Left Ventricular Hypertrophy in Asians Differs from Criteria Derived from Western Populations--Community-based Data from an Asian Population.

PubMed

Xu, Chang Fen; Tan, Eugene S J; Feng, Liang; Santhanakrishnan, Rajalakshmi; Chan, Michelle M Y; Nyunt, Shwe Zin; Ng, Tze Pin; Ling, Lieng Hsi; Richards, A Mark; Lam, Carolyn S P; Lim, Toon Wei

2015-08-01

Electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH), such as the Cornell and Sokolow-Lyon voltage criteria were derived from Western populations. However, their utility and accuracy for diagnosing echocardiographic LVH in Asian populations is unclear. The objective of this study was to assess the accuracy of ECG criteria for LVH in Asians and to determine if alternative gender-specific ECG cut-offs may improve its diagnostic accuracy. ECG and echocardiographic assessments were performed on 668 community-dwelling Asian adults (50.9% women; 57 ± 10 years) in Singapore. The accuracy of ECG voltage criteria was compared to echocardiographic LVH criteria based on the American Society of Echocardiography guidelines, and Asian ethnicity and gender-specific partition values. Echocardiographic LVH was present in 93 (13.6%) adults. Cornell criteria had low sensitivity (5.5%) and high specificity (98.9%) for diagnosing LVH. Modified gender specific cut-offs (18 mm in women, 22 mm in men) improved sensitivity (8.8% to 17.5%, 0% to 14.7%, respectively) whilst preserving specificity (98.2% to 94.2%, 100% to 95.8%). Similarly, Sokolow-Lyon criteria had poor sensitivity (7.7%) and high specificity (96.1%) for diagnosing LVH. Lowering the cut-off value from 35 mm to 31 mm improved the sensitivity in women from 3.5% to 14% while preserving specificity at 94.2%. A cut-off of 36 mm was optimal in men (sensitivity of 14.7%, specificity of 95.5%). Current ECG criteria for LVH derived in Western cohorts have limited sensitivity in Asian populations. Our data suggests that ethnicity- and gender-specific ECG criteria may be needed.

Integrity of the Plasma Magnetic Nozzle

NASA Technical Reports Server (NTRS)

Gerwin, Richard A.

2009-01-01

This report examines the physics governing certain aspects of plasma propellant flow through a magnetic nozzle, specifically the integrity of the interface between the plasma and the nozzle s magnetic field. The injection of 100s of eV plasma into a magnetic flux nozzle that converts thermal energy into directed thrust is fundamental to enabling 10 000s of seconds specific impulse and 10s of kW/kg specific power piloted interplanetary propulsion. An expression for the initial thickness of the interface is derived and found to be approx.10(exp -2) m. An algorithm is reviewed and applied to compare classical resistivity to gradient-driven microturbulent (anomalous) resistivity, in terms of the spatial rate and time integral of resistive interface broadening, which can then be related to the geometry of the nozzle. An algorithm characterizing plasma temperature, density, and velocity dependencies is derived and found to be comparable to classical resistivity at local plasma temperatures of approx. 200 eV. Macroscopic flute-mode instabilities in regions of "adverse magnetic curvature" are discussed; a growth rate formula is derived and found to be one to two e-foldings of the most unstable Rayleigh-Taylor (RT) mode. After establishing the necessity of incorporating the Hall effect into Ohm s law (allowing full Hall current to flow and concomitant plasma rotation), a critical nozzle length expression is derived in which the interface thickness is limited to about 1 ion gyroradius.

Excitation Anisotropy in Laser-Induced-Fluorescence Spectroscopy —High-Intensity, Broad-Line Excitation

NASA Astrophysics Data System (ADS)

Hirabayashi, Atsumu; Nambu, Yoshihiro; Fujimoto, Takashi

1986-10-01

The problem of excitation anisotropy in laser-induced-fluorescence spectroscopy (LIFS) was investigated for the intense excitation case under the broad-line condition. The depolarization coefficient for the fluorescence light was derived in the intense-excitation limit (linearly-polarized or unpolarized light excitation) and the results are presented in tables. In the region of intermediate intensity, between the weak and intense-excitation limits, the master equation was solved for a specific example of atomic transitions and its result is compared with experimental results.

A choline derivate-modified nanoprobe for glioma diagnosis using MRI

NASA Astrophysics Data System (ADS)

Li, Jianfeng; Huang, Shixian; Shao, Kun; Liu, Yang; An, Sai; Kuang, Yuyang; Guo, Yubo; Ma, Haojun; Wang, Xuxia; Jiang, Chen

2013-04-01

Gadolinium (Gd) chelate contrast-enhanced magnetic resonance imaging (MRI) is a preferred method of glioma detection and preoperative localisation because it offers high spatial resolution and non-invasive deep tissue penetration. Gd-based contrast agents, such as Gd-diethyltriaminepentaacetic acid (DTPA-Gd, Magnevist), are widely used clinically for tumor diagnosis. However, the Gd-based MRI approach is limited for patients with glioma who have an uncompromised blood-brain barrier (BBB). Moreover, the rapid renal clearance and non-specificity of such contrast agents further hinders their prevalence. We present a choline derivate (CD)-modified nanoprobe with BBB permeability, glioma specificity and a long blood half-life. Specific accumulation of the nanoprobe in gliomas and subsequent MRI contrast enhancement are demonstrated in vitro in U87 MG cells and in vivo in a xenograft nude model. BBB and glioma dual targeting by this nanoprobe may facilitate precise detection of gliomas with an uncompromised BBB and may offer better preoperative and intraoperative tumor localization.

Preliminary remediation goals for use at the U.S. Department of Energy Oak Ridge Operations Office

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

NONE

1995-06-01

This report presents Preliminary Remediation Goals (PRGs) for use in human health risk assessment efforts under the United States Department of Energy, Oak Ridge Operations Office Environmental Restoration (ER) Division. Chemical-specific PRGs are concentration goals for individual chemicals for specific medium and land use combinations. The PRGs are referred to as risk-based because they have been calculated using risk assessment procedures. Risk-based calculations set concentration limits using both carcinogenic or noncarcinogenic toxicity values under specific exposure pathways. The PRG is a concentration that is derived from a specified excess cancer risk level or hazard quotient. This report provides the ERmore » Division with standardized PRGs which are integral to the Remedial Investigation/Feasibility Study process. By managing the assumptions and systems used in PRG derivation, the Environmental Restoration Risk Assessment Program will be able to control the level of quality assurance associated with these risk-based guideline values.« less

Conditionally reprogrammed primary airway epithelial cells maintain morphology, lineage and disease specific functional characteristics.

PubMed

Martinovich, Kelly M; Iosifidis, Thomas; Buckley, Alysia G; Looi, Kevin; Ling, Kak-Ming; Sutanto, Erika N; Kicic-Starcevich, Elizabeth; Garratt, Luke W; Shaw, Nicole C; Montgomery, Samuel; Lannigan, Francis J; Knight, Darryl A; Kicic, Anthony; Stick, Stephen M

2017-12-21

Current limitations to primary cell expansion led us to test whether airway epithelial cells derived from healthy children and those with asthma and cystic fibrosis (CF), co-cultured with an irradiated fibroblast feeder cell in F-medium containing 10 µM ROCK inhibitor could maintain their lineage during expansion and whether this is influenced by underlying disease status. Here, we show that conditionally reprogrammed airway epithelial cells (CRAECs) can be established from both healthy and diseased phenotypes. CRAECs can be expanded, cryopreserved and maintain phenotypes over at least 5 passages. Population doublings of CRAEC cultures were significantly greater than standard cultures, but maintained their lineage characteristics. CRAECs from all phenotypes were also capable of fully differentiating at air-liquid interface (ALI) and maintained disease specific characteristics including; defective CFTR channel function cultures and the inability to repair wounds. Our findings indicate that CRAECs derived from children maintain lineage, phenotypic and importantly disease-specific functional characteristics over a specified passage range.

Effects of Active Learning Classrooms on Student Learning: A Two-Year Empirical Investigation on Student Perceptions and Academic Performance

ERIC Educational Resources Information Center

Chiu, Pit Ho Patrio; Cheng, Shuk Han

2017-01-01

Recent studies on active learning classrooms (ACLs) have demonstrated their positive influence on student learning. However, most of the research evidence is derived from a few subject-specific courses or limited student enrolment. Empirical studies on this topic involving large student populations are rare. The present work involved a large-scale…

Pure Lovelock gravity and Chern-Simons theory

NASA Astrophysics Data System (ADS)

Concha, P. K.; Durka, R.; Inostroza, C.; Merino, N.; Rodríguez, E. K.

2016-07-01

We explore the possibility of finding pure Lovelock gravity as a particular limit of a Chern-Simons action for a specific expansion of the AdS algebra in odd dimensions. We derive in detail this relation at the level of the action in five and seven dimensions. We provide a general result for higher dimensions and discuss some issues arising from the obtained dynamics.

Genetic Targeting of an Adenovirus Vector via Replacement of the Fiber Protein with the Phage T4 Fibritin

PubMed Central

Krasnykh, Victor; Belousova, Natalya; Korokhov, Nikolay; Mikheeva, Galina; Curiel, David T.

2001-01-01

The utility of adenovirus (Ad) vectors for gene therapy is restricted by their inability to selectively transduce disease-affected tissues. This limitation may be overcome by the derivation of vectors capable of interacting with receptors specifically expressed in the target tissue. Previous attempts to alter Ad tropism by genetic modification of the Ad fiber have had limited success due to structural conflicts between the fiber and the targeting ligand. Here we present a strategy to derive an Ad vector with enhanced targeting potential by a radical replacement of the fiber protein in the Ad capsid with a chimeric molecule containing a heterologous trimerization motif and a receptor-binding ligand. Our approach, which capitalized upon the overall structural similarity between the human Ad type 5 (Ad5) fiber and bacteriophage T4 fibritin proteins, has resulted in the generation of a genetically modified Ad5 incorporating chimeric fiber-fibritin proteins targeted to artificial receptor molecules. Gene transfer studies employing this novel viral vector have demonstrated its capacity to efficiently deliver a transgene payload to the target cells in a receptor-specific manner. PMID:11287567

Development and validation of liquid chromatographic and UV derivative spectrophotometric methods for the determination of famciclovir in pharmaceutical dosage forms.

PubMed

Srinubabu, Gedela; Sudharani, Batchu; Sridhar, Lade; Rao, Jvln Seshagiri

2006-06-01

A high-performance liquid chromatographic method and a UV derivative spectrophotometric method for the determination of famciclovir, a highly active antiviral agent, in tablets were developed in the present work. The various parameters, such as linearity, precision, accuracy, specificity, robustness, limit of detection and limit of quantitation were studied according to International Conference on Harmonization guidelines. HPLC was carried out by using the reversed-phase technique on an RP-18 column with a mobile phase composed of 50 mM monobasic phosphate buffer and methanol (50 : 50; v/v), adjusted to pH 3.05 with orthophosphoric acid. The mobile phase was pumped at a flow rate of 1 ml/min and detection was made at 242 nm with UV dual absorbance detector. The first derivative UV spectrophotometric method was performed at 226.5 nm. Statistical analysis was done by Student's t-test and F-test, which showed no significant difference between the results obtained by the two methods. The proposed methods are highly sensitive, precise and accurate and therefore can be used for its Intended purpose.

[Preclinical evaluation of the safety of biotechnology products: specific aspects].

PubMed

Descotes, Jacques; Ravel, Guillaume; Vial, Thierry

2003-01-01

Biotechnology-derived products represent a class of increasingly numerous drugs. One of their major characteristics is extreme diversity, which requires specific approaches for the preclinical evaluation of their safety. The selection of relevant animal species is not easy, as most of these products are human-specific. Thus, only one species will often be used, i.e. primates. As most of these products are large molecules, they can be directly immunogenic. When they are human-specific, no animal model is available to predict the risk. Many biotechnology-derived products have an expected influence on the immune system. This must be taken into account in the preclinical strategy of immunotoxicity evaluation that is now required for every new drug. As conventional toxicity testing is generally limited, safety pharmacology studies should include more than the core battery of assays required by current guidelines in order to complement missing data as much as possible. Because of these particularities, a comprehensive investigation of metabolism and pharmacokinetics is not usually needed. Some products can cross-react with cellular components not intended as therapeutic targets. It is, therefore, essential to rule out the risk of possible cross-reactions that can result in adverse effects. Finally, viral safety is a crucial component of the preclinical safety evaluation of these products. Overall, biotechnology-derived products raise specific issues because of their innovative and original characteristics, and it is difficult to address all these issues if not by using a case-by-case approach.

Site-specific standard request for Underground Storage Tanks 1219-U, 1222-U, 2082-U, and 2068-U at the Rust Garage Facility Buildings 9754-1 and 9720-15

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

Not Available

1994-08-01

This document is a site-specific standard request for underground storage tanks located at the Rust Garage Facility. These standards are justified based on conclusion derived from the exposure assessment that indicates there is no current or forseeable future human health risk associated with petroleum contaminants on the site, that current and future ecological risks would be generally limited to subsurface species and plant life with roots extending into the area, and that most of the impacted area at the site is covered by asphalt or concrete. The vertical and horizontal extent of soil and ground water contamination are limited tomore » immediate area of the Rust Garage Facility.« less

Precision Medicine in Myelodysplastic Syndromes and Leukemias: Lessons from Sequential Mutations.

PubMed

Nazha, Aziz; Sekeres, Mikkael A

2017-01-14

Precision medicine can be simply defined as the identification of personalized treatment that matches patient-specific clinical and genomic characteristics. Since the completion of the Human Genome Project in 2003, significant advances have been made in our understanding of the genetic makeup of diseases, especially cancers. The identification of somatic mutations that can drive cancer has led to the development of therapies that specifically target the abnormal proteins derived from these mutations. This has led to a paradigm shift in our treatment methodology. Although some success has been achieved in targeting some genetic abnormalities, several challenges and limitations exist when applying precision-medicine concepts in leukemia and myelodysplastic syndromes. We review the current understanding of genomics in myelodysplastic syndromes (MDS) and leukemias and the limitations of precision-medicine concepts in MDS.

The SI strain of measles virus derived from a patient with subacute sclerosing panencephalitis possesses typical genome alterations and unique amino acid changes that modulate receptor specificity and reduce membrane fusion activity.

PubMed

Seki, Fumio; Yamada, Kentaro; Nakatsu, Yuichiro; Okamura, Koji; Yanagi, Yusuke; Nakayama, Tetsuo; Komase, Katsuhiro; Takeda, Makoto

2011-11-01

Subacute sclerosing panencephalitis (SSPE) is a fatal sequela associated with measles and is caused by persistent infection of the brain with measles virus (MV). The SI strain was isolated in 1976 from a patient with SSPE and shows neurovirulence in animals. Genome nucleotide sequence analyses showed that the SI strain genome possesses typical genome alterations for SSPE-derived strains, namely, accumulated amino acid substitutions in the M protein and cytoplasmic tail truncation of the F protein. Through the establishment of an efficient reverse genetics system, a recombinant SI strain expressing a green fluorescent protein (rSI-AcGFP) was generated. The infection of various cell types with rSI-AcGFP was evaluated by fluorescence microscopy. rSI-AcGFP exhibited limited syncytium-forming activity and spread poorly in cells. Analyses using a recombinant MV possessing a chimeric genome between those of the SI strain and a wild-type MV strain indicated that the membrane-associated protein genes (M, F, and H) were responsible for the altered growth phenotype of the SI strain. Functional analyses of viral glycoproteins showed that the F protein of the SI strain exhibited reduced fusion activity because of an E300G substitution and that the H protein of the SI strain used CD46 efficiently but used the original MV receptors on immune and epithelial cells poorly because of L482F, S546G, and F555L substitutions. The data obtained in the present study provide a new platform for analyses of SSPE-derived strains as well as a clear example of an SSPE-derived strain that exhibits altered receptor specificity and limited fusion activity.

The SI Strain of Measles Virus Derived from a Patient with Subacute Sclerosing Panencephalitis Possesses Typical Genome Alterations and Unique Amino Acid Changes That Modulate Receptor Specificity and Reduce Membrane Fusion Activity ▿ ‡

PubMed Central

Seki, Fumio; Yamada, Kentaro; Nakatsu, Yuichiro; Okamura, Koji; Yanagi, Yusuke; Nakayama, Tetsuo; Komase, Katsuhiro; Takeda, Makoto

2011-01-01

Subacute sclerosing panencephalitis (SSPE) is a fatal sequela associated with measles and is caused by persistent infection of the brain with measles virus (MV). The SI strain was isolated in 1976 from a patient with SSPE and shows neurovirulence in animals. Genome nucleotide sequence analyses showed that the SI strain genome possesses typical genome alterations for SSPE-derived strains, namely, accumulated amino acid substitutions in the M protein and cytoplasmic tail truncation of the F protein. Through the establishment of an efficient reverse genetics system, a recombinant SI strain expressing a green fluorescent protein (rSI-AcGFP) was generated. The infection of various cell types with rSI-AcGFP was evaluated by fluorescence microscopy. rSI-AcGFP exhibited limited syncytium-forming activity and spread poorly in cells. Analyses using a recombinant MV possessing a chimeric genome between those of the SI strain and a wild-type MV strain indicated that the membrane-associated protein genes (M, F, and H) were responsible for the altered growth phenotype of the SI strain. Functional analyses of viral glycoproteins showed that the F protein of the SI strain exhibited reduced fusion activity because of an E300G substitution and that the H protein of the SI strain used CD46 efficiently but used the original MV receptors on immune and epithelial cells poorly because of L482F, S546G, and F555L substitutions. The data obtained in the present study provide a new platform for analyses of SSPE-derived strains as well as a clear example of an SSPE-derived strain that exhibits altered receptor specificity and limited fusion activity. PMID:21917959

EXPECT: Explicit Representations for Flexible Acquisition

NASA Technical Reports Server (NTRS)

Swartout, BIll; Gil, Yolanda

1995-01-01

To create more powerful knowledge acquisition systems, we not only need better acquisition tools, but we need to change the architecture of the knowledge based systems we create so that their structure will provide better support for acquisition. Current acquisition tools permit users to modify factual knowledge but they provide limited support for modifying problem solving knowledge. In this paper, the authors argue that this limitation (and others) stem from the use of incomplete models of problem-solving knowledge and inflexible specification of the interdependencies between problem-solving and factual knowledge. We describe the EXPECT architecture which addresses these problems by providing an explicit representation for problem-solving knowledge and intent. Using this more explicit representation, EXPECT can automatically derive the interdependencies between problem-solving and factual knowledge. By deriving these interdependencies from the structure of the knowledge-based system itself EXPECT supports more flexible and powerful knowledge acquisition.

Modeling ALS and FTD with iPSC-derived Neurons

PubMed Central

Lee, Sebum; Huang, Eric J.

2015-01-01

Recent advances in genetics and neuropathology support the idea that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTD) are two ends of a disease spectrum. Although several animal models have been developed to investigate the pathogenesis and disease progression in ALS and FTD, there are significant limitations that hamper our ability to connect these models with the neurodegenerative processes in human diseases. With the technical breakthrough in reprogramming biology, it is now possible to generate patient-specific induced pluripotent stem cells (iPSCs) and disease-relevant neuron subtypes. This review provides a comprehensive summary of studies that use iPSC-derived neurons to model ALS and FTD. We discuss the unique capabilities of iPSC-derived neurons that capture some key features of ALS and FTD, and underscore their potential roles in drug discovery. There are, however, several critical caveats that require improvements before iPSC-derived neurons can become highly effective disease models. PMID:26462653

Next-generation text-mining mediated generation of chemical response-specific gene sets for interpretation of gene expression data.

PubMed

Hettne, Kristina M; Boorsma, André; van Dartel, Dorien A M; Goeman, Jelle J; de Jong, Esther; Piersma, Aldert H; Stierum, Rob H; Kleinjans, Jos C; Kors, Jan A

2013-01-29

Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles. We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD-derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals. Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals. Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect.

Next-generation text-mining mediated generation of chemical response-specific gene sets for interpretation of gene expression data

PubMed Central

2013-01-01

Background Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles. Methods We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD-derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals. Results Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals. Conclusions Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect. PMID:23356878

Soil C dynamics under intensive oil palm plantations in poor tropical soils

NASA Astrophysics Data System (ADS)

Guillaume, Thomas; Ruegg, Johanna; Quezada, Juan Carlos; Buttler, Alexandre

2017-04-01

Oil palm cultivation mainly takes place on heavily-weathered tropical soils where nutrients are limiting factors for plant growth and microbial activity. Intensive fertilization and changes of C input by oil palms strongly affects soil C and nutrient dynamics, challenging long-term soil fertility. Oil palm plantations management offers unique opportunities to study soil C and nutrients interactions in field conditions because 1) they can be considered as long-term litter manipulation experiments since all aboveground C inputs are concentrated in frond pile areas and 2) mineral fertilizers are only applied in specific areas, i.e. weeded circle around the tree and interrows, but not in harvest paths. Here, we determined impacts of mineral fertilizer and organic matter input on soil organic carbon dynamics and microbial activity in mature oil palm plantation established on savanna grasslands. Rates of savanna-derived soil organic carbon (SOC) decomposition and oil palm-derived SOC net stabilization were determined using changes in isotopic signature of in C input following a shift from C4 (savanna) to C3 (oil palm) vegetation. Application of mineral fertilizer alone did not affect savanna-derived SOC decomposition or oil palm-derived SOC stabilization rates, but fertilization associated with higher C input lead to an increase of oil palm-derived SOC stabilization rates, with about 50% of topsoil SOC derived from oil palm after 9 years. High carbon and nutrients inputs did not increase microbial biomass but microorganisms were more active per unit of biomass and SOC. In conclusion, soil organic matter decomposition was limited by C rather than nutrients in the studied heavily-weathered soils. Fresh C and nutrient inputs did not lead to priming of old savanna-derived SOC but increased turnover and stabilization of new oil palm-derived SOC.

The transcriptomes of novel marmoset monkey embryonic stem cell lines reflect distinct genomic features

PubMed Central

Debowski, Katharina; Drummer, Charis; Lentes, Jana; Cors, Maren; Dressel, Ralf; Lingner, Thomas; Salinas-Riester, Gabriela; Fuchs, Sigrid; Sasaki, Erika; Behr, Rüdiger

2016-01-01

Embryonic stem cells (ESCs) are useful for the study of embryonic development. However, since research on naturally conceived human embryos is limited, non-human primate (NHP) embryos and NHP ESCs represent an excellent alternative to the corresponding human entities. Though, ESC lines derived from naturally conceived NHP embryos are still very rare. Here, we report the generation and characterization of four novel ESC lines derived from natural preimplantation embryos of the common marmoset monkey (Callithrix jacchus). For the first time we document derivation of NHP ESCs derived from morula stages. We show that quantitative chromosome-wise transcriptome analyses precisely reflect trisomies present in both morula-derived ESC lines. We also demonstrate that the female ESC lines exhibit different states of X-inactivation which is impressively reflected by the abundance of the lncRNA X inactive-specific transcript (XIST). The novel marmoset ESC lines will promote basic primate embryo and ESC studies as well as preclinical testing of ESC-based regenerative approaches in NHP. PMID:27385131

The transcriptomes of novel marmoset monkey embryonic stem cell lines reflect distinct genomic features.

PubMed

Debowski, Katharina; Drummer, Charis; Lentes, Jana; Cors, Maren; Dressel, Ralf; Lingner, Thomas; Salinas-Riester, Gabriela; Fuchs, Sigrid; Sasaki, Erika; Behr, Rüdiger

2016-07-07

Embryonic stem cells (ESCs) are useful for the study of embryonic development. However, since research on naturally conceived human embryos is limited, non-human primate (NHP) embryos and NHP ESCs represent an excellent alternative to the corresponding human entities. Though, ESC lines derived from naturally conceived NHP embryos are still very rare. Here, we report the generation and characterization of four novel ESC lines derived from natural preimplantation embryos of the common marmoset monkey (Callithrix jacchus). For the first time we document derivation of NHP ESCs derived from morula stages. We show that quantitative chromosome-wise transcriptome analyses precisely reflect trisomies present in both morula-derived ESC lines. We also demonstrate that the female ESC lines exhibit different states of X-inactivation which is impressively reflected by the abundance of the lncRNA X inactive-specific transcript (XIST). The novel marmoset ESC lines will promote basic primate embryo and ESC studies as well as preclinical testing of ESC-based regenerative approaches in NHP.

A multiplex degenerate PCR analytical approach targeting to eight genes for screening GMOs.

PubMed

Guo, Jinchao; Chen, Lili; Liu, Xin; Gao, Ying; Zhang, Dabing; Yang, Litao

2012-06-01

Currently, the detection methods with lower cost and higher throughput are the major trend in screening genetically modified (GM) food or feed before specific identification. In this study, we developed a quadruplex degenerate PCR screening approach for more than 90 approved GMO events. This assay is consisted of four PCR systems targeting on nine DNA sequences from eight trait genes widely introduced into GMOs, such as CP4-EPSPS derived from Acetobacterium tumefaciens sp. strain CP4, phosphinothricin acetyltransferase gene derived from Streptomyceshygroscopicus (bar) and Streptomyces viridochromogenes (pat), and Cry1Ab, Cry1Ac, Cry1A(b/c), mCry3A, and Cry3Bb1 derived from Bacillus thuringiensis. The quadruplex degenerate PCR assay offers high specificity and sensitivity with the absolute limit of detection (LOD) of approximate 80targetcopies. Furthermore, the applicability of the quadruplex PCR assay was confirmed by screening either several artificially prepared samples or samples of Grain Inspection, Packers and Stockyards Administration (GIPSA) proficiency program. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.

PubMed

Hagiwara, Kyoji; Ishii, Hideki; Murakami, Tomoyuki; Takeshima, Shin-nosuke; Chutiwitoonchai, Nopporn; Kodama, Eiichi N; Kawaji, Kumi; Kondoh, Yasumitsu; Honda, Kaori; Osada, Hiroyuki; Tsunetsugu-Yokota, Yasuko; Suzuki, Masaaki; Aida, Yoko

2015-01-01

The emergence of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus type 1 (HIV-1) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. We previously identified a potential parent compound, hematoxylin, which suppresses the nuclear import of HIV-1 via the Vpr-importin α interaction and inhibits HIV-1 replication in a Vpr-dependent manner by blocking nuclear import of the pre-integration complex. However, it was unstable. Here, we synthesized a stable derivative of hematoxylin that bound specifically and stably to Vpr and inhibited HIV-1 replication in macrophages. Furthermore, like hematoxylin, the derivative inhibited nuclear import of Vpr in an in vitro nuclear import assay, but had no effect on Vpr-induced G2/M phase cell cycle arrest or caspase activity. Interestingly, this derivative bound strongly to amino acid residues 54-74 within the C-terminal α-helical domain (αH3) of Vpr. These residues are highly conserved among different HIV strains, indicating that this region is a potential target for drug-resistant HIV-1 infection. Thus, we succeeded in developing a stable hematoxylin derivative that bound directly to Vpr, suggesting that specific inhibitors of the interaction between cells and viral accessory proteins may provide a new strategy for the treatment of HIV-1 infection.

Construction of a Phonotactic Dialect Corpus using Semiautomatic Annotation

DTIC Science & Technology

2007-01-01

phonological or phonetic feature is speaker specific or commonly found in that speaker’s dialect. Historically, the sociolinguistic study of dialect...variation in speech has been limited to small-scale population studies , usually conducted through sociolinguistic interviews [1]. Dialect analysis of... study , we created a superset of rules 943 derived from phenomena described in the sociolinguistic literature [8][9][10][11]. Rule Example ROI [r]->0

Synovium-derived stem cells: a tissue-specific stem cell for cartilage engineering and regeneration.

PubMed

Jones, Brendan A; Pei, Ming

2012-08-01

Articular cartilage is difficult to heal once injury or disease occurs. Autologous chondrocyte transplantation is a biological treatment with good prognosis, but donor site morbidity and limited cell source are disadvantages. Currently, mesenchymal stem cells (MSCs) are a promising approach for cartilage regeneration. Despite there being various sources, the best candidate for cartilage regeneration is the one with the greatest chondrogenic potential and the least hypertrophic differentiation. These properties are able to insure that the regenerated tissue is hyaline cartilage of high quality. This review article will summarize relevant literature to justify synovium-derived stem cells (SDSCs) as a tissue-specific stem cell for chondrogenesis by comparing synovium and cartilage with respect to anatomical location and functional structure, comparing the growth characterization and chondrogenic capacity of SDSCs and MSCs, evaluating the application of SDSCs in regenerative medicine and diseases, and discussing potential future directions.

Metabolic rate does not calibrate the molecular clock

PubMed Central

Lanfear, Robert; Thomas, Jessica A.; Welch, John J.; Brey, Thomas; Bromham, Lindell

2007-01-01

Rates of molecular evolution vary widely among lineages, but the causes of this variation remain poorly understood. It has been suggested that mass-specific metabolic rate may be one of the key factors determining the rate of molecular evolution, and that it can be used to derive “corrected” molecular clocks. However, previous studies have been hampered by a paucity of mass-specific metabolic rate data and have been largely limited to vertebrate taxa. Using mass-specific metabolic rate measurements and DNA sequence data for >300 metazoan species for 12 different genes, we find no evidence that mass-specific metabolic rate drives substitution rates. The mechanistic basis of the metabolic rate hypothesis is discussed in light of these findings. PMID:17881572

Magnetic-field-free thermoelectronic power conversion based on graphene and related two-dimensional materials

NASA Astrophysics Data System (ADS)

Wanke, R.; Hassink, G. W. J.; Stephanos, C.; Rastegar, I.; Braun, W.; Mannhart, J.

2016-06-01

Mobile energy converters require, in addition to high conversion efficiency and low cost, a low mass. We propose to utilize thermoelectronic converters that use 2D-materials such as graphene for their gate electrodes. Deriving the ultimate limit for their specific energy output, we show that the positive energy output is likely close to the fundamental limit for any conversion of heat into electric power. These converters may be valuable as electric power sources of spacecraft, and with the addition of vacuum enclosures, for power generation in electric planes and cars.

Non-Fermi Liquid Behavior in the Single-Impurity Mixed Valence Problem

NASA Astrophysics Data System (ADS)

Zhang, Guang-Ming; Su, Zhao-Bin; Yu, Lu

An effective Hamiltonian of the Anderson single-impurity model with finite-range Coulomb interactions is derived near a particular limit, which is analogous to the Toulouse limit of the ordinary Kondo problem, and the physical properties around the mixed valence quantum critical point are calculated. At this quantum critical point, the local moment is only partially quenched and X-ray edge singularities are exhibited. Around this point, a new type of non-Fermi liquid behavior is predicted with an extra specific heat Cimp ~ T1/4 + AT ln T and spin-susceptibility χimp ~T-3/4 + B ln T.

Thermodynamic limits of energy harvesting from outgoing thermal radiation.

PubMed

Buddhiraju, Siddharth; Santhanam, Parthiban; Fan, Shanhui

2018-04-17

We derive the thermodynamic limits of harvesting power from the outgoing thermal radiation from the ambient to the cold outer space. The derivations are based on a duality relation between thermal engines that harvest solar radiation and those that harvest outgoing thermal radiation. In particular, we derive the ultimate limit for harvesting outgoing thermal radiation, which is analogous to the Landsberg limit for solar energy harvesting, and show that the ultimate limit far exceeds what was previously thought to be possible. As an extension of our work, we also derive the ultimate limit of efficiency of thermophotovoltaic systems.

Food Composition Database Format and Structure: A User Focused Approach

PubMed Central

Clancy, Annabel K.; Woods, Kaitlyn; McMahon, Anne; Probst, Yasmine

2015-01-01

This study aimed to investigate the needs of Australian food composition database user’s regarding database format and relate this to the format of databases available globally. Three semi structured synchronous online focus groups (M = 3, F = 11) and n = 6 female key informant interviews were recorded. Beliefs surrounding the use, training, understanding, benefits and limitations of food composition data and databases were explored. Verbatim transcriptions underwent preliminary coding followed by thematic analysis with NVivo qualitative analysis software to extract the final themes. Schematic analysis was applied to the final themes related to database format. Desktop analysis also examined the format of six key globally available databases. 24 dominant themes were established, of which five related to format; database use, food classification, framework, accessibility and availability, and data derivation. Desktop analysis revealed that food classification systems varied considerably between databases. Microsoft Excel was a common file format used in all databases, and available software varied between countries. User’s also recognised that food composition databases format should ideally be designed specifically for the intended use, have a user-friendly food classification system, incorporate accurate data with clear explanation of data derivation and feature user input. However, such databases are limited by data availability and resources. Further exploration of data sharing options should be considered. Furthermore, user’s understanding of food composition data and databases limitations is inherent to the correct application of non-specific databases. Therefore, further exploration of user FCDB training should also be considered. PMID:26554836

A Multistep Maturity Model for the Implementation of Electronic and Computable Diagnostic Clinical Prediction Rules (eCPRs).

PubMed

Corrigan, Derek; McDonnell, Ronan; Zarabzadeh, Atieh; Fahey, Tom

2015-01-01

The use of Clinical Prediction Rules (CPRs) has been advocated as one way of implementing actionable evidence-based rules in clinical practice. The current highly manual nature of deriving CPRs makes them difficult to use and maintain. Addressing the known limitations of CPRs requires implementing more flexible and dynamic models of CPR development. We describe the application of Information and Communication Technology (ICT) to provide a platform for the derivation and dissemination of CPRs derived through analysis and continual learning from electronic patient data. We propose a multistep maturity model for constructing electronic and computable CPRs (eCPRs). The model has six levels - from the lowest level of CPR maturity (literaturebased CPRs) to a fully electronic and computable service-oriented model of CPRs that are sensitive to specific demographic patient populations. We describe examples of implementations of the core model components - focusing on CPR representation, interoperability, electronic dissemination, CPR learning, and user interface requirements. The traditional focus on derivation and narrow validation of CPRs has severely limited their wider acceptance. The evolution and maturity model described here outlines a progression toward eCPRs consistent with the vision of a learning health system (LHS) - using central repositories of CPR knowledge, accessible open standards, and generalizable models to avoid repetition of previous work. This is useful for developing more ambitious strategies to address limitations of the traditional CPR development life cycle. The model described here is a starting point for promoting discussion about what a more dynamic CPR development process should look like.

Ice shelf snow accumulation rates from the Amundsen-Bellingshausen Sea sector of West Antarctica derived from airborne radar

NASA Astrophysics Data System (ADS)

Medley, B.; Kurtz, N. T.; Brunt, K. M.

2015-12-01

The large ice shelves surrounding the Antarctic continent buttress inland ice, limiting the grounded ice-sheet flow. Many, but not all, of the thick ice shelves located along the Amundsen-Bellingshausen Seas are experiencing rapid thinning due to enhanced basal melting driven by the intrusion of warm circumpolar deep water. Determination of their mass balance provides an indicator as to the future of the shelves buttressing capability; however, measurements of surface accumulation are few, limiting the precision of the mass balance estimates. Here, we present new radar-derived measurements of snow accumulation primarily over the Getz and Abbott Ice Shelves, as well as the Dotson and Crosson, which have been the focus of several of NASA's Operation IceBridge airborne surveys between 2009 and 2014. Specifically, we use the Center for Remote Sensing of Ice Sheets (CReSIS) snow radar to map the near-surface (< 30 m) internal stratigraphy to measure snow accumulation. Due to the complexities of the local topography (e.g., ice rises and rumples) and their relative proximity to the ocean, the spatial pattern of accumulation can be equally varied. Therefore, atmospheric models might not be able to reproduce these small-scale features because of their limited spatial resolution. To evaluate whether this is the case over these narrow shelves, we will compare the radar-derived accumulation rates with those from atmospheric models.

Derivation of safe health-based exposure limits for potential consumer exposure to styrene migrating into food from food containers.

PubMed

Gelbke, Heinz-Peter; Banton, Marcy; Faes, Eric; Leibold, Edgar; Pemberton, Mark; Duhayon, Sophie

2014-02-01

Residual styrene present in polystyrene food packaging may migrate into food at low levels. To assure safe use, safe exposure levels are derived for consumers potentially exposed via food using No/Low Adverse Effect Levels from animal and human studies and assessment factors proposed by European organisations (EFSA, ECHA, ECETOC). Ototoxicity and developmental toxicity in rats and human ototoxicity and effects on colour discrimination have been identified as the most relevant toxicological properties for styrene health assessments. Safe exposure levels derived from animal studies with assessment factors of EFSA and ECHA were expectedly much lower than those using the ECETOC approach. Comparable safe exposure levels were obtained from human data with all sets of assessment factors while ototoxicity in rats led to major differences. The safe exposure levels finally selected based on criteria of science and health protection converged to the range of 90-120 mg/person/d. Assuming a consumption of 1 kg food/d for an adult, this translates to 90 mg styrene migration into 1 kg food as safe for consumers. This assessment supports a health based Specific Migration Limit of 90 ppm, a value somewhat higher than the current overall migration limit of 60 ppm in the European Union. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes

PubMed Central

Bizy, Alexandra; Guerrero-Serna, Guadalupe; Hu, Bin; Ponce-Balbuena, Daniela; Willis, B. Cicero; Zarzoso, Manuel; Ramirez, Rafael J.; Sener, Michelle F.; Mundada, Lakshmi V.; Klos, Matthew; Devaney, Eric J.; Vikstrom, Karen L.; Herron, Todd J.; Jalife, José

2014-01-01

Applications of human induced pluripotent stemcell derived-cardiac myocytes (hiPSC-CMs) would be strengthened by the ability to generate specific cardiac myocyte (CM) lineages. However, purification of lineage-specific hiPSC-CMs is limited by the lack of cell marking techniques. Here, we have developed an iPSC-CM marking system using recombinant adenoviral reporter constructs with atrial- or ventricular-specific myosin light chain-2 (MLC-2) promoters. MLC-2a and MLC-2v selected hiPSC-CMs were purified by fluorescence-activated cell sorting and their biochemical and electrophysiological phenotypes analyzed. We demonstrate that the phenotype of both populations remained stable in culture and they expressed the expected sarcomeric proteins, gap junction proteins and chamber-specific transcription factors. Compared to MLC-2a cells, MLC-2v selected CMs had larger action potential amplitudes and durations. In addition, by immunofluorescence, we showed that MLC-2 isoform expression can be used to enrich hiPSC-CM consistent with early atrial and ventricularmyocyte lineages. However, only the ventricular myosin light chain-2 promoter was able to purify a highly homogeneous population of iPSC-CMs. Using this approach, it is now possible to develop ventricular-specific disease models using iPSC-CMs while atrial-specific iPSC-CM cultures may require additional chamber-specific markers. PMID:24095945

Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes.

PubMed

Bizy, Alexandra; Guerrero-Serna, Guadalupe; Hu, Bin; Ponce-Balbuena, Daniela; Willis, B Cicero; Zarzoso, Manuel; Ramirez, Rafael J; Sener, Michelle F; Mundada, Lakshmi V; Klos, Matthew; Devaney, Eric J; Vikstrom, Karen L; Herron, Todd J; Jalife, José

2013-11-01

Applications of human induced pluripotent stem cell derived-cardiac myocytes (hiPSC-CMs) would be strengthened by the ability to generate specific cardiac myocyte (CM) lineages. However, purification of lineage-specific hiPSC-CMs is limited by the lack of cell marking techniques. Here, we have developed an iPSC-CM marking system using recombinant adenoviral reporter constructs with atrial- or ventricular-specific myosin light chain-2 (MLC-2) promoters. MLC-2a and MLC-2v selected hiPSC-CMs were purified by fluorescence-activated cell sorting and their biochemical and electrophysiological phenotypes analyzed. We demonstrate that the phenotype of both populations remained stable in culture and they expressed the expected sarcomeric proteins, gap junction proteins and chamber-specific transcription factors. Compared to MLC-2a cells, MLC-2v selected CMs had larger action potential amplitudes and durations. In addition, by immunofluorescence, we showed that MLC-2 isoform expression can be used to enrich hiPSC-CM consistent with early atrial and ventricular myocyte lineages. However, only the ventricular myosin light chain-2 promoter was able to purify a highly homogeneous population of iPSC-CMs. Using this approach, it is now possible to develop ventricular-specific disease models using iPSC-CMs while atrial-specific iPSC-CM cultures may require additional chamber-specific markers. © 2013.

Deriving low-risk gambling limits from longitudinal data collected in two independent Canadian studies.

PubMed

Currie, Shawn R; Hodgins, David C; Casey, David M; El-Guebaly, Nady; Smith, Garry J; Williams, Robert J; Schopflocher, Don P

2017-11-01

To derive low-risk gambling limits using the method developed by Currie et al. (2006) applied to longitudinal data. Secondary analysis of data from the Quinte Longitudinal Study (n = 3054) and Leisure, Lifestyle and Lifecycle Project (n = 809), two independently conducted cohort studies of the natural progression of gambling in Canadian adults. Community-dwelling adults in Southeastern Ontario and Alberta, Canada. A total of 3863 adults (50% male; median age = 44) who reported gambling in the past year. Gambling behaviours (typical monthly frequency, total expenditure and percentage of income spent on gambling) and harm (experiencing two or more consequences of gambling in the past 12 months) were assessed with the Canadian Problem Gambling Index. The dose-response relationship was comparable in both studies for frequency of gambling (days per month), total expenditure and percentage of household income spent on gambling (area under the curve values ranged from 0.66 to 0.74). Based on the optimal sensitivity and specificity values, the low-risk gambling cut-offs were eight times per month, $75CAN total per month and 1.7% of income spent on gambling. Gamblers who exceeded any of these limits at time 1 were approximately four times more likely to report harm at time 2 [95% confidence interval (CI) = 2.9-6.6]. Longitudinal data in Canada suggest low-risk gambling thresholds of eight times per month, $75CAN total per month and 1.7% of income spent on gambling, all of which are higher than previously derived limits from cross-sectional data. Gamblers who exceed any of the three low-risk limits are four times more likely to experience future harm than those who do not. © 2017 Society for the Study of Addiction.

Application of the "threshold of toxicological concern" to derive tolerable concentrations of "non-relevant metabolites" formed from plant protection products in ground and drinking water.

PubMed

Melching-Kollmuss, Stephanie; Dekant, Wolfgang; Kalberlah, Fritz

2010-03-01

Limits for tolerable concentrations of ground water metabolites ("non-relevant metabolites" without targeted toxicities and specific classification and labeling) derived from active ingredients (AI) of plant protection products (PPPs) are discussed in the European Union. Risk assessments for "non-relevant metabolites" need to be performed when concentrations are above 0.75 microg/L. Since oral uptake is the only relevant exposure pathway for "non-relevant metabolites", risk assessment approaches as used for other chemicals with predominantly oral exposure in humans are applicable. The concept of "thresholds of toxicological concern" (TTC) defines tolerable dietary intakes for chemicals without toxicity data and is widely applied to chemicals present in food in low concentrations such as flavorings. Based on a statistical evaluation of the results of many toxicity studies and considerations of chemical structures, the TTC concept derives a maximum daily oral intake without concern of 90 microg/person/day for non-genotoxic chemicals, even for those with appreciable toxicity. When using the typical exposure assessment for drinking water contaminants (consumption of 2L of drinking water/person/day, allocation of 10% of the tolerable daily intake to drinking water), a TTC-based upper concentration limit of 4.5 microg/L for "non-relevant metabolites" in ground/drinking water is delineated. In the present publication it has been evaluated, whether this value would cover all relevant toxicities (repeated dose, reproductive and developmental, and immune effects). Taking into account, that after evaluation of specific reproduction toxicity data from chemicals and pharmaceuticals, a value of 1 microg/kgbw/day has been assessed as to cover developmental and reproduction toxicity, a TTC value of 60 microg/person/day was assessed as to represent a safe value. Based on these reasonable worst case assumptions, a TTC-derived threshold of 3 microg/L in drinking water is derived. When a non-relevant metabolite is present in concentration below 3 microg/L, animal testing for toxicity is not considered necessary for a compound-specific risk assessment since the application of the TTC covers all relevant toxicities to be considered in such assessment and any health risk resulting from these exposures is very low. (c) 2009 Elsevier Inc. All rights reserved.

Fate-mapping the mammalian hindbrain: segmental origins of vestibular projection neurons assessed using rhombomere-specific Hoxa2 enhancer elements in the mouse embryo.

PubMed

Pasqualetti, Massimo; Díaz, Carmen; Renaud, Jean-Sébastien; Rijli, Filippo M; Glover, Joel C

2007-09-05

As a step toward generating a fate map of identified neuron populations in the mammalian hindbrain, we assessed the contributions of individual rhombomeres to the vestibular nuclear complex, a major sensorimotor area that spans the entire rhombencephalon. Transgenic mice harboring either the lacZ or the enhanced green fluorescent protein reporter genes under the transcriptional control of rhombomere-specific Hoxa2 enhancer elements were used to visualize rhombomere-derived domains. We labeled functionally identifiable vestibular projection neuron groups retrogradely with conjugated dextran-amines at successive embryonic stages and obtained developmental fate maps through direct comparison with the rhombomere-derived domains in the same embryos. The fate maps show that each vestibular neuron group derives from a unique rostrocaudal domain that is relatively stable developmentally, suggesting that anteroposterior migration is not a major contributor to the rostrocaudal patterning of the vestibular system. Most of the groups are multisegmental in origin, and each rhombomere is fated to give rise to two or more vestibular projection neuron types, in a complex pattern that is not segmentally iterated. Comparison with studies in the chicken embryo shows that the rostrocaudal patterning of identified vestibular projection neuron groups is generally well conserved between avians and mammalians but that significant species-specific differences exist in the rostrocaudal limits of particular groups. This mammalian hindbrain fate map can be used as the basis for targeting genetic manipulation to specific subpopulations of vestibular projection neurons.

Evaluation of exposure-response relationships for health effects of microbial bioaerosols - A systematic review.

PubMed

Walser, Sandra M; Gerstner, Doris G; Brenner, Bernhard; Bünger, Jürgen; Eikmann, Thomas; Janssen, Barbara; Kolb, Stefanie; Kolk, Annette; Nowak, Dennis; Raulf, Monika; Sagunski, Helmut; Sedlmaier, Nadja; Suchenwirth, Roland; Wiesmüller, Gerhard; Wollin, Klaus-Michael; Tesseraux, Irene; Herr, Caroline E W

2015-10-01

Studies suggest adverse health effects following exposure to bioaerosols in the environment and in particular at workplaces. However, there is still a lack of health-related exposure limits based on toxicological or epidemiological studies from environmental health or from the working environment. The aim of this study was to derive health-based exposure limits for bioaerosols that can protect the general population as group "at risk" via environmental exposure using analysis of peer-reviewed studies related to occupational medicine, indoor air and environmental health. The derivation of exposure limits should be conducted by the members of a bioaerosol expert panel according to established toxicological criteria. A systematic review was performed in Medline (PubMed) including studies containing both data on exposure measurements and observed health outcomes. In addition, literature recommended by the experts was considered. A comprehensive search strategy was generated and resulted in a total of n=1569 studies in combination with the literature recommendations. Subsequently, abstracts were screened using defined exclusion criteria yielding a final number of n=44 studies. A standardized extraction sheet was used to combine data on health effects and exposure to different bioaerosols. After full-text screening and extraction according to the defined exclusion criteria n=20 studies were selected all related to occupational exposures comprising the working areas wood processing, farming, waste processing and others. These studies were analyzed in collaboration with the bioaerosol expert network in terms of suitability for derivation of health-related exposure limits. The bioaerosol expert network concluded that none of the analyzed studies provided suitable dose-response relationships for derivation of exposure limits. The main reasons were: (1) lack of studies with valid dose-response data; (2) diversity of employed measuring methods for microorganisms and bioaerosol-emitting facilities; (3) heterogeneity of health effects; (4) insufficient exposure assessment. However, several indicator parameters and exposure concentrations could be identified for different bioaerosol-emitting facilities. Nevertheless, health-related exposure limits are urgently needed especially in approval procedures of facilities like composting plants or livestock farms emitting bioaerosols in the neighbourhood of residents. In the regulatory toxicology framework, it is common to use animal experimental studies for derivation of general exposure limits if appropriate environmental epidemiological studies on harmful substances are lacking. This might be another possibility to obtain health-related exposure limits for specific bioaerosol parameters. Furthermore, we recommend to use suitable measurable outcome parameters related to bioaerosols; to measure bioaerosols according to a protocol representative for exposure pattern and duration at the particular work place; to develop standardized detection methods for indicator parameters; to combine different detection methods to compensate for the limitations of each method; to apply new analysis methods to identify the real risk potential. Copyright © 2015 Elsevier GmbH. All rights reserved.

Stem Cell-Derived Exosome in Cardiovascular Diseases: Macro Roles of Micro Particles.

PubMed

Yuan, Ye; Du, Weijie; Liu, Jiaqi; Ma, Wenya; Zhang, Lai; Du, Zhimin; Cai, Benzhi

2018-01-01

The stem cell-based therapy has emerged as the promising therapeutic strategies for cardiovascular diseases (CVDs). Recently, increasing evidence suggest stem cell-derived active exosomes are important communicators among cells in the heart via delivering specific substances to the adjacent/distant target cells. These exosomes and their contents such as certain proteins, miRNAs and lncRNAs exhibit huge beneficial effects on preventing heart damage and promoting cardiac repair. More importantly, stem cell-derived exosomes are more effective and safer than stem cell transplantation. Therefore, administration of stem cell-derived exosomes will expectantly be an alternative stem cell-based therapy for the treatment of CVDs. Furthermore, modification of stem cell-derived exosomes or artificial synthesis of exosomes will be the new therapeutic tools for CVDs in the future. In addition, stem cell-derived exosomes also have been implicated in the diagnosis and prognosis of CVDs. In this review, we summarize the current advances of stem cell-derived exosome-based treatment and prognosis for CVDs, including their potential benefits, underlying mechanisms and limitations, which will provide novel insights of exosomes as a new tool in clinical therapeutic translation in the future.

A Functional High-Throughput Assay of Myelination in Vitro

DTIC Science & Technology

2014-07-01

iPS cells derived from human astrocytes. These cell lines will serve as an excellent source of human cells from which our model systems may be...image the 3D rat dorsal root ganglion ( DRG ) cultures with sufficiently low background as to detect electrically-evoked depolarization events, as...stimulation and recording system specifically for this purpose. Further, we found that the limitations inherent in optimizing speed and FOV may

Identification of Novel Avian Influenza Virus Derived CD8+ T-Cell Epitopes

PubMed Central

Reemers, Sylvia S. N.; van Haarlem, Daphne A.; Sijts, Alice J. A. M.; Vervelde, Lonneke; Jansen, Christine A.

2012-01-01

Avian influenza virus (AIV) infection is a continuing threat to both humans and poultry. Influenza virus specific CD8+ T cells are associated with protection against homologous and heterologous influenza strains. In contrast to what has been described for humans and mice, knowledge on epitope-specific CD8+ T cells in chickens is limited. Therefore, we set out to identify AIV-specific CD8+ T-cell epitopes. Epitope predictions based on anchor residues resulted in 33 candidate epitopes. MHC I inbred chickens were infected with a low pathogenic AIV strain and sacrificed at 5, 7, 10 and 14 days post infection (dpi). Lymphocytes isolated from lung, spleen and blood were stimulated ex vivo with AIV-specific pooled or individual peptides and the production of IFNγ was determined by ELIspot. This resulted in the identification of 12 MHC B12-restricted, 3 B4-restricted and 1 B19-restricted AIV- specific CD8+ T-cell epitopes. In conclusion, we have identified novel AIV-derived CD8+ T-cell epitopes for several inbred chicken strains. This knowledge can be used to study the role of CD8+ T cells against AIV infection in a natural host for influenza, and may be important for vaccine development. PMID:22384112

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

PubMed Central

Kuempel, Eileen D.; Sweeney, Lisa M.; Morris, John B.; Jarabek, Annie M.

2015-01-01

The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates. PMID:26551218

Understanding Chemistry-Specific Fuel Differences at a Constant RON in a Boosted SI Engine

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

Szybist, James P.; Splitter, Derek A.

The goal of the US Department of Energy Co-Optimization of Fuels and Engines (Co-Optima) initiative is to accelerate the development of advanced fuels and engines for higher efficiency and lower emissions. A guiding principle of this initiative is the central fuel properties hypothesis (CFPH), which states that fuel properties provide an indication of a fuel’s performance, regardless of its chemical composition. This is an important consideration for Co-Optima because many of the fuels under consideration are from bio-derived sources with chemical compositions that are unconventional relative to petroleum-derived gasoline or ethanol. In this study, we investigated a total of sevenmore » fuels in a spark ignition engine under boosted operating conditions to determine whether knock propensity is predicted by fuel antiknock metrics: antiknock index (AKI), research octane number (RON), and octane index (OI). Six of these fuels have a constant RON value but otherwise represent a wide range of fuel properties and chemistry. Consistent with previous studies, we found that OI was a much better predictor of knock propensity that either AKI or RON. However, we also found that there were significant fuel-specific deviations from the OI predictions. Combustion analysis provided insight that fuel kinetic complexities, including the presence of pre-spark heat release, likely limits the ability of standardized tests and metrics to accurately predict knocking tendency at all operating conditions. While limitations of OI were revealed in this study, we found that fuels with unconventional chemistry, in particular esters and ethers, behaved in accordance with CFPH as well as petroleum-derived fuels.« less

Understanding Chemistry-Specific Fuel Differences at a Constant RON in a Boosted SI Engine

DOE PAGES

Szybist, James P.; Splitter, Derek A.

2018-01-02

The goal of the US Department of Energy Co-Optimization of Fuels and Engines (Co-Optima) initiative is to accelerate the development of advanced fuels and engines for higher efficiency and lower emissions. A guiding principle of this initiative is the central fuel properties hypothesis (CFPH), which states that fuel properties provide an indication of a fuel’s performance, regardless of its chemical composition. This is an important consideration for Co-Optima because many of the fuels under consideration are from bio-derived sources with chemical compositions that are unconventional relative to petroleum-derived gasoline or ethanol. In this study, we investigated a total of sevenmore » fuels in a spark ignition engine under boosted operating conditions to determine whether knock propensity is predicted by fuel antiknock metrics: antiknock index (AKI), research octane number (RON), and octane index (OI). Six of these fuels have a constant RON value but otherwise represent a wide range of fuel properties and chemistry. Consistent with previous studies, we found that OI was a much better predictor of knock propensity that either AKI or RON. However, we also found that there were significant fuel-specific deviations from the OI predictions. Combustion analysis provided insight that fuel kinetic complexities, including the presence of pre-spark heat release, likely limits the ability of standardized tests and metrics to accurately predict knocking tendency at all operating conditions. While limitations of OI were revealed in this study, we found that fuels with unconventional chemistry, in particular esters and ethers, behaved in accordance with CFPH as well as petroleum-derived fuels.« less

Finding Horndeski theories with Einstein gravity limits

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

McManus, Ryan; Lombriser, Lucas; Peñarrubia, Jorge, E-mail: ryanm@roe.ac.uk, E-mail: llo@roe.ac.uk, E-mail: jorpega@roe.ac.uk

The Horndeski action is the most general scalar-tensor theory with at most second-order derivatives in the equations of motion, thus evading Ostrogradsky instabilities and making it of interest when modifying gravity at large scales. To pass local tests of gravity, these modifications predominantly rely on nonlinear screening mechanisms that recover Einstein's Theory of General Relativity in regions of high density. We derive a set of conditions on the four free functions of the Horndeski action that examine whether a specific model embedded in the action possesses an Einstein gravity limit or not. For this purpose, we develop a new andmore » surprisingly simple scaling method that identifies dominant terms in the equations of motion by considering formal limits of the couplings that enter through the new terms in the modified action. This enables us to find regimes where nonlinear terms dominate and Einstein's field equations are recovered to leading order. Together with an efficient approximation of the scalar field profile, one can then further evaluate whether these limits can be attributed to a genuine screening effect. For illustration, we apply the analysis to both a cubic galileon and a chameleon model as well as to Brans-Dicke theory. Finally, we emphasise that the scaling method also provides a natural approach for performing post-Newtonian expansions in screened regimes.« less

Diagnostic accuracy of urinary creatinine concentration in the estimation of differential renal function in patients with obstructive uropathy.

PubMed

Al-Hunayan, A; Al-Ateeqi, A; Kehinde, E O; Thalib, L; Loutfi, I; Mojiminiyi, O A

2008-01-01

To determine the diagnostic accuracy of spot urine creatinine concentration (UCC) as a new test for the evaluation of differential renal function in obstructed kidneys (DRF(ok)) drained by percutaneous nephrostomy tube (PCNT). In patients with obstructed kidneys drained by PCNT, DRF(ok) was derived from UCC by comparing the value of UCC in the obstructed kidney to the value in the contralateral kidney, and was derived from dimercaptosuccinic acid (DMSA) renal scans and creatinine clearance (CCr) using standard methods. Subsequently, the results of UCC were compared to the results of DMSA and CCr. 61 patients were enrolled. Bland-Altman plots to compare DMSA and UCC showed that the upper limit of agreement was 14.8% (95% CI 10.7-18.5) and the lower limit was -19.9% (95% CI -23.8 to -16.1). The sensitivity and specificity of detecting DMSA DRF(ok) < or = 35% using UCC was 85.2 and 91.2%, respectively. When UCC was compared to CCr, Bland-Altman tests gave an upper limit of agreement of 10.4% (95% CI 7.9-12.8) and a lower limit of agreement of -11.3% (95% CI -13.8 to -8.9). UCC is accurate in the estimation of DRF(ok) drained by PCNT. 2008 S. Karger AG, Basel

Planar spatial correlations, anisotropy, and specific surface area of stationary random porous media

NASA Astrophysics Data System (ADS)

Berryman, James G.

1998-02-01

An earlier result of the author showed that an anisotropic spatial correlation function of a random porous medium could be used to compute the specific surface area when it is stationary as well as anisotropic by first performing a three-dimensional radial average and then taking the first derivative with respect to lag at the origin. This result generalized the earlier result for isotropic porous media of Debye et al. [J. Appl. Phys. 28, 679 (1957)]. The present article provides more detailed information about the use of spatial correlation functions for anisotropic porous media and in particular shows that, for stationary anisotropic media, the specific surface area can be related to the derivative of the two-dimensional radial average of the correlation function measured from cross sections taken through the anisotropic medium. The main concept is first illustrated using a simple pedagogical example for an anisotropic distribution of spherical voids. Then, a general derivation of formulas relating the derivative of the planar correlation functions to surface integrals is presented. When the surface normal is uniformly distributed (as is the case for any distribution of spherical voids), our formulas can be used to relate a specific surface area to easily measurable quantities from any single cross section. When the surface normal is not distributed uniformly (as would be the case for an oriented distribution of ellipsoidal voids), our results show how to obtain valid estimates of specific surface area by averaging measurements on three orthogonal cross sections. One important general observation for porous media is that the surface area from nearly flat cracks may be underestimated from measurements on orthogonal cross sections if any of the cross sections happen to lie in the plane of the cracks. This result is illustrated by taking the very small aspect ratio (penny-shaped crack) limit of an oblate spheroid, but holds for other types of flat surfaces as well.

Planar spatial correlations, anisotropy, and specific surface area of stationary random porous media

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

Berryman, J.G.

1998-02-01

An earlier result of the author showed that an anisotropic spatial correlation function of a random porous medium could be used to compute the specific surface area when it is stationary as well as anisotropic by first performing a three-dimensional radial average and then taking the first derivative with respect to lag at the origin. This result generalized the earlier result for isotropic porous media of Debye {ital et al.} [J. Appl. Phys. {bold 28}, 679 (1957)]. The present article provides more detailed information about the use of spatial correlation functions for anisotropic porous media and in particular shows that,more » for stationary anisotropic media, the specific surface area can be related to the derivative of the two-dimensional radial average of the correlation function measured from cross sections taken through the anisotropic medium. The main concept is first illustrated using a simple pedagogical example for an anisotropic distribution of spherical voids. Then, a general derivation of formulas relating the derivative of the planar correlation functions to surface integrals is presented. When the surface normal is uniformly distributed (as is the case for any distribution of spherical voids), our formulas can be used to relate a specific surface area to easily measurable quantities from any single cross section. When the surface normal is not distributed uniformly (as would be the case for an oriented distribution of ellipsoidal voids), our results show how to obtain valid estimates of specific surface area by averaging measurements on three orthogonal cross sections. One important general observation for porous media is that the surface area from nearly flat cracks may be underestimated from measurements on orthogonal cross sections if any of the cross sections happen to lie in the plane of the cracks. This result is illustrated by taking the very small aspect ratio (penny-shaped crack) limit of an oblate spheroid, but holds for other types of flat surfaces as well.« less

Conditionally reprogrammed cells (CRC) methodology does not allow the in vitro expansion of patient-derived primary and metastatic lung cancer cells.

PubMed

Sette, Giovanni; Salvati, Valentina; Giordani, Ilenia; Pilozzi, Emanuela; Quacquarini, Denise; Duranti, Enrico; De Nicola, Francesca; Pallocca, Matteo; Fanciulli, Maurizio; Falchi, Mario; Pallini, Roberto; De Maria, Ruggero; Eramo, Adriana

2018-07-01

Availability of tumor and non-tumor patient-derived models would promote the development of more effective therapeutics for non-small cell lung cancer (NSCLC). Recently, conditionally reprogrammed cells (CRC) methodology demonstrated exceptional potential for the expansion of epithelial cells from patient tissues. However, the possibility to expand patient-derived lung cancer cells using CRC protocols is controversial. Here, we used CRC approach to expand cells from non-tumoral and tumor biopsies of patients with primary or metastatic NSCLC as well as pulmonary metastases of colorectal or breast cancers. CRC cultures were obtained from both tumor and non-malignant tissues with extraordinary high efficiency. Tumor cells were tracked in vitro through tumorigenicity assay, monitoring of tumor-specific genetic alterations and marker expression. Cultures were composed of EpCAM+ lung epithelial cells lacking tumorigenic potential. NSCLC biopsies-derived cultures rapidly lost patient-specific genetic mutations or tumor antigens. Similarly, pulmonary metastases of colon or breast cancer generated CRC cultures of lung epithelial cells. All CRC cultures examined displayed epithelial lung stem cell phenotype and function. In contrast, brain metastatic lung cancer biopsies failed to generate CRC cultures. In conclusion, patient-derived primary and metastatic lung cancer cells were negatively selected under CRC conditions, limiting the expansion to non-malignant lung epithelial stem cells from either tumor or non-tumor tissue sources. Thus, CRC approach cannot be applied for direct therapeutic testing of patient lung tumor cells, as the tumor-derived CRC cultures are composed of (non-tumoral) airway basal cells. © 2018 UICC.

A novel patient-derived xenograft model for claudin-low triple-negative breast cancer.

PubMed

Matossian, Margarite D; Burks, Hope E; Bowles, Annie C; Elliott, Steven; Hoang, Van T; Sabol, Rachel A; Pashos, Nicholas C; O'Donnell, Benjamen; Miller, Kristin S; Wahba, Bahia M; Bunnell, Bruce A; Moroz, Krzysztof; Zea, Arnold H; Jones, Steven D; Ochoa, Augusto C; Al-Khami, Amir A; Hossain, Fokhrul; Riker, Adam I; Rhodes, Lyndsay V; Martin, Elizabeth C; Miele, Lucio; Burow, Matthew E; Collins-Burow, Bridgette M

2018-06-01

Triple-negative breast cancer (TNBC) subtypes are clinically aggressive and cannot be treated with targeted therapeutics commonly used in other breast cancer subtypes. The claudin-low (CL) molecular subtype of TNBC has high rates of metastases, chemoresistance and recurrence. There exists an urgent need to identify novel therapeutic targets in TNBC; however, existing models utilized in target discovery research are limited. Patient-derived xenograft (PDX) models have emerged as superior models for target discovery experiments because they recapitulate features of patient tumors that are limited by cell-line derived xenograft methods. We utilize immunohistochemistry, qRT-PCR and Western Blot to visualize tumor architecture, cellular composition, genomic and protein expressions of a new CL-TNBC PDX model (TU-BcX-2O0). We utilize tissue decellularization techniques to examine extracellular matrix composition of TU-BcX-2O0. Our laboratory successfully established a TNBC PDX tumor, TU-BCX-2O0, which represents a CL-TNBC subtype and maintains this phenotype throughout subsequent passaging. We dissected TU-BCx-2O0 to examine aspects of this complex tumor that can be targeted by developing therapeutics, including the whole and intact breast tumor, specific cell populations within the tumor, and the extracellular matrix. Here, we characterize a claudin-low TNBC patient-derived xenograft model that can be utilized for therapeutic research studies.

Induced pluripotent stem cells: challenges and opportunities for cancer immunotherapy.

PubMed

Sachamitr, Patty; Hackett, Simon; Fairchild, Paul Jonathan

2014-01-01

Despite recent advances in cancer treatment over the past 30 years, therapeutic options remain limited and do not always offer a cure for malignancy. Given that tumor-associated antigens (TAA) are, by definition, self-proteins, the need to productively engage autoreactive T cells remains at the heart of strategies for cancer immunotherapy. These have traditionally focused on the administration of autologous monocyte-derived dendritic cells (moDC) pulsed with TAA, or the ex vivo expansion and adoptive transfer of tumor-infiltrating lymphocytes (TIL) as a source of TAA-specific cytotoxic T cells (CTL). Although such approaches have shown some efficacy, success has been limited by the poor capacity of moDC to cross present exogenous TAA to the CD8(+) T-cell repertoire and the potential for exhaustion of CTL expanded ex vivo. Recent advances in induced pluripotency offer opportunities to generate patient-specific stem cell lines with the potential to differentiate in vitro into cell types whose properties may help address these issues. Here, we review recent success in the differentiation of NK cells from human induced pluripotent stem (iPS) cells as well as minor subsets of dendritic cells (DCs) with therapeutic potential, including CD141(+)XCR1(+) DC, capable of cross presenting TAA to naïve CD8(+) T cells. Furthermore, we review recent progress in the use of TIL as the starting material for the derivation of iPSC lines, thereby capturing their antigen specificity in a self-renewing stem cell line, from which potentially unlimited numbers of naïve TAA-specific T cells may be differentiated, free of the risks of exhaustion.

Complete Mie-Gruneisen Equation of State (update)

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

Menikoff, Ralph

2016-03-14

The Mie-Gruneisen equation of state (EOS) is frequently used in hydro simulations to model solids at high pressure (up to a few Mb). It is an incomplete EOS characterized by a Gr¨uneisen coefficient, = -V (@eP)V , that is a function of only V . Expressions are derived for isentropes and isotherms. This enables the extension to a complete EOS. Thermodynamic consistency requires that the specific heat is a function of a single scaled-temperature. A complete extension is uniquely determined by the temperature dependence of the specific heat at a fixed reference density. In addition we show that if themore » domain of the EOS extends to T = 0 and the specific heat vanishes on the zero isotherm then a function of only V is equivalent to a specific heat with a single temperature scale. If the EOS domain does not include the zero isotherm, then a specific heat with a single temperature scale leads to a generalization of the Mie-Gr¨uneisen EOS in which the pressure is linear in both the specific energy and the temperature. This corresponds to the limiting case of two temperature scales with one of the scales in the high temperature limit. Such an EOS has previously been used to model liquid nitromethane.« less

Analysis of amino acids by HPLC/electrospray negative ion tandem mass spectrometry using 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) derivatization.

PubMed

Ziegler, Jörg; Abel, Steffen

2014-12-01

A new method for the determination of amino acids is presented. It combines established methods for the derivatization of primary and secondary amino groups with 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) with the subsequent amino acid specific detection of the derivatives by LC-ESI-MS/MS using multiple reaction monitoring (MRM). The derivatization proceeds within 5 min, and the resulting amino acid derivatives can be rapidly purified from matrix by solid-phase extraction (SPE) on HR-X resin and separated by reversed-phase HPLC. The Fmoc derivatives yield several amino acid specific fragment ions which opened the possibility to select amino acid specific MRM transitions. The method was applied to all 20 proteinogenic amino acids, and the quantification was performed using L-norvaline as standard. A limit of detection as low as 1 fmol/µl with a linear range of up to 125 pmol/µl could be obtained. Intraday and interday precisions were lower than 10 % relative standard deviations for most of the amino acids. Quantification using L-norvaline as internal standard gave very similar results compared to the quantification using deuterated amino acid as internal standards. Using this protocol, it was possible to record the amino acid profiles of only a single root from Arabidopsis thaliana seedlings and to compare it with the amino acid profiles of 20 dissected root meristems (200 μm).

On the distribution of saliency.

PubMed

Berengolts, Alexander; Lindenbaum, Michael

2006-12-01

Detecting salient structures is a basic task in perceptual organization. Saliency algorithms typically mark edge-points with some saliency measure, which grows with the length and smoothness of the curve on which these edge-points lie. Here, we propose a modified saliency estimation mechanism that is based on probabilistically specified grouping cues and on curve length distributions. In this framework, the Shashua and Ullman saliency mechanism may be interpreted as a process for detecting the curve with maximal expected length. Generalized types of saliency naturally follow. We propose several specific generalizations (e.g., gray-level-based saliency) and rigorously derive the limitations on generalized saliency types. We then carry out a probabilistic analysis of expected length saliencies. Using ergodicity and asymptotic analysis, we derive the saliency distributions associated with the main curves and with the rest of the image. We then extend this analysis to finite-length curves. Using the derived distributions, we derive the optimal threshold on the saliency for discriminating between figure and background and bound the saliency-based figure-from-ground performance.

Black hole thermodynamics under the microscope

NASA Astrophysics Data System (ADS)

Falls, Kevin; Litim, Daniel F.

2014-04-01

A coarse-grained version of the effective action is used to study the thermodynamics of black holes, interpolating from largest to smallest masses. The physical parameters of the black hole are linked to the running couplings by thermodynamics, and the corresponding equation of state includes quantum corrections for temperature, specific heat, and entropy. If quantum gravity becomes asymptotically safe, the state function predicts conformal scaling in the limit of small horizon area and bounds on black hole mass and temperature. A metric-based derivation for the equation of state and quantum corrections to the thermodynamical, statistical, and phenomenological definition of entropy are also given. Further implications and limitations of our study are discussed.

An Iron 13S-Lipoxygenase with an α-Linolenic Acid Specific Hydroperoxidase Activity from Fusarium oxysporum

PubMed Central

Brodhun, Florian; Cristobal-Sarramian, Alvaro; Zabel, Sebastian; Newie, Julia; Hamberg, Mats; Feussner, Ivo

2013-01-01

Jasmonates constitute a family of lipid-derived signaling molecules that are abundant in higher plants. The biosynthetic pathway leading to plant jasmonates is initiated by 13-lipoxygenase-catalyzed oxygenation of α-linolenic acid into its 13-hydroperoxide derivative. A number of plant pathogenic fungi (e.g. Fusarium oxysporum) are also capable of producing jasmonates, however, by a yet unknown biosynthetic pathway. In a search for lipoxygenase in F. oxysporum, a reverse genetic approach was used and one of two from the genome predicted lipoxygenases (FoxLOX) was cloned. The enzyme was heterologously expressed in E. coli, purified via affinity chromatography, and its reaction mechanism characterized. FoxLOX was found to be a non-heme iron lipoxygenase, which oxidizes C18-polyunsaturated fatty acids to 13S-hydroperoxy derivatives by an antarafacial reaction mechanism where the bis-allylic hydrogen abstraction is the rate-limiting step. With α-linolenic acid as substrate FoxLOX was found to exhibit a multifunctional activity, because the hydroperoxy derivatives formed are further converted to dihydroxy-, keto-, and epoxy alcohol derivatives. PMID:23741422

Precursor ion scan driven fast untargeted screening and semi-determination of caffeoylquinic acid derivatives in Cynara scolymus L.

PubMed

Shen, Qing; Lu, Yanbin; Dai, Zhiyuan; Cheung, Hon-Yeung

2015-01-01

A precursor ion scan (PIS) technique based strategy was developed for rapid screening and semi-determination of caffeoylquinic acid derivatives (CADs) in artichoke (Cynara scolymus L.) using ultra-performance liquid chromatography (UPLC) coupled with tandem mass spectrometry. 1,5-Dicaffeoylquinic acid and 5-caffeoylquinic acid were used for studying the fragmentation behaviour of two classes of CADs, setting m/z 191 as a diagnostic moiety. When it was applied to artichoke sample, ten CADs were detected and elucidated in a single PIS run. Furthermore, method validation was implemented including: specificity (no interference), linearity (≥0.9993), limit of detection (LOD<0.12 ng mL(-1)) and limit of quantification (LOQ<0.25 ng mL(-1)), precision (RSD≤3.6), recovery (91.4-95.9%) and stability (at least 12 h). This approach was proven to be a powerful, selective and sensitive tool for rapid screening and semi-determination of untargeted components in natural products. Copyright © 2014 Elsevier Ltd. All rights reserved.

An event-specific method for the detection and quantification of ML01, a genetically modified Saccharomyces cerevisiae wine strain, using quantitative PCR.

PubMed

Vaudano, Enrico; Costantini, Antonella; Garcia-Moruno, Emilia

2016-10-03

The availability of genetically modified (GM) yeasts for winemaking and, in particular, transgenic strains based on the integration of genetic constructs deriving from other organisms into the genome of Saccharomyces cerevisiae, has been a reality for several years. Despite this, their use is only authorized in a few countries and limited to two strains: ML01, able to convert malic acid into lactic acid during alcoholic fermentation, and ECMo01 suitable for reducing the risk of carbamate production. In this work we propose a quali-quantitative culture-independent method for the detection of GM yeast ML01 in commercial preparations of ADY (Active Dry Yeast) consisting of efficient extraction of DNA and qPCR (quantitative PCR) analysis based on event-specific assay targeting MLC (malolactic cassette), and a taxon-specific S. cerevisiae assay detecting the MRP2 gene. The ADY DNA extraction methodology has been shown to provide good purity DNA suitable for subsequent qPCR. The MLC and MRP2 qPCR assay showed characteristics of specificity, dynamic range, limit of quantification (LOQ) limit of detection (LOD), precision and trueness, which were fully compliant with international reference guidelines. The method has been shown to reliably detect 0.005% (mass/mass) of GM ML01 S. cerevisiae in commercial preparations of ADY. Copyright © 2016 Elsevier B.V. All rights reserved.

Reaction rates for a generalized reaction-diffusion master equation

DOE PAGES

Hellander, Stefan; Petzold, Linda

2016-01-19

It has been established that there is an inherent limit to the accuracy of the reaction-diffusion master equation. Specifically, there exists a fundamental lower bound on the mesh size, below which the accuracy deteriorates as the mesh is refined further. In this paper we extend the standard reaction-diffusion master equation to allow molecules occupying neighboring voxels to react, in contrast to the traditional approach in which molecules react only when occupying the same voxel. We derive reaction rates, in two dimensions as well as three dimensions, to obtain an optimal match to the more fine-grained Smoluchowski model, and show inmore » two numerical examples that the extended algorithm is accurate for a wide range of mesh sizes, allowing us to simulate systems that are intractable with the standard reaction-diffusion master equation. In addition, we show that for mesh sizes above the fundamental lower limit of the standard algorithm, the generalized algorithm reduces to the standard algorithm. We derive a lower limit for the generalized algorithm which, in both two dimensions and three dimensions, is on the order of the reaction radius of a reacting pair of molecules.« less

Reaction rates for a generalized reaction-diffusion master equation

PubMed Central

Hellander, Stefan; Petzold, Linda

2016-01-01

It has been established that there is an inherent limit to the accuracy of the reaction-diffusion master equation. Specifically, there exists a fundamental lower bound on the mesh size, below which the accuracy deteriorates as the mesh is refined further. In this paper we extend the standard reaction-diffusion master equation to allow molecules occupying neighboring voxels to react, in contrast to the traditional approach in which molecules react only when occupying the same voxel. We derive reaction rates, in two dimensions as well as three dimensions, to obtain an optimal match to the more fine-grained Smoluchowski model, and show in two numerical examples that the extended algorithm is accurate for a wide range of mesh sizes, allowing us to simulate systems that are intractable with the standard reaction-diffusion master equation. In addition, we show that for mesh sizes above the fundamental lower limit of the standard algorithm, the generalized algorithm reduces to the standard algorithm. We derive a lower limit for the generalized algorithm which, in both two dimensions and three dimensions, is on the order of the reaction radius of a reacting pair of molecules. PMID:26871190

Prefocal station mechanical design concept study for the E-ELT

NASA Astrophysics Data System (ADS)

Jolley, Paul; Brunetto, Enzo; Frank, Christoph; Lewis, Steffan; Marchetti, Enrico

2016-07-01

The Nasmyth platforms of the E-ELT will contain one Prefocal Station (PFS) each. The main PFS functional requirements are to provide a focal plane to the three Nasmyth focal stations and the Coudé focus, optical sensing supporting telescope low order optimisation and seeing limited image quality, and optical sensing supporting characterising and phasing of M1 and other telescope subsystems. The PFS user requirements are used to derive the PFS technical requirements specification that will form the basis for design, development and production of the system. This specification process includes high-level architectural decisions and technical performance budget allocations. The mechanical design concepts reported here have been developed in order to validate key system specifications and associated technical budgets.

Coronary CT Angiography-derived Fractional Flow Reserve: Machine Learning Algorithm versus Computational Fluid Dynamics Modeling.

PubMed

Tesche, Christian; De Cecco, Carlo N; Baumann, Stefan; Renker, Matthias; McLaurin, Tindal W; Duguay, Taylor M; Bayer, Richard R; Steinberg, Daniel H; Grant, Katharine L; Canstein, Christian; Schwemmer, Chris; Schoebinger, Max; Itu, Lucian M; Rapaka, Saikiran; Sharma, Puneet; Schoepf, U Joseph

2018-04-10

Purpose To compare two technical approaches for determination of coronary computed tomography (CT) angiography-derived fractional flow reserve (FFR)-FFR derived from coronary CT angiography based on computational fluid dynamics (hereafter, FFR CFD ) and FFR derived from coronary CT angiography based on machine learning algorithm (hereafter, FFR ML )-against coronary CT angiography and quantitative coronary angiography (QCA). Materials and Methods A total of 85 patients (mean age, 62 years ± 11 [standard deviation]; 62% men) who had undergone coronary CT angiography followed by invasive FFR were included in this single-center retrospective study. FFR values were derived on-site from coronary CT angiography data sets by using both FFR CFD and FFR ML . The performance of both techniques for detecting lesion-specific ischemia was compared against visual stenosis grading at coronary CT angiography, QCA, and invasive FFR as the reference standard. Results On a per-lesion and per-patient level, FFR ML showed a sensitivity of 79% and 90% and a specificity of 94% and 95%, respectively, for detecting lesion-specific ischemia. Meanwhile, FFR CFD resulted in a sensitivity of 79% and 89% and a specificity of 93% and 93%, respectively, on a per-lesion and per-patient basis (P = .86 and P = .92). On a per-lesion level, the area under the receiver operating characteristics curve (AUC) of 0.89 for FFR ML and 0.89 for FFR CFD showed significantly higher discriminatory power for detecting lesion-specific ischemia compared with that of coronary CT angiography (AUC, 0.61) and QCA (AUC, 0.69) (all P < .0001). Also, on a per-patient level, FFR ML (AUC, 0.91) and FFR CFD (AUC, 0.91) performed significantly better than did coronary CT angiography (AUC, 0.65) and QCA (AUC, 0.68) (all P < .0001). Processing time for FFR ML was significantly shorter compared with that of FFR CFD (40.5 minutes ± 6.3 vs 43.4 minutes ± 7.1; P = .042). Conclusion The FFR ML algorithm performs equally in detecting lesion-specific ischemia when compared with the FFR CFD approach. Both methods outperform accuracy of coronary CT angiography and QCA in the detection of flow-limiting stenosis. © RSNA, 2018.

Production of monoclonal antibody to acaricide dicofol and its derivatives.

PubMed

Hongsibsong, Surat; Prapamontol, Tippawan; Suphavilai, Chaisuree; Wipasa, Jiraprapa; Pattarawarapan, Mookda; Kasinrerk, Watchara

2010-12-01

In Thailand detection of acaricide dicofol residues has been sporadically performed due to the limitation of analytical techniques. Conventional analytical methods for detecting dicofol residues most often use chromatographic-based techniques. Our ultimate aim is to develop an alternative method for rapidly analyzing dicofol residues in vegetables and fruit samples. Here we report the production of monoclonal antibodies specific to dicofol and its derivatives. Hapten-protein carriers were prepared by linking succinic anhydride to dichlorobenzhydrol (DCBH), which was then conjugated to bovine serum albumin (BSA) and oval albumin (OVA). DCBH-BSA conjugate was used as immunogen while DCBH-OVA conjugate was used as capture antigen for competitive inhibition assay. Female BALB/c mice were immunized with DCBH-BSA conjugate subcutaneously, and antibody (Ab) level was determined 2 weeks after the last immunization. Spleen cells producing high titer antibody were isolated and fused with myeloma cells of P3.X6.Ag8.653. After limiting dilutions, antibody produced by one clone had high affinity, which was found to be of IgG1 with κ light chain. Specificity and inhibition concentrations of the monoclonal antibody (MAb) were determined by competitive indirect ELISA with dicofol, and its 50% (IC(50)) was 0.28 μg/mL. Working ranges of the developed immunoassay were from 0.07 to 25 μg/mL. Hence, the prepared MAb will be able to be applied for immunoassay development for detecting dicofol residue in vegetables and fruits far below the maximum residue limit such that 5 g of fruits and berries can be detected below 0.1 mg/kg.

Discovery of novel selenium derivatives as Pin1 inhibitors by high-throughput screening

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

Subedi, Amit; Graduate School of Science and Engineering, Saitama University, Saitama, 338-8570; Shimizu, Takeshi

2016-06-03

Peptidyl prolyl cis/trans isomerization by Pin1 regulates various oncogenic signals during cancer progression, and its inhibition through multiple approaches has established Pin1 as a therapeutic target. However, lack of simplified screening systems has limited the discovery of potent Pin1 inhibitors. We utilized phosphorylation-dependent binding of Pin1 to its specific substrate to develop a screening system for Pin1 inhibitors. Using this system, we screened a chemical library, and identified a novel selenium derivative as Pin1 inhibitor. Based on structure-activity guided chemical synthesis, we developed more potent Pin1 inhibitors that inhibited cancer cell proliferation. -- Highlights: •Novel screening for Pin1 inhibitors basedmore » on Pin1 binding is developed. •A novel selenium compound is discovered as Pin1 inhibitor. •Activity guided chemical synthesis of selenium derivatives resulted potent Pin1 inhibitors.« less

In Vivo Delivery of Cytoplasmic RNA Virus-derived miRNAs

PubMed Central

Langlois, Ryan A; Shapiro, Jillian S; Pham, Alissa M; tenOever, Benjamin R

2012-01-01

The discovery of microRNAs (miRNAs) revealed an unappreciated level of post-transcriptional control used by the cell to maintain optimal protein levels. This process has represented an attractive strategy for therapeutics that is currently limited by in vivo delivery constraints. Here, we describe the generation of a single-stranded, cytoplasmic virus of negative polarity capable of producing functional miRNAs. Cytoplasmic RNA virus-derived miRNAs accumulated to high levels in vitro, generated significant amounts of miRNA star strand, associated with the RNA-induced silencing complex (RISC), and conferred post transcriptional gene silencing in a sequence-specific manner. Furthermore, we demonstrate that these vectors could deliver miRNAs to a wide range of tissues, and sustain prolonged expression capable of achieving measurable knockdown of physiological targets in vivo. Taken together, these results validate noncanonical processing of cytoplasmic-derived miRNAs and provide a novel platform for small RNA delivery. PMID:22086233

Synthesis and evaluation of benzo[b]thiophene derivatives as inhibitors of alkaline phosphatases.

PubMed

Li, Lina; Chang, Lei; Pellet-Rostaing, Stéphane; Liger, François; Lemaire, Marc; Buchet, René; Wu, Yuqing

2009-10-15

Presence of basic calcium phosphate in knee joints of osteoarthritis patients could be prevented by inhibiting tissue non-specific alkaline phosphatase (TNAP) activity. Levamisole or the L stereoisomer of tetramisole (a known TNAP inhibitor) has been used as a treatment for curing rheumatoid arthritis but its therapeutical use is limited due to side effects. We report the synthesis and the TNAP inhibition property of benzo[b]thiophene derivatives, among which benzothiopheno-tetramisole and benzothiopheno-2,3-dehydrotetramisole, which could be involved in a drug therapy for osteoarthritis. Two water soluble racemic benzothiopheno-tetramisole and -2,3-dehydrotetramisole with apparent inhibition constants K(i)=85+/-6 microM and 135+/-3 microM (n=3) comparable to that of enantiomeric levamisole 93+/-4 microM were found. Several novel derivatives showed more pronounced inhibition properties towards intestinal alkaline phosphatase than TNAP.

Effects of spatial grouping on the functional response of predators

USGS Publications Warehouse

Cosner, C.; DeAngelis, D.L.; Ault, J.S.; Olson, D.B.

1999-01-01

A unified mechanistic approach is given for the derivation of various forms of functional response in predator-prey models. The derivation is based on the principle-of-mass action but with the crucial refinement that the nature of the spatial distribution of predators and/or opportunities for predation are taken into account in an implicit way. If the predators are assumed to have a homogeneous spatial distribution, then the derived functional response is prey-dependent. If the predators are assumed to form a dense colony or school in a single (possibly moving) location, or if the region where predators can encounter prey is assumed to be of limited size, then the functional response depends on both predator and prey densities in a manner that reflects feeding interference between predators. Depending on the specific assumptions, the resulting functional response may be of Beddington-DeAngelis type, of Hassell-Varley type, or ratio-dependent.

Identification of ethylene oxide in herbs, spices and other dried vegetables imported into Italy.

PubMed

Bononi, Monica; Quaglia, Giancarlo; Tateo, Fernando

2014-01-01

Gas chromatography-mass spectrometry was used to analyse ethylene oxide (EO) in 63 samples of dried vegetable materials for food use derived from import commodities and subjected to quality control for three food-transformation industries. EO residues were quantified through the determination of ethylene chlorohydrin (ECH). About 29% of the samples analysed contained more than 0.3 mg kg(-1) of EO. Thus, this specific analytical control limited to 20% of import aromatic matters needs to be increased. This paper demonstrates the importance of this specific control considering the banned use of microbial decontamination EO treatment in the European Union.

Attention and driving in traumatic brain injury: a question of coping with time-pressure.

PubMed

Brouwer, Wiebo H; Withaar, Frederiec K; Tant, Mark L M; van Zomeren, Adriaan H

2002-02-01

Diffuse and focal traumatic brain injury (TBI) can result in perceptual, cognitive, and motor dysfunction possibly leading to activity limitations in driving. Characteristic dysfunctions for severe diffuse TBI are confronted with function requirements derived from the hierarchical task analysis of driving skill. Specifically, we focus on slow information processing, divided attention, and the development of procedural knowledge. Also the effects of a combination of diffuse and focal dysfunctions, specifically homonymous hemianopia and the dysexecutive syndrome, are discussed. Finally, we turn to problems and challenges with regard to assessment and rehabilitation methods in the areas of driving and fitness to drive.

Psychosocial Pain Management Moderation: The Limit, Activate, and Enhance Model.

PubMed

Day, Melissa A; Ehde, Dawn M; Jensen, Mark P

2015-10-01

There is a growing emphasis in the pain literature on understanding the following second-order research questions: Why do psychosocial pain treatments work? For whom do various treatments work? This critical review summarizes research that addresses the latter question and proposes a moderation model to help guide future research. A theoretical moderation framework for matching individuals to specific psychosocial pain interventions has been lacking. However, several such frameworks have been proposed in the broad psychotherapy and implementation science literature. Drawing on these theories and adapting them specifically for psychosocial pain treatment, here we propose a Limit, Activate, and Enhance model of pain treatment moderation. This model is unique in that it includes algorithms not only for matching treatments on the basis of patient weaknesses but also for directing patients to interventions that build on their strengths. Critically, this model provides a basis for specific a priori hypothesis generation, and a selection of the possible hypotheses drawn from the model are proposed and discussed. Future research considerations are presented that could refine and expand the model based on theoretically driven empirical evidence. The Limit, Activate, and Enhance model presented here is a theoretically derived framework that provides an a priori basis for hypothesis generation regarding psychosocial pain treatment moderators. The model will advance moderation research via its unique focus on matching patients to specific treatments that (1) limit maladaptive responses, (2) activate adaptive responses, and (3) enhance treatment outcomes based on patient strengths and resources. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Objective sea level pressure analysis for sparse data areas

NASA Technical Reports Server (NTRS)

Druyan, L. M.

1972-01-01

A computer procedure was used to analyze the pressure distribution over the North Pacific Ocean for eleven synoptic times in February, 1967. Independent knowledge of the central pressures of lows is shown to reduce the analysis errors for very sparse data coverage. The application of planned remote sensing of sea-level wind speeds is shown to make a significant contribution to the quality of the analysis especially in the high gradient mid-latitudes and for sparse coverage of conventional observations (such as over Southern Hemisphere oceans). Uniform distribution of the available observations of sea-level pressure and wind velocity yields results far superior to those derived from a random distribution. A generalization of the results indicates that the average lower limit for analysis errors is between 2 and 2.5 mb based on the perfect specification of the magnitude of the sea-level pressure gradient from a known verification analysis. A less than perfect specification will derive from wind-pressure relationships applied to satellite observed wind speeds.

Comparative study of P19 EC stem cell differentiation in between conventional hanging drop and the zebrafish chorion as a bio-derived material.

PubMed

Dae Seok Na; Lee, Hwang; Sun Uk Kim; Chang Nam Hwang; Sang Ho Lee; Ji Yoon Kang; Jai Kyeong Kim; James Jungho Pak

2008-07-01

Various materials including glass and polymers have been widely used for stem cell culture due to their biocompatibility. However, the roles of these materials are fundamentally limited because they cannot realize or imitate the complex biological functions of living tissues, except in very simple cases. Here, the development of a bio-derived material suitable for stem cell culture and improvement of differentiation efficiency to specific cell lineages with no stimulating agents by using a chorion obtained from a fertilized zebrafish egg through the removal of the yolk and embryonic cell mass from the egg is reported. Mouse P19 EC stem cells introduced into the empty chorion form a uniform embryoid body (EB) without addition of any inducing agent. It is demonstrated that the zebrafish chorion with nanopores improves efficiencies greatly in the EB formation, cell proliferation, and lineage-specific differentiations compared to those of the conventional hanging drop culture method.

Deriving persistence indicators from regulatory water-sediment studies – opportunities and limitations in OECD 308 data.

PubMed

Honti, Mark; Fenner, Kathrin

2015-05-19

The OECD guideline 308 describes a laboratory test method to assess aerobic and anaerobic transformation of organic chemicals in aquatic sediment systems and is an integral part of tiered testing strategies in different legislative frameworks for the environmental risk assessment of chemicals. The results from experiments carried out according to OECD 308 are generally used to derive persistence indicators for hazard assessment or half-lives for exposure assessment. We used Bayesian parameter estimation and system representations of various complexities to systematically assess opportunities and limitations for estimating these indicators from existing data generated according to OECD 308 for 23 pesticides and pharmaceuticals. We found that there is a disparity between the uncertainty and the conceptual robustness of persistence indicators. Disappearance half-lives are directly extractable with limited uncertainty, but they lump degradation and phase transfer information and are not robust against changes in system geometry. Transformation half-lives are less system-specific but require inverse modeling to extract, resulting in considerable uncertainty. Available data were thus insufficient to derive indicators that had both acceptable robustness and uncertainty, which further supports previously voiced concerns about the usability and efficiency of these costly experiments. Despite the limitations of existing data, we suggest the time until 50% of the parent compound has been transformed in the entire system (DegT(50,system)) could still be a useful indicator of persistence in the upper, partially aerobic sediment layer in the context of PBT assessment. This should, however, be accompanied by a mandatory reporting or full standardization of the geometry of the experimental system. We recommend transformation half-lives determined by inverse modeling to be used as input parameters into fate models for exposure assessment, if due consideration is given to their uncertainty.

Evaluation of the toxicity data for peracetic acid in deriving occupational exposure limits: a minireview.

PubMed

Pechacek, Nathan; Osorio, Magdalena; Caudill, Jeff; Peterson, Bridget

2015-02-17

Peracetic acid (PAA) is a peroxide-based chemistry that is highly reactive and can produce strong local effects upon direct contact with the eyes, skin and respiratory tract. Given its increasing prominence in industry, attention has focused on health hazards and associated risks for PAA in the workplace. Occupational exposure limits (OEL) are one means to mitigate risks associated with chemical hazards in the workplace. A mini-review of the toxicity data for PAA was conducted in order to determine if the data were sufficient to derive health-based OELs. The available data for PAA frequently come from unpublished studies that lack sufficient study details, suffer from gaps in available information and often follow unconventional testing methodology. Despite these limitations, animal and human data suggest sensory irritation as the most sensitive endpoint associated with inhalation of PAA. Rodent RD50 data (the concentration estimated to cause a 50% depression in respiratory rate) were selected as the critical studies in deriving OELs. Based on these data, a range of 0.36-0.51mg/m(3) (0.1-0.2ppm) was calculated for a time-weighted average (TWA), and 1.2-1.7mg/m(3) (0.4-0.5ppm) as a range for a short-term exposure limit (STEL). These ranges compare favorably to other published OELs for PAA. Considering the applicable health hazards for this chemistry, a joint TWA/STEL OEL approach for PAA is deemed the most appropriate in assessing workplace exposures to PAA, and the selection of specific values within these proposed ranges represents a risk management decision. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Overexpression of Polysialylated Neural Cell Adhesion Molecule Improves the Migration Capacity of Induced Pluripotent Stem Cell-Derived Oligodendrocyte Precursors

PubMed Central

Czepiel, Marcin; Leicher, Lasse; Becker, Katja; Boddeke, Erik

2014-01-01

Cell replacement therapy aiming at the compensation of lost oligodendrocytes and restoration of myelination in acquired or congenital demyelination disorders has gained considerable interest since the discovery of induced pluripotent stem cells (iPSCs). Patient-derived iPSCs provide an inexhaustible source for transplantable autologous oligodendrocyte precursors (OPCs). The first transplantation studies in animal models for demyelination with iPSC-derived OPCs demonstrated their survival and remyelinating capacity, but also revealed their limited migration capacity. In the present study, we induced overexpression of the polysialylating enzyme sialyltransferase X (STX) in iPSC-derived OPCs to stimulate the production of polysialic acid-neuronal cell adhesion molecules (PSA-NCAMs), known to promote and facilitate the migration of OPCs. The STX-overexpressing iPSC-derived OPCs showed a normal differentiation and maturation pattern and were able to downregulate PSA-NCAMs when they became myelin-forming oligodendrocytes. After implantation in the demyelinated corpus callosum of cuprizone-fed mice, STX-expressing iPSC-derived OPCs demonstrated a significant increase in migration along the axons. Our findings suggest that the reach and efficacy of iPSC-derived OPC transplantation can be improved by stimulating the OPC migration potential via specific gene modulation. PMID:25069776

Applicability of the chymopapain gene used as endogenous reference gene for transgenic huanong no. 1 papaya detection.

PubMed

Guo, Jinchao; Yang, Litao; Liu, Xin; Zhang, Haibo; Qian, Bingjun; Zhang, Dabing

2009-08-12

The virus-resistant papaya (Carica papaya L.), Huanong no. 1, was the genetically modified (GM) fruit approved for growing in China in 2006. To implement the labeling regulation of GM papaya and its derivates, the development of papaya endogenous reference gene is very necessary for GM papaya detection. Herein, we reported one papaya specific gene, Chymopapain (CHY), as one suitable endogenous reference gene, used for GM papaya identification. Thereafter, we established the conventional and real-time quantitative PCR assays of the CHY gene. In the CHY conventional PCR assay, the limit of detection (LOD) was 25 copies of haploid papaya genome. In the CHY real-time quantitative PCR assay, both the LOD and the limit of quantification (LOQ) were as low as 12.5 copies of haploid papaya genome. Furthermore, we revealed the construct-specific sequence of Chinese GM papaya Huanong no. 1 and developed its conventional and quantitative PCR systems employing the CHY gene as endogenous reference gene. This work is useful for papaya specific identification and GM papaya detection.

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion.

PubMed

Kolter, Julia; Feuerstein, Reinhild; Spoeri, Evelyne; Gharun, Kourosh; Elling, Roland; Trieu-Cuot, Patrick; Goldmann, Tobias; Waskow, Claudia; Chen, Zhijian J; Kirschning, Carsten J; Deshmukh, Sachin D; Henneke, Philipp

2016-03-15

Streptococci are common human colonizers with a species-specific mucocutaneous distribution. At the same time, they are among the most important and most virulent invasive bacterial pathogens. Thus, site-specific cellular innate immunity, which is predominantly executed by resident and invading myeloid cells, has to be adapted with respect to streptococcal sensing, handling, and response. In this article, we show that TLR13 is the critical mouse macrophage (MΦ) receptor in the response to group B Streptococcus, both in bone marrow-derived MΦs and in mature tissue MΦs, such as those residing in the lamina propria of the colon and the dermis, as well as in microglia. In contrast, TLR13 and its chaperone UNC-93B are dispensable for a potent cytokine response of blood monocytes to group B Streptococcus, although monocytes serve as the key progenitors of intestinal and dermal MΦs. Furthermore, a specific role for TLR13 with respect to MΦ function is supported by the response to staphylococci, where TLR13 and UNC-93B limit the cytokine response in bone marrow-derived MΦs and microglia, but not in dermal MΦs. In summary, TLR13 is a critical and site-specific receptor in the single MΦ response to β-hemolytic streptococci. Copyright © 2016 by The American Association of Immunologists, Inc.

Stability of large DC power systems using switching converters, with application to the international space station

NASA Technical Reports Server (NTRS)

Manners, B.; Gholdston, E. W.; Karimi, K.; Lee, F. C.; Rajagopalan, J.; Panov, Y.

1996-01-01

As space direct current (dc) power systems continue to grow in size, switching power converters are playing an ever larger role in power conditioning and control. When designing a large dc system using power converters of this type, special attention must be placed on the electrical stability of the system and of the individual loads on the system. In the design of the electric power system (EPS) of the International Space Station (ISS), the National Aeronautics and Space Administration (NASA) and its contractor team led by Boeing Defense & Space Group has placed a great deal of emphasis on designing for system and load stability. To achieve this goal, the team has expended considerable effort deriving a dear concept on defining system stability in both a general sense and specifically with respect to the space station. The ISS power system presents numerous challenges with respect to system stability, such as high power, complex sources and undefined loads. To complicate these issues, source and load components have been designed in parallel by three major subcontractors (Boeing, Rocketdyne, and McDonnell Douglas) with interfaces to both sources and loads being designed in different countries (Russia, Japan, Canada, Europe, etc.). These issues, coupled with the program goal of limiting costs, have proven a significant challenge to the program. As a result, the program has derived an impedance specification approach for system stability. This approach is based on the significant relationship between source and load impedances and the effect of this relationship on system stability. This approach is limited in its applicability by the theoretical and practical limits on component designs as presented by each system segment. As a result, the overall approach to system stability implemented by the ISS program consists of specific hardware requirements coupled with extensive system analysis and hardware testing. Following this approach, the ISS program plans to begin construction of the world's largest orbiting power system in 1997.

Current and Emerging Technologies for the Analysis of the Genome-Wide and Locus-Specific DNA Methylation Patterns.

PubMed

Tost, Jörg

2016-01-01

DNA methylation is the most studied epigenetic modification, and altered DNA methylation patterns have been identified in cancer and more recently also in many other complex diseases. Furthermore, DNA methylation is influenced by a variety of environmental factors, and the analysis of DNA methylation patterns might allow deciphering previous exposure. Although a large number of techniques to study DNA methylation either genome-wide or at specific loci have been devised, they all are based on a limited number of principles for differentiating the methylation state, viz., methylation-specific/methylation-dependent restriction enzymes, antibodies or methyl-binding proteins, chemical-based enrichment, or bisulfite conversion. Second-generation sequencing has largely replaced microarrays as readout platform and is also becoming more popular for locus-specific DNA methylation analysis. In this chapter, the currently used methods for both genome-wide and locus-specific analysis of 5-methylcytosine and as its oxidative derivatives, such as 5-hydroxymethylcytosine, are reviewed in detail, and the advantages and limitations of each approach are discussed. Furthermore, emerging technologies avoiding PCR amplification and allowing a direct readout of DNA methylation are summarized, together with novel applications, such as the detection of DNA methylation in single cells or in circulating cell-free DNA.

Development and in-house validation of the event-specific polymerase chain reaction detection methods for genetically modified soybean MON89788 based on the cloned integration flanking sequence.

PubMed

Liu, Jia; Guo, Jinchao; Zhang, Haibo; Li, Ning; Yang, Litao; Zhang, Dabing

2009-11-25

Various polymerase chain reaction (PCR) methods were developed for the execution of genetically modified organism (GMO) labeling policies, of which an event-specific PCR detection method based on the flanking sequence of exogenous integration is the primary trend in GMO detection due to its high specificity. In this study, the 5' and 3' flanking sequences of the exogenous integration of MON89788 soybean were revealed by thermal asymmetric interlaced PCR. The event-specific PCR primers and TaqMan probe were designed based upon the revealed 5' flanking sequence, and the qualitative and quantitative PCR assays were established employing these designed primers and probes. In qualitative PCR, the limit of detection (LOD) was about 0.01 ng of genomic DNA corresponding to 10 copies of haploid soybean genomic DNA. In the quantitative PCR assay, the LOD was as low as two haploid genome copies, and the limit of quantification was five haploid genome copies. Furthermore, the developed PCR methods were in-house validated by five researchers, and the validated results indicated that the developed event-specific PCR methods can be used for identification and quantification of MON89788 soybean and its derivates.

A better sequence-read simulator program for metagenomics.

PubMed

Johnson, Stephen; Trost, Brett; Long, Jeffrey R; Pittet, Vanessa; Kusalik, Anthony

2014-01-01

There are many programs available for generating simulated whole-genome shotgun sequence reads. The data generated by many of these programs follow predefined models, which limits their use to the authors' original intentions. For example, many models assume that read lengths follow a uniform or normal distribution. Other programs generate models from actual sequencing data, but are limited to reads from single-genome studies. To our knowledge, there are no programs that allow a user to generate simulated data following non-parametric read-length distributions and quality profiles based on empirically-derived information from metagenomics sequencing data. We present BEAR (Better Emulation for Artificial Reads), a program that uses a machine-learning approach to generate reads with lengths and quality values that closely match empirically-derived distributions. BEAR can emulate reads from various sequencing platforms, including Illumina, 454, and Ion Torrent. BEAR requires minimal user input, as it automatically determines appropriate parameter settings from user-supplied data. BEAR also uses a unique method for deriving run-specific error rates, and extracts useful statistics from the metagenomic data itself, such as quality-error models. Many existing simulators are specific to a particular sequencing technology; however, BEAR is not restricted in this way. Because of its flexibility, BEAR is particularly useful for emulating the behaviour of technologies like Ion Torrent, for which no dedicated sequencing simulators are currently available. BEAR is also the first metagenomic sequencing simulator program that automates the process of generating abundances, which can be an arduous task. BEAR is useful for evaluating data processing tools in genomics. It has many advantages over existing comparable software, such as generating more realistic reads and being independent of sequencing technology, and has features particularly useful for metagenomics work.

Engineering peptide ligase specificity by proteomic identification of ligation sites.

PubMed

Weeks, Amy M; Wells, James A

2018-01-01

Enzyme-catalyzed peptide ligation is a powerful tool for site-specific protein bioconjugation, but stringent enzyme-substrate specificity limits its utility. We developed an approach for comprehensively characterizing peptide ligase specificity for N termini using proteome-derived peptide libraries. We used this strategy to characterize the ligation efficiency for >25,000 enzyme-substrate pairs in the context of the engineered peptide ligase subtiligase and identified a family of 72 mutant subtiligases with activity toward N-terminal sequences that were previously recalcitrant to modification. We applied these mutants individually for site-specific bioconjugation of purified proteins, including antibodies, and in algorithmically selected combinations for sequencing of the cellular N terminome with reduced sequence bias. We also developed a web application to enable algorithmic selection of the most efficient subtiligase variant(s) for bioconjugation to user-defined sequences. Our methods provide a new toolbox of enzymes for site-specific protein modification and a general approach for rapidly defining and engineering peptide ligase specificity.

Targeted Deletion of Sox10 by Wnt1-cre Defects Neuronal Migration and Projection in the Mouse Inner Ear

PubMed Central

Mao, YanYan; Reiprich, Simone; Wegner, Michael; Fritzsch, Bernd

2014-01-01

Sensory nerves of the brainstem are mostly composed of placode-derived neurons, neural crest-derived neurons and neural crest-derived Schwann cells. This mixed origin of cells has made it difficult to dissect interdependence for fiber guidance. Inner ear-derived neurons are known to connect to the brain after delayed loss of Schwann cells in ErbB2 mutants. However, the ErbB2 mutant related alterations in the ear and the brain compound interpretation of the data. We present here a new model to evaluate exclusively the effect of Schwann cell loss on inner ear innervation. Conditional deletion of the neural crest specific transcription factor, Sox10, using the rhombic lip/neural crest specific Wnt1-cre driver spares Sox10 expression in the ear. We confirm that neural crest-derived cells provide a stop signal for migrating spiral ganglion neurons. In the absence of Schwann cells, spiral ganglion neurons migrate into the center of the cochlea and even out of the ear toward the brain. Spiral ganglion neuron afferent processes reach the organ of Corti, but many afferent fibers bypass the organ of Corti to enter the lateral wall of the cochlea. In contrast to this peripheral disorganization, the central projection to cochlear nuclei is normal. Compared to ErbB2 mutants, conditional Sox10 mutants have limited cell death in spiral ganglion neurons, indicating that the absence of Schwann cells alone contributes little to the embryonic survival of neurons. These data suggest that neural crest-derived cells are dispensable for all central and some peripheral targeting of inner ear neurons. However, Schwann cells provide a stop signal for migratory spiral ganglion neurons and facilitate proper targeting of the organ of Corti by spiral ganglion afferents. PMID:24718611

ATLAS, an integrated structural analysis and design system. Volume 6: Design module theory

NASA Technical Reports Server (NTRS)

Backman, B. F.

1979-01-01

The automated design theory underlying the operation of the ATLAS Design Module is decribed. The methods, applications and limitations associated with the fully stressed design, the thermal fully stressed design and a regional optimization algorithm are presented. A discussion of the convergence characteristics of the fully stressed design is also included. Derivations and concepts specific to the ATLAS design theory are shown, while conventional terminology and established methods are identified by references.

The theoretical tools of experimental gravitation

NASA Technical Reports Server (NTRS)

Will, C. M.

1972-01-01

Theoretical frameworks for testing relativistic gravity are presented in terms of a system for analyzing theories of gravity invented as alternatives to Einstein. The parametrized post-Newtonian (PPN) formalism, based on the Dicke framework and the Eotvos-Dicke-Braginsky experiment, is discussed in detail. The metric theories of gravity, and their post-Newtonian limits are reviewed, and PPN equations of motion are derived. These equations are used to analyze specific effects and experimental tests in the solar system.

Interacting Effects of Light and Iron Availability on the Coupling of Photosynthetic Electron Transport and CO2-Assimilation in Marine Phytoplankton

PubMed Central

Schuback, Nina; Schallenberg, Christina; Duckham, Carolyn; Maldonado, Maria T.; Tortell, Philippe D.

2015-01-01

Iron availability directly affects photosynthesis and limits phytoplankton growth over vast oceanic regions. For this reason, the availability of iron is a crucial variable to consider in the development of active chlorophyll a fluorescence based estimates of phytoplankton primary productivity. These bio-optical approaches require a conversion factor to derive ecologically-relevant rates of CO2-assimilation from estimates of electron transport in photosystem II. The required conversion factor varies significantly across phytoplankton taxa and environmental conditions, but little information is available on its response to iron limitation. In this study, we examine the role of iron limitation, and the interacting effects of iron and light availability, on the coupling of photosynthetic electron transport and CO2-assimilation in marine phytoplankton. Our results show that excess irradiance causes increased decoupling of carbon fixation and electron transport, particularly under iron limiting conditions. We observed that reaction center II specific rates of electron transport (ETRRCII, mol e- mol RCII-1 s-1) increased under iron limitation, and we propose a simple conceptual model for this observation. We also observed a strong correlation between the derived conversion factor and the expression of non-photochemical quenching. Utilizing a dataset from in situ phytoplankton assemblages across a coastal – oceanic transect in the Northeast subarctic Pacific, this relationship was used to predict ETRRCII: CO2-assimilation conversion factors and carbon-based primary productivity from FRRF data, without the need for any additional measurements. PMID:26171963

Interacting Effects of Light and Iron Availability on the Coupling of Photosynthetic Electron Transport and CO2-Assimilation in Marine Phytoplankton.

PubMed

Schuback, Nina; Schallenberg, Christina; Duckham, Carolyn; Maldonado, Maria T; Tortell, Philippe D

2015-01-01

Iron availability directly affects photosynthesis and limits phytoplankton growth over vast oceanic regions. For this reason, the availability of iron is a crucial variable to consider in the development of active chlorophyll a fluorescence based estimates of phytoplankton primary productivity. These bio-optical approaches require a conversion factor to derive ecologically-relevant rates of CO2-assimilation from estimates of electron transport in photosystem II. The required conversion factor varies significantly across phytoplankton taxa and environmental conditions, but little information is available on its response to iron limitation. In this study, we examine the role of iron limitation, and the interacting effects of iron and light availability, on the coupling of photosynthetic electron transport and CO2-assimilation in marine phytoplankton. Our results show that excess irradiance causes increased decoupling of carbon fixation and electron transport, particularly under iron limiting conditions. We observed that reaction center II specific rates of electron transport (ETR(RCII), mol e- mol RCII(-1) s(-1)) increased under iron limitation, and we propose a simple conceptual model for this observation. We also observed a strong correlation between the derived conversion factor and the expression of non-photochemical quenching. Utilizing a dataset from in situ phytoplankton assemblages across a coastal--oceanic transect in the Northeast subarctic Pacific, this relationship was used to predict ETR(RCII): CO2-assimilation conversion factors and carbon-based primary productivity from FRRF data, without the need for any additional measurements.

A selective biomarker for confirming nitrofurazone residues in crab and shrimp using ultra-performance liquid chromatography-tandem mass spectrometry.

PubMed

Zhang, Shuai; Guo, Yuanming; Yan, Zhongyong; Sun, Xiumei; Zhang, Xiaojun

2015-12-01

Reliably detecting nitrofurazone (NFZ) residues in farmed crab and shrimp was previously hindered by lack of appropriately specific analytical methodology. Parent NFZ rapidly breaks down in meat, and the commonly used side-chain metabolite, semicarbazide (SEM), is non-specific as it occurs naturally in crustacean shell often leading to 'false positive' detections in meat. Using 5-nitro-2-furaldehyde (NF) as marker metabolite, following pre-column derivatization with 2,4-dinitrophenylhydrazine (DNPH), ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis in negative electrospray ionization mode enabled confirmation of NFZ residues in deliberately treated whole crab, crab meat and shrimp meat, with a limit of detection (LOD) and limit of quantification (LOQ) below 1 ng g(-1). Meanwhile, the derivatives of DNPH-NF were synthesized for the first time, purified by preparative liquid chromatography and structure characterized with nuclear magnetic resonance spectroscopy ((1)H-NMR). The purity of derivative was checked by ultra-performance liquid chromatography-tunable ultraviolet (UPLC-TUV), and the contents were beyond 99.9%. For comparison purposes, crustacean samples were analysed using both NF and SEM marker metabolites. NFZ treatment was revealed by both NF and SEM marker metabolites, but untreated crab also showed measurable levels of SEM which could potentially be misinterpreted as evidence of illegal NFZ use.

Estimating economic thresholds for site-specific weed control using manual weed counts and sensor technology: an example based on three winter wheat trials.

PubMed

Keller, Martina; Gutjahr, Christoph; Möhring, Jens; Weis, Martin; Sökefeld, Markus; Gerhards, Roland

2014-02-01

Precision experimental design uses the natural heterogeneity of agricultural fields and combines sensor technology with linear mixed models to estimate the effect of weeds, soil properties and herbicide on yield. These estimates can be used to derive economic thresholds. Three field trials are presented using the precision experimental design in winter wheat. Weed densities were determined by manual sampling and bi-spectral cameras, yield and soil properties were mapped. Galium aparine, other broad-leaved weeds and Alopecurus myosuroides reduced yield by 17.5, 1.2 and 12.4 kg ha(-1) plant(-1)  m(2) in one trial. The determined thresholds for site-specific weed control with independently applied herbicides were 4, 48 and 12 plants m(-2), respectively. Spring drought reduced yield effects of weeds considerably in one trial, since water became yield limiting. A negative herbicide effect on the crop was negligible, except in one trial, in which the herbicide mixture tended to reduce yield by 0.6 t ha(-1). Bi-spectral cameras for weed counting were of limited use and still need improvement. Nevertheless, large weed patches were correctly identified. The current paper presents a new approach to conducting field trials and deriving decision rules for weed control in farmers' fields. © 2013 Society of Chemical Industry.

Decay of homogeneous turbulence from a specified state

NASA Technical Reports Server (NTRS)

Deissler, R. G.

1972-01-01

The homogeneous turbulence problem is formulated by first specifying the multipoint velocity correlations or their spectral equivalents at an initial time. Those quantities, together with the correlation or spectral equations, are then used to calculate initial time derivatives of correlations or spectra. The derivatives in turn are used in time series to calculate the evolution of turbulence quantities with time. When the problem is treated in this way, the correlation equations are closed by the initial specification of the turbulence and no closure assumption is necessary. An exponential series which is an iterative solution of the Navier stokes equations gave much better results than a Taylor power series when used with the limited available initial data. In general, the agreement between theory and experiment was good.

The final stages of the global eradication of poliomyelitis.

PubMed

Grassly, Nicholas C

2013-08-05

The global incidence of poliomyelitis has dropped by more than 99 per cent since the governments of the world committed to eradication in 1988. One of the three serotypes of wild poliovirus has been eradicated and the remaining two serotypes are limited to just a small number of endemic regions. However, the Global Polio Eradication Initiative (GPEI) has faced a number of challenges in eradicating the last 1 per cent of wild-virus transmission. The polio endgame has also been complicated by the recognition that vaccination with the oral poliovirus vaccine (OPV) must eventually cease because of the risk of outbreaks of vaccine-derived polioviruses. I describe the major challenges to wild poliovirus eradication, focusing on the poor immunogenicity of OPV in lower-income countries, the inherent limitations to the sensitivity and specificity of surveillance, the international spread of poliovirus and resulting outbreaks, and the potential significance of waning intestinal immunity induced by OPV. I then focus on the challenges to eradicating all polioviruses, the problem of vaccine-derived polioviruses and the risk of wild-type or vaccine-derived poliovirus re-emergence after the cessation of oral vaccination. I document the role of research in the GPEI's response to these challenges and ultimately the feasibility of achieving a world without poliomyelitis.

Hydrogels Derived from Central Nervous System Extracellular Matrix

PubMed Central

Medberry, Christopher J.; Crapo, Peter M.; Siu, Bernard F.; Carruthers, Christopher A.; Wolf, Matthew T.; Nagarkar, Shailesh P.; Agrawal, Vineet; Jones, Kristen E.; Kelly, Jeremy; Johnson, Scott A.; Velankar, Sachin S.; Watkins, Simon C.; Modo, Michel

2012-01-01

Biologic scaffolds composed of extracellular matrix (ECM) are commonly used repair devices in preclinical and clinical settings; however the use of these scaffolds for peripheral and central nervous system (CNS) repair has been limited. Biologic scaffolds developed from brain and spinal cord tissue have recently been described, yet the conformation of the harvested ECM limits therapeutic utility. An injectable CNS-ECM derived hydrogel capable of in vivo polymerization and conformation to irregular lesion geometries may aid in tissue reconstruction efforts following complex neurologic trauma. The objectives of the present study were to develop hydrogel forms of brain and spinal cord ECM and compare the resulting biochemical composition, mechanical properties, and neurotrophic potential of a brain derived cell line to a non-CNS-ECM hydrogel, urinary bladder matrix. Results showed distinct differences between compositions of brain ECM, spinal cord ECM, and urinary bladder matrix. The rheologic modulus of spinal cord ECM hydrogel was greater than that of brain ECM and urinary bladder matrix. All ECMs increased the number of cells expressing neurites, but only brain ECM increased neurite length, suggesting a possible tissue-specific effect. All hydrogels promoted three-dimensional uni- or bi-polar neurite outgrowth following 7 days in culture. These results suggest that CNS-ECM hydrogels may provide supportive scaffolding to promote in vivo axonal repair. PMID:23158935

Hyperspectral wide gap second derivative analysis for in vivo detection of cervical intraepithelial neoplasia

NASA Astrophysics Data System (ADS)

Zheng, Wenli; Wang, Chaojian; Chang, Shufang; Zhang, Shiwu; Xu, Ronald X.

2015-12-01

Hyperspectral reflectance imaging technique has been used for in vivo detection of cervical intraepithelial neoplasia. However, the clinical outcome of this technique is suboptimal owing to multiple limitations such as nonuniform illumination, high-cost and bulky setup, and time-consuming data acquisition and processing. To overcome these limitations, we acquired the hyperspectral data cube in a wavelength ranging from 600 to 800 nm and processed it by a wide gap second derivative analysis method. This method effectively reduced the image artifacts caused by nonuniform illumination and background absorption. Furthermore, with second derivative analysis, only three specific wavelengths (620, 696, and 772 nm) are needed for tissue classification with optimal separability. Clinical feasibility of the proposed image analysis and classification method was tested in a clinical trial where cervical hyperspectral images from three patients were used for classification analysis. Our proposed method successfully classified the cervix tissue into three categories of normal, inflammation and high-grade lesion. These classification results were coincident with those by an experienced gynecology oncologist after applying acetic acid. Our preliminary clinical study has demonstrated the technical feasibility for in vivo and noninvasive detection of cervical neoplasia without acetic acid. Further clinical research is needed in order to establish a large-scale diagnostic database and optimize the tissue classification technique.

Hyperspectral wide gap second derivative analysis for in vivo detection of cervical intraepithelial neoplasia.

PubMed

Zheng, Wenli; Wang, Chaojian; Chang, Shufang; Zhang, Shiwu; Xu, Ronald X

2015-12-01

Hyperspectral reflectance imaging technique has been used for in vivo detection of cervical intraepithelial neoplasia. However, the clinical outcome of this technique is suboptimal owing to multiple limitations such as nonuniform illumination, high-cost and bulky setup, and time-consuming data acquisition and processing. To overcome these limitations, we acquired the hyperspectral data cube in a wavelength ranging from 600 to 800 nm and processed it by a wide gap second derivative analysis method. This method effectively reduced the image artifacts caused by nonuniform illumination and background absorption. Furthermore, with second derivative analysis, only three specific wavelengths (620, 696, and 772 nm) are needed for tissue classification with optimal separability. Clinical feasibility of the proposed image analysis and classification method was tested in a clinical trial where cervical hyperspectral images from three patients were used for classification analysis. Our proposed method successfully classified the cervix tissue into three categories of normal, inflammation and high-grade lesion. These classification results were coincident with those by an experienced gynecology oncologist after applying acetic acid. Our preliminary clinical study has demonstrated the technical feasibility for in vivo and noninvasive detection of cervical neoplasia without acetic acid. Further clinical research is needed in order to establish a large-scale diagnostic database and optimize the tissue classification technique.

The final stages of the global eradication of poliomyelitis

PubMed Central

Grassly, Nicholas C.

2013-01-01

The global incidence of poliomyelitis has dropped by more than 99 per cent since the governments of the world committed to eradication in 1988. One of the three serotypes of wild poliovirus has been eradicated and the remaining two serotypes are limited to just a small number of endemic regions. However, the Global Polio Eradication Initiative (GPEI) has faced a number of challenges in eradicating the last 1 per cent of wild-virus transmission. The polio endgame has also been complicated by the recognition that vaccination with the oral poliovirus vaccine (OPV) must eventually cease because of the risk of outbreaks of vaccine-derived polioviruses. I describe the major challenges to wild poliovirus eradication, focusing on the poor immunogenicity of OPV in lower-income countries, the inherent limitations to the sensitivity and specificity of surveillance, the international spread of poliovirus and resulting outbreaks, and the potential significance of waning intestinal immunity induced by OPV. I then focus on the challenges to eradicating all polioviruses, the problem of vaccine-derived polioviruses and the risk of wild-type or vaccine-derived poliovirus re-emergence after the cessation of oral vaccination. I document the role of research in the GPEI's response to these challenges and ultimately the feasibility of achieving a world without poliomyelitis. PMID:23798688

Mice maintain predominantly maternal Gαs expression throughout life in brown fat tissue (BAT), but not other tissues.

PubMed

Tafaj, Olta; Hann, Steven; Ayturk, Ugur; Warman, Matthew L; Jüppner, Harald

2017-10-01

The murine Gnas (human GNAS) locus gives rise to Gαs and different splice variants thereof. The Gαs promoter is not methylated thus allowing biallelic expression in most tissues. In contrast, the alternative first Gnas/GNAS exons and their promoters undergo parent specific methylation, which limits transcription to the non-methylated allele. Pseudohypoparathyroidism type Ia (PHP1A) or type Ib (PHP1B) are caused by heterozygous maternal GNAS mutations suggesting that little or no Gαs is derived in some tissues from the non-mutated paternal GNAS thereby causing hormonal resistance. Previous data had indicated that Gαs is mainly derived from the maternal Gnas allele in brown adipose tissue (BAT) of newborn mice, yet it is biallelically expressed in adult BAT. This suggested that paternal Gαs expression is regulated by an unknown factor(s) that varies considerably with age. To extend these findings, we now used a strain-specific SNP in Gnas exon 11 (rs13460569) for evaluation of parent-specific Gαs expression through the densitometric quantification of BanII-digested RT-PCR products and digital droplet PCR (ddPCR). At all investigated ages, Gαs transcripts were derived in BAT predominantly from the maternal Gnas allele, while kidney and liver showed largely biallelic Gαs expression. Only low or undetectable levels of other paternally Gnas-derived transcripts were observed, making it unlikely that these are involved in regulating paternal Gαs expression. Our findings suggest that a cis-acting factor could be implicated in reducing paternal Gαs expression in BAT and presumably in proximal renal tubules, thereby causing PTH-resistance if the maternal GNAS/Gnas allele is mutated. Copyright © 2017 Elsevier Inc. All rights reserved.

Limits on dark matter annihilation signals from the Fermi LAT 4-year measurement of the isotropic gamma-ray background

DOE PAGES

Ackermann, M.

2015-09-02

We search for evidence of dark matter (DM) annihilation in the isotropic gamma-ray background (IGRB) measured with 50 months of Fermi Large Area Telescope (LAT) observations. An improved theoretical description of the cosmological DM annihilation signal, based on two complementary techniques and assuming generic weakly interacting massive particle (WIMP) properties, renders more precise predictions compared to previous work. More specifically, we estimate the cosmologically-induced gamma-ray intensity to have an uncertainty of a factor ~ 20 in canonical setups. We consistently include both the Galactic and extragalactic signals under the same theoretical framework, and study the impact of the former onmore » the IGRB spectrum derivation. We find no evidence for a DM signal and we set limits on the DM-induced isotropic gamma-ray signal. Our limits are competitive for DM particle masses up to tens of TeV and, indeed, are the strongest limits derived from Fermi LAT data at TeV energies. This is possible thanks to the new Fermi LAT IGRB measurement, which now extends up to an energy of 820 GeV. As a result, we quantify uncertainties in detail and show the potential this type of search offers for testing the WIMP paradigm with a complementary and truly cosmological probe of DM particle signals.« less

Limits on dark matter annihilation signals from the Fermi LAT 4-year measurement of the isotropic gamma-ray background

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

Collaboration: Fermi LAT Collaboration

2015-09-01

We search for evidence of dark matter (DM) annihilation in the isotropic gamma-ray background (IGRB) measured with 50 months of Fermi Large Area Telescope (LAT) observations. An improved theoretical description of the cosmological DM annihilation signal, based on two complementary techniques and assuming generic weakly interacting massive particle (WIMP) properties, renders more precise predictions compared to previous work. More specifically, we estimate the cosmologically-induced gamma-ray intensity to have an uncertainty of a factor ∼ 20 in canonical setups. We consistently include both the Galactic and extragalactic signals under the same theoretical framework, and study the impact of the former on themore » IGRB spectrum derivation. We find no evidence for a DM signal and we set limits on the DM-induced isotropic gamma-ray signal. Our limits are competitive for DM particle masses up to tens of TeV and, indeed, are the strongest limits derived from Fermi LAT data at TeV energies. This is possible thanks to the new Fermi LAT IGRB measurement, which now extends up to an energy of 820 GeV. We quantify uncertainties in detail and show the potential this type of search offers for testing the WIMP paradigm with a complementary and truly cosmological probe of DM particle signals.« less

An efficient representation of spatial information for expert reasoning in robotic vehicles

NASA Technical Reports Server (NTRS)

Scott, Steven; Interrante, Mark

1987-01-01

The previous generation of robotic vehicles and drones was designed for a specific task, with limited flexibility in executing their mission. This limited flexibility arises because the robotic vehicles do not possess the intelligence and knowledge upon which to make significant tactical decisions. Current development of robotic vehicles is toward increased intelligence and capabilities, adapting to a changing environment and altering mission objectives. The latest techniques in artificial intelligence (AI) are being employed to increase the robotic vehicle's intelligent decision-making capabilities. This document describes the design of the SARA spatial database tool, which is composed of request parser, reasoning, computations, and database modules that collectively manage and derive information useful for robotic vehicles.

Thermal infrared imaging in psychophysiology: Potentialities and limits

PubMed Central

Ioannou, Stephanos; Gallese, Vittorio; Merla, Arcangelo

2014-01-01

Functional infrared thermal imaging (fITI) is considered an upcoming, promising methodology in the emotional arena. Driven by sympathetic nerves, observations of affective nature derive from muscular activity subcutaneous blood flow as well as perspiration patterns in specific body parts. A review of 23 experimental procedures that employed fITI for investigations of affective nature is provided, along with the adopted experimental protocol and the thermal changes that took place on selected regions of interest in human and nonhuman subjects. Discussion is provided regarding the selection of an appropriate baseline, the autonomic nature of the thermal print, the experimental setup, methodological issues, limitations, and considerations, as well as future directions. PMID:24961292

Real-time calculation of a limiting form of the Renyi entropy applied to detection of subtle changes in scattering architecture

PubMed Central

Hughes, M. S.; McCarthy, J. E.; Wickerhauser, M. V.; Marsh, J. N.; Arbeit, J. M.; Fuhrhop, R. W.; Wallace, K. D.; Thomas, T.; Smith, J.; Agyem, K.; Lanza, G. M.; Wickline, S. A.

2009-01-01

Previously a new method for ultrasound signal characterization using entropy Hf was reported, and it was demonstrated that in certain settings, further improvements in signal characterization could be obtained by generalizing to Renyi entropy-based signal characterization If(r) with values of r near 2 (specifically r=1.99) [M. S. Hughes et al., J. Acoust. Soc. Am. 125, 3141–3145 (2009)]. It was speculated that further improvements in sensitivity might be realized at the limit r→2. At that time, such investigation was not feasible due to excessive computational time required to calculate If(r) near this limit. In this paper, an asymptotic expression for the limiting behavior of If(r) as r→2 is derived and used to present results analogous to those obtained with If(1.99). Moreover, the limiting form If,∞ is computable directly from the experimentally measured waveform f(t) by an algorithm that is suitable for real-time calculation and implementation. PMID:19894818

Detection of hydroxyl radicals by D-phenylalanine hydroxylation: a specific assay for hydroxyl radical generation in biological systems.

PubMed

Biondi, R; Xia, Y; Rossi, R; Paolocci, N; Ambrosio, G; Zweier, J L

2001-03-01

Hydroxylation of l-phenylalanine (Phe) by hydroxyl radical (*OH) yields 4-, 3-, and 2-hydroxyl-Phe (para-, meta-, and ortho-tyrosine, respectively). Phe derivative measurements have been employed to detect *OH formation in cells and tissues, however, the specificity of this assay is limited since Phe derivatives also arise from intracellular Phe hydroxylase. d-Phe, the d-type enantiomer, is not hydroxylated by Phe hydroxylase. We evaluate whether d-Phe reacts with *OH as well as l-Phe, providing a more reliable probe for *OH generation in biological systems. With *OH generated by a Fenton reaction or xanthine oxidase, d- and l-Phe equally gave rise to p, m, o-tyr and this could be prevented by *OH scavengers. Resting human neutrophils (PMNs) markedly converted l-Phe to p-tyr, through non-oxidant-mediated reactions, whereas d-Phe was unaffected. In contrast, when PMNs were stimulated in the presence of redox cycling iron the *OH formed resulted in more significant rise of p-tyr from d-Phe (9.4-fold) than l-Phe (3.6-fold) due to the significant background formation of p-tyr from l-Phe. Together, these data indicated that d- and l-Phe were equally hydroxylated by *OH. Using d-Phe instead of l-Phe can eliminate the formation of Phe derivatives from Phe hydroxylase and achieve more specific, sensitive measurement of *OH in biological systems.

Perfluorocarbon Nanoparticles as Delivery Vehicles for Melittin and Its Protease-Activated Derivatives

NASA Astrophysics Data System (ADS)

Jallouk, Andrew Philip

Melittin is a cytolytic peptide derived from honeybee venom which inserts into lipid membranes and oligomerizes to form membrane pores. While this peptide is an attractive candidate for treatment of cancers and infectious processes, its nonspecific cytotoxicity and hemolytic activity have limited its therapeutic applications. The goal of this dissertation was to enhance the specificity of melittin therapy through the use of perfluorocarbon nanoparticles to minimize nonspecific cytotoxicity and the development of melittin prodrugs which only exhibit cytolytic activity following activation by site-specific proteases. Although previous studies have characterized the biological effects of melittin-loaded nanoparticles following intravenous administration, we first investigated their use as topical agents for prevention of HIV infection. We found that incorporation of native melittin onto perfluorocarbon nanoparticles maintained antiviral activity while substantially reducing contact toxicity to sperm and vaginal epithelium. These results demonstrated the potential utility of melittin-loaded nanoparticles as a topical vaginal virucide. To further enhance melittin specificity, we developed melittin derivatives which could be activated by matrix metalloproteinase-9, a protease which is overexpressed in many tumors and which plays a critical role in cancer invasion and metastasis. We then characterized the interactions of these peptides with perfluorocarbon nanoparticles and demonstrated the safety and efficacy of intravenous prodrug-loaded nanoparticle therapy in a mouse model of melanoma. The versatility of this platform could facilitate development of personalized cancer therapies directed towards a patient's individual protease expression profile.

Model-based derivation, analysis and control of unstable microaerobic steady-states--considering Rhodospirillum rubrum as an example.

PubMed

Carius, Lisa; Rumschinski, Philipp; Faulwasser, Timm; Flockerzi, Dietrich; Grammel, Hartmut; Findeisen, Rolf

2014-04-01

Microaerobic (oxygen-limited) conditions are critical for inducing many important microbial processes in industrial or environmental applications. At very low oxygen concentrations, however, the process performance often suffers from technical limitations. Available dissolved oxygen measurement techniques are not sensitive enough and thus control techniques, that can reliable handle these conditions, are lacking. Recently, we proposed a microaerobic process control strategy, which overcomes these restrictions and allows to assess different degrees of oxygen limitation in bioreactor batch cultivations. Here, we focus on the design of a control strategy for the automation of oxygen-limited continuous cultures using the microaerobic formation of photosynthetic membranes (PM) in Rhodospirillum rubrum as model phenomenon. We draw upon R. rubrum since the considered phenomenon depends on the optimal availability of mixed-carbon sources, hence on boundary conditions which make the process performance challenging. Empirically assessing these specific microaerobic conditions is scarcely practicable as such a process reacts highly sensitive to changes in the substrate composition and the oxygen availability in the culture broth. Therefore, we propose a model-based process control strategy which allows to stabilize steady-states of cultures grown under these conditions. As designing the appropriate strategy requires a detailed knowledge of the system behavior, we begin by deriving and validating an unstructured process model. This model is used to optimize the experimental conditions, and identify properties of the system which are critical for process performance. The derived model facilitates the good process performance via the proposed optimal control strategy. In summary the presented model-based control strategy allows to access and maintain microaerobic steady-states of interest and to precisely and efficiently transfer the culture from one stable microaerobic steady-state into another. Therefore, the presented approach is a valuable tool to study regulatory mechanisms of microaerobic phenomena in response to oxygen limitation alone. Biotechnol. Bioeng. 2014;111: 734-747. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

Compatibility of household budget and individual nutrition surveys: results of the preliminary analysis.

PubMed

Naska, A; Trichopoulou, A

2001-08-01

The EU-supported project entitled: "Compatibility of household budget and individual nutrition surveys and disparities in food habits" aimed at comparing individualised household budget survey (HBS) data with food consumption values derived from individual nutrition surveys (INS). The present paper provides a brief description of the methodology applied for rendering the datasets at a comparable level. Results of the preliminary evaluation of their compatibility are also presented. A non parametric modelling approach was used for the individualisation (age and gender-specific) of the food data collected at household level, in the context of the national HBSs and the bootstrap technique was used for the derivation of 95% confidence intervals. For each food group, INS and HBS-derived mean values were calculated for twenty-four research units, jointly defined by country (four countries involved), gender (male, female) and age (younger, middle-aged and older). Pearson correlation coefficients were calculated. The results of this preliminary analysis show that there is considerable scope in the nutritional information derived from HBSs. Additional and more sophisticated work is however required, putting particular emphasis on addressing limitations present in both surveys and on deriving reliable individual consumption point and interval estimates, on the basis of HBS data.

Variable promoter methylation contributes to differential expression of key genes in human placenta-derived venous and arterial endothelial cells.

PubMed

Joo, Jihoon E; Hiden, Ursula; Lassance, Luciana; Gordon, Lavinia; Martino, David J; Desoye, Gernot; Saffery, Richard

2013-07-15

The endothelial compartment, comprising arterial, venous and lymphatic cell types, is established prenatally in association with rapid phenotypic and functional changes. The molecular mechanisms underpinning this process in utero have yet to be fully elucidated. The aim of this study was to investigate the potential for DNA methylation to act as a driver of the specific gene expression profiles of arterial and venous endothelial cells. Placenta-derived venous and arterial endothelial cells were collected at birth prior to culturing. DNA methylation was measured at >450,000 CpG sites in parallel with expression measurements taken from 25,000 annotated genes. A consistent set of genomic loci was found to show coordinate differential methylation between the arterial and venous cell types. This included many loci previously not investigated in relation to endothelial function. An inverse relationship was observed between gene expression and promoter methylation levels for a limited subset of genes implicated in endothelial function, including NOS3, encoding endothelial Nitric Oxide Synthase. Endothelial cells derived from the placental vasculature at birth contain widespread methylation of key regulatory genes. These are candidates involved in the specification of different endothelial cell types and represent potential target genes for environmentally mediated epigenetic disruption in utero in association with cardiovascular disease risk later in life.

Distinct Inflammatory Profiles of Myelin-Reactive T cells from Patients with Multiple Sclerosis

PubMed Central

Cao, Yonghao; Goods, Brittany A.; Raddassi, Khadir; Nepom, Gerald T.; Kwok, William W.; Love, J. Christopher; Hafler, David A.

2015-01-01

Myelin-reactive T cells have been identified in patients with multiple sclerosis (MS) and healthy subjects with comparable frequencies, but the functional programs of self-reactive T cells that promote disease remain unknown. A total of 13,324 T cell libraries generated from blood of 23 patients and 22 healthy controls were interrogated for reactivity to myelin antigens. Libraries derived from CCR6+ myelin-reactive T cells from patients with MS exhibited significantly enhanced production of IFN-γ, IL-17, and GM-CSF compared to healthy controls. Single-cell clones isolated by MHC/peptide tetramers from CCR6+ T cell libraries also secreted more pro-inflammatory cytokines while clones isolated from controls secreted more IL-10. The transcriptomes of myelin-specific CCR6+ T cells from patients with MS were distinct from those derived from healthy controls, and of note, were enriched in Th17-induced experimental autoimmune encephalitis (EAE) gene signatures and gene signatures derived from Th17 cells isolated other human autoimmune diseases. These data, although not casual, imply that functional differences between antigen specific T cells from MS and healthy controls is fundamental to disease development and support the notion that IL-10 production from myelin-reactive T cells may act to limit disease progression, or even pathogenesis. PMID:25972006

Incorporation of dosimetry in the derivation of reference concentrations for ambient or workplace air: a conceptual approach.

PubMed

Oller, Adriana R; Oberdörster, Günter

2016-09-01

Dosimetric models are essential tools to refine inhalation risk assessments based on local respiratory effects. Dosimetric adjustments to account for differences in aerosol particle size and respiratory tract deposition and/or clearance among rodents, workers, and the general public can be applied to experimentally- and epidemiologically-determined points of departure (PODs) to calculate size-selected (e.g., PM 10 , inhalable aerosol fraction, respirable aerosol fraction) equivalent concentrations (e.g., HEC or Human Equivalent Concentration; REC or Rodent Equivalent Concentration). A modified POD (e.g., HEC) can then feed into existing frameworks for the derivation of occupational or ambient air concentration limits or reference concentrations. HECs that are expressed in terms of aerosol particle sizes experienced by humans but are derived from animal studies allow proper comparison of exposure levels and associated health effects in animals and humans. This can inform differences in responsiveness between animals and humans, based on the same deposited or retained doses and can also allow the use of both data sources in an integrated weight of evidence approach for hazard and risk assessment purposes. Whenever possible, default values should be replaced by substance-specific and target population-specific parameters. Assumptions and sources of uncertainty need to be clearly reported.

Incorporation of dosimetry in the derivation of reference concentrations for ambient or workplace air: a conceptual approach

PubMed Central

Oberdörster, Günter

2016-01-01

Dosimetric models are essential tools to refine inhalation risk assessments based on local respiratory effects. Dosimetric adjustments to account for differences in aerosol particle size and respiratory tract deposition and/or clearance among rodents, workers, and the general public can be applied to experimentally- and epidemiologically-determined points of departure (PODs) to calculate size-selected (e.g., PM10, inhalable aerosol fraction, respirable aerosol fraction) equivalent concentrations (e.g., HEC or Human Equivalent Concentration; REC or Rodent Equivalent Concentration). A modified POD (e.g., HEC) can then feed into existing frameworks for the derivation of occupational or ambient air concentration limits or reference concentrations. HECs that are expressed in terms of aerosol particle sizes experienced by humans but are derived from animal studies allow proper comparison of exposure levels and associated health effects in animals and humans. This can inform differences in responsiveness between animals and humans, based on the same deposited or retained doses and can also allow the use of both data sources in an integrated weight of evidence approach for hazard and risk assessment purposes. Whenever possible, default values should be replaced by substance-specific and target population-specific parameters. Assumptions and sources of uncertainty need to be clearly reported. PMID:27721518

HLA Engineering of Human Pluripotent Stem Cells

PubMed Central

Riolobos, Laura; Hirata, Roli K; Turtle, Cameron J; Wang, Pei-Rong; Gornalusse, German G; Zavajlevski, Maja; Riddell, Stanley R; Russell, David W

2013-01-01

The clinical use of human pluripotent stem cells and their derivatives is limited by the rejection of transplanted cells due to differences in their human leukocyte antigen (HLA) genes. This has led to the proposed use of histocompatible, patient-specific stem cells; however, the preparation of many different stem cell lines for clinical use is a daunting task. Here, we develop two distinct genetic engineering approaches that address this problem. First, we use a combination of gene targeting and mitotic recombination to derive HLA-homozygous embryonic stem cell (ESC) subclones from an HLA-heterozygous parental line. A small bank of HLA-homozygous stem cells with common haplotypes would match a significant proportion of the population. Second, we derive HLA class I–negative cells by targeted disruption of both alleles of the Beta-2 Microglobulin (B2M) gene in ESCs. Mixed leukocyte reactions and peptide-specific HLA-restricted CD8+ T cell responses were reduced in class I–negative cells that had undergone differentiation in embryoid bodies. These B2M−/− ESCs could act as universal donor cells in applications where the transplanted cells do not express HLA class II genes. Both approaches used adeno-associated virus (AAV) vectors for efficient gene targeting in the absence of potentially genotoxic nucleases, and produced pluripotent, transgene-free cell lines. PMID:23629003

HLA engineering of human pluripotent stem cells.

PubMed

Riolobos, Laura; Hirata, Roli K; Turtle, Cameron J; Wang, Pei-Rong; Gornalusse, German G; Zavajlevski, Maja; Riddell, Stanley R; Russell, David W

2013-06-01

The clinical use of human pluripotent stem cells and their derivatives is limited by the rejection of transplanted cells due to differences in their human leukocyte antigen (HLA) genes. This has led to the proposed use of histocompatible, patient-specific stem cells; however, the preparation of many different stem cell lines for clinical use is a daunting task. Here, we develop two distinct genetic engineering approaches that address this problem. First, we use a combination of gene targeting and mitotic recombination to derive HLA-homozygous embryonic stem cell (ESC) subclones from an HLA-heterozygous parental line. A small bank of HLA-homozygous stem cells with common haplotypes would match a significant proportion of the population. Second, we derive HLA class I-negative cells by targeted disruption of both alleles of the Beta-2 Microglobulin (B2M) gene in ESCs. Mixed leukocyte reactions and peptide-specific HLA-restricted CD8(+) T cell responses were reduced in class I-negative cells that had undergone differentiation in embryoid bodies. These B2M(-/-) ESCs could act as universal donor cells in applications where the transplanted cells do not express HLA class II genes. Both approaches used adeno-associated virus (AAV) vectors for efficient gene targeting in the absence of potentially genotoxic nucleases, and produced pluripotent, transgene-free cell lines.

A Framework for Architecture-Based Planning and Assessment to Support Modeling and Simulation of Network-Centric Command and Control

DTIC Science & Technology

2006-02-17

included system-unique specifications derived to counter these threats. But the international security environment has changed --- and it will continue... Netowrk -Centric Command and Control 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK...contains color images. 14. ABSTRACT 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 20 19a. NAME

Evaluation of in-hospital electrocardiography versus 24-hour Holter for rate control in dogs with atrial fibrillation.

PubMed

Gelzer, A R; Kraus, M S; Rishniw, M

2015-07-01

To determine if the in-clinic ECG-derived heart rate could predict the at-home Holter-derived 24-hour average heart rate (Holter24h ), and whether it is useful to identify slow versus fast atrial fibrillation in dogs. 82 pairs of 1-minute ECGs and 24-hour Holter recordings were acquired in 34 dogs with atrial fibrillation. The initial 24-hour Holter was used to test if the ECG heart rate can identify dogs with "slow" versus "fast" atrial fibrillation based on a Holter24h threshold value of 140 bpm. ECG heart rate overestimated Holter24h by 26 bpm (95% CI: 3 bpm, 48 bpm; P < 0 · 015) with a 95% limit of agreement of -21 to 83 bpm. The in-clinic ECG-derived heart rate Ä155 bpm had a sensitivity of 73% and a specificity of 100% for identifying a Holter24h HR Ä140 bpm; an in-clinic ECG-derived HR <160 bpm had a sensitivity and specificity of 91% each. In-clinic ECG assessment of heart rate in dogs with atrial fibrillation does not reliably predict the heart rate in their home environment. However, an in-clinic heart rate greater than 155 bpm is useful in identifying "fast" atrial fibrillation, allowing clinicians to stratify which case may benefit from antiarrhythmic therapy. © 2015 British Small Animal Veterinary Association.

Concise review: Patient-derived olfactory stem cells: new models for brain diseases.

PubMed

Mackay-Sim, Alan

2012-11-01

Traditional models of brain diseases have had limited success in driving candidate drugs into successful clinical translation. This has resulted in large international pharmaceutical companies moving out of neuroscience research. Cells are not brains, obviously, but new patient-derived stem models have the potential to elucidate cell biological aspects of brain diseases that are not present in worm, fly, or rodent models, the work horses of disease investigations and drug discovery. Neural stem cells are present in the olfactory mucosa, the organ of smell in the nose. Patient-derived olfactory mucosa has demonstrated disease-associated differences in a variety of brain diseases and recently olfactory mucosa stem cells have been generated from patients with schizophrenia, Parkinson's disease, and familial dysautonomia. By comparison with cells from healthy controls, patient-derived olfactory mucosa stem cells show disease-specific alterations in gene expression and cell functions including: a shorter cell cycle and faster proliferation in schizophrenia, oxidative stress in Parkinson's disease, and altered cell migration in familial dysautonomia. Olfactory stem cell cultures thus reveal patient-control differences, even in complex genetic diseases such as schizophrenia and Parkinson's disease, indicating that multiple genes of small effect can converge on shared cell signaling pathways to present as a disease-specific cellular phenotype. Olfactory mucosa stem cells can be maintained in homogeneous cultures that allow robust and repeatable multiwell assays suitable for screening libraries of drug candidate molecules. Copyright © 2012 AlphaMed Press.

Magnetic porous carbon derived from a bimetallic metal-organic framework for magnetic solid-phase extraction of organochlorine pesticides from drinking and environmental water samples.

PubMed

Liu, Yaxi; Gao, Zongjun; Wu, Ri; Wang, Zhenhua; Chen, Xiangfeng; Chan, T-W Dominic

2017-01-06

In this work, magnetic porous carbon material derived from a bimetallic metal-organic framework was explored as an adsorbent for magnetic solid-phase extraction of organochlorine pesticides (OCPs). The synthesized porous carbon possessed a high specific surface area and magnetization saturation. The OCPs in the samples were quantified using gas chromatography coupled with a triple quadrupole mass spectrometer. The experimental parameters, including the desorption solvent and conditions, amount of adsorbent, extraction time, extraction temperature, and ionic strength of the solution, were optimized. Under optimal conditions, the developed method displayed good linearity (r>0.99) within the concentration range of 2-500ngL -1 . Low limits of detection (0.39-0.70ngL -1 , signal-to-noise ratio=3:1) and limits of quantification (1.45-2.0ngL -1 , signal-to-noise ratio=10:1) as well as good precision (relative standard deviation<10%) were also obtained. The developed method was applied in the analysis of OCPs in drinking and environmental water samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Magnetosonic cnoidal waves and solitons in a magnetized dusty plasma

NASA Astrophysics Data System (ADS)

Kaur, Nimardeep; Singh, Manpreet; Saini, N. S.

2018-04-01

An investigation of magnetosonic nonlinear periodic (cnoidal) waves is presented in a magnetized electron-ion-dust ( e -i -d ) plasma having cold dust fluid with inertialess warm ions and electrons. The reductive perturbation method is employed to derive the Korteweg-de Vries equation. The dispersion relation for magnetosonic cnoidal waves is determined in the linear limit. The magnetosonic cnoidal wave solution is derived using the Sagdeev pseudopotential approach under the specific boundary conditions. There is the formation of only positive potential magnetosonic cnoidal waves and solitary structures in the high plasma-β limit. The effects of various plasma parameters, viz., plasma beta (β), σ (temperature ratio of electrons to ions), and μd (ratio of the number density of dust to electrons) on the characteristics of magnetosonic cnoidal waves are also studied numerically. The findings of the present investigation may be helpful in describing the characteristics of various nonlinear excitations in Earth's magnetosphere, solar wind, Saturn's magnetosphere, and space/astrophysical environments, where many space observations by various satellites confirm the existence of dust grains, highly energetic electrons, and high plasma-β.

Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Eye Diseases.

PubMed

Harrell, C Randall; Simovic Markovic, Bojana; Fellabaum, Crissy; Arsenijevic, Aleksandar; Djonov, Valentin; Arsenijevic, Nebojsa; Volarevic, Vladislav

2018-05-18

Mesenchymal stem cells (MSCs) were, due to their immunomodulatory and pro-angiogenic characteristics, extensively explored as new therapeutic agents in cell-based therapy of uveitis, glaucoma, retinal and ocular surface diseases.Since it was recently revealed that exosomes play an important role in biological functions of MSCs, herewith we summarized current knowledge about the morphology, structure, phenotype and functional characteristics of MSC-derived exosomes emphasizing their therapeutic potential in the treatment of eye diseases.MSC-derived exosomes were as efficient as transplanted MSCs in limiting the extent of eye injury and inflammation. Immediately after intravitreal injection, MSC-derived exosomes, due to nano-dimension, diffused rapidly throughout the retina and significantly attenuated retinal damage and inflammation. MSC-derived exosomes successfully delivered trophic and immunomodulatory factors to the inner retina and efficiently promoted survival and neuritogenesis of injured retinal ganglion cells. MSC-derived exosomes efficiently suppressed migration of inflammatory cells, attenuated detrimental Th1 and Th17 cell-driven immune response and ameliorated experimental autoimmune uveitis. MSC-derived exosomes were able to fuse with the lysosomes within corneal cells, enabling delivering of MSC-derived active β-glucuronidase and consequent catabolism of accumulated glycosaminoglycans, indicating their therapeutic potential in the treatment of Mucopolysaccharidosis VII (Sly Syndrome). Importantly, beneficent effects were noticed only in animals that received MSC-derived exosomes and were not seen after therapy with fibroblasts-derived exosomes confirming specific therapeutic potential of MSCs and their products in the treatment of eye diseases.In conclusion, MSC-derived exosomes represent potentially new therapeutic agents in the therapy of degenerative and inflammatory ocular diseases.

Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-β Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease.

PubMed

Zhang, Qiang; Helfand, Brian T; Carneiro, Benedito A; Qin, Weijun; Yang, Ximing J; Lee, Chung; Zhang, Weipeng; Giles, Francis J; Cristofanilli, Massimo; Kuzel, Timothy M

2018-05-01

Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8 + T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-β (TGF-ß) under the control of herpes simplex virus-1 thymidine kinase. CD8 + T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(ζ) gene (PZ1) and dominant negative TGF-ß type II receptor (TßRIIDN), that could induce CD8 + T-cells to be PSMA reactive and insensitive to TGF-ß. Cr 51 release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-ß insensitive CD8 + T-cells was evaluated using an immunodeficient RAG-1 -/- mouse model. We found PSMA-specific, TGF-ß insensitive CD8 + T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-ß. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-ß, insensitive CD8 + T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8 + T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-ß insensitive CD8 + T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy. We investigated the role of a novel chimeric antigen receptor T-immunotherapy based on autologous metastatic castrate-resistant prostate cancer patient-derived prostate-specific membrane antigen (PSMA)-specific, transforming growth factor-ß insensitive CD8 + T-cells on PSMA-positive prostate cancer. We found that this chimeric antigen receptor T-cells could kill PSMA-positive prostate cancer specifically. The results suggest that this novel immunotherapy treatment is a potential new approach for men with metastatic castrate-resistant prostate cancer. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

The Effect of Music on the Test Scores of the Students in Limits and Derivatives Subject in the Mathematics Exams Done with Music

ERIC Educational Resources Information Center

Kesan, Cenk; Ozkalkan, Zuhal; Iric, Hamdullah; Kaya, Deniz

2012-01-01

In the exams based on limits and derivatives, in this study, it was tried to determine that if there was any difference in students' test scores according to the type of music listened to and environment without music. For this purpose, the achievement test including limits and derivatives and whose reliability coefficient of Cronbach Alpha is…

Microscale oxygraphy reveals OXPHOS impairment in MRC mutant cells

PubMed Central

Invernizzi, F.; D'Amato, I.; Jensen, P.B.; Ravaglia, S.; Zeviani, M.; Tiranti, V.

2012-01-01

Given the complexity of the respiratory chain structure, assembly and regulation, the diagnostic workout for the identification of defects of oxidative phosphorylation (OXPHOS) is a major challenge. Spectrophotometric assays, that measure the activity of individual respiratory complexes in tissue and cell homogenates or isolated mitochondria, are highly specific, but their utilization is limited by the availability of sufficient biological material and intrinsic sensitivity. A further limitation is tissue specificity, which usually determines attenuation, or disappearance, in cultured fibroblasts, of defects detected in muscle or liver. We used numerous fibroblast cell lines derived from patients with OXPHOS deficiencies to set up experimental protocols required for the direct readout of cellular respiration using the Seahorse XF96 apparatus, which measures oxygen consumption rate (OCR) and extra-cellular acidification rate (ECAR) in 96 well plates. Results demonstrate that first level screening based on microscale oxygraphy is more sensitive, cheaper and rapid than spectrophotometry for the biochemical evaluation of cells from patients with suspected mitochondrial disorders. PMID:22310368

Core-shell magnetic molecularly imprinted polymers used rhodamine B hydroxyproline derivate as template combined with in situ derivatization for the specific measurement of L-hydroxyproline.

PubMed

Zheng, Longfang; Zhao, Xian-En; Ji, Wenhua; Wang, Xiao; Tao, Yanduo; Sun, Jing; Xu, Yanqiu; Wang, Xin; Zhu, Shuyun; You, Jinmao

2018-01-12

In this work, a novel core-shell magnetic molecularly imprinted polymers (MMIPs) for the measurement of L-Hydroxyproline (Hyp) in dairy products was prepared. The derivative of Hyp using N-hydroxysuccinimidyl rhodamine B ester (RBS) as derivatization reagent was employed as template to prepare RBS-Hyp-MMIPs (Fe 3 O 4 @MIPs for RBS-Hyp). A new analytical procedure of in situ derivatization with MMIPs (ISD-MMIPs) has been developed for the specific extraction and determination of Hyp in dairy products by ultra high performance liquid chromatography tandem mass spectrometry. The RBS-Hyp-MMIPs was characterized by fourier transform infrared spectrometer and transmission electron microscopy, and evaluated by adsorption experiments. The adsorption process followed Langumuir adsorption isotherm with maximum adsorption capacity of RBS-Hyp on RBS-Hyp-MMIPs at 96 mg/g. In addition, RBS-Hyp-MMIPs showed a short equilibrium time (15.0 min), rapid magnetic separation (5 s) and high stability (retained 95.3% after six cycles). Under the optimized conditions, good linearity was observed with the limits of detection (S/N > 3) and limits of quantification (S/N > 10) at 0.1 and 0.5 ng/mL, respectively. On account of the specific extraction performance of RBS-Hyp-MMIPs, not any interference peak from real sample matrix was observed in the chromatograms of milk powder, liquid milk and milk drink. The proposed procedure was successfully applied for selective determination of Hyp from dairy products with satisfactory validation results, which is of great significance to food safety. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of the efficiency of antibody selection from semi-synthetic scFv and non-immune Fab phage display libraries against protein targets for rapid development of diagnostic immunoassays.

PubMed

Chan, Conrad E Z; Chan, Annie H Y; Lim, Angeline P C; Hanson, Brendon J

2011-10-28

Rapid development of diagnostic immunoassays against novel emerging or genetically modified pathogens in an emergency situation is dependent on the timely isolation of specific antibodies. Non-immune antibody phage display libraries are an efficient in vitro method for selecting monoclonal antibodies and hence ideal in these circumstances. Such libraries can be constructed from a variety of sources e.g. B cell cDNA or synthetically generated, and use a variety of antibody formats, typically scFv or Fab. However, antibody source and format can impact on the quality of antibodies generated and hence the effectiveness of this methodology for the timely production of antibodies. We have carried out a comparative screening of two antibody libraries, a semi-synthetic scFv library and a human-derived Fab library against the protective antigen toxin component of Bacillus anthracis and the epsilon toxin of Clostridium botulinum. We have shown that while the synthetic library produced a diverse collection of specific scFv-phage, these contained a high frequency of unnatural amber stops and glycosylation sites which limited their conversion to IgG, and also a high number which lost specificity when expressed as IgG. In contrast, these limitations were overcome by the use of a natural human library. Antibodies from both libraries could be used to develop sandwich ELISA assays with similar sensitivity. However, the ease and speed with which full-length IgG could be generated from the human-derived Fab library makes screening this type of library the preferable method for rapid antibody generation for diagnostic assay development. Copyright © 2011 Elsevier B.V. All rights reserved.

Generating autologous hematopoietic cells from human-induced pluripotent stem cells through ectopic expression of transcription factors.

PubMed

Hwang, Yongsung; Broxmeyer, Hal E; Lee, Man Ryul

2017-07-01

Hematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells. Advancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells. IPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.

Derivation and validation of two decision instruments for selective chest CT in blunt trauma: a multicenter prospective observational study (NEXUS Chest CT).

PubMed

Rodriguez, Robert M; Langdorf, Mark I; Nishijima, Daniel; Baumann, Brigitte M; Hendey, Gregory W; Medak, Anthony J; Raja, Ali S; Allen, Isabel E; Mower, William R

2015-10-01

Unnecessary diagnostic imaging leads to higher costs, longer emergency department stays, and increased patient exposure to ionizing radiation. We sought to prospectively derive and validate two decision instruments (DIs) for selective chest computed tomography (CT) in adult blunt trauma patients. From September 2011 to May 2014, we prospectively enrolled blunt trauma patients over 14 y of age presenting to eight US, urban level 1 trauma centers in this observational study. During the derivation phase, physicians recorded the presence or absence of 14 clinical criteria before viewing chest imaging results. We determined injury outcomes by CT radiology readings and categorized injuries as major or minor according to an expert-panel-derived clinical classification scheme. We then employed recursive partitioning to derive two DIs: Chest CT-All maximized sensitivity for all injuries, and Chest CT-Major maximized sensitivity for only major thoracic injuries (while increasing specificity). In the validation phase, we employed similar methodology to prospectively test the performance of both DIs. We enrolled 11,477 patients-6,002 patients in the derivation phase and 5,475 patients in the validation phase. The derived Chest CT-All DI consisted of (1) abnormal chest X-ray, (2) rapid deceleration mechanism, (3) distracting injury, (4) chest wall tenderness, (5) sternal tenderness, (6) thoracic spine tenderness, and (7) scapular tenderness. The Chest CT-Major DI had the same criteria without rapid deceleration mechanism. In the validation phase, Chest CT-All had a sensitivity of 99.2% (95% CI 95.4%-100%), a specificity of 20.8% (95% CI 19.2%-22.4%), and a negative predictive value (NPV) of 99.8% (95% CI 98.9%-100%) for major injury, and a sensitivity of 95.4% (95% CI 93.6%-96.9%), a specificity of 25.5% (95% CI 23.5%-27.5%), and a NPV of 93.9% (95% CI 91.5%-95.8%) for either major or minor injury. Chest CT-Major had a sensitivity of 99.2% (95% CI 95.4%-100%), a specificity of 31.7% (95% CI 29.9%-33.5%), and a NPV of 99.9% (95% CI 99.3%-100%) for major injury and a sensitivity of 90.7% (95% CI 88.3%-92.8%), a specificity of 37.9% (95% CI 35.8%-40.1%), and a NPV of 91.8% (95% CI 89.7%-93.6%) for either major or minor injury. Regarding the limitations of our work, some clinicians may disagree with our injury classification and sensitivity thresholds for injury detection. We prospectively derived and validated two DIs (Chest CT-All and Chest CT-Major) that identify blunt trauma patients with clinically significant thoracic injuries with high sensitivity, allowing for a safe reduction of approximately 25%-37% of unnecessary chest CTs. Trauma evaluation protocols that incorporate these DIs may decrease unnecessary costs and radiation exposure in the disproportionately young trauma population.

Statistical Mechanical Derivation of Jarzynski's Identity for Thermostated Non-Hamiltonian Dynamics

NASA Astrophysics Data System (ADS)

Cuendet, Michel A.

2006-03-01

The recent Jarzynski identity (JI) relates thermodynamic free energy differences to nonequilibrium work averages. Several proofs of the JI have been provided on the thermodynamic level. They rely on assumptions such as equivalence of ensembles in the thermodynamic limit or weakly coupled infinite heat baths. However, the JI is widely applied to NVT computer simulations involving finite numbers of particles, whose equations of motion are strongly coupled to a few extra degrees of freedom modeling a thermostat. In this case, the above assumptions are no longer valid. We propose a statistical mechanical approach to the JI solely based on the specific equations of motion, without any further assumption. We provide a detailed derivation for the non-Hamiltonian Nosé-Hoover dynamics, which is routinely used in computer simulations to produce canonical sampling.

Comparison of 3D Echocardiogram-Derived 3D Printed Valve Models to Molded Models for Simulated Repair of Pediatric Atrioventricular Valves.

PubMed

Scanlan, Adam B; Nguyen, Alex V; Ilina, Anna; Lasso, Andras; Cripe, Linnea; Jegatheeswaran, Anusha; Silvestro, Elizabeth; McGowan, Francis X; Mascio, Christopher E; Fuller, Stephanie; Spray, Thomas L; Cohen, Meryl S; Fichtinger, Gabor; Jolley, Matthew A

2018-03-01

Mastering the technical skills required to perform pediatric cardiac valve surgery is challenging in part due to limited opportunity for practice. Transformation of 3D echocardiographic (echo) images of congenitally abnormal heart valves to realistic physical models could allow patient-specific simulation of surgical valve repair. We compared materials, processes, and costs for 3D printing and molding of patient-specific models for visualization and surgical simulation of congenitally abnormal heart valves. Pediatric atrioventricular valves (mitral, tricuspid, and common atrioventricular valve) were modeled from transthoracic 3D echo images using semi-automated methods implemented as custom modules in 3D Slicer. Valve models were then both 3D printed in soft materials and molded in silicone using 3D printed "negative" molds. Using pre-defined assessment criteria, valve models were evaluated by congenital cardiac surgeons to determine suitability for simulation. Surgeon assessment indicated that the molded valves had superior material properties for the purposes of simulation compared to directly printed valves (p < 0.01). Patient-specific, 3D echo-derived molded valves are a step toward realistic simulation of complex valve repairs but require more time and labor to create than directly printed models. Patient-specific simulation of valve repair in children using such models may be useful for surgical training and simulation of complex congenital cases.

Refining Ovarian Cancer Test accuracy Scores (ROCkeTS): protocol for a prospective longitudinal test accuracy study to validate new risk scores in women with symptoms of suspected ovarian cancer.

PubMed

Sundar, Sudha; Rick, Caroline; Dowling, Francis; Au, Pui; Snell, Kym; Rai, Nirmala; Champaneria, Rita; Stobart, Hilary; Neal, Richard; Davenport, Clare; Mallett, Susan; Sutton, Andrew; Kehoe, Sean; Timmerman, Dirk; Bourne, Tom; Van Calster, Ben; Gentry-Maharaj, Aleksandra; Menon, Usha; Deeks, Jon

2016-08-09

Ovarian cancer (OC) is associated with non-specific symptoms such as bloating, making accurate diagnosis challenging: only 1 in 3 women with OC presents through primary care referral. National Institute for Health and Care Excellence guidelines recommends sequential testing with CA125 and routine ultrasound in primary care. However, these diagnostic tests have limited sensitivity or specificity. Improving accurate triage in women with vague symptoms is likely to improve mortality by streamlining referral and care pathways. The Refining Ovarian Cancer Test Accuracy Scores (ROCkeTS; HTA 13/13/01) project will derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This protocol refers to the prospective study only (phase III). ROCkeTS comprises four parallel phases. The full ROCkeTS protocol can be found at http://www.birmingham.ac.uk/ROCKETS. Phase III is a prospective test accuracy study. The study will recruit 2450 patients from 15 UK sites. Recruited patients complete symptom and anxiety questionnaires, donate a serum sample and undergo ultrasound scored as per International Ovarian Tumour Analysis (IOTA) criteria. Recruitment is at rapid access clinics, emergency departments and elective clinics. Models to be evaluated include those based on ultrasound derived by the IOTA group and novel models derived from analysis of existing data sets. Estimates of sensitivity, specificity, c-statistic (area under receiver operating curve), positive predictive value and negative predictive value of diagnostic tests are evaluated and a calibration plot for models will be presented. ROCkeTS has received ethical approval from the NHS West Midlands REC (14/WM/1241) and is registered on the controlled trials website (ISRCTN17160843) and the National Institute of Health Research Cancer and Reproductive Health portfolios. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Decellularized Tissue and Cell-Derived Extracellular Matrices as Scaffolds for Orthopaedic Tissue Engineering

PubMed Central

Cheng, Christina W.; Solorio, Loran D.; Alsberg, Eben

2014-01-01

The reconstruction of musculoskeletal defects is a constant challenge for orthopaedic surgeons. Musculoskeletal injuries such as fractures, chondral lesions, infections and tumor debulking can often lead to large tissue voids requiring reconstruction with tissue grafts. Autografts are currently the gold standard in orthopaedic tissue reconstruction; however, there is a limit to the amount of tissue that can be harvested before compromising the donor site. Tissue engineering strategies using allogeneic or xenogeneic decellularized bone, cartilage, skeletal muscle, tendon and ligament have emerged as promising potential alternative treatment. The extracellular matrix provides a natural scaffold for cell attachment, proliferation and differentiation. Decellularization of in vitro cell-derived matrices can also enable the generation of autologous constructs from tissue specific cells or progenitor cells. Although decellularized bone tissue is widely used clinically in orthopaedic applications, the exciting potential of decellularized cartilage, skeletal muscle, tendon and ligament cell-derived matrices has only recently begun to be explored for ultimate translation to the orthopaedic clinic. PMID:24417915

Modeling the Capacitive Deionization Process in Dual-Porosity Electrodes

DOE PAGES

Gabitto, Jorge; Tsouris, Costas

2016-04-28

In many areas of the world, there is a need to increase water availability. Capacitive deionization (CDI) is an electrochemical water treatment process that can be a viable alternative for treating water and for saving energy. A model is presented to simulate the CDI process in heterogeneous porous media comprising two different pore sizes. It is based on a theory for capacitive charging by ideally polarizable porous electrodes without Faradaic reactions or specific adsorption of ions. A two steps volume averaging technique is used to derive the averaged transport equations in the limit of thin electrical double layers. A one-equationmore » model based on the principle of local equilibrium is derived. The constraints determining the range of application of the one-equation model are presented. The effective transport parameters for isotropic porous media are calculated solving the corresponding closure problems. The source terms that appear in the average equations are calculated using theoretical derivations. The global diffusivity is calculated by solving the closure problem.« less

3D-CAM: Derivation and Validation of a 3-Minute Diagnostic Interview for CAM-defined Delirium

PubMed Central

Marcantonio, Edward R.; Ngo, Long H.; O’Connor, Margaret; Jones, Richard N.; Crane, Paul K.; Metzger, Eran D.; Inouye, Sharon K.

2015-01-01

Background Delirium is common, morbid, and costly, yet remains often unrecognized in most clinical settings. The Confusion Assessment Method (CAM) is the most widely used diagnostic algorithm, and operationalizing its features would represent a substantial advance for clinical care. Objective To derive the 3D-CAM, a new 3-minute diagnostic assessment for CAM-defined delirium, and to validate it against a clinical reference standard. Design Diagnostic test study Setting 4 general medicine units in an academic medical center Participants 201 inpatients aged ≥ 75 years old Measurements We identified 20 items that best operationalized the 4 CAM diagnostic features to create the 3D-CAM. For prospective validation, 3D-CAM assessments were administered by trained research assistants. Independently, clinicians performed an extensive assessment that included patient interviews, family interviews, and review of the medical record. These data were considered by an expert panel to determine the presence or absence of delirium and dementia (reference standard). We compared the 3D-CAM delirium determination to the reference standard in all patients and in subgroups with and without dementia. Results The 201 participants in the prospective validation study had mean age (SD) of 84 (5.5) years, and 27% had dementia. The expert panel identified delirium in 21%. Median administration time for 3D-CAM was 3 minutes (inter-quartile range: 2–5 minutes). The sensitivity [95% CI] of 3D-CAM was 95% [84%, 99%] and the specificity was 94% [90%, 97%]. The 3D-CAM performed well in patients both with dementia (sensitivity=96% [82%, 100%], specificity=86% [67%, 96%]) and without dementia (sensitivity=93% [66%, 100%], specificity=96% [91%,99%]). Limitations Limited to single center, cross-sectional, and medicine patients only Conclusion The 3D-CAM operationalizes the CAM algorithm using a 3-minute structured assessment with high sensitivity and specificity relative to a reference standard and could be an important tool for improving recognition of delirium. PMID:25329203

A PEGylated platelet free plasma hydrogel based composite scaffold enables stable vascularization and targeted cell delivery for volumetric muscle loss.

PubMed

Aurora, Amit; Wrice, Nicole; Walters, Thomas J; Christy, Robert J; Natesan, Shanmugasundaram

2018-01-01

Extracellular matrix (ECM) scaffolds are being used for the clinical repair of soft tissue injuries. Although improved functional outcomes have been reported, ECM scaffolds show limited tissue specific remodeling response with concomitant deposition of fibrotic tissue. One plausible explanation is the regression of blood vessels which may be limiting the diffusion of oxygen and nutrients across the scaffold. Herein we develop a composite scaffold as a vasculo-inductive platform by integrating PEGylated platelet free plasma (PFP) hydrogel with a muscle derived ECM scaffold (m-ECM). In vitro, adipose derived stem cells (ASCs) seeded onto the composite scaffold differentiated into two distinct morphologies, a tubular network in the hydrogel, and elongated structures along the m-ECM scaffold. The composite scaffold showed a high expression of ITGA5, ITGB1, and FN and a synergistic up-regulation of ang1 and tie-2 transcripts. The in vitro ability of the composite scaffold to provide extracellular milieu for cell adhesion and molecular cues to support vessel formation was investigated in a rodent volumetric muscle loss (VML) model. The composite scaffold delivered with ASCs supported robust and stable vascularization. Additionally, the composite scaffold supported increased localization of ASCs in the defect demonstrating its ability for localized cell delivery. Interestingly, ASCs were observed homing in the injured muscle and around the perivascular space possibly to stabilize the host vasculature. In conclusion, the composite scaffold delivered with ASCs presents a promising approach for scaffold vascularization. The versatile nature of the composite scaffold also makes it easily adaptable for the repair of soft tissue injuries. Decellularized extracellular matrix (ECM) scaffolds when used for soft tissue repair is often accompanied by deposition of fibrotic tissue possibly due to limited scaffold vascularization, which limits the diffusion of oxygen and nutrients across the scaffold. Although a variety of scaffold vascularization strategies has been investigated, their limitations preclude rapid clinical translation. In this study we have developed a composite scaffold by integrating bi-functional polyethylene glycol modified platelet free plasma (PEGylated PFP) with adipose derived stem cells (ASCs) along with a muscle derived ECM scaffold (m-ECM). The composite scaffold provides a vasculo-inductive and an effective cell delivery platform for volumetric muscle loss. Copyright © 2017 Acta Materialia Inc. All rights reserved.

Helicopter noise regulations: An industry perspective

NASA Technical Reports Server (NTRS)

Wagner, R. A.

1978-01-01

A review of helicopter noise measurement programs and noise reduction/economic studies of FAA is given along with a critique of a study which addresses the economic impact of noise reduction on helicopter noise. Modification of several helicopters to reduce noise and demonstrate the economic impact of the application of the current state-of-the-art technology is discussed. Specific helicopters described include Boeing Vertol 347 Helicopter, Hughes OH-6 Helicopter, and Hughes 269C Helicopter. Other topics covered include: (1) noise trends and possible noise limits; (2) accuracy of helicopter noise prediction techniques; (3) limited change possibilities of derivatives; and (4) rotor impulsive noise. The unique operational capabilities of helicopters and the implications relative to noise regulations and certification are discussed.

Molecular beacon-enabled purification of living cells by targeting cell type-specific mRNAs.

PubMed

Wile, Brian M; Ban, Kiwon; Yoon, Young-Sup; Bao, Gang

2014-10-01

Molecular beacons (MBs) are dual-labeled oligonucleotides that fluoresce only in the presence of complementary mRNA. The use of MBs to target specific mRNAs allows sorting of specific cells from a mixed cell population. In contrast to existing approaches that are limited by available surface markers or selectable metabolic characteristics, the MB-based method enables the isolation of a wide variety of cells. For example, the ability to purify specific cell types derived from pluripotent stem cells (PSCs) is important for basic research and therapeutics. In addition to providing a general protocol for MB design, validation and nucleofection into cells, we describe how to isolate a specific cell population from differentiating PSCs. By using this protocol, we have successfully isolated cardiomyocytes differentiated from mouse or human PSCs (hPSCs) with ∼ 97% purity, as confirmed by electrophysiology and immunocytochemistry. After designing MBs, their ordering and validation requires 2 weeks, and the isolation process requires 3 h.

Modeling to Optimize Terminal Stem Cell Differentiation

PubMed Central

Gallicano, G. Ian

2013-01-01

Embryonic stem cell (ESC), iPCs, and adult stem cells (ASCs) all are among the most promising potential treatments for heart failure, spinal cord injury, neurodegenerative diseases, and diabetes. However, considerable uncertainty in the production of ESC-derived terminally differentiated cell types has limited the efficiency of their development. To address this uncertainty, we and other investigators have begun to employ a comprehensive statistical model of ESC differentiation for determining the role of intracellular pathways (e.g., STAT3) in ESC differentiation and determination of germ layer fate. The approach discussed here applies the Baysian statistical model to cell/developmental biology combining traditional flow cytometry methodology and specific morphological observations with advanced statistical and probabilistic modeling and experimental design. The final result of this study is a unique tool and model that enhances the understanding of how and when specific cell fates are determined during differentiation. This model provides a guideline for increasing the production efficiency of therapeutically viable ESCs/iPSCs/ASC derived neurons or any other cell type and will eventually lead to advances in stem cell therapy. PMID:24278782

A PITX3-EGFP Reporter Line Reveals Connectivity of Dopamine and Non-dopamine Neuronal Subtypes in Grafts Generated from Human Embryonic Stem Cells.

PubMed

Niclis, Jonathan C; Gantner, Carlos W; Hunt, Cameron P J; Kauhausen, Jessica A; Durnall, Jennifer C; Haynes, John M; Pouton, Colin W; Parish, Clare L; Thompson, Lachlan H

2017-09-12

Development of safe and effective stem cell-based therapies for brain repair requires an in-depth understanding of the in vivo properties of neural grafts generated from human stem cells. Replacing dopamine neurons in Parkinson's disease remains one of the most anticipated applications. Here, we have used a human PITX3-EGFP embryonic stem cell line to characterize the connectivity of stem cell-derived midbrain dopamine neurons in the dopamine-depleted host brain with an unprecedented level of specificity. The results show that the major A9 and A10 subclasses of implanted dopamine neurons innervate multiple, developmentally appropriate host targets but also that the majority of graft-derived connectivity is non-dopaminergic. These findings highlight the promise of stem cell-based procedures for anatomically correct reconstruction of specific neuronal pathways but also emphasize the scope for further refinement in order to limit the inclusion of uncharacterized and potentially unwanted cell types. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via re-specification of lineage-restricted precursors

PubMed Central

Doulatov, Sergei; Vo, Linda T.; Chou, Stephanie S.; Kim, Peter G.; Arora, Natasha; Li, Hu; Hadland, Brandon K.; Bernstein, Irwin D.; Collins, James J.; Zon, Leonard I.; Daley, George Q.

2013-01-01

Summary Human pluripotent stem cells (hPSCs) represent a promising source of patient-specific cells for disease modeling, drug screens, and cellular therapies. However, the inability to derive engraftable human hematopoietic stem and progenitor (HSPCs) has limited their characterization to in vitro assays. We report a strategy to re-specify lineage-restricted CD34+CD45+ myeloid precursors derived from hPSCs into multilineage progenitors that can be expanded in vitro and engraft in vivo. HOXA9, ERG, and RORA conferred self-renewal and multilineage potential in vitro and maintained primitive CD34+CD38− cells. Screening cells via transplantation revealed that two additional factors, SOX4 and MYB, were required for engraftment. Progenitors specified with all five factors gave rise to reproducible short-term engraftment with myeloid and erythroid lineages. Erythroid precursors underwent hemoglobin switching in vivo, silencing embryonic and activating adult globin expression. Our combinatorial screening approach establishes a strategy for obtaining transcription factor-mediated engraftment of blood progenitors from human pluripotent cells. PMID:24094326

Nuclear Medicine Imaging of Prostate Cancer.

PubMed

Schreiter, V; Reimann, C; Geisel, D; Schreiter, N F

2016-11-01

The new tracer Gallium-68 prostate-specific membrane antigen (Ga-68 PSMA) yields new promising options for the PET/CT diagnosis of prostate cancer (PCa) and its metastases. To overcome limitations of hybrid imaging, known from the use of choline derivatives, seems to be possible with the use of Ga-68 PSMA for PCa. The benefits of hybrid imaging with Ga-68 PSMA for PCa compared to choline derivatives shall be discussed in this article based on an overview of the current literature. Key Points: • Ga-68 PSMA PET/CT can achieve higher detection rates of PCa lesions than PET/CT performed with choline derivatives• The new tracer Ga-68 PSMA has the advantage of high specificity, independence of PSA-level and low nonspecific tracer uptake in surrounding tissue• The new tracer Ga-68 PSMA seems very suitable for MR-PET diagnostic Citation Format: • Schreiter V, Reimann C, Geisel D et al. Nuclear Medicine Imaging of Prostate Cancer. Fortschr Röntgenstr 2016; 188: 1037 - 1044. © Georg Thieme Verlag KG Stuttgart · New York.

Transgenic Citrus Expressing an Arabidopsis NPR1 Gene Exhibit Enhanced Resistance against Huanglongbing (HLB; Citrus Greening).

PubMed

Dutt, Manjul; Barthe, Gary; Irey, Michael; Grosser, Jude

2015-01-01

Commercial sweet orange cultivars lack resistance to Huanglongbing (HLB), a serious phloem limited bacterial disease that is usually fatal. In order to develop sustained disease resistance to HLB, transgenic sweet orange cultivars 'Hamlin' and 'Valencia' expressing an Arabidopsis thaliana NPR1 gene under the control of a constitutive CaMV 35S promoter or a phloem specific Arabidopsis SUC2 (AtSUC2) promoter were produced. Overexpression of AtNPR1 resulted in trees with normal phenotypes that exhibited enhanced resistance to HLB. Phloem specific expression of NPR1 was equally effective for enhancing disease resistance. Transgenic trees exhibited reduced diseased severity and a few lines remained disease-free even after 36 months of planting in a high-disease pressure field site. Expression of the NPR1 gene induced expression of several native genes involved in the plant defense signaling pathways. The AtNPR1 gene being plant derived can serve as a component for the development of an all plant T-DNA derived consumer friendly GM tree.

Development and evaluation of event-specific quantitative PCR method for genetically modified soybean A2704-12.

PubMed

Takabatake, Reona; Akiyama, Hiroshi; Sakata, Kozue; Onishi, Mari; Koiwa, Tomohiro; Futo, Satoshi; Minegishi, Yasutaka; Teshima, Reiko; Mano, Junichi; Furui, Satoshi; Kitta, Kazumi

2011-01-01

A novel real-time PCR-based analytical method was developed for the event-specific quantification of a genetically modified (GM) soybean event; A2704-12. During the plant transformation, DNA fragments derived from pUC19 plasmid were integrated in A2704-12, and the region was found to be A2704-12 specific. The pUC19-derived DNA sequences were used as primers for the specific detection of A2704-12. We first tried to construct a standard plasmid for A2704-12 quantification using pUC19. However, non-specific signals appeared with both qualitative and quantitative PCR analyses using the specific primers with pUC19 as a template, and we then constructed a plasmid using pBR322. The conversion factor (C(f)), which is required to calculate the amount of the genetically modified organism (GMO), was experimentally determined with two real-time PCR instruments, the Applied Biosystems 7900HT and the Applied Biosystems 7500. The determined C(f) values were both 0.98. The quantitative method was evaluated by means of blind tests in multi-laboratory trials using the two real-time PCR instruments. The limit of quantitation for the method was estimated to be 0.1%. The trueness and precision were evaluated as the bias and reproducibility of relative standard deviation (RSD(R)), and the determined bias and RSD(R) values for the method were each less than 20%. These results suggest that the developed method would be suitable for practical analyses for the detection and quantification of A2704-12.

Limits on tensor coupling from neutron β decay

NASA Astrophysics Data System (ADS)

Pattie, R. W., Jr.; Hickerson, K. P.; Young, A. R.

2013-10-01

Limits on the tensor couplings generating a Fierz interference term b in mixed Gamow-Teller Fermi decays can be derived by combining data from measurements of angular correlation parameters in neutron decay, the neutron lifetime, and GV=GFVud as extracted from measurements of the Ft values from the 0+→0+ superallowed decay data set. These limits are derived by comparing the neutron β-decay rate as predicted in the standard model with the measured decay rate while allowing for the existence of beyond the standard model (BSM) couplings. We analyze limits derived from the electron-neutrino asymmetry a, or the beta asymmetry A, finding that the most stringent limits for CT/CA under the assumption of no right-handed neutrinos is -0.0026

Low-mass dark matter search with CDMSlite

NASA Astrophysics Data System (ADS)

Agnese, R.; Anderson, A. J.; Aralis, T.; Aramaki, T.; Arnquist, I. J.; Baker, W.; Balakishiyeva, D.; Barker, D.; Basu Thakur, R.; Bauer, D. A.; Binder, T.; Bowles, M. A.; Brink, P. L.; Bunker, R.; Cabrera, B.; Caldwell, D. O.; Calkins, R.; Cartaro, C.; Cerdeño, D. G.; Chang, Y.; Chagani, H.; Chen, Y.; Cooley, J.; Cornell, B.; Cushman, P.; Daal, M.; Di Stefano, P. C. F.; Doughty, T.; Esteban, L.; Fascione, E.; Figueroa-Feliciano, E.; Fritts, M.; Gerbier, G.; Ghaith, M.; Godfrey, G. L.; Golwala, S. R.; Hall, J.; Harris, H. R.; Hong, Z.; Hoppe, E. W.; Hsu, L.; Huber, M. E.; Iyer, V.; Jardin, D.; Jastram, A.; Jena, C.; Kelsey, M. H.; Kennedy, A.; Kubik, A.; Kurinsky, N. A.; Leder, A.; Loer, B.; Lopez Asamar, E.; Lukens, P.; MacDonell, D.; Mahapatra, R.; Mandic, V.; Mast, N.; Miller, E. H.; Mirabolfathi, N.; Moffatt, R. A.; Mohanty, B.; Morales Mendoza, J. D.; Nelson, J.; Orrell, J. L.; Oser, S. M.; Page, K.; Page, W. A.; Partridge, R.; Pepin, M.; Peñalver Martinez, M.; Phipps, A.; Poudel, S.; Pyle, M.; Qiu, H.; Rau, W.; Redl, P.; Reisetter, A.; Reynolds, T.; Roberts, A.; Robinson, A. E.; Rogers, H. E.; Saab, T.; Sadoulet, B.; Sander, J.; Schneck, K.; Schnee, R. W.; Scorza, S.; Senapati, K.; Serfass, B.; Speller, D.; Stein, M.; Street, J.; Tanaka, H. A.; Toback, D.; Underwood, R.; Villano, A. N.; von Krosigk, B.; Welliver, B.; Wilson, J. S.; Wilson, M. J.; Wright, D. H.; Yellin, S.; Yen, J. J.; Young, B. A.; Zhang, X.; Zhao, X.; SuperCDMS Collaboration

2018-01-01

The SuperCDMS experiment is designed to directly detect weakly interacting massive particles (WIMPs) that may constitute the dark matter in our Galaxy. During its operation at the Soudan Underground Laboratory, germanium detectors were run in the CDMSlite mode to gather data sets with sensitivity specifically for WIMPs with masses <10 GeV /c2 . In this mode, a higher detector-bias voltage is applied to amplify the phonon signals produced by drifting charges. This paper presents studies of the experimental noise and its effect on the achievable energy threshold, which is demonstrated to be as low as 56 eVee (electron equivalent energy). The detector-biasing configuration is described in detail, with analysis corrections for voltage variations to the level of a few percent. Detailed studies of the electric-field geometry, and the resulting successful development of a fiducial parameter, eliminate poorly measured events, yielding an energy resolution ranging from ˜9 eVee at 0 keV to 101 eVee at ˜10 keVee . New results are derived for astrophysical uncertainties relevant to the WIMP-search limits, specifically examining how they are affected by variations in the most probable WIMP velocity and the Galactic escape velocity. These variations become more important for WIMP masses below 10 GeV /c2 . Finally, new limits on spin-dependent low-mass WIMP-nucleon interactions are derived, with new parameter space excluded for WIMP masses ≲3 GeV /c2.

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

Agnese, R.; Anderson, A. J.; Aralis, T.

The SuperCDMS experiment is designed to directly detect weakly interacting massive particles (WIMPs) that may constitute the dark matter in our Galaxy. During its operation at the Soudan Underground Laboratory, germanium detectors were run in the CDMSlite mode to gather data sets with sensitivity specifically for WIMPs with masses < 10 GeV/c 2. In this mode, a higher detector-bias voltage is applied to amplify the phonon signals produced by drifting charges. This article presents studies of the experimental noise and its effect on the achievable energy threshold, which is demonstrated to be as low as 56 eV ee (electron equivalentmore » energy). The detector-biasing configuration is described in detail, with analysis corrections for voltage variations to the level of a few percent. Detailed studies of the electric-field geometry, and the resulting successful development of a fiducial parameter, eliminate poorly measured events, yielding an energy resolution ranging from ~ 9 eV ee at 0 keV to 101 eV ee at ~ 10 keV ee. New results are derived for astrophysical uncertainties relevant to the WIMP-search limits, specifically examining how they are affected by variations in the most probable WIMP velocity and the Galactic escape velocity. These variations become more important for WIMP masses below 10 GeV/c 2. Finally, new limits on spin-dependent low-mass WIMP-nucleon interactions are derived, with new parameter space excluded for WIMP masses ≲ 3 GeV/c 2.« less

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

Agnese, R.; Anderson, A. J.; Aralis, T.

The SuperCDMS experiment is designed to directly detect WIMPs (Weakly Interacting Massive Particles) that may constitute the dark matter in our galaxy. During its operation at the Soudan Underground Laboratory, germanium detectors were run in the CDMSlite (Cryogenic Dark Matter Search low ionization threshold experiment) mode to gather data sets with sensitivity specifically for WIMPs with massesmore » $${<}10$$ GeV/$c^2$. In this mode, a large detector-bias voltage is applied to amplify the phonon signals produced by drifting charges. This paper presents studies of the experimental noise and its effect on the achievable energy threshold, which is demonstrated to be as low as 56 eV$$_{\\text{ee}}$$ (electron equivalent energy). The detector biasing configuration is described in detail, with analysis corrections for voltage variations to the level of a few percent. Detailed studies of the electric-field geometry, and the resulting successful development of a fiducial parameter, eliminate poorly measured events, yielding an energy resolution ranging from $${\\sim}$$9 eV$$_{\\text{ee}}$$ at 0 keV to 101 eV$$_{\\text{ee}}$$ at $${\\sim}$$10 keV$$_{\\text{ee}}$$. New results are derived for astrophysical uncertainties relevant to the WIMP-search limits, specifically examining how they are affected by variations in the most probable WIMP velocity and the galactic escape velocity. These variations become more important for WIMP masses below 10 GeV/$c^2$. Finally, new limits on spin-dependent low-mass WIMP-nucleon interactions are derived, with new parameter space excluded for WIMP masses $${\\lesssim}$$3 GeV/$c^2$.« less

Ion-channel genosensor for the detection of specific DNA sequences derived from Plum Pox Virus in plant extracts.

PubMed

Malecka, Kamila; Michalczuk, Lech; Radecka, Hanna; Radecki, Jerzy

2014-10-09

A DNA biosensor for detection of specific oligonucleotides sequences of Plum Pox Virus (PPV) in plant extracts and buffer is proposed. The working principles of a genosensor are based on the ion-channel mechanism. The NH2-ssDNA probe was deposited onto a glassy carbon electrode surface to form an amide bond between the carboxyl group of oxidized electrode surface and amino group from ssDNA probe. The analytical signals generated as a result of hybridization were registered in Osteryoung square wave voltammetry in the presence of [Fe(CN)6]3-/4- as a redox marker. The 22-mer and 42-mer complementary ssDNA sequences derived from PPV and DNA samples from plants infected with PPV were used as targets. Similar detection limits of 2.4 pM (31.0 pg/mL) and 2.3 pM (29.5 pg/mL) in the concentration range 1-8 pM were observed in the presence of the 22-mer ssDNA and 42-mer complementary ssDNA sequences of PPV, respectively. The genosensor was capable of discriminating between samples consisting of extracts from healthy plants and leaf extracts from infected plants in the concentration range 10-50 pg/mL. The detection limit was 12.8 pg/mL. The genosensor displayed good selectivity and sensitivity. The 20-mer partially complementary DNA sequences with four complementary bases and DNA samples from healthy plants used as negative controls generated low signal.

Low-mass dark matter search with CDMSlite

DOE PAGES

Agnese, R.; Anderson, A. J.; Aralis, T.; ...

2018-01-17

The SuperCDMS experiment is designed to directly detect weakly interacting massive particles (WIMPs) that may constitute the dark matter in our Galaxy. During its operation at the Soudan Underground Laboratory, germanium detectors were run in the CDMSlite mode to gather data sets with sensitivity specifically for WIMPs with masses < 10 GeV/c 2. In this mode, a higher detector-bias voltage is applied to amplify the phonon signals produced by drifting charges. This article presents studies of the experimental noise and its effect on the achievable energy threshold, which is demonstrated to be as low as 56 eV ee (electron equivalentmore » energy). The detector-biasing configuration is described in detail, with analysis corrections for voltage variations to the level of a few percent. Detailed studies of the electric-field geometry, and the resulting successful development of a fiducial parameter, eliminate poorly measured events, yielding an energy resolution ranging from ~ 9 eV ee at 0 keV to 101 eV ee at ~ 10 keV ee. New results are derived for astrophysical uncertainties relevant to the WIMP-search limits, specifically examining how they are affected by variations in the most probable WIMP velocity and the Galactic escape velocity. These variations become more important for WIMP masses below 10 GeV/c 2. Finally, new limits on spin-dependent low-mass WIMP-nucleon interactions are derived, with new parameter space excluded for WIMP masses ≲ 3 GeV/c 2.« less

In vivo imaging of cancer cell size and cellularity using temporal diffusion spectroscopy.

PubMed

Jiang, Xiaoyu; Li, Hua; Xie, Jingping; McKinley, Eliot T; Zhao, Ping; Gore, John C; Xu, Junzhong

2017-07-01

A temporal diffusion MRI spectroscopy based approach has been developed to quantify cancer cell size and density in vivo. A novel imaging microstructural parameters using limited spectrally edited diffusion (IMPULSED) method selects a specific limited diffusion spectral window for an accurate quantification of cell sizes ranging from 10 to 20 μm in common solid tumors. In practice, it is achieved by a combination of a single long diffusion time pulsed gradient spin echo (PGSE) and three low-frequency oscillating gradient spin echo (OGSE) acquisitions. To validate our approach, hematoxylin and eosin staining and immunostaining of cell membranes, in concert with whole slide imaging, were used to visualize nuclei and cell boundaries, and hence, enabled accurate estimates of cell size and cellularity. Based on a two compartment model (incorporating intra- and extracellular spaces), accurate estimates of cell sizes were obtained in vivo for three types of human colon cancers. The IMPULSED-derived apparent cellularities showed a stronger correlation (r = 0.81; P < 0.0001) with histology-derived cellularities than conventional ADCs (r = -0.69; P < 0.03). The IMPULSED approach samples a specific region of temporal diffusion spectra with enhanced sensitivity to length scales of 10-20 μm, and enables measurements of cell sizes and cellularities in solid tumors in vivo. Magn Reson Med 78:156-164, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Estimating Highway Volumes Using Vehicle Probe Data - Proof of Concept: Preprint

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

Hou, Yi; Young, Stanley E; Sadabadi, Kaveh

This paper examines the feasibility of using sampled commercial probe data in combination with validated continuous counter data to accurately estimate vehicle volume across the entire roadway network, for any hour during the year. Currently either real time or archived volume data for roadways at specific times are extremely sparse. Most volume data are average annual daily traffic (AADT) measures derived from the Highway Performance Monitoring System (HPMS). Although methods to factor the AADT to hourly averages for typical day of week exist, actual volume data is limited to a sparse collection of locations in which volumes are continuously recorded.more » This paper explores the use of commercial probe data to generate accurate volume measures that span the highway network providing ubiquitous coverage in space, and specific point-in-time measures for a specific date and time. The paper examines the need for the data, fundamental accuracy limitations based on a basic statistical model that take into account the sampling nature of probe data, and early results from a proof of concept exercise revealing the potential of probe type data calibrated with public continuous count data to meet end user expectations in terms of accuracy of volume estimates.« less

Modification of Expanded NK Cells with Chimeric Antigen Receptor mRNA for Adoptive Cellular Therapy.

PubMed

Chu, Yaya; Flower, Allyson; Cairo, Mitchell S

2016-01-01

NK cells are bone marrow-derived cytotoxic lymphocytes that play a major role in the rejection of tumors and cells infected by viruses. The regulation of NK activation vs inhibition is regulated by the expression of a variety of NK receptors (NKRs) and specific NKRs' ligands expressed on their targets. However, factors limiting NK therapy include small numbers of active NK cells in unexpanded peripheral blood and lack of specific tumor targeting. Chimeric antigen receptors (CAR) usually include a single-chain Fv variable fragment from a monoclonal antibody, a transmembrane hinge region, and a signaling domain such as CD28, CD3-zeta, 4-1BB (CD137), or 2B4 (CD244) endodimers. Redirecting NK cells with a CAR will circumvent the limitations of the lack of NK targeting specificity. This chapter focuses on the methods to expand human NK cells from peripheral blood by co-culturing with feeder cells and to modify the expanded NK cells efficiently with the in vitro transcribed CAR mRNA by electroporation and to test the functionality of the CAR-modified expanded NK cells for use in adoptive cellular immunotherapy.

Genomic Alterations in Advanced Esophageal Cancer May Lead to Subtype-Specific Therapies

PubMed Central

Forde, Patrick M.

2013-01-01

The development of targeted agents for metastatic esophageal or gastroesophageal junction (GEJ) tumors has been limited when compared with that for other common tumors. To date, the anti-human epidermal growth factor receptor-2 (HER-2) antibody, trastuzumab, in combination with chemotherapy, is the only approved novel agent for these cancers, and its use is limited to the small population of patients whose tumors overexpress HER-2. Despite recent progress in the field, median overall survival remains only 8–12 months for patients with stage IV esophageal or GEJ cancer. In this article, we examine the molecular aberrations thought to drive the development and spread of esophageal cancer and identify promising targets for specific tumor inhibition. Data from clinical studies of targeted agents are reviewed, including epidermal growth factor receptor antibodies, tyrosine kinase inhibitors, HER-2, and vascular endothelial growth factor-directed therapy. Current and future targets include MET, fibroblast growth factor receptor, and immune-based therapies. Evidence from trials to date suggests that molecularly unselected patient cohorts derive minimal benefit from most target-specific agents, suggesting that future collaborative investigation should focus on preselected molecular subgroups of patients with this challenging heterogeneous disease. PMID:23853247

An Excel tool for deriving key photosynthetic parameters from combined gas exchange and chlorophyll fluorescence: theory and practice.

PubMed

Bellasio, Chandra; Beerling, David J; Griffiths, Howard

2016-06-01

Combined photosynthetic gas exchange and modulated fluorometres are widely used to evaluate physiological characteristics associated with phenotypic and genotypic variation, whether in response to genetic manipulation or resource limitation in natural vegetation or crops. After describing relatively simple experimental procedures, we present the theoretical background to the derivation of photosynthetic parameters, and provide a freely available Excel-based fitting tool (EFT) that will be of use to specialists and non-specialists alike. We use data acquired in concurrent variable fluorescence-gas exchange experiments, where A/Ci and light-response curves have been measured under ambient and low oxygen. From these data, the EFT derives light respiration, initial PSII (photosystem II) photochemical yield, initial quantum yield for CO2 fixation, fraction of incident light harvested by PSII, initial quantum yield for electron transport, electron transport rate, rate of photorespiration, stomatal limitation, Rubisco (ribulose 1·5-bisphosphate carboxylase/oxygenase) rate of carboxylation and oxygenation, Rubisco specificity factor, mesophyll conductance to CO2 diffusion, light and CO2 compensation point, Rubisco apparent Michaelis-Menten constant, and Rubisco CO2 -saturated carboxylation rate. As an example, a complete analysis of gas exchange data on tobacco plants is provided. We also discuss potential measurement problems and pitfalls, and suggest how such empirical data could subsequently be used to parameterize predictive photosynthetic models. © 2015 John Wiley & Sons Ltd.

Maintenance of Ecosystem Nitrogen Limitation by Ephemeral Forest Disturbance: An Assessment using MODIS, Hyperion, and Landsat ETM+

NASA Technical Reports Server (NTRS)

McNeil, Brenden E.; deBeurs, Kirsten M.; Eshleman, Keith N.; Foster, Jane R.; Townsend, Philip A.

2007-01-01

Ephemeral disturbances, such as non-lethal insect defoliations and crown damage from meteorological events, can significantly affect the delivery of ecosystem services by helping maintain nitrogen (N) limitation in temperate forest ecosystems. However, the impacts of these disturbances are difficult to observe across the broad-scales at which they affect ecosystem function. Using remotely sensed measures and field data, we find support for the hypothesis that ephemeral disturbances help maintain landscape-wide ecosystem N limitation. Specifically, a phenology-based defoliation index derived from daily MODIS satellite imagery predicts three ecosystem responses from oak-dominated forested watersheds: elevated stream water N export (R(exp 2) = 0.48), decreased foliar N (R(exp 2) = 0.69, assessed with Hyperion imagery), and reduced vegetation growth vigor (R(exp 2) = 0.49, assessed with Landsat ETM+ imagery). The results indicate that ephemeral disturbances and other forest stressors may sustain N limitation by reducing the ability of trees to compete for--and retain--soil available N.

Automated design of degenerate codon libraries.

PubMed

Mena, Marco A; Daugherty, Patrick S

2005-12-01

Degenerate codon libraries are frequently used in protein engineering and evolution studies but are often limited to targeting a small number of positions to adequately limit the search space. To mitigate this, codon degeneracy can be limited using heuristics or previous knowledge of the targeted positions. To automate design of libraries given a set of amino acid sequences, an algorithm (LibDesign) was developed that generates a set of possible degenerate codon libraries, their resulting size, and their score relative to a user-defined scoring function. A gene library of a specified size can then be constructed that is representative of the given amino acid distribution or that includes specific sequences or combinations thereof. LibDesign provides a new tool for automated design of high-quality protein libraries that more effectively harness existing sequence-structure information derived from multiple sequence alignment or computational protein design data.

Enhanced Detectability of Community Structure in Multilayer Networks through Layer Aggregation.

PubMed

Taylor, Dane; Shai, Saray; Stanley, Natalie; Mucha, Peter J

2016-06-03

Many systems are naturally represented by a multilayer network in which edges exist in multiple layers that encode different, but potentially related, types of interactions, and it is important to understand limitations on the detectability of community structure in these networks. Using random matrix theory, we analyze detectability limitations for multilayer (specifically, multiplex) stochastic block models (SBMs) in which L layers are derived from a common SBM. We study the effect of layer aggregation on detectability for several aggregation methods, including summation of the layers' adjacency matrices for which we show the detectability limit vanishes as O(L^{-1/2}) with increasing number of layers, L. Importantly, we find a similar scaling behavior when the summation is thresholded at an optimal value, providing insight into the common-but not well understood-practice of thresholding pairwise-interaction data to obtain sparse network representations.

Elucidating the role of the phenylacetic acid metabolic complex in the pathogenic activity of Rhizoctonia solani anastomosis group 3.

PubMed

Bartz, Faith E; Glassbrook, Norman J; Danehower, David A; Cubeta, Marc A

2012-01-01

The soil fungus Rhizoctonia solani produces phytotoxic phenylacetic acid (PAA) and hydroxy (OH-) and methoxy (MeO-) derivatives of PAA. However, limited information is available on the specific role that these compounds play in the development of Rhizoctonia disease symptoms and concentration(s) required to induce a host response. Reports that PAA inhibits the growth of R. solani conflict with the established ability of the fungus to produce and metabolize PAA. Experiments were conducted to clarify the role of the PAA metabolic complex in Rhizoctonia disease. In this study the concentration of PAA and derivatives required to induce tomato root necrosis and stem canker, in the absence of the fungus, and the concentration that inhibits mycelial growth of R. solani were determined. The effect of exogenous PAA and derivatives of PAA on tomato seedling growth also was investigated. Growth of tomato seedlings in medium containing 0.1-7.5 mM PAA and derivatives induced necrosis of up to 85% of root system. Canker development resulted from injection of tomato seedling stems with 7.5 mM PAA, 3-OH-PAA, or 3-MeO-PAA. PAA in the growth medium reduced R. solani biomass, with 50% reduction observed at 7.5 mM. PAA, and derivatives were quantified from the culture medium of 14 isolates of R. solani belonging to three distinct anastomosis groups by GC-MS. The quantities ranged from below the limit of detection to 678 nM, below the concentrations experimentally determined to be phytotoxic. Correlation analyses revealed that isolates of R. solani that produced high PAA and derivatives in vitro also caused high mortality on tomato seedlings. The results of this investigation add to the body of evidence that the PAA metabolic complex is involved in Rhizoctonia disease development but do not indicate that production of these compounds is the primary or the only determinant of pathogenicity.

Free-Energy Landscape of Protein-Ligand Interactions Coupled with Protein Structural Changes.

PubMed

Moritsugu, Kei; Terada, Tohru; Kidera, Akinori

2017-02-02

Protein-ligand interactions are frequently coupled with protein structural changes. Focusing on the coupling, we present the free-energy surface (FES) of the ligand-binding process for glutamine-binding protein (GlnBP) and its ligand, glutamine, in which glutamine binding accompanies large-scale domain closure. All-atom simulations were performed in explicit solvents by multiscale enhanced sampling (MSES), which adopts a multicopy and multiscale scheme to achieve enhanced sampling of systems with a large number of degrees of freedom. The structural ensemble derived from the MSES simulation yielded the FES of the coupling, described in terms of both the ligand's and protein's degrees of freedom at atomic resolution, and revealed the tight coupling between the two degrees of freedom. The derived FES led to the determination of definite structural states, which suggested the dominant pathways of glutamine binding to GlnBP: first, glutamine migrates via diffusion to form a dominant encounter complex with Arg75 on the large domain of GlnBP, through strong polar interactions. Subsequently, the closing motion of GlnBP occurs to form ligand interactions with the small domain, finally completing the native-specific complex structure. The formation of hydrogen bonds between glutamine and the small domain is considered to be a rate-limiting step, inducing desolvation of the protein-ligand interface to form the specific native complex. The key interactions to attain high specificity for glutamine, the "door keeper" existing between the two domains (Asp10-Lys115) and the "hydrophobic sandwich" formed between the ligand glutamine and Phe13/Phe50, have been successfully mapped on the pathway derived from the FES.

Methodology for the Absolute Configuration Determination of Epoxythymols Using the Constituents of Ageratina glabrata.

PubMed

Arreaga-González, Héctor M; Pardo-Novoa, Julio C; Del Río, Rosa E; Rodríguez-García, Gabriela; Torres-Valencia, J Martín; Manríquez-Torres, J Jesús; Cerda-García-Rojas, Carlos M; Joseph-Nathan, Pedro; Gómez-Hurtado, Mario A

2018-01-26

A methodology to determine the enantiomeric excess and the absolute configuration (AC) of natural epoxythymols was developed and tested using five constituents of Ageratina glabrata. The methodology is based on enantiomeric purity determination employing 1,1'-bi-2-naphthol (BINOL) as a chiral solvating agent combined with vibrational circular dichroism (VCD) measurements and calculations. The conformational searching included an extensive Monte Carlo protocol that considered the rotational barriers to cover the whole conformational spaces. (+)-(8S)-10-Benzoyloxy-6-hydroxy-8,9-epoxythymol isobutyrate (1), (+)-(8S)-10-acetoxy-6-methoxy-8,9-epoxythymol isobutyrate (4), and (+)-(8S)-10-benzoyloxy-6-methoxy-8,9-epoxythymol isobutyrate (5) were isolated as enantiomerically pure constituents, while 10-isobutyryloxy-8,9-epoxythymol isobutyrate (2) was obtained as a 75:25 (8S)/(8R) scalemic mixture. In the case of 10-benzoyloxy-8,9-epoxythymol isobutyrate (3), the BINOL methodology revealed a 56:44 scalemic mixture and the VCD measurement was beyond the limit of sensitivity since the enantiomeric excess is only 12%. The racemization process of epoxythymol derivatives was studied using compound 1 and allowed the clarification of some stereochemical aspects of epoxythymol derivatives since their ACs have been scarcely analyzed and a particular behavior in their specific rotations was detected. In more than 30 oxygenated thymol derivatives, including some epoxythymols, the reported specific rotation values fluctuate from -1.6 to +1.4 passing through zero, suggesting the presence of scalemic and close to racemic mixtures, since enantiomerically pure natural constituents showed positive or negative specific rotations greater than 10 units.

Applications of conformal field theory to problems in 2D percolation

NASA Astrophysics Data System (ADS)

Simmons, Jacob Joseph Harris

This thesis explores critical two-dimensional percolation in bounded regions in the continuum limit. The main method which we employ is conformal field theory (CFT). Our specific results follow from the null-vector structure of the c = 0 CFT that applies to critical two-dimensional percolation. We also make use of the duality symmetry obeyed at the percolation point, and the fact that percolation may be understood as the q-state Potts model in the limit q → 1. Our first results describe the correlations between points in the bulk and boundary intervals or points, i.e. the probability that the various points or intervals are in the same percolation cluster. These quantities correspond to order-parameter profiles under the given conditions, or cluster connection probabilities. We consider two specific cases: an anchoring interval, and two anchoring points. We derive results for these and related geometries using the CFT null-vectors for the corresponding boundary condition changing (bcc) operators. In addition, we exhibit several exact relationships between these probabilities. These relations between the various bulk-boundary connection probabilities involve parameters of the CFT called operator product expansion (OPE) coefficients. We then compute several of these OPE coefficients, including those arising in our new probability relations. Beginning with the familiar CFT operator φ1,2, which corresponds to a free-fixed spin boundary change in the q-state Potts model, we then develop physical interpretations of the bcc operators. We argue that, when properly normalized, higher-order bcc operators correspond to successive fusions of multiple φ1,2, operators. Finally, by identifying the derivative of φ1,2 with the operator φ1,4, we derive several new quantities called first crossing densities. These new results are then combined and integrated to obtain the three previously known crossing quantities in a rectangle: the probability of a horizontal crossing cluster, the probability of a cluster crossing both horizontally and vertically, and the expected number of horizontal crossing clusters. These three results were known to be solutions to a certain fifth-order differential equation, but until now no physically meaningful explanation had appeared. This differential equation arises naturally in our derivation.

Production of phytotoxic cationic α-helical antimicrobial peptides in plant cells using inducible promoters.

PubMed

Company, Nuri; Nadal, Anna; Ruiz, Cristina; Pla, Maria

2014-01-01

Synthetic linear antimicrobial peptides with cationic α-helical structures, such as BP100, have potent and specific activities against economically important plant pathogenic bacteria. They are also recognized as valuable therapeutics and preservatives. However, highly active BP100 derivatives are often phytotoxic when expressed at high levels as recombinant peptides in plants. Here we demonstrate that production of recombinant phytotoxic peptides in transgenic plants is possible by strictly limiting transgene expression to certain tissues and conditions, and specifically that minimization of this expression during transformation and regeneration of transgenic plants is essential to obtain viable plant biofactories. On the basis of whole-genome transcriptomic data available online, we identified the Os.hsp82 promoter that fulfilled this requirement and was highly induced in response to heat shock. Using this strategy, we generated transgenic rice lines producing moderate yields of severely phytotoxic BP100 derivatives on exposure to high temperature. In addition, a threshold for gene expression in selected tissues and stages was experimentally established, below which the corresponding promoters should be suitable for driving the expression of recombinant phytotoxic proteins in genetically modified plants. In view of the growing transcriptomics data available, this approach is of interest to assist promoter selection for specific purposes.

A prior-based integrative framework for functional transcriptional regulatory network inference

PubMed Central

Siahpirani, Alireza F.

2017-01-01

Abstract Transcriptional regulatory networks specify regulatory proteins controlling the context-specific expression levels of genes. Inference of genome-wide regulatory networks is central to understanding gene regulation, but remains an open challenge. Expression-based network inference is among the most popular methods to infer regulatory networks, however, networks inferred from such methods have low overlap with experimentally derived (e.g. ChIP-chip and transcription factor (TF) knockouts) networks. Currently we have a limited understanding of this discrepancy. To address this gap, we first develop a regulatory network inference algorithm, based on probabilistic graphical models, to integrate expression with auxiliary datasets supporting a regulatory edge. Second, we comprehensively analyze our and other state-of-the-art methods on different expression perturbation datasets. Networks inferred by integrating sequence-specific motifs with expression have substantially greater agreement with experimentally derived networks, while remaining more predictive of expression than motif-based networks. Our analysis suggests natural genetic variation as the most informative perturbation for network inference, and, identifies core TFs whose targets are predictable from expression. Multiple reasons make the identification of targets of other TFs difficult, including network architecture and insufficient variation of TF mRNA level. Finally, we demonstrate the utility of our inference algorithm to infer stress-specific regulatory networks and for regulator prioritization. PMID:27794550

Production of Phytotoxic Cationic α-Helical Antimicrobial Peptides in Plant Cells Using Inducible Promoters

PubMed Central

Company, Nuri; Nadal, Anna; Ruiz, Cristina; Pla, Maria

2014-01-01

Synthetic linear antimicrobial peptides with cationic α-helical structures, such as BP100, have potent and specific activities against economically important plant pathogenic bacteria. They are also recognized as valuable therapeutics and preservatives. However, highly active BP100 derivatives are often phytotoxic when expressed at high levels as recombinant peptides in plants. Here we demonstrate that production of recombinant phytotoxic peptides in transgenic plants is possible by strictly limiting transgene expression to certain tissues and conditions, and specifically that minimization of this expression during transformation and regeneration of transgenic plants is essential to obtain viable plant biofactories. On the basis of whole-genome transcriptomic data available online, we identified the Os.hsp82 promoter that fulfilled this requirement and was highly induced in response to heat shock. Using this strategy, we generated transgenic rice lines producing moderate yields of severely phytotoxic BP100 derivatives on exposure to high temperature. In addition, a threshold for gene expression in selected tissues and stages was experimentally established, below which the corresponding promoters should be suitable for driving the expression of recombinant phytotoxic proteins in genetically modified plants. In view of the growing transcriptomics data available, this approach is of interest to assist promoter selection for specific purposes. PMID:25387106

PEGylated DX-1000: pharmacokinetics and antineoplastic activity of a specific plasmin inhibitor.

PubMed

Devy, Laetitia; Rabbani, Shafaat A; Stochl, Mark; Ruskowski, Mary; Mackie, Ian; Naa, Laurent; Toews, Mark; van Gool, Reinoud; Chen, Jie; Ley, Art; Ladner, Robert C; Dransfield, Daniel T; Henderikx, Paula

2007-11-01

Novel inhibitors of the urokinase-mediated plasminogen (plg) activation system are potentially of great clinical benefit as anticancer treatments. Using phage display, we identified DX-1000 a tissue factor pathway inhibitor-derived Kunitz domain protein which is a specific high-affinity inhibitor of plasmin (pln) (K(i) = 99 pM). When tested in vitro, DX-1000 blocks plasmin-mediated pro-matrix metalloproteinase-9 (proMMP-9) activation on cells and dose-dependently inhibits tube formation, while not significantly affecting hemostasis and coagulation. However, this low-molecular weight protein inhibitor ( approximately 7 kDa) exhibits rapid plasma clearance in mice and rabbits, limiting its potential clinical use in chronic diseases. After site-specific PEGylation, DX-1000 retains its activity and exhibits a decreased plasma clearance. This PEGylated derivative is effective in vitro, as well as potent in inhibiting tumor growth of green fluorescent protein (GFP)-labeled MDA-MB-231 cells. 4PEG-DX-1000 treatment causes a significant reduction of urokinase-type plasminogen activator (uPA) and plasminogen expressions, a reduction of tumor proliferation, and vascularization. 4PEG-DX-1000 treatment significantly decreases the level of active mitogen-activated protein kinase (MAPK) in the primary tumors and reduces metastasis incidence. Together, our results demonstrate the potential value of plasmin inhibitors as therapeutic agents for blocking breast cancer growth and metastasis.

Morse oscillator propagator in the high temperature limit I: Theory

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

Toutounji, Mohamad, E-mail: Mtoutounji@uaeu.ac.ae

2017-02-15

In an earlier work of the author the time evolution of Morse oscillator was studied analytically and exactly at low temperatures whereupon optical correlation functions were calculated using Morse oscillator coherent states were employed. Morse oscillator propagator in the high temperature limit is derived and a closed form of its corresponding canonical partition function is obtained. Both diagonal and off-diagonal forms of Morse oscillator propagator are derived in the high temperature limit. Partition functions of diatomic molecules are calculated. - Highlights: • Derives the quantum propagator of Morse oscillator in the high temperature limit. • Uses the resulting diagonal propagatormore » to derive a closed form of Morse oscillator partition function. • Provides a more sophisticated formula of the quantum propagator to test the accuracy of the herein results.« less

Real-time calculation of a limiting form of the Renyi entropy applied to detection of subtle changes in scattering architecture.

PubMed

Hughes, M S; McCarthy, J E; Wickerhauser, M V; Marsh, J N; Arbeit, J M; Fuhrhop, R W; Wallace, K D; Thomas, T; Smith, J; Agyem, K; Lanza, G M; Wickline, S A

2009-11-01

Previously a new method for ultrasound signal characterization using entropy H(f) was reported, and it was demonstrated that in certain settings, further improvements in signal characterization could be obtained by generalizing to Renyi entropy-based signal characterization I(f)(r) with values of r near 2 (specifically r=1.99) [M. S. Hughes et al., J. Acoust. Soc. Am. 125, 3141-3145 (2009)]. It was speculated that further improvements in sensitivity might be realized at the limit r-->2. At that time, such investigation was not feasible due to excessive computational time required to calculate I(f)(r) near this limit. In this paper, an asymptotic expression for the limiting behavior of I(f)(r) as r-->2 is derived and used to present results analogous to those obtained with I(f)(1.99). Moreover, the limiting form I(f,infinity) is computable directly from the experimentally measured waveform f(t) by an algorithm that is suitable for real-time calculation and implementation.

A study of interactive control scheduling and economic assessment for robotic systems

NASA Technical Reports Server (NTRS)

1982-01-01

A class of interactive control systems is derived by generalizing interactive manipulator control systems. Tasks of interactive control systems can be represented as a network of a finite set of actions which have specific operational characteristics and specific resource requirements, and which are of limited duration. This has enabled the decomposition of the overall control algorithm simultaneously and asynchronously. The performance benefits of sensor referenced and computer-aided control of manipulators in a complex environment is evaluated. The first phase of the CURV arm control system software development and the basic features of the control algorithms and their software implementation are presented. An optimal solution for a production scheduling problem that will be easy to implement in practical situations is investigated.

Overview of a HLA-Ig based "Lego-like system" for T cell monitoring, modulation and expansion.

PubMed

Oelke, Mathias; Schneck, Jonathan P

2010-07-01

Recent advances in molecular medicine have shown that soluble MHC-multimers can be valuable tools for both analysis and modulation of antigen-specific immune responses in vitro and in vivo. In this review, we describe the use of dimeric human and mouse major histocompatibility complexes, MHC-Ig, as part of an artificial Antigen-Presenting Cell (aAPC). MHC-Ig-based aAPC and its derivatives represent an exciting new platform technology for measuring and manipulating immune responses in vitro as well as in vivo. This new technology has the potential to help overcome many of the obstacles associated with limitations in current antigen-specific approaches of immunotherapy for the treatment of cancer, infectious diseases and autoimmunity.

Synthesis of Porous Carbon Monoliths Using Hard Templates.

PubMed

Klepel, Olaf; Danneberg, Nina; Dräger, Matti; Erlitz, Marcel; Taubert, Michael

2016-03-21

The preparation of porous carbon monoliths with a defined shape via template-assisted routes is reported. Monoliths made from porous concrete and zeolite were each used as the template. The porous concrete-derived carbon monoliths exhibited high gravimetric specific surface areas up to 2000 m²·g -1 . The pore system comprised macro-, meso-, and micropores. These pores were hierarchically arranged. The pore system was created by the complex interplay of the actions of both the template and the activating agent as well. On the other hand, zeolite-made template shapes allowed for the preparation of microporous carbon monoliths with a high volumetric specific surface area. This feature could be beneficial if carbon monoliths must be integrated into technical systems under space-limited conditions.

Synthesis of Porous Carbon Monoliths Using Hard Templates

PubMed Central

Klepel, Olaf; Danneberg, Nina; Dräger, Matti; Erlitz, Marcel; Taubert, Michael

2016-01-01

The preparation of porous carbon monoliths with a defined shape via template-assisted routes is reported. Monoliths made from porous concrete and zeolite were each used as the template. The porous concrete-derived carbon monoliths exhibited high gravimetric specific surface areas up to 2000 m2·g−1. The pore system comprised macro-, meso-, and micropores. These pores were hierarchically arranged. The pore system was created by the complex interplay of the actions of both the template and the activating agent as well. On the other hand, zeolite-made template shapes allowed for the preparation of microporous carbon monoliths with a high volumetric specific surface area. This feature could be beneficial if carbon monoliths must be integrated into technical systems under space-limited conditions. PMID:28773338

Thermodynamic properties of Dynes superconductors

NASA Astrophysics Data System (ADS)

Herman, František; Hlubina, Richard

2018-01-01

The tunneling density of states in dirty s -wave superconductors is often well described by the phenomenological Dynes formula. Recently we have shown that this formula can be derived, within the coherent potential approximation, for superconductors with simultaneously present pair-conserving and pair-breaking impurity scattering. Here we demonstrate that the theory of such so-called Dynes superconductors is thermodynamically consistent. We calculate the specific heat and critical field of the Dynes superconductors, and we show that their gap parameter, specific heat, critical field, and penetration depth exhibit power-law scaling with temperature in the low-temperature limit. We also show that in the vicinity of a coupling-constant-controlled superconductor to normal metal transition, the Homes law is replaced by a different, pair-breaking-dominated scaling law.

Nanobody-derived nanobiotechnology tool kits for diverse biomedical and biotechnology applications.

PubMed

Wang, Yongzhong; Fan, Zhen; Shao, Lei; Kong, Xiaowei; Hou, Xianjuan; Tian, Dongrui; Sun, Ying; Xiao, Yazhong; Yu, Li

2016-01-01

Owing to peculiar properties of nanobody, including nanoscale size, robust structure, stable and soluble behaviors in aqueous solution, reversible refolding, high affinity and specificity for only one cognate target, superior cryptic cleft accessibility, and deep tissue penetration, as well as a sustainable source, it has been an ideal research tool for the development of sophisticated nanobiotechnologies. Currently, the nanobody has been evolved into versatile research and application tool kits for diverse biomedical and biotechnology applications. Various nanobody-derived formats, including the nanobody itself, the radionuclide or fluorescent-labeled nanobodies, nanobody homo- or heteromultimers, nanobody-coated nanoparticles, and nanobody-displayed bacteriophages, have been successfully demonstrated as powerful nanobiotechnological tool kits for basic biomedical research, targeting drug delivery and therapy, disease diagnosis, bioimaging, and agricultural and plant protection. These applications indicate a special advantage of these nanobody-derived technologies, already surpassing the "me-too" products of other equivalent binders, such as the full-length antibodies, single-chain variable fragments, antigen-binding fragments, targeting peptides, and DNA-based aptamers. In this review, we summarize the current state of the art in nanobody research, focusing on the nanobody structural features, nanobody production approach, nanobody-derived nanobiotechnology tool kits, and the potentially diverse applications in biomedicine and biotechnology. The future trends, challenges, and limitations of the nanobody-derived nanobiotechnology tool kits are also discussed.

Functional screening assays with neurons generated from pluripotent stem cell-derived neural stem cells.

PubMed

Efthymiou, Anastasia; Shaltouki, Atossa; Steiner, Joseph P; Jha, Balendu; Heman-Ackah, Sabrina M; Swistowski, Andrzej; Zeng, Xianmin; Rao, Mahendra S; Malik, Nasir

2014-01-01

Rapid and effective drug discovery for neurodegenerative disease is currently impeded by an inability to source primary neural cells for high-throughput and phenotypic screens. This limitation can be addressed through the use of pluripotent stem cells (PSCs), which can be derived from patient-specific samples and differentiated to neural cells for use in identifying novel compounds for the treatment of neurodegenerative diseases. We have developed an efficient protocol to culture pure populations of neurons, as confirmed by gene expression analysis, in the 96-well format necessary for screens. These differentiated neurons were subjected to viability assays to illustrate their potential in future high-throughput screens. We have also shown that organelles such as nuclei and mitochondria could be live-labeled and visualized through fluorescence, suggesting that we should be able to monitor subcellular phenotypic changes. Neurons derived from a green fluorescent protein-expressing reporter line of PSCs were live-imaged to assess markers of neuronal maturation such as neurite length and co-cultured with astrocytes to demonstrate further maturation. These studies confirm that PSC-derived neurons can be used effectively in viability and functional assays and pave the way for high-throughput screens on neurons derived from patients with neurodegenerative disorders.

Modular organisation and functional analysis of dissected modular beta-mannanase CsMan26 from Caldicellulosiruptor Rt8B.4.

PubMed

Sunna, Anwar

2010-03-01

CsMan26 from Caldicellulosiruptor strain Rt8.B4 is a modular beta-mannanase consisting of two N-terminal family 27 carbohydrate-binding modules (CBMs), followed by a family 35 CBM and a family 26 glycoside hydrolase catalytic module (mannanase). A functional dissection of the full-length CsMan26 and a comprehensive characterisation of the truncated derivatives were undertaken to evaluate the role of the CBMs. Limited proteolysis was used to define biochemically the boundaries of the different structural modules in CsMan26. The full-length CsMan26 and three truncated derivatives were produced in Escherichia coli, purified and characterised. The systematic removal of the CBMs resulted in a decrease in the optimal temperature for activity and in the overall thermostability of the derivatives. Kinetic experiments indicated that the presence of the mannan-specific family 27 CBMs increased the affinity of the enzyme towards the soluble galactomannan substrate but this was accompanied by lower catalytic efficiency. The full-length CsMan26 and its truncated derivatives were unable to hydrolyse mannooligosaccharides with degree of polymerisation (DP) of three or less. The major difference in the hydrolysis pattern of larger mannooligosaccharides (DP >3) by the derivatives was determined by their abilities to further hydrolyse the intermediate sugar mannotetraose.

Platelet lysate as a substitute for animal serum for the ex-vivo expansion of mesenchymal stem/stromal cells: present and future.

PubMed

Astori, Giuseppe; Amati, Eliana; Bambi, Franco; Bernardi, Martina; Chieregato, Katia; Schäfer, Richard; Sella, Sabrina; Rodeghiero, Francesco

2016-07-13

The use of fetal bovine serum (FBS) as a cell culture supplement is discouraged by regulatory authorities to limit the risk of zoonoses and xenogeneic immune reactions in the transplanted host. Additionally, FBS production came under scrutiny due to animal welfare concerns. Platelet derivatives have been proposed as FBS substitutes for the ex-vivo expansion of mesenchymal stem/stromal cells (MSCs) since platelet-derived growth factors can promote MSC ex-vivo expansion. Platelet-derived growth factors are present in platelet lysate (PL) obtained after repeated freezing-thawing cycles of the platelet-rich plasma or by applying physiological stimuli such as thrombin or CaCl2.PL-expanded MSCs have been used already in the clinic, taking advantage of their faster proliferation compared with FBS-expanded preparations. Should PL be applied to other biopharmaceutical products, its demand is likely to increase dramatically. The use of fresh platelet units for the production of PL raises concerns due to limited availability of platelet donors. Expired units might represent an alternative, but further data are needed to define safety, including pathogen reduction, and functionality of the obtained PL. In addition, relevant questions concerning the definition of PL release criteria, including concentration ranges of specific growth factors in PL batches for various clinical indications, also need to be addressed. We are still far from a common definition of PL and standardized PL manufacture due to our limited knowledge of the mechanisms that mediate PL-promoting cell growth. Here, we concisely discuss aspects of PL as MSC culture supplement as a preliminary step towards an agreed definition of the required characteristics of PL for the requirements of manufacturers and users.

Using deconvolution to improve the metrological performance of the grid method

NASA Astrophysics Data System (ADS)

Grédiac, Michel; Sur, Frédéric; Badulescu, Claudiu; Mathias, Jean-Denis

2013-06-01

The use of various deconvolution techniques to enhance strain maps obtained with the grid method is addressed in this study. Since phase derivative maps obtained with the grid method can be approximated by their actual counterparts convolved by the envelope of the kernel used to extract phases and phase derivatives, non-blind restoration techniques can be used to perform deconvolution. Six deconvolution techniques are presented and employed to restore a synthetic phase derivative map, namely direct deconvolution, regularized deconvolution, the Richardson-Lucy algorithm and Wiener filtering, the last two with two variants concerning their practical implementations. Obtained results show that the noise that corrupts the grid images must be thoroughly taken into account to limit its effect on the deconvolved strain maps. The difficulty here is that the noise on the grid image yields a spatially correlated noise on the strain maps. In particular, numerical experiments on synthetic data show that direct and regularized deconvolutions are unstable when noisy data are processed. The same remark holds when Wiener filtering is employed without taking into account noise autocorrelation. On the other hand, the Richardson-Lucy algorithm and Wiener filtering with noise autocorrelation provide deconvolved maps where the impact of noise remains controlled within a certain limit. It is also observed that the last technique outperforms the Richardson-Lucy algorithm. Two short examples of actual strain fields restoration are finally shown. They deal with asphalt and shape memory alloy specimens. The benefits and limitations of deconvolution are presented and discussed in these two cases. The main conclusion is that strain maps are correctly deconvolved when the signal-to-noise ratio is high and that actual noise in the actual strain maps must be more specifically characterized than in the current study to address higher noise levels with Wiener filtering.

Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism

PubMed Central

Yan, Fang; Cao, Hanwei; Cover, Timothy L.; Washington, M. Kay; Shi, Yan; Liu, LinShu; Chaturvedi, Rupesh; Peek, Richard M.; Wilson, Keith T.; Polk, D. Brent

2011-01-01

Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria–derived soluble protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40’s effects on experimental colitis using mouse models. We show that the recombinant p40 protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived soluble proteins in protecting the intestine from injury and inflammation. PMID:21606592

Hematopoietic-to-mesenchymal transition of adipose tissue macrophages is regulated by integrin β1 and fabricated fibrin matrices

PubMed Central

Majka, Susan M.; Kohrt, Wendy M.; Miller, Heidi L.; Sullivan, Timothy M.; Klemm, Dwight J.

2017-01-01

ABSTRACT Some bona fide adult adipocytes arise de novo from a bone marrow-derived myeloid lineage. These studies further demonstrate that adipose tissue stroma contains a resident population of myeloid cells capable of adipocyte and multilineage mesenchymal differentiation. These resident myeloid cells lack hematopoietic markers and express mesenchymal and progenitor cell markers. Because bone marrow mesenchymal progenitor cells have not been shown to enter the circulation, we hypothesized that myeloid cells acquire mesenchymal differentiation capacity in adipose tissue. We fabricated a 3-dimensional fibrin matrix culture system to define the adipose differentiation potential of adipose tissue-resident myeloid subpopulations, including macrophages, granulocytes and dendritic cells. Our data show that multilineage mesenchymal potential was limited to adipose tissue macrophages, characterized by the acquisition of adipocyte, osteoblast, chondrocyte and skeletal muscle myocyte phenotypes. Fibrin hydrogel matrices stimulated macrophage loss of hematopoietic cell lineage determinants and the expression of mesenchymal and progenitor cell markers, including integrin β1. Ablation of integrin β1 in macrophages inhibited adipocyte specification. Therefore, some bona fide adipocytes are specifically derived from adipose tissue-resident macrophages via an integrin β1-dependent hematopoietic-to-mesenchymal transition, whereby they become capable of multipotent mesenchymal differentiation. The requirement for integrin β1 highlights this molecule as a potential target for controlling the production of marrow-derived adipocytes and their contribution to adipose tissue development and function. PMID:28441086

Discovery of new MD2 inhibitor from chalcone derivatives with anti-inflammatory effects in LPS-induced acute lung injury

PubMed Central

Zhang, Yali; Wu, Jianzhang; Ying, Shilong; Chen, Gaozhi; Wu, Beibei; Xu, Tingting; Liu, Zhiguo; Liu, Xing; Huang, Lehao; Shan, Xiaoou; Dai, Yuanrong; Liang, Guang

2016-01-01

Acute lung injury (ALI) is a life-threatening acute inflammatory disease with limited options available for therapy. Myeloid differentiation protein 2, a co-receptor of TLR4, is absolutely required for TLR4 sense LPS, and represents an attractive target for treating severe inflammatory diseases. In this study, we designed and synthesized 31 chalcone derivatives that contain the moiety of (E)-4-phenylbut-3-en-2-one, which we consider the core structure of current MD2 inhibitors. We first evaluated the anti-inflammatory activities of these compounds in MPMs. For the most active compound 20, we confirmed that it is a specific MD2 inhibitor through a series of biochemical experiments and elucidated that it binds to the hydrophobic pocket of MD2 via hydrogen bonds with Arg90 and Tyr102 residues. Compound 20 also blocked the LPS-induced activation of TLR4/MD2 -downstream pro-inflammatory MAPKs/NF-κB signaling pathways. In a rat model with ALI induced by intracheal LPS instillation, administration with compound 20 exhibited significant protective effect against ALI, accompanied by the inhibition of TLR4/MD2 complex formation in lung tissues. Taken together, the results of this study suggest the specific MD2 inhibitor from chalcone derivatives we identified is a potential candidate for treating acute inflammatory diseases. PMID:27118147

Crosslinkable hydrogels derived from cartilage, meniscus, and tendon tissue.

PubMed

Visser, Jetze; Levett, Peter A; te Moller, Nikae C R; Besems, Jeremy; Boere, Kristel W M; van Rijen, Mattie H P; de Grauw, Janny C; Dhert, Wouter J A; van Weeren, P René; Malda, Jos

2015-04-01

Decellularized tissues have proven to be versatile matrices for the engineering of tissues and organs. These matrices usually consist of collagens, matrix-specific proteins, and a set of largely undefined growth factors and signaling molecules. Although several decellularized tissues have found their way to clinical applications, their use in the engineering of cartilage tissue has only been explored to a limited extent. We set out to generate hydrogels from several tissue-derived matrices, as hydrogels are the current preferred cell carriers for cartilage repair. Equine cartilage, meniscus, and tendon tissue was harvested, decellularized, enzymatically digested, and functionalized with methacrylamide groups. After photo-cross-linking, these tissue digests were mechanically characterized. Next, gelatin methacrylamide (GelMA) hydrogel was functionalized with these methacrylated tissue digests. Equine chondrocytes and mesenchymal stromal cells (MSCs) (both from three donors) were encapsulated and cultured in vitro up to 6 weeks. Gene expression (COL1A1, COL2A1, ACAN, MMP-3, MMP-13, and MMP-14), cartilage-specific matrix formation, and hydrogel stiffness were analyzed after culture. The cartilage, meniscus, and tendon digests were successfully photo-cross-linked into hydrogels. The addition of the tissue-derived matrices to GelMA affected chondrogenic differentiation of MSCs, although no consequent improvement was demonstrated. For chondrocytes, the tissue-derived matrix gels performed worse compared to GelMA alone. This work demonstrates for the first time that native tissues can be processed into crosslinkable hydrogels for the engineering of tissues. Moreover, the differentiation of encapsulated cells can be influenced in these stable, decellularized matrix hydrogels.

Sex-specific 99th percentiles derived from the AACC Universal Sample Bank for the Roche Gen 5 cTnT assay: Comorbidities and statistical methods influence derivation of reference limits.

PubMed

Gunsolus, Ian L; Jaffe, Allan S; Sexter, Anne; Schulz, Karen; Ler, Ranka; Lindgren, Brittany; Saenger, Amy K; Love, Sara A; Apple, Fred S

2017-12-01

Our purpose was to determine a) overall and sex-specific 99th percentile upper reference limits (URL) and b) influences of statistical methods and comorbidities on the URLs. Heparin plasma from 838 normal subjects (423 men, 415 women) were obtained from the AACC (Universal Sample Bank). The cobas e602 measured cTnT (Roche Gen 5 assay); limit of detection (LoD), 3ng/L. Hemoglobin A1c (URL 6.5%), NT-proBNP (URL 125ng/L) and eGFR (60mL/min/1.73m 2 ) were measured, along with identification of statin use, to better define normality. 99th percentile URLs were determined by the non-parametric (NP), Harrell-Davis Estimator (HDE) and Robust (R) methods. 355 men and 339 women remained after exclusions. Overall<50% of subjects had measureable concentrations ≥ LoD: 45.6% no exclusion, 43.5% after exclusion; compared to men: 68.1% no exclusion, 65.1% post exclusion; women: 22.7% no exclusion, 20.9% post exclusion. The statistical method used influenced URLs as follows: pre/post exclusion overall, NP 16/16ng/L, HDE 17/17ng/L, R not available; men NP 18/16ng/L, HDE 21/19ng/L, R 16/11ng/L; women NP 13/10ng/L, HDE 14/14ng/L, R not available. We demonstrated that a) the Gen 5 cTnT assay does not meet the IFCC guideline for high-sensitivity assays, b) surrogate biomarkers significantly lowers the URLs and c) statistical methods used impact URLs. Our data suggest lower sex-specific cTnT 99th percentiles than reported in the FDA approved package insert. We emphasize the importance of detailing the criteria used to include and exclude subjects for defining a healthy population and the statistical method used to calculate 99th percentiles and identify outliers. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Altimetric system: Earth observing system. Volume 2h: Panel report

NASA Technical Reports Server (NTRS)

Bindschadler, Robert A.; Born, George; Chase, Robert R. P.; Fu, Lee-Lueng; Mouginis-Mark, Peter; Parsons, Chester; Tapley, Byron

1987-01-01

A rationale and recommendations for planning, implementing, and operating an altimetric system aboard the Earth observing system (Eos) spacecraft is provided. In keeping with the recommendations of the Eos Science and Mission Requirements Working Group, a complete altimetric system is defined that is capable of perpetuating the data set to be derived from TOPEX/Poseidon, enabling key scientific questions to be addressed. Since the scientific utility and technical maturity of spaceborne radar altimeters is well documented, the discussion is limited to highlighting those Eos-specific considerations that materially impact upon radar altimetric measurements.

Heavy-light mesons in chiral AdS/QCD

NASA Astrophysics Data System (ADS)

Liu, Yizhuang; Zahed, Ismail

2017-06-01

We discuss a minimal holographic model for the description of heavy-light and light mesons with chiral symmetry, defined in a slab of AdS space. The model consists of a pair of chiral Yang-Mills and tachyon fields with specific boundary conditions that break spontaneously chiral symmetry in the infrared. The heavy-light spectrum and decay constants are evaluated explicitly. In the heavy mass limit the model exhibits both heavy-quark and chiral symmetry and allows for the explicit derivation of the one-pion axial couplings to the heavy-light mesons.

Fluorescence Immunoassay for Cocaine Detection.

PubMed

Nakayama, Hiroshi; Kenjjou, Noriko; Shigetoh, Nobuyuki; Ito, Yuji

2016-04-01

A fluorescence immunoassay (FIA) has been developed for the detection of cocaine using norcocaine labeled with merocyanine dye and a monoclonal antibody specific to cocaine. Using this FIA, the detection range for cocaine was between 20.0 and 1700 μg/L with a limit of detection of 20.0 μg/L. Other cocaine derivatives did not interfere significantly with the detection when using this immunoassay technique with cross-reactivity values of less than 20%. Thus this FIA could be considered a useful tool for the detection of cocaine.

Quantitative depth resolved microcirculation imaging with optical coherence tomography angiography (Part ΙΙ): Microvascular network imaging.

PubMed

Gao, Wanrong

2017-04-17

In this work, we review the main phenomena that have been explored in OCT angiography to image the vessels of the microcirculation within living tissues with the emphasis on how the different processing algorithms were derived to circumvent specific limitations. Parameters are then discussed that can quantitatively describe the depth-resolved microvascular network for possible clinic diagnosis applications. Finally,future directions in continuing OCT development are discussed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

A Cloud Mask for AIRS

NASA Technical Reports Server (NTRS)

Brubaker, N.; Jedlovec, G. J.

2004-01-01

With the preliminary release of AIRS Level 1 and 2 data to the scientific community, there is a growing need for an accurate AIRS cloud mask for data assimilation studies and in producing products derived from cloud free radiances. Current cloud information provided with the AIRS data are limited or based on simplified threshold tests. A multispectral cloud detection approach has been developed for AIRS that utilizes the hyper-spectral capabilities to detect clouds based on specific cloud signatures across the short wave and long wave infrared window regions. This new AIRS cloud mask has been validated against the existing AIRS Level 2 cloud product and cloud information derived from MODIS. Preliminary results for both day and night applications over the continental U.S. are encouraging. Details of the cloud detection approach and validation results will be presented at the conference.

A Bearingless Switched-Reluctance Motor for High Specific Power Applications

NASA Technical Reports Server (NTRS)

Choi, Benjamin B.; Siebert, Mark

2006-01-01

A 12-8 switched-reluctance motor (SRM) is studied in bearingless (or self-levitated) operation with coil currents limited to the linear region to avoid magnetic saturation. The required motoring and levitating currents are summed and go into a single motor coil per pole to obtain the highest power output of the motor by having more space for motor coil winding. Two controllers are investigated for the bearingless SRM operation. First, a model-based controller using the radial force, which is adjusted by a factor derived from finite element analysis, is presented. Then a simple and practical observation-based controller using a PD (proportional-derivative) control algorithm is presented. Both controllers were experimentally demonstrated to 6500 rpm. This paper reports the initial efforts toward eventual self levitation of a SRM operating into strong magnetic core saturation at liquid nitrogen temperature.

Different spectrophotometric methods applied for the analysis of simeprevir in the presence of its oxidative degradation product: Acomparative study

NASA Astrophysics Data System (ADS)

Attia, Khalid A. M.; El-Abasawi, Nasr M.; El-Olemy, Ahmed; Serag, Ahmed

2018-02-01

Five simple spectrophotometric methods were developed for the determination of simeprevir in the presence of its oxidative degradation product namely, ratio difference, mean centering, derivative ratio using the Savitsky-Golay filters, second derivative and continuous wavelet transform. These methods are linear in the range of 2.5-40 μg/mL and validated according to the ICH guidelines. The obtained results of accuracy, repeatability and precision were found to be within the acceptable limits. The specificity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. Furthermore, these methods were statistically comparable to RP-HPLC method and good results were obtained. So, they can be used for the routine analysis of simeprevir in quality-control laboratories.

Red meat-derived heterocyclic amines increase risk of colon cancer: a population-based case-control study

PubMed Central

Helmus, Drew S.; Thompson, Cheryl L.; Zelenskiy, Svetlana; Tucker, Thomas C.; Li, Li

2014-01-01

Formation of mutagenic heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) is one pathway believed to drive the association of colon cancer with meat consumption. Limited data exist on the associations of individual HCAs and PAHs in red or white meat with colon cancer. Analyzing data from a validated meat preparation questionnaire completed by 1,062 incident colon cancer cases and 1,645 population controls from an ongoing case-control study, risks of colon cancer were estimated using unconditional logistic regression models, comparing the fourth to the first quartile of mutagen estimates derived from a CHARRED based food frequency questionnaire. Total dietary intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (adjusted odds ratio (aOR) = 1.88, 95% CI = 1.45–2.43, Ptrend < 0.0001), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) (aOR = 1.73, 95% CI = 1.34–2.23, Ptrend < 0.0001) and meat-derived mutagenic activity (aOR = 1.84, 95% CI = 1.42–2.39, Ptrend < 0.0001) were statistically significantly associated with colon cancer risk. Meat type specific analyses revealed statistically significant associations for red meat-derived MeIQx, DiMeIQx and mutagenic activity, but not for the same mutagens derived from white meat. Our study adds evidence supporting red meat-derived, but not white-meat derived HCAs and PAHs, as an important pathway for environmental colon cancer carcinogenesis. PMID:24168237

Trigger values for investigation of hormonal activity in drinking water and its sources using CALUX bioassays.

PubMed

Brand, Walter; de Jongh, Cindy M; van der Linden, Sander C; Mennes, Wim; Puijker, Leo M; van Leeuwen, Cornelis J; van Wezel, Annemarie P; Schriks, Merijn; Heringa, Minne B

2013-05-01

To screen for hormonal activity in water samples, highly sensitive in vitro CALUX bioassays are available which allow detection of estrogenic (ERα), androgenic (AR), progestagenic (PR), and glucocorticoid (GR) activities. This paper presents trigger values for the ERα, AR, PR, and GR CALUX bioassays for agonistic hormonal activities in (drinking) water, which define a level above which human health risk cannot be waived a priori and additional examination of specific endocrine activity may be warranted. The trigger values are based on 1) acceptable or tolerable daily intake (ADI/TDI) values of specific compounds, 2) pharmacokinetic factors defining their bioavailability, 3) estimations of the bioavailability of unknown compounds with equivalent hormonal activity, 4) relative endocrine potencies, and 5) physiological, and drinking water allocation factors. As a result, trigger values of 3.8ng 17β-estradiol (E2)-equivalents (eq)/L, 11ng dihydrotestosterone (DHT)-eq/L, 21ng dexamethasone (DEX)-eq/L, and 333ng Org2058-eq/L were derived. Benchmark Quotient (BQ) values were derived by dividing hormonal activity in water samples by the derived trigger using the highest concentrations detected in a recent, limited screening of Dutch water samples, and were in the order of (value) AR (0.41)>ERα (0.13)>GR (0.06)>PR (0.04). The application of trigger values derived in the present study can help to judge measured agonistic hormonal activities in water samples using the CALUX bioassays and help to decide whether further examination of specific endocrine activity followed by a subsequent safety evaluation may be warranted, or whether concentrations of such activity are of low priority with respect to health concerns in the human population. For instance, at one specific drinking water production site ERα and AR (but no GR and PR) activities were detected in drinking water, however, these levels are at least a factor 83 smaller than the respective trigger values, and therefore no human health risks are to be expected from hormonal activity in Dutch drinking water from this site. Copyright © 2013 Elsevier Ltd. All rights reserved.

Derivative spectrophotometric analysis of benzophenone (as an impurity) in phenytoin

PubMed Central

2011-01-01

Three simple and rapid spectrophotometric methods were developed for detection and trace determination of benzophenone (the main impurity) in phenytoin bulk powder and pharmaceutical formulations. The first method, zero-crossing first derivative spectrophotometry, depends on measuring the first derivative trough values at 257.6 nm for benzophenone. The second method, zero-crossing third derivative spectrophotometry, depends on measuring the third derivative peak values at 263.2 nm. The third method, ratio first derivative spectrophotometry, depends on measuring the peak amplitudes of the first derivative of the ratio spectra (the spectra of benzophenone divided by the spectrum of 5.0 μg/mL phenytoin solution) at 272 nm. The calibration graphs were linear over the range of 1-10 μg/mL. The detection limits of the first and the third derivative methods were found to be 0.04 μg/mL and 0.11 μg/mL and the quantitation limits were 0.13 μg/mL and 0.34 μg/mL, respectively, while for the ratio derivative method, the detection limit was 0.06 μg/mL and the quantitation limit was 0.18 μg/mL. The proposed methods were applied successfully to the assay of the studied drug in phenytoin bulk powder and certain pharmaceutical preparations. The results were statistically compared to those obtained using a polarographic method and were found to be in good agreement. PMID:22152156

Re-evaluation of a novel approach for quantitative myocardial oedema detection by analysing tissue inhomogeneity in acute myocarditis using T2-mapping.

PubMed

Baeßler, Bettina; Schaarschmidt, Frank; Treutlein, Melanie; Stehning, Christian; Schnackenburg, Bernhard; Michels, Guido; Maintz, David; Bunck, Alexander C

2017-12-01

To re-evaluate a recently suggested approach of quantifying myocardial oedema and increased tissue inhomogeneity in myocarditis by T2-mapping. Cardiac magnetic resonance data of 99 patients with myocarditis were retrospectively analysed. Thirthy healthy volunteers served as controls. T2-mapping data were acquired at 1.5 T using a gradient-spin-echo T2-mapping sequence. T2-maps were segmented according to the 16-segments AHA-model. Segmental T2-values, segmental pixel-standard deviation (SD) and the derived parameters maxT2, maxSD and madSD were analysed and compared to the established Lake Louise criteria (LLC). A re-estimation of logistic regression models revealed that all models containing an SD-parameter were superior to any model containing global myocardial T2. Using a combined cut-off of 1.8 ms for madSD + 68 ms for maxT2 resulted in a diagnostic sensitivity of 75% and specificity of 80% and showed a similar diagnostic performance compared to LLC in receiver-operating-curve analyses. Combining madSD, maxT2 and late gadolinium enhancement (LGE) in a model resulted in a superior diagnostic performance compared to LLC (sensitivity 93%, specificity 83%). The results show that the novel T2-mapping-derived parameters exhibit an additional diagnostic value over LGE with the inherent potential to overcome the current limitations of T2-mapping. • A novel quantitative approach to myocardial oedema imaging in myocarditis was re-evaluated. • The T2-mapping-derived parameters maxT2 and madSD were compared to traditional Lake-Louise criteria. • Using maxT2 and madSD with dedicated cut-offs performs similarly to Lake-Louise criteria. • Adding maxT2 and madSD to LGE results in further increased diagnostic performance. • This novel approach has the potential to overcome the limitations of T2-mapping.

Derivation and Validation of Two Decision Instruments for Selective Chest CT in Blunt Trauma: A Multicenter Prospective Observational Study (NEXUS Chest CT)

PubMed Central

Rodriguez, Robert M.; Langdorf, Mark I.; Nishijima, Daniel; Baumann, Brigitte M.; Hendey, Gregory W.; Medak, Anthony J.; Raja, Ali S.; Allen, Isabel E.; Mower, William R.

2015-01-01

Background Unnecessary diagnostic imaging leads to higher costs, longer emergency department stays, and increased patient exposure to ionizing radiation. We sought to prospectively derive and validate two decision instruments (DIs) for selective chest computed tomography (CT) in adult blunt trauma patients. Methods and Findings From September 2011 to May 2014, we prospectively enrolled blunt trauma patients over 14 y of age presenting to eight US, urban level 1 trauma centers in this observational study. During the derivation phase, physicians recorded the presence or absence of 14 clinical criteria before viewing chest imaging results. We determined injury outcomes by CT radiology readings and categorized injuries as major or minor according to an expert-panel-derived clinical classification scheme. We then employed recursive partitioning to derive two DIs: Chest CT-All maximized sensitivity for all injuries, and Chest CT-Major maximized sensitivity for only major thoracic injuries (while increasing specificity). In the validation phase, we employed similar methodology to prospectively test the performance of both DIs. We enrolled 11,477 patients—6,002 patients in the derivation phase and 5,475 patients in the validation phase. The derived Chest CT-All DI consisted of (1) abnormal chest X-ray, (2) rapid deceleration mechanism, (3) distracting injury, (4) chest wall tenderness, (5) sternal tenderness, (6) thoracic spine tenderness, and (7) scapular tenderness. The Chest CT-Major DI had the same criteria without rapid deceleration mechanism. In the validation phase, Chest CT-All had a sensitivity of 99.2% (95% CI 95.4%–100%), a specificity of 20.8% (95% CI 19.2%–22.4%), and a negative predictive value (NPV) of 99.8% (95% CI 98.9%–100%) for major injury, and a sensitivity of 95.4% (95% CI 93.6%–96.9%), a specificity of 25.5% (95% CI 23.5%–27.5%), and a NPV of 93.9% (95% CI 91.5%–95.8%) for either major or minor injury. Chest CT-Major had a sensitivity of 99.2% (95% CI 95.4%–100%), a specificity of 31.7% (95% CI 29.9%–33.5%), and a NPV of 99.9% (95% CI 99.3%–100%) for major injury and a sensitivity of 90.7% (95% CI 88.3%–92.8%), a specificity of 37.9% (95% CI 35.8%–40.1%), and a NPV of 91.8% (95% CI 89.7%–93.6%) for either major or minor injury. Regarding the limitations of our work, some clinicians may disagree with our injury classification and sensitivity thresholds for injury detection. Conclusions We prospectively derived and validated two DIs (Chest CT-All and Chest CT-Major) that identify blunt trauma patients with clinically significant thoracic injuries with high sensitivity, allowing for a safe reduction of approximately 25%–37% of unnecessary chest CTs. Trauma evaluation protocols that incorporate these DIs may decrease unnecessary costs and radiation exposure in the disproportionately young trauma population. PMID:26440607

Non-invasive prenatal diagnosis.

PubMed

Meaney, Cathy; Norbury, Gail

2011-01-01

The discovery of cell-free fetal DNA in the maternal plasma of pregnant women has facilitated the development of non-invasive prenatal diagnosis (NIPD). This has been successfully implemented in diagnostic laboratories for Rhesus typing and fetal sex determination for X-linked disorders and congenital adrenal hyperplasia (CAH) from 7 weeks gestation. Using real-time PCR, fluorescently labelled target gene specific probes can identify and quantify low copy number fetal-specific sequences in a high background of maternal DNA in the cell-free DNA extracted from maternal plasma.NIPD to detect specific fetal mutations in single gene disorders, currently by standard PCR techniques, can only be undertaken for paternally derived or de novo mutations because of the background maternal DNA. For routine use, this testing is limited by the large amounts of cell-free maternal DNA in the sample, the lack of universal fetal markers, and appropriate reference materials.

Beyond valence in the perception of likelihood: the role of emotion specificity.

PubMed

DeSteno, D; Petty, R E; Wegener, D T; Rucker, D D

2000-03-01

Positive and negative moods have been shown to increase likelihood estimates of future events matching these states in valence (e.g., E. J. Johnson & A. Tversky, 1983). In the present article, 4 studies provide evidence that this congruency bias (a) is not limited to valence but functions in an emotion-specific manner, (b) derives from the informational value of emotions, and (c) is not the inevitable outcome of likelihood assessment under heightened emotion. Specifically, Study 1 demonstrates that sadness and anger, 2 distinct, negative emotions, differentially bias likelihood estimates of sad and angering events. Studies 2 and 3 replicate this finding in addition to supporting an emotion-as-information (cf. N. Schwarz & G. L. Clore, 1983), as opposed to a memory-based, mediating process for the bias. Finally, Study 4 shows that when the source of the emotion is salient, a reversal of the bias can occur given greater cognitive effort aimed at accuracy.

Glycan microarray analysis of the carbohydrate-recognition specificity of native and recombinant forms of the lectin ArtinM.

PubMed

Liu, Y; Cecílio, N T; Carvalho, F C; Roque-Barreira, M C; Feizi, T

2015-12-01

This article contains data related to the researc.h article entitled "Yeast-derived ArtinM shares structure, carbohydrate recognition, and biological effects with native ArtinM" by Cecílio et al. (2015) [1]. ArtinM, a D-mannose-binding lectin isolated from the seeds of Artocarpus heterophyllus, exerts immunomodulatory and regenerative activities through its Carbohydrate Recognition Domain (CRD) (Souza et al., 2013; Mariano et al., 2014 [2], [3]). The limited availability of the native lectin (n-ArtinM) led us to characterize a recombinant form of the protein, obtained by expression in Saccharomyces cerevisiae (y-ArtinM). We compared the carbohydrate-binding specificities of y-ArtinM and n-ArtinM by analyzing the binding of biotinylated preparations of the two lectin forms using a neoglycolipid (NGL)-based glycan microarray. Data showed that y-ArtinM mirrored the specificity exhibited by n-ArtinM.

Clopidogrel use and cancer-specific mortality: a population-based cohort study of colorectal, breast and prostate cancer patients.

PubMed

Hicks, Blánaid M; Murray, Liam J; Hughes, Carmel; Cardwell, Chris R

2015-08-01

Concerns were raised about the safety of antiplatelet thienopyridine derivatives after a randomized control trial reported increased risks of cancer and cancer deaths in prasugrel users. We investigate whether clopidogrel, a widely used thienopyridine derivative, was associated with increased risk of cancer-specific or all-cause mortality in cancer patients. Colorectal, breast and prostate cancer patients, newly diagnosed from 1998 to 2009, were identified from the National Cancer Data Repository. Cohorts were linked to the UK Clinical Practice Research Datalink, providing prescription records, and to the Office of National Statistics mortality data (up to 2012). Unadjusted and adjusted hazard ratios (HRs) for cancer-specific and all-cause mortality in post-diagnostic clopidogrel users were calculated using time-dependent Cox regression models. The analysis included 10 359 colorectal, 17 889 breast and 13 155 prostate cancer patients. There was no evidence of an increase in cancer-specific mortality in clopidogrel users with colorectal (HR = 0.98 95% confidence interval (CI) 0.77, 1.24) or prostate cancer (HR = 1.03 95%CI 0.82, 1.28). There was limited evidence of an increase in breast cancer patients (HR = 1.22 95%CI 0.90, 1.65); however, this was attenuated when removing prescriptions in the year prior to death. This novel study of large population-based cohorts of colorectal, breast and prostate cancer patients found no evidence of an increased risk of cancer-specific mortality among colorectal, breast and prostate cancer patients using clopidogrel. Copyright © 2015 John Wiley & Sons, Ltd.

P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins.

PubMed

Hostettler, Nina; Naggi, Annamaria; Torri, Giangiacomo; Ishai-Michaeli, Riva; Casu, Benito; Vlodavsky, Israel; Borsig, Lubor

2007-11-01

Vascular cell adhesion molecules, P- and L-selectins, facilitate metastasis of cancer cells in mice by mediating interactions with platelets, endothelium, and leukocytes. Heparanase is an endoglycosidase that degrades heparan sulfate of extracellular matrix, thereby promoting tumor invasion and metastasis. Heparin is known to efficiently attenuate metastasis in different tumor models. Here we identified modified, nonanticoagulant species of heparin that specifically inhibit selectin-mediated cell-cell interactions, heparanase enzymatic activity, or both. We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC-38 colon carcinoma and B16-BL6 melanoma attenuates metastasis. Selectin-specific heparin derivatives attenuated metastasis of MC-38 carcinoma, but heparanase-specific derivatives had no effect, in accordance with the virtual absence of heparanase activity in these cells. Heparin derivatives had no further effect on metastasis in mice deficient in P- and L-selectin, indicating that selectins are the primary targets of heparin antimetastatic activity. Selectin-specific and heparanase-specific derivatives attenuated metastasis of B16-BL6 melanomas to a similar extent. When mice were injected with a derivative containing both heparanase and selectin inhibitory activity, no additional attenuation of metastasis could be observed. Thus, selectin-specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase.

Phosphorus Availability, Phytoplankton Community Dynamics, and Taxon-Specific Phosphorus Status in the Gulf of Aqaba, Red Sea

NASA Astrophysics Data System (ADS)

Mackey, K. R.; Labiosa, R. G.; Calhoun, M.; Street, J. H.; Post, A. F.; Paytan, A.

2006-12-01

The relationships among phytoplankton taxon-specific phosphorus-status, phytoplankton community composition, and nutrient levels were assessed over three seasons in the Gulf of Aqaba, Red Sea. During summer and fall, stratified surface waters were depleted of nutrients and picophytoplankton populations comprised the majority of cells (80% and 88% respectively). In winter, surface nutrient concentrations were higher and larger phytoplankton were more abundant (63%). Cell specific alkaline phosphatase activity (APA) derived from enzyme labeled fluorescence was consistently low (less than 5%) in the picophytoplankton throughout the year, whereas larger cells expressed elevated APA during the summer and fall but less in the winter. A nutrient addition bioassay during the fall showed that, relative to control, APA was reduced by half in larger cells following addition of orthophosphate, whereas the APA of picophytoplankton remained low (less than 1%) across all treatments and the control. These results indicate that the most abundant phytoplankton are not limited by orthophosphate and only some subpopulations (particularly of larger cells) exhibit orthophosphate-limitation throughout the year. Our results indicate that orthophosphate availability influences phytoplankton ecology, correlating with shifts in phytoplankton community structure and the nutrient status of individual cells. The role of dissolved organic phosphorus as an important phosphorus source for marine phytoplankton in oligotrophic settings and the need for evaluating nutrient limitation at the taxa and/or single cell level (rather than inferring it from nutrient concentrations and ratios or bulk enzyme activity measurements) are highlighted.

Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening.

PubMed

Gómez-Lechón, María José; Tolosa, Laia

2016-09-01

Drug-induced liver injury (DILI) is a frequent cause of failure in both clinical and post-approval stages of drug development, and poses a key challenge to the pharmaceutical industry. Current animal models offer poor prediction of human DILI. Although several human cell-based models have been proposed for the detection of human DILI, human primary hepatocytes remain the gold standard for preclinical toxicological screening. However, their use is hindered by their limited availability, variability and phenotypic instability. In contrast, pluripotent stem cells, which include embryonic and induced pluripotent stem cells (iPSCs), proliferate extensively in vitro and can be differentiated into hepatocytes by the addition of soluble factors. This provides a stable source of hepatocytes for multiple applications, including early preclinical hepatotoxicity screening. In addition, iPSCs also have the potential to establish genotype-specific cells from different individuals, which would increase the predictivity of toxicity assays allowing more successful clinical trials. Therefore, the generation of human hepatocyte-like cells derived from pluripotent stem cells seems to be promising for overcoming limitations of hepatocyte preparations, and it is expected to have a substantial repercussion in preclinical hepatotoxicity risk assessment in early drug development stages.

hTERT gene immortalized human adipose-derived stem cells and its multiple differentiations: a preliminary investigation.

PubMed

Wang, L; Song, K; Qu, X; Wang, H; Zhu, H; Xu, X; Zhang, M; Tang, Y; Yang, X

2013-03-01

Human adipose-derived adult stem cells (hADSCs) can express human telomerase reverse transcriptase phenotypes under an appropriate culture condition. Because adipose tissue is abundant and easily accessible, hADSCs offer a promising source of stem cells for tissue engineering application and other cell-based therapies. However, the shortage of cells number and the difficulty to proliferate, known as the "Hayflick limit" in vitro, limit their further clinical application. Here, hADSCs were transfected with human telomerase reverse transcriptase (hTERT) gene by the lentiviral vector to prolong the lifespan of stem cells and even immortalize them. Following to this, the cellular properties and functionalities of the transfected cell lines were assayed. The results demonstrated that hADSCs had been successfully transfected with hTERT gene (hTERT-ADSCs). Then, hTERT-ADSCs were initially selected by G418 and subsequently expanded over 20 passages in vitro. Moreover, the qualitative and quantitative differentiation criteria for 20 passages of hTERT-ADSCs also demonstrated that hTERT-ADSCs could differentiate into osteogenesis, chondrogenesis, and adipogenesis phenotypes in lineage-specific differentiation media. These findings confirmed that this transfection could prolong the lifespan of hADSCs.

The IDF Diabetes Atlas methodology for estimating global prevalence of hyperglycaemia in pregnancy.

PubMed

Linnenkamp, U; Guariguata, L; Beagley, J; Whiting, D R; Cho, N H

2014-02-01

Hyperglycaemia is one of the most prevalent metabolic disorders occurring during pregnancy. Limited data are available on the global prevalence of hyperglycaemia in pregnancy. The International Diabetes Federation (IDF) has developed a methodology for generating estimates of the prevalence of hyperglycaemia in pregnancy, including hyperglycaemia first detected in pregnancy and live births to women with known diabetes, among women of childbearing age (20-49 years). A systematic review of the literature for studies reporting the prevalence of gestational diabetes was conducted. Studies were evaluated and scored to favour those that were representative of a large population, conducted recently, reported age-specific estimates, and case identification was based on blood test. Age-specific prevalence data from studies were entered to produce estimates for five-year age groups using logistic regression to smooth curves, with age as the independent variable. The derived age-specific prevalence was adjusted for differences in diagnostic criteria in the underlying data. Cases of hyperglycaemia in pregnancy were derived from age-specific estimates of fertility and age-specific population estimates. Country-specific estimates were generated for countries with available data. Regional and global estimates were generated based on aggregation and extrapolation for 219 countries and territories. Available fertility rates and diabetes prevalence estimates were used to estimate the proportion of hyperglycaemia in pregnancy that may be due to total diabetes in pregnancy - pregnancy in women with known diabetes and diabetes first detected in pregnancy. The literature review identified 199 studies that were eligible for characterisation and selection. After scoring and exclusion requirements, 46 studies were selected representing 34 countries. More than 50% of selected studies came from Europe and North America and Caribbean. The smallest number of identified studies came from sub-Saharan Africa. The majority of studies were for high-income countries, although low- and middle-income countries were also represented. Prevalence estimates of hyperglycaemia in pregnancy are sensitive to the data from which they are derived. The IDF methodology is a transparent, reproducible, and modifiable method for estimating the burden of hyperglycaemia in pregnancy. More data are needed, in particular from developing countries, to strengthen the methodology. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Calibration and evaluation of CCD spectroradiometers for ground-based and airborne measurements of spectral actinic flux densities

NASA Astrophysics Data System (ADS)

Bohn, Birger; Lohse, Insa

2017-09-01

The properties and performance of charge-coupled device (CCD) array spectroradiometers for the measurement of atmospheric spectral actinic flux densities (280-650 nm) and photolysis frequencies were investigated. These instruments are widely used in atmospheric research and are suitable for aircraft applications because of high time resolutions and high sensitivities in the UV range. The laboratory characterization included instrument-specific properties like the wavelength accuracy, dark signal, dark noise and signal-to-noise ratio (SNR). Spectral sensitivities were derived from measurements with spectral irradiance standards. The calibration procedure is described in detail, and a straightforward method to minimize the influence of stray light on spectral sensitivities is introduced. From instrument dark noise, minimum detection limits ≈ 1 × 1010 cm-2 s-1 nm-1 were derived for spectral actinic flux densities at wavelengths around 300 nm (1 s integration time). As a prerequisite for the determination of stray light under field conditions, atmospheric cutoff wavelengths were defined using radiative transfer calculations as a function of the solar zenith angle (SZA) and total ozone column (TOC). The recommended analysis of field data relies on these cutoff wavelengths and is also described in detail taking data from a research flight on HALO (High Altitude and Long Range Research Aircraft) as an example. An evaluation of field data was performed by ground-based comparisons with a double-monochromator-based, highly sensitive reference spectroradiometer. Spectral actinic flux densities were compared as well as photolysis frequencies j(NO2) and j(O1D), representing UV-A and UV-B ranges, respectively. The spectra expectedly revealed increased daytime levels of stray-light-induced signals and noise below atmospheric cutoff wavelengths. The influence of instrument noise and stray-light-induced noise was found to be insignificant for j(NO2) and rather limited for j(O1D), resulting in estimated detection limits of 5 × 10-7 and 1 × 10-7 s-1, respectively, derived from nighttime measurements on the ground (0.3 s integration time, 10 s averages). For j(O1D) the detection limit could be further reduced by setting spectral actinic flux densities to zero below atmospheric cutoff wavelengths. The accuracies of photolysis frequencies were determined from linear regressions with data from the double-monochromator reference instrument. The agreement was typically within ±5 %. Because optical-receiver aspects are not specific for the CCD spectroradiometers, they were widely excluded in this work and will be treated in a separate paper, in particular with regard to airborne applications.

Tumour-derived exosomes as a signature of pancreatic cancer - liquid biopsies as indicators of tumour progression.

PubMed

Nuzhat, Zarin; Kinhal, Vyjayanthi; Sharma, Shayna; Rice, Gregory E; Joshi, Virendra; Salomon, Carlos

2017-03-07

Pancreatic cancer is the fourth most common cause of death due to cancer in the world. It is known to have a poor prognosis, mostly because early stages of the disease are generally asymptomatic. Progress in pancreatic cancer research has been slow, leaving several fundamental questions pertaining to diagnosis and treatment unanswered. Recent studies highlight the putative utility of tissue-specific vesicles (i.e. extracellular vesicles) in the diagnosis of disease onset and treatment monitoring in pancreatic cancer. Extracellular vesicles are membrane-limited structures derived from the cell membrane. They contain specific molecules including proteins, mRNA, microRNAs and non-coding RNAs that are secreted in the extracellular space. Extracellular vesicles can be classified according to their size and/or origin into microvesicles (~150-1000 nm) and exosomes (~40-120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosomes are released via the endocytic pathway by fusion of multivesicular bodies with the plasmatic membrane. This endosomal origin means that exosomes contain an abundance of cell-specific biomolecules which may act as a 'fingerprint' of the cell of origin. In this review, we discuss our current knowledge in the diagnosis and treatment of pancreatic cancer, particularly the potential role of EVs in these facets of disease management. In particular, we suggest that as exosomes contain cellular protein and RNA molecules in a cell type-specific manner, they may provide extensive information about the signature of the tumour and pancreatic cancer progression.

Direction-specific impairment of stability limits and falls in children with developmental coordination disorder: Implications for rehabilitation.

PubMed

Fong, Shirley S M; Ng, Shamay S M; Chung, Louisa M Y; Ki, W Y; Chow, Lina P Y; Macfarlane, Duncan J

2016-01-01

Limit of stability (LOS) is an important yet under-examined postural control ability in children with developmental coordination disorder (DCD). This study aimed to (1) compare the LOS and fall frequencies of children with and without DCD, and (2) explore the relationships between LOS parameters and falls in the DCD population. Thirty primary school-aged children with DCD and twenty age- and sex-matched typically-developing children participated in the study. Postural control ability, specifically LOS in standing, was evaluated using the LOS test. Reaction time, movement velocity, maximum excursion, end point excursion, and directional control were then calculated. Self-reported fall incidents in the previous week were also documented. Multivariate analysis of variance results revealed that children with DCD had shorter LOS maximum excursion in the backward direction compared to the control group (p=0.003). This was associated with a higher number of falls in daily life (rho=-0.556, p=0.001). No significant between-groups differences were found in other LOS-derived outcomes (p>0.05). Children with DCD had direction-specific postural control impairment, specifically, diminished LOS in the backward direction. This is related to their falls in daily life. Therefore, improving LOS should be factored into rehabilitation treatment for children with DCD. Copyright © 2015 Elsevier B.V. All rights reserved.

Setting population targets for mammals using body mass as a predictor of population persistence.

PubMed

Hilbers, Jelle P; Santini, Luca; Visconti, Piero; Schipper, Aafke M; Pinto, Cecilia; Rondinini, Carlo; Huijbregts, Mark A J

2017-04-01

Conservation planning and biodiversity assessments need quantitative targets to optimize planning options and assess the adequacy of current species protection. However, targets aiming at persistence require population-specific data, which limit their use in favor of fixed and nonspecific targets, likely leading to unequal distribution of conservation efforts among species. We devised a method to derive equitable population targets; that is, quantitative targets of population size that ensure equal probabilities of persistence across a set of species and that can be easily inferred from species-specific traits. In our method, we used models of population dynamics across a range of life-history traits related to species' body mass to estimate minimum viable population targets. We applied our method to a range of body masses of mammals, from 2 g to 3825 kg. The minimum viable population targets decreased asymptotically with increasing body mass and were on the same order of magnitude as minimum viable population estimates from species- and context-specific studies. Our approach provides a compromise between pragmatic, nonspecific population targets and detailed context-specific estimates of population viability for which only limited data are available. It enables a first estimation of species-specific population targets based on a readily available trait and thus allows setting equitable targets for population persistence in large-scale and multispecies conservation assessments and planning. © 2016 The Authors. Conservation Biology published by Wiley Periodicals, Inc. on behalf of Society for Conservation Biology.

Development and application of a universal Hemoplasma screening assay based on the SYBR green PCR principle.

PubMed

Willi, Barbara; Meli, Marina L; Lüthy, Ruedi; Honegger, Hanspeter; Wengi, Nicole; Hoelzle, Ludwig E; Reusch, Claudia E; Lutz, Hans; Hofmann-Lehmann, Regina

2009-12-01

Hemotropic mycoplasmas (hemoplasmas) are the causative agents of infectious anemia in several mammalian species. Their zoonotic potential has recently been substantiated by the identification of a feline hemoplasma isolate in an immunocompromised human patient. Although species-specific diagnostic molecular methods have been developed, their application as screening tools is limited due to the species diversity of hemoplasmas. The goals of this study were to develop a universal hemoplasma screening assay with broad specificity based on the SYBR green PCR principle, to compare the assay with hemoplasma-specific TaqMan PCR, and to analyze potential tick vectors and human blood samples to address the zoonotic potential. The newly developed PCR assay based on the 16S rRNA gene amplified feline, canine, bovine, porcine, camelid, and murine hemoplasmas, as well as Mycoplasma penetrans and Mycoplasma pneumoniae. The lower detection limit for feline and canine hemoplasmas was 1 to 10 copies/PCR. The assay exhibited 98.2% diagnostic sensitivity and 92.1% diagnostic specificity for feline hemoplasmas. All 1,950 Ixodes ticks were PCR negative, suggesting that Ixodes ticks are not relevant vectors for the above-mentioned hemoplasma species in Switzerland. None of the 414 blood samples derived from anemic or immunocompromised human patients revealed a clear positive result. The SYBR green PCR assay described here is a suitable tool to screen for known and so-far-undiscovered hemoplasma species. Positive results should be confirmed by specific TaqMan PCR or sequencing.

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

PubMed

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

2016-02-28

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

Differential renormalization-group generators for static and dynamic critical phenomena

NASA Astrophysics Data System (ADS)

Chang, T. S.; Vvedensky, D. D.; Nicoll, J. F.

1992-09-01

The derivation of differential renormalization-group (DRG) equations for applications to static and dynamic critical phenomena is reviewed. The DRG approach provides a self-contained closed-form representation of the Wilson renormalization group (RG) and should be viewed as complementary to the Callan-Symanzik equations used in field-theoretic approaches to the RG. The various forms of DRG equations are derived to illustrate the general mathematical structure of each approach and to point out the advantages and disadvantages for performing practical calculations. Otherwise, the review focuses upon the one-particle-irreducible DRG equations derived by Nicoll and Chang and by Chang, Nicoll, and Young; no attempt is made to provide a general treatise of critical phenomena. A few specific examples are included to illustrate the utility of the DRG approach: the large- n limit of the classical n-vector model (the spherical model), multi- or higher-order critical phenomena, and crit ical dynamics far from equilibrium. The large- n limit of the n-vector model is used to introduce the application of DRG equations to a well-known example, with exact solution obtained for the nonlinear trajectories, generating functions for nonlinear scaling fields, and the equation of state. Trajectory integrals and nonlinear scaling fields within the framework of ɛ-expansions are then discussed for tricritical crossover, and briefly for certain aspects of multi- or higher-order critical points, including the derivation of the Helmholtz free energy and the equation of state. The discussion then turns to critical dynamics with a development of the path integral formulation for general dynamic processes. This is followed by an application to a model far-from-equilibrium system that undergoes a phase transformation analogous to a second-order critical point, the Schlögl model for a chemical instability.

The estimation of electrical cable fire-induced damage limits

NASA Astrophysics Data System (ADS)

Nowlen, S. P.; Jacobus, M. J.

Sandia National Laboratories has, for several years, been engaged in the performance of both fire safety and electrical equipment qualification research under independent programs sponsored by the US Nuclear Regulatory Commission. Recent comparisons between electrical cable thermal damageability data gathered independently in these two efforts indicate that a direct correlation exists between certain of the recent cable thermal vulnerability information gathered under equipment qualification conditions and thermal damageability in a fire environment. This direct correlation allows for a significant expansion of the data base on estimated cable thermal vulnerability limits in a fire environment because of the wide range of cable types and products that have been evaluated as a part of the equipment qualification research. This paper provides a discussion of the basis for the derived correlation, and presents estimated cable thermal damage limits for a wide range of generic cable types and specific cable products. The supposition that a direct correlation exists is supported through direct comparisons of the test results for certain specific cable products. The proposed supplemental cable fire vulnerability data gained from examination of the equipment qualification results is presented. These results should be of particular interest to those engaged in the evaluation of fire risk for industrial facilities, including nuclear power plants.

Mycotoxin food and feed regulation and the specific case of ochratoxin A: a review of the worldwide status.

PubMed

Duarte, S C; Lino, C M; Pena, A

2010-10-01

Mycotoxins are naturally occurring contaminants whose presence in food- and feedstuffs cannot be completely avoided. The safety and economic impact arising from the commercialization of mycotoxin-contaminated food and feed supply chain is considerable and acknowledged. To protect consumers from mycotoxin-derived health risks, many countries have adopted regulations or guidelines to limit exposure. Similar to regulation for other mycotoxins, the regulatory status of ochratoxin A (OTA) lacks consensus. Although this was one of the first fungal toxins to be subjected to compliance control due to its toxic properties, the conflict between the prime objective of consumer health safeguard and the economic interests of producers and traders remains. One of the key challenges facing policymakers is to balance these conflicting demands and reach consensual regulatory actions or limits. The noteworthy transboundary implications are recognized, both in the case of absence as the unsubstantiated tightening of regulatory limits. This paper scrutinizes the rationales and implications of mycotoxin regulation, with special attention devoted to OTA. In view of the ongoing debate concerning this complex issue, a review of the arguments and suggested strategies proposed by different parties is also made. The specific case of OTA regulation in food and feed is updated and analysed at a European Union and global level.

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

Ouji, Yukiteru, E-mail: oujix@naramed-u.ac.jp; Nakamura-Uchiyama, Fukumi; Yoshikawa, Masahide, E-mail: myoshika@naramed-u.ac.jp

Highlights: •First report on effects of various Wnts on DP cells. •Wnt-10b promoted trichogenesis, while Wnt-3a showed to a limited extent. •Canonical Wnts, specifically Wnt-10b, is important for DP cells maintenance. -- Abstract: Although Wnts are expressed in hair follicles (HFs) and considered to be crucial for maintaining dermal papilla (DP) cells, the functional differences among them remain largely unknown. In the present study, we investigated the effects of Wnts (Wnt-3a, 5a, 10b, 11) on the proliferation of mouse-derived primary DP cells in vitro as well as their trichogenesis-promoting ability using an in vivo skin reconstitution protocol. Wnt-10b promoted cellmore » proliferation and trichogenesis, while Wnt-3a showed those abilities to a limited extent, and Wnt-5a and 11 had no effects. Furthermore, we investigated the effects of these Wnts on cultured DP cells obtained from versican-GFP transgenic mice and found that Wnt-10b had a potent ability to sustain their GFP-positivity. These results suggest that canonical Wnts, specifically Wnt-10b, play important roles in the maintenance of DP cells and trichogenesis.« less

Insulator charging limits direct current across tunneling metal-insulator-semiconductor junctions

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

Vilan, Ayelet

Molecular electronics studies how the molecular nature affects the probability of charge carriers to tunnel through the molecules. Nevertheless, transport is also critically affected by the contacts to the molecules, an aspect that is often overlooked. Specifically, the limited ability of non-metallic contacts to maintain the required charge balance across the fairly insulating molecule often have dramatic effects. This paper shows that in the case of lead/organic monolayer-silicon junctions, a charge balance is responsible for an unusual current scaling, with the junction diameter (perimeter), rather than its area. This is attributed to the balance between the 2D charging at themore » metal/insulator interface and the 3D charging of the semiconductor space-charge region. A derivative method is developed to quantify transport across tunneling metal-insulator-semiconductor junctions; this enables separating the tunneling barrier from the space-charge barrier for a given current-voltage curve, without complementary measurements. The paper provides practical tools to analyze specific molecular junctions compatible with existing silicon technology, and demonstrates the importance of contacts' physics in modeling charge transport across molecular junctions.« less

Salmonella and cancer: from pathogens to therapeutics.

PubMed

Chorobik, Paulina; Czaplicki, Dominik; Ossysek, Karolina; Bereta, Joanna

2013-01-01

Bacterial cancer therapy is a concept more than 100 years old - yet, all things considered, it is still in early development. While the use of many passive therapeutics is hindered by the complexity of tumor biology, bacteria offer unique features that can overcome these limitations. Microbial metabolism, motility and sensitivity can lead to site-specific treatment, highly focused on the tumor and safe to other tissues. Activation of tumor-specific immunity is another important mechanism of such therapies. Several bacterial strains have been evaluated as cancer therapeutics so far, Salmonella Typhimurium being one of the most promising. S. Typhimurium and its derivatives have been used both as direct tumoricidal agents and as cancer vaccine vectors. VNP20009, an attenuated mutant of S. Typhimurium, shows significant native toxicity against murine tumors and was studied in a first-in-man phase I clinical trial for toxicity and anticancer activity. While proved to be safe in cancer patients, insufficient tumor colonization of VNP20009 was identified as a major limitation for further clinical development. Antibody-fragment-based targeting of cancer cells is one of the few approaches proposed to overcome this drawback.

Analysis of glycosaminoglycans in cerebrospinal fluid from patients with mucopolysaccharidoses by isotope-dilution ultra-performance liquid chromatography-tandem mass spectrometry.

PubMed

Zhang, Haoyue; Young, Sarah P; Auray-Blais, Christiane; Orchard, Paul J; Tolar, Jakub; Millington, David S

2011-07-01

New therapies for the treatment of mucopolysaccharidoses that target the brain, including intrathecal enzyme replacement, are being explored. Quantitative analysis of the glycosaminoglycans (GAGs) that accumulate in these disorders is required to assess the disease burden and monitor the effect of therapy in affected patients. Because current methods lack the required limit of quantification and specificity to analyze GAGs in small volumes of cerebrospinal fluid (CSF), we developed a method based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Samples of CSF (25 μL) were evaporated to dryness and subjected to methanolysis. The GAGs were degraded to uronic acid-N-acetylhexosamine dimers and mixed with internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from heparan, dermatan and chondroitin sulfates (HS, DS and CS) were separated by UPLC and analyzed by electrospray ionization MS/MS using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. CSF from control pediatric subjects (n = 22) contained <0.38 mg/L HS, 0.26 mg/L DS, and 2.8 mg/L CS, whereas CSF from patients with Hurler syndrome (n = 7) contained concentrations of DS and HS that were at least 6-fold greater than the upper control limits. These concentrations were reduced by 17.5% to 82.5% after allogeneic transplantation and treatment with intrathecal and intravenous enzyme replacement therapy. The method described here has potential value in monitoring patients with mucopolysaccharidoses receiving treatment targeted to the brain.

A review of chamber experiments for determining specific emission rates and investigating migration pathways of flame retardants

NASA Astrophysics Data System (ADS)

Rauert, Cassandra; Lazarov, Borislav; Harrad, Stuart; Covaci, Adrian; Stranger, Marianne

2014-01-01

The widespread use of flame retardants (FRs) in indoor products has led to their ubiquitous distribution within indoor microenvironments with many studies reporting concentrations in indoor air and dust. Little information is available however on emission of these compounds to air, particularly the measurement of specific emission rates (SERs), or the migration pathways leading to dust contamination. Such knowledge gaps hamper efforts to develop understanding of human exposure. This review summarizes published data on SERs of the following FRs released from treated products: polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDs), tetrabromobisphenol-A (TBBPA), novel brominated flame retardants (NBFRs) and organophosphate flame retardants (PFRs), including a brief discussion of the methods used to derive these SERs. Also reviewed are published studies that utilize emission chambers for investigations/measurements of mass transfer of FRs to dust, discussing the chamber configurations and methods used for these experiments. A brief review of studies investigating correlations between concentrations detected in indoor air/dust and possible sources in the microenvironment is included along with efforts to model contamination of indoor environments. Critical analysis of the literature reveals that the major limitations with utilizing chambers to derive SERs for FRs arise due to the physicochemical properties of FRs. In particular, increased partitioning to chamber surfaces, airborne particles and dust, causes loss through “sink” effects and results in long times to reach steady state conditions inside the chamber. The limitations of chamber experiments are discussed as well as their potential for filling gaps in knowledge in this area.

Immunohistochemistry for the detection of neural and inflammatory cells in equine brain tissue

PubMed Central

Liu, Junjie; Herrington, Jenna M.; Vallario, Kelsey

2016-01-01

Phenotypic characterization of cellular responses in equine infectious encephalitides has had limited description of both peripheral and resident cell populations in central nervous system (CNS) tissues due to limited species-specific reagents that react with formalin-fixed, paraffin embedded tissue (FFPE). This study identified a set of antibodies for investigating the immunopathology of infectious CNS diseases in horses. Multiple commercially available staining reagents and antibodies derived from antigens of various species for manual immunohistochemistry (IHC) were screened. Several techniques and reagents for heat-induced antigen retrieval, non-specific protein blocking, endogenous peroxidase blocking, and visualization-detection systems were tested during IHC protocol development. Boiling of slides in a low pH, citrate-based buffer solution in a double-boiler system was most consistent for epitope retrieval. Pressure-cooking, microwaving, high pH buffers, and proteinase K solutions often resulted in tissue disruption or no reactivity. Optimal blocking reagents and concentrations of each working antibody were determined. Ultimately, a set of monoclonal (mAb) and polyclonal antibodies (pAb) were identified for CD3+ (pAb A0452, Dako) T-lymphocytes, CD79αcy+ B-lymphocytes (mAb HM57, Dako), macrophages (mAb MAC387, Leica), NF-H+ neurons (mAb NAP4, EnCor Biotechnology), microglia/macrophage (pAb Iba-1, Wako), and GFAP+ astrocytes (mAb 5C10, EnCor Biotechnology). In paraffin embedded tissues, mAbs and pAbs derived from human and swine antigens were very successful at binding equine tissue targets. Individual, optimized protocols are provided for each positively reactive antibody for analyzing equine neuroinflammatory disease histopathology. PMID:26855862

Low-mass dark matter search with CDMSlite

DOE PAGES

Agnese, R.; Anderson, A. J.; Aralis, T.; ...

2018-01-01

The SuperCDMS experiment is designed to directly detect WIMPs (Weakly Interacting Massive Particles) that may constitute the dark matter in our galaxy. During its operation at the Soudan Underground Laboratory, germanium detectors were run in the CDMSlite (Cryogenic Dark Matter Search low ionization threshold experiment) mode to gather data sets with sensitivity specifically for WIMPs with massesmore » $${<}10$$ GeV/$c^2$. In this mode, a large detector-bias voltage is applied to amplify the phonon signals produced by drifting charges. This paper presents studies of the experimental noise and its effect on the achievable energy threshold, which is demonstrated to be as low as 56 eV$$_{\\text{ee}}$$ (electron equivalent energy). The detector biasing configuration is described in detail, with analysis corrections for voltage variations to the level of a few percent. Detailed studies of the electric-field geometry, and the resulting successful development of a fiducial parameter, eliminate poorly measured events, yielding an energy resolution ranging from $${\\sim}$$9 eV$$_{\\text{ee}}$$ at 0 keV to 101 eV$$_{\\text{ee}}$$ at $${\\sim}$$10 keV$$_{\\text{ee}}$$. New results are derived for astrophysical uncertainties relevant to the WIMP-search limits, specifically examining how they are affected by variations in the most probable WIMP velocity and the galactic escape velocity. These variations become more important for WIMP masses below 10 GeV/$c^2$. Finally, new limits on spin-dependent low-mass WIMP-nucleon interactions are derived, with new parameter space excluded for WIMP masses $${\\lesssim}$$3 GeV/$c^2$.« less

Collaborative derivation of reference intervals for major clinical laboratory tests in Japan.

PubMed

Ichihara, Kiyoshi; Yomamoto, Yoshikazu; Hotta, Taeko; Hosogaya, Shigemi; Miyachi, Hayato; Itoh, Yoshihisa; Ishibashi, Midori; Kang, Dongchon

2016-05-01

Three multicentre studies of reference intervals were conducted recently in Japan. The Committee on Common Reference Intervals of the Japan Society of Clinical Chemistry sought to establish common reference intervals for 40 laboratory tests which were measured in common in the three studies and regarded as well harmonized in Japan. The study protocols were comparable with recruitment mostly from hospital workers with body mass index ≤28 and no medications. Age and sex distributions were made equal to obtain a final data size of 6345 individuals. Between-subgroup differences were expressed as the SD ratio (between-subgroup SD divided by SD representing the reference interval). Between-study differences were all within acceptable levels, and thus the three datasets were merged. By adopting SD ratio ≥0.50 as a guide, sex-specific reference intervals were necessary for 12 assays. Age-specific reference intervals for females partitioned at age 45 were required for five analytes. The reference intervals derived by the parametric method resulted in appreciable narrowing of the ranges by applying the latent abnormal values exclusion method in 10 items which were closely associated with prevalent disorders among healthy individuals. Sex- and age-related profiles of reference values, derived from individuals with no abnormal results in major tests, showed peculiar patterns specific to each analyte. Common reference intervals for nationwide use were developed for 40 major tests, based on three multicentre studies by advanced statistical methods. Sex- and age-related profiles of reference values are of great relevance not only for interpreting test results, but for applying clinical decision limits specified in various clinical guidelines. © The Author(s) 2015.

Extracellular vesicles for liquid biopsy in prostate cancer: where are we and where are we headed?

PubMed

Minciacchi, V R; Zijlstra, A; Rubin, M A; Di Vizio, D

2017-09-01

Extracellular vesicles (EVs) are a heterogeneous class of lipid bound particles shed by any cell in the body in physiological and pathological conditions. EVs play critical functions in intercellular communication. EVs can actively travel in intercellular matrices and eventually reach the circulation. They can also be released directly in biological fluids where they appear to be stable. Because the molecular content of EVs reflects the composition of the cell of origin, they have recently emerged as a promising source of biomarkers in a number of diseases. EV analysis is particularly attractive in cancer patients that frequently present with increased numbers of circulating EVs. We sought to review the current literature on the molecular profile of prostate cancer-derived EVs in model systems and patient biological fluids in an attempt to draw some practical and universal conclusions on the use of EVs as a tool for liquid biopsy in clinical specimens. We discuss advantages and limitations of EV-based liquid biopsy approaches summarizing salient studies on protein, DNA and RNA. Several candidate biomarkers have been identified so far but these results are difficult to apply to the clinic. However, the field is rapidly moving toward the implementation of novel tools to isolate cancer-specific EVs that are free of benign EVs and extra-vesicular contaminants. This can be achieved by identifying markers that are exquisitely present in tumor cell-derived EVs. An important contribution might also derive from a better understanding of EV types that may play specific functions in tumor progression and that may be a source of cancer-specific markers. EV analysis holds strong promises for the development of non-invasive biomarkers in patients with prostate cancer. Implementation of modern methods for EV isolation and characterization will enable to interrogate circulating EVs in vivo.

A SNAP-Tagged Derivative of HIV-1—A Versatile Tool to Study Virus-Cell Interactions

PubMed Central

Eckhardt, Manon; Anders, Maria; Muranyi, Walter; Heilemann, Mike; Krijnse-Locker, Jacomine; Müller, Barbara

2011-01-01

Fluorescently labeled human immunodeficiency virus (HIV) derivatives, combined with the use of advanced fluorescence microscopy techniques, allow the direct visualization of dynamic events and individual steps in the viral life cycle. HIV proteins tagged with fluorescent proteins (FPs) have been successfully used for live-cell imaging analyses of HIV-cell interactions. However, FPs display limitations with respect to their physicochemical properties, and their maturation kinetics. Furthermore, several independent FP-tagged constructs have to be cloned and characterized in order to obtain spectral variations suitable for multi-color imaging setups. In contrast, the so-called SNAP-tag represents a genetically encoded non-fluorescent tag which mediates specific covalent coupling to fluorescent substrate molecules in a self-labeling reaction. Fusion of the SNAP-tag to the protein of interest allows specific labeling of the fusion protein with a variety of synthetic dyes, thereby offering enhanced flexibility for fluorescence imaging approaches. Here we describe the construction and characterization of the HIV derivative HIVSNAP, which carries the SNAP-tag as an additional domain within the viral structural polyprotein Gag. Introduction of the tag close to the C-terminus of the matrix domain of Gag did not interfere with particle assembly, release or proteolytic virus maturation. The modified virions were infectious and could be propagated in tissue culture, albeit with reduced replication capacity. Insertion of the SNAP domain within Gag allowed specific staining of the viral polyprotein in the context of virus producing cells using a SNAP reactive dye as well as the visualization of individual virions and viral budding sites by stochastic optical reconstruction microscopy. Thus, HIVSNAP represents a versatile tool which expands the possibilities for the analysis of HIV-cell interactions using live cell imaging and sub-diffraction fluorescence microscopy. PMID:21799764

Tracing notochord-derived cells using a Noto-cre mouse: implications for intervertebral disc development.

PubMed

McCann, Matthew R; Tamplin, Owen J; Rossant, Janet; Séguin, Cheryle A

2012-01-01

Back pain related to intervertebral disc degeneration is the most common musculoskeletal problem, with a lifetime prevalence of 82%. The lack of effective treatment for this widespread problem is directly related to our limited understanding of disc development, maintenance and degeneration. The aim of this study was to determine the developmental origins of nucleus pulposus cells within the intervertebral disc using a novel notochord-specific Cre mouse. To trace the fate of notochordal cells within the intervertebral disc, we derived a notochord-specific Cre mouse line by targeting the homeobox gene Noto. Expression of this gene is restricted to the node and the posterior notochord during gastrulation [embryonic day 7.5 (E7.5)-E12.5]. The Noto-cre mice were crossed with a conditional lacZ reporter for visualization of notochord fate in whole-mount embryos. We performed lineage-tracing experiments to examine the contribution of the notochord to spinal development from E12.5 through to skeletally mature mice (9 months). Fate mapping studies demonstrated that, following elongation and formation of the primitive axial skeleton, the notochord gives rise to the nucleus pulposus in fully formed intervertebral discs. Cellular localization of β-galactosidase (encoded by lacZ) and cytokeratin-8 demonstrated that both notochordal cells and chondrocyte-like nucleus pulposus cells are derived from the embryonic notochord. These studies establish conclusively that notochordal cells act as embryonic precursors to all cells found within the nucleus pulposus of the mature intervertebral disc. This suggests that notochordal cells might serve as tissue-specific progenitor cells within the disc and establishes the Noto-cre mouse as a unique tool to interrogate the contribution of notochordal cells to both intervertebral disc development and disc degeneration.

Tracing notochord-derived cells using a Noto-cre mouse: implications for intervertebral disc development

PubMed Central

McCann, Matthew R.; Tamplin, Owen J.; Rossant, Janet; Séguin, Cheryle A.

2012-01-01

SUMMARY Back pain related to intervertebral disc degeneration is the most common musculoskeletal problem, with a lifetime prevalence of 82%. The lack of effective treatment for this widespread problem is directly related to our limited understanding of disc development, maintenance and degeneration. The aim of this study was to determine the developmental origins of nucleus pulposus cells within the intervertebral disc using a novel notochord-specific Cre mouse. To trace the fate of notochordal cells within the intervertebral disc, we derived a notochord-specific Cre mouse line by targeting the homeobox gene Noto. Expression of this gene is restricted to the node and the posterior notochord during gastrulation [embryonic day 7.5 (E7.5)-E12.5]. The Noto-cre mice were crossed with a conditional lacZ reporter for visualization of notochord fate in whole-mount embryos. We performed lineage-tracing experiments to examine the contribution of the notochord to spinal development from E12.5 through to skeletally mature mice (9 months). Fate mapping studies demonstrated that, following elongation and formation of the primitive axial skeleton, the notochord gives rise to the nucleus pulposus in fully formed intervertebral discs. Cellular localization of β-galactosidase (encoded by lacZ) and cytokeratin-8 demonstrated that both notochordal cells and chondrocyte-like nucleus pulposus cells are derived from the embryonic notochord. These studies establish conclusively that notochordal cells act as embryonic precursors to all cells found within the nucleus pulposus of the mature intervertebral disc. This suggests that notochordal cells might serve as tissue-specific progenitor cells within the disc and establishes the Noto-cre mouse as a unique tool to interrogate the contribution of notochordal cells to both intervertebral disc development and disc degeneration. PMID:22028328

Dynamics with a Nonstandard Inertia-Acceleration Relation: An Alternative to Dark Matter in Galactic Systems

NASA Astrophysics Data System (ADS)

Milgrom, M.

1994-02-01

We investigate particle dynamics that is governed by a nonstandard kinetic action of a special form. We are guided by a phenomenological scheme-the modified dynamics (MOND)-that imputes the mass discrepancy, observed in galactic systems, not to the presence of dark matter, but to a departure from Newtonian dynamics below a certain scale of accelerations, a0. The particle's equation of motion in a potential φ is derived from an action, S, of the form S ~ Sk[r(t), a0] - ∫ φ dt. The limit a0 --> 0 corresponds to Newtonian dynamics, and there the kinetic action Sk must take the standard form. In the opposite limit, a0 --> ∞ we require Sk --> 0-and more specifically, for circular orbits Sk ~ a-10-in order to attain the phenomenological success of MOND. Galilei-invariant such theories must be strongly nonlocal. This is a blessing, as such theories need not suffer from the illnesses that are endemic to higher-derivative theories. We comment on the possibility that such a modified law of motion is an effective theory resulting from the elimination of degrees of freedom pertaining to the universe at large (the near equality a0 ≍ cH0 being a trace of that connection). We derive a general virial relation for bounded trajectories. Exact solutions are obtained for circular orbits, which pertain to rotation curves of disk galaxies. We also explore, in passing, theories that depart from the conventional Newtonian dynamics for very low frequencies.

Epicardially-derived Fibroblasts Preferentially Contribute to the Parietal Leaflets of the Atrioventricular Valves in the Murine Heart

PubMed Central

Wessels, Andy; van den Hoff, Maurice J. B.; Adamo, Richard F.; Phelps, Aimee L.; Lockhart, Marie M.; Sauls, Kimberly; Briggs, Laura E.; Norris, Russell A.; van Wijk, Bram; Perez-Pomares, Jose M.; Dettman, Robert W.; Burch, John B. E.

2012-01-01

The importance of the epicardium for myocardial and valvuloseptal development has been well established; perturbation of epicardial development results in cardiac abnormalities, including thinning of the ventricular myocardial wall and malformations of the atrioventricular valvuloseptal complex. To determine the spatiotemporal contribution of epicardially derived cells to the developing fibroblast population in the heart we have used a mWt1/IRES/GFP-Cre mouse to trace the fate of EPDCs from embryonic day (ED)10 until birth. EPDCs begin to populate the compact ventricular myocardium around ED12. The migration of epicardially-derived fibroblasts toward the interface between compact and trabecular myocardium is completed around ED14. Remarkably, epicardially-derived fibroblasts do not migrate into the trabecular myocardium until after ED17. Migration of EPDCs into the atrioventricular cushion mesenchyme commences around ED12. As development progresses, the number of EPDCs increases significantly, specifically in the leaflets which derive from the lateral atrioventricular cushions. In these developing leaflets the epicardially-derived fibroblasts eventually largely replace the endocardially-derived cells. Importantly, the contribution of EPDCs to the leaflets derived from the major AV cushions is very limited. The differential contribution of EPDCs to the various leaflets of the atrioventricular valves provides a new paradigm in valve development and could lead to new insights into the pathogenesis of abnormalities that preferentially affect individual components of this region of the heart. The notion that there is a significant difference in the contribution of epicardially and endocardially derived cells to the individual leaflets of the atrioventricular valves has also important pragmatic consequences for the use of endocardial and epicardial cre-mouse models in studies of heart development. PMID:22546693

Analytical description of the modern steam automobile

NASA Technical Reports Server (NTRS)

Peoples, J. A.

1974-01-01

The sensitivity of operating conditions upon performance of the modern steam automobile is discussed. The word modern has been used in the title to indicate that emphasis is upon miles per gallon rather than theoretical thermal efficiency. This has been accomplished by combining classical power analysis with the ideal Pressure-Volume diagram. Several parameters are derived which characterize performance capability of the modern steam car. The report illustrates that performance is dictated by the characteristics of the working medium, and the supply temperature. Performance is nearly independent of pressures above 800 psia. Analysis techniques were developed specifically for reciprocating steam engines suitable for automotive application. Specific performance charts have been constructed on the basis of water as a working medium. The conclusions and data interpretation are therefore limited within this scope.

The Arabidopsis translatome cell-specific mRNA atlas: Mining suberin and cutin lipid monomer biosynthesis genes as an example for data application.

PubMed

Mustroph, Angelika; Bailey-Serres, Julia

2010-03-01

Plants consist of distinct cell types distinguished by position, morphological features and metabolic activities. We recently developed a method to extract cell-type specific mRNA populations by immunopurification of ribosome-associated mRNAs. Microarray profiles of 21 cell-specific mRNA populations from seedling roots and shoots comprise the Arabidopsis Translatome dataset. This gene expression atlas provides a new tool for the study of cell-specific processes. Here we provide an example of how genes involved in a pathway limited to one or few cell-types can be further characterized and new candidate genes can be predicted. Cells of the root endodermis produce suberin as an inner barrier between the cortex and stele, whereas the shoot epidermal cells form cutin as a barrier to the external environment. Both polymers consist of fatty acid derivates, and share biosynthetic origins. We use the Arabidopsis Translatome dataset to demonstrate the significant cell-specific expression patterns of genes involved in those biosynthetic processes and suggest new candidate genes in the biosynthesis of suberin and cutin.

Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers

PubMed Central

Kebebe, Dereje; Liu, Yuanyuan; Wu, Yumei; Vilakhamxay, Maikhone; Liu, Zhidong; Li, Jiawei

2018-01-01

Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents. PMID:29563797

Antigen challenge leads to in vivo activation and elimination of highly polarized TH1 memory T cells

PubMed Central

Hayashi, Nobuki; Liu, Dacai; Min, Booki; Ben-Sasson, Shlomo Z.; Paul, William E.

2002-01-01

TH1 memory T cells derived from T cell receptor transgenic mice, in which the T cell antigen receptor is specific for a cytochrome C peptide in association with I-Ek, were transferred into normal B10.A mice and allowed to adopt a resting phenotype. When challenged, 30–60 days after transfer, with i.v. cytochrome C, the transgenic cells rapidly became activated, expressed mRNA for IFNγ, and began to divide. However, after 48 h, the frequency of the cells fell progressively, reaching levels only slightly above the limit of detection by day 8 and thereafter remain depressed for up to 90 days. The remaining cells were anergic as shown by limitation in proliferation and IFNγ production in response to in vitro antigen stimulation. Even if challenged with antigen emulsified in complete Freund's adjuvant, the overall pattern was similar, except that in the draining lymph nodes, the surviving antigen-specific cells were not anergic, although spleen cells were still strikingly anergic. Thus, antigenic challenge of mice possessing resting memory TH1 CD4 T cells leads to the unanticipated loss of most of the specific cells and an apparent depletion rather than enhancement of immunologic memory. PMID:11959916

Comparative evaluation of post-column free radical scavenging and ferric reducing antioxidant power assays for screening of antioxidants in strawberries.

PubMed

Raudonis, Raimondas; Raudone, Lina; Jakstas, Valdas; Janulis, Valdimaras

2012-04-13

ABTS and FRAP post-column techniques evaluate the antioxidant characteristics of HPLC separated compounds with specific reagents. ABTS characterize their ability to scavenge free radicals by electron-donating antioxidants, resulting in the absorbance decrease of the chromophoric radical. FRAP - is based on the reduction of Fe(III)-tripyridyltriazine complex to Fe(II)-tripyridyltriazine at low pH by electron-donating antioxidants, resulting in an absorbance increase. Both post-column assays were evaluated and compared according to the following validation parameters: specificity, precision, limit of detection (LoD), limit of quantitation (LoQ) and linearity. ABTS and FRAP post-column assays were specific, repeatable and sensitive and thus can be used for the evaluation of antioxidant active compounds. Antioxidant active compounds were quantified according to TEAC for each assay and ABTS/FRAP ratio was derived. No previous records of antioxidative activity of leaves and fruits of strawberries (Fragaria viridis, Fragaria moschata) research have been found. The research results confirm the reliability of ABTS and FRAP post-column assays for screening of antioxidants in complex mixtures and the determination of radical scavenging and ferric reducing ability by their TEAC values. Copyright © 2012 Elsevier B.V. All rights reserved.

Development and in-house validation of the event-specific qualitative and quantitative PCR detection methods for genetically modified cotton MON15985.

PubMed

Jiang, Lingxi; Yang, Litao; Rao, Jun; Guo, Jinchao; Wang, Shu; Liu, Jia; Lee, Seonghun; Zhang, Dabing

2010-02-01

To implement genetically modified organism (GMO) labeling regulations, an event-specific analysis method based on the junction sequence between exogenous integration and host genomic DNA has become the preferential approach for GMO identification and quantification. In this study, specific primers and TaqMan probes based on the revealed 5'-end junction sequence of GM cotton MON15985 were designed, and qualitative and quantitative polymerase chain reaction (PCR) assays were established employing the designed primers and probes. In the qualitative PCR assay, the limit of detection (LOD) was 0.5 g kg(-1) in 100 ng total cotton genomic DNA, corresponding to about 17 copies of haploid cotton genomic DNA, and the LOD and limit of quantification (LOQ) for quantitative PCR assay were 10 and 17 copies of haploid cotton genomic DNA, respectively. Furthermore, the developed quantitative PCR assays were validated in-house by five different researchers. Also, five practical samples with known GM contents were quantified using the developed PCR assay in in-house validation, and the bias between the true and quantification values ranged from 2.06% to 12.59%. This study shows that the developed qualitative and quantitative PCR methods are applicable for the identification and quantification of GM cotton MON15985 and its derivates.

Baicalin maintains late-stage functional cardiomyocytes in embryoid bodies derived from murine embryonic stem cells.

PubMed

Tang, Meilin; Yin, Mengmeng; Tang, Ming; Liang, Huamin; Yu, Chong; Hu, Xinwu; Luo, Hongyan; Baudis, Birte; Haustein, Moritz; Khalil, Markus; Sarić, Tomo; Hescheler, Jürgen; Xi, Jiaoya

2013-01-01

Low efficiency of cardiomyocyte (CM) differentiation from embryonic stem (ES) cells limits their therapeutic use. The objective of this study was to investigate the effect of baicalin, a natural flavonoid compound, on the in vitro cardiac differentiation of murine ES cells. The induction of ES cells into cardiac-like cells was performed by embryoid body (EB)-based differentiation method. The electrophysiological properties of the ES cell-derived CMs (ES-CMs) were measured by patch-clamp. The biomarkers of ES-CMs were determined by quantitative RT-PCR and immunofluorescence. Continuous baicalin treatment decreased the size of EBs, and increased the proportion of α-actinin-positive CMs and transcript level of cardiac specific markers in beating EBs by inducing cell death of non-CMs. Baicalin increased the percentage of working ES-CMs which had typical responses to β-adrenergic and muscarinic stimulations. Baicalin maintains the late-stage functional CMs in EBs derived from murine ES cells. This study describes a new insight into the various biological effects of baicalin on cardiac differentiation of pluripotent stem cells. Copyright © 2013 S. Karger AG, Basel.

Integrands for QCD rational terms and {N} = {4} SYM from massive CSW rules

NASA Astrophysics Data System (ADS)

Elvang, Henriette; Freedman, Daniel Z.; Kiermaier, Michael

2012-06-01

We use massive CSW rules to derive explicit compact expressions for integrands of rational terms in QCD with any number of external legs. Specifically, we present all- n integrands for the one-loop all-plus and one-minus gluon amplitudes in QCD. We extract the finite part of spurious external-bubble contributions systematically; this is crucial for the application of integrand-level CSW rules in theories without supersymmetry. Our approach yields integrands that are independent of the choice of CSW reference spinor even before integration. Furthermore, we present a recursive derivation of the recently proposed massive CSW-style vertex expansion for massive tree amplitudes and loop integrands on the Coulomb-branch of {N} = {4} SYM. The derivation requires a careful study of boundary terms in all-line shift recursion relations, and provides a rigorous (albeit indirect) proof of the recently proposed construction of massive amplitudes from soft-limits of massless on-shell amplitudes. We show that the massive vertex expansion manifestly preserves all holomorphic and half of the anti-holomorphic supercharges, diagram-by-diagram, even off-shell.

Grafting polyethylenimine with quinoline derivatives for targeted imaging of intracellular Zn(2+) and logic gate operations.

PubMed

Pan, Yi; Shi, Yupeng; Chen, Junying; Wong, Chap-Mo; Zhang, Heng; Li, Mei-Jin; Li, Cheuk-Wing; Yi, Changqing

2016-12-01

In this study, a highly sensitive and selective fluorescent Zn(2+) probe which exhibited excellent biocompatibility, water solubility, and cell-membrane permeability, was facilely synthesized in a single step by grafting polyethyleneimine (PEI) with quinoline derivatives. The primary amino groups in the branched PEI can increase water solubility and cell permeability of the probe PEIQ, while quinoline derivatives can specifically recognize Zn(2+) and reduce the potential cytotoxicity of PEI. Basing on fluorescence off-on mechanism, PEIQ demonstrated excellent sensing capability towards Zn(2+) in absolute aqueous solution, where a high sensitivity with a detection limit as low as 38.1nM, and a high selectivity over competing metal ions and potential interfering amino acids, were achieved. Inspired by these results, elementary logic operations (YES, NOT and INHIBIT) have been constructed by employing PEIQ as the gate while Zn(2+) and EDTA as chemical inputs. Together with the low cytotoxicity and good cell-permeability, the practical application of PEIQ in living cell imaging was satisfactorily demonstrated, emphasizing its wide application in fundamental biology research. Copyright © 2016. Published by Elsevier B.V.

Primary energy: Present status and future perspectives

NASA Astrophysics Data System (ADS)

Thielheim, K. O.

A survey of the base-load energy sources available to humans is presented, starting from the point of view that all energy used is ultimately derived from nuclear processes within the sun. Specific note is made of European energy options, noting the large dependence on imported oil. Detailed exploration of available nuclear fuel resources is carried out, with attention given to fission, fusion, and breeder reactor plants and to the state-of-the-art and technology for each. The problems of nuclear waste disposal are discussed, and long term burial in salt domes is outlined as a satisfactory method of containing the materials for acceptable periods of time. The CO2-greenhouse effect hazards caused by increased usage of coal-derived fuels are considered and precautions to be taken on a global scale to ameliorate the warming effects are recommended. The limitations to hydropower are examined, as are those of tidal power. Solar cells are projected to be produced in GW quantities by the year 2000, while wind-derived electricity is predicted to provide a minimum of 5% of the world energy needs in the future.

Perspectives in metabolic engineering: understanding cellular regulation towards the control of metabolic routes.

PubMed

Zadran, Sohila; Levine, Raphael D

2013-01-01

Metabolic engineering seeks to redirect metabolic pathways through the modification of specific biochemical reactions or the introduction of new ones with the use of recombinant technology. Many of the chemicals synthesized via introduction of product-specific enzymes or the reconstruction of entire metabolic pathways into engineered hosts that can sustain production and can synthesize high yields of the desired product as yields of natural product-derived compounds are frequently low, and chemical processes can be both energy and material expensive; current endeavors have focused on using biologically derived processes as alternatives to chemical synthesis. Such economically favorable manufacturing processes pursue goals related to sustainable development and "green chemistry". Metabolic engineering is a multidisciplinary approach, involving chemical engineering, molecular biology, biochemistry, and analytical chemistry. Recent advances in molecular biology, genome-scale models, theoretical understanding, and kinetic modeling has increased interest in using metabolic engineering to redirect metabolic fluxes for industrial and therapeutic purposes. The use of metabolic engineering has increased the productivity of industrially pertinent small molecules, alcohol-based biofuels, and biodiesel. Here, we highlight developments in the practical and theoretical strategies and technologies available for the metabolic engineering of simple systems and address current limitations.

Preexisting CD8+ T-cell immunity to the H7N9 influenza A virus varies across ethnicities

PubMed Central

Quiñones-Parra, Sergio; Grant, Emma; Loh, Liyen; Nguyen, Thi H. O.; Campbell, Kristy-Anne; Tong, Steven Y. C.; Miller, Adrian; Doherty, Peter C.; Vijaykrishna, Dhanasekaran; Rossjohn, Jamie; Gras, Stephanie; Kedzierska, Katherine

2014-01-01

The absence of preexisting neutralizing antibodies specific for the novel A (H7N9) influenza virus indicates a lack of prior human exposure. As influenza A virus–specific CD8+ T lymphocytes (CTLs) can be broadly cross-reactive, we tested whether immunogenic peptides derived from H7N9 might be recognized by memory CTLs established following infection with other influenza strains. Probing across multiple ethnicities, we identified 32 conserved epitopes derived from the nucleoprotein (NP) and matrix-1 (M1) proteins. These NP and M1 peptides are presented by HLAs prevalent in 16–57% of individuals. Remarkably, some HLA alleles (A*0201, A*0301, B*5701, B*1801, and B*0801) elicit robust CTL responses against any human influenza A virus, including H7N9, whereas ethnicities where HLA-A*0101, A*6801, B*1501, and A*2402 are prominent, show limited CTL response profiles. By this criterion, some groups, especially the Alaskan and Australian Indigenous peoples, would be particularly vulnerable to H7N9 infection. This dissection of CTL-mediated immunity to H7N9 thus suggests strategies for both vaccine delivery and development. PMID:24395804

Specific and sensitive enzyme-linked immunosorbent assays for analysis of residual allergenic food proteins in commercial bottled wine fined with egg white, milk, and nongrape-derived tannins.

PubMed

Rolland, Jennifer M; Apostolou, Effie; de Leon, Maria P; Stockley, Creina S; O'Hehir, Robyn E

2008-01-23

Regulations introduced by the Food Standards Australia New Zealand in December 2002 require all wine and wine product labels in Australia to identify the presence of a processing aid, additive or other ingredient, which is known to be a potential allergen. The objective of this study was to establish sensitive assays to detect and measure allergenic proteins from commonly used processing aids in final bottled wine. Sensitive and specific enzyme-linked immunosorbent assays (ELISA) were developed and established for the proteins casein, ovalbumin, and peanut. Lower limits of detection of these proteins were 8, 1, and 8 ng/mL, respectively. A panel of 153 commercially available bottled Australian wines were tested by these ELISA, and except for two red wines known to contain added whole eggs, residuals of these food allergens were not detected in any wine. These findings are consistent with a lack of residual potentially allergenic egg-, milk-, or nut-derived processing aids in final bottled wine produced in Australia according to good manufacturing practice at a concentration that could cause an adverse reaction in egg, milk, or peanut/tree-nut allergic adult consumers.

Biosynthesis of nucleotide sugars by a promiscuous UDP-sugar pyrophosphorylase from Arabidopsis thaliana (AtUSP).

PubMed

Liu, Jun; Zou, Yang; Guan, Wanyi; Zhai, Yafei; Xue, Mengyang; Jin, Lan; Zhao, Xueer; Dong, Junkai; Wang, Wenjun; Shen, Jie; Wang, Peng George; Chen, Min

2013-07-01

Nucleotide sugars are activated forms of monosaccharides and key intermediates of carbohydrate metabolism in all organisms. The availability of structurally diverse nucleotide sugars is particularly important for the characterization of glycosyltransferases. Given that limited methods are available for preparation of nucleotide sugars, especially their useful non-natural derivatives, we introduced herein an efficient one-step three-enzyme catalytic system for the synthesis of nucleotide sugars from monosaccharides. In this study, a promiscuous UDP-sugar pyrophosphorylase (USP) from Arabidopsis thaliana (AtUSP) was used with a galactokinase from Streptococcus pneumoniae TIGR4 (SpGalK) and an inorganic pyrophosphatase (PPase) to effectively synthesize four UDP-sugars. AtUSP has better tolerance for C4-derivatives of Gal-1-P compared to UDP-glucose pyrophosphorylase from S. pneumoniae TIGR4 (SpGalU). Besides, the nucleotide substrate specificity and kinetic parameters of AtUSP were systematically studied. AtUSP exhibited considerable activity toward UTP, dUTP and dTTP, the yield of which was 87%, 85% and 84%, respectively. These results provide abundant information for better understanding of the relationship between substrate specificity and structural features of AtUSP. Copyright © 2013 Elsevier Ltd. All rights reserved.

In Vitro Hepatic Trans-Differentiation of Human Mesenchymal Stem Cells Using Sera from Congestive/Ischemic Liver during Cardiac Failure

PubMed Central

Bishi, Dillip Kumar; Mathapati, Santosh; Cherian, Kotturathu Mammen; Guhathakurta, Soma; Verma, Rama Shanker

2014-01-01

Cellular therapy for end-stage liver failures using human mesenchymal stem cells (hMSCs)-derived hepatocytes is a potential alternative to liver transplantation. Hepatic trans-differentiation of hMSCs is routinely accomplished by induction with commercially available recombinant growth factors, which is of limited clinical applications. In the present study, we have evaluated the potential of sera from cardiac-failure-associated congestive/ischemic liver patients for hepatic trans-differentiation of hMSCs. Results from such experiments were confirmed through morphological changes and expression of hepatocyte-specific markers at molecular and cellular level. Furthermore, the process of mesenchymal-to-epithelial transition during hepatic trans-differentiation of hMSCs was confirmed by elevated expression of E-Cadherin and down-regulation of Snail. The functionality of hMSCs-derived hepatocytes was validated by various liver function tests such as albumin synthesis, urea release, glycogen accumulation and presence of a drug inducible cytochrome P450 system. Based on these findings, we conclude that sera from congestive/ischemic liver during cardiac failure support a liver specific microenvironment for effective hepatic trans-differentiation of hMSCs in vitro. PMID:24642599

Porous organic polymers with different pore structures for sensitive solid-phase microextraction of environmental organic pollutants.

PubMed

Huang, Zhoubing; Liu, Shuqin; Xu, Jianqiao; Yin, Li; Zheng, Juan; Zhou, Ningbo; Ouyang, Gangfeng

2017-10-09

Adsorption capacity is the major sensitivity-limited factor in solid-phase microextraction. Due to its light-weight properties, large specific surface area and high porosity, especially tunable pore structures, the utilization of porous organic polymers as solid-phase microextraction adsorbents has attracting researchers' attentions. However, these works mostly concentrated on the utilization of specific porous organic polymers for preparing high-performance solid-phase microextraction coatings. The relationship between pore structures and adsorption performance of the porous organic polymers still remain unclear. Herein, three porous organic polymers with similar properties but different pore distributions were prepared by condensation polymerization reaction of phloroglucinol and terephthalaldehyde, which were fabricated as solid-phase microextraction coatings subsequently. The adsorption capacity of the porous organic polymers-coated fibers were evaluated by using benzene and its derivatives (i.e.,benzene, toluene, ethylbenzene and m-xylene) and polycyclic aromatic hydrocarbons as the target analytes. The results showed that the different adsorption performance of these porous organic polymers was mainly caused by their different pore volumes instead of their surface areas or pore sizes. Finally, the proposed method by using the mesoporous organic polymer coating was successfully applied to the determination of benzene and its derivatives in environmental water samples. As for analytical performance, high pre-concentration factors (74-2984), satisfactory relative recoveries (94.5 ± 18.5-116.9 ± 12.5%), intraday precision (2.44-5.34%), inter-day precision (4.62-7.02%), low limit of detections (LODs, 0.10-0.29 ng L -1 ) and limit of quantifications (LOQs, 0.33-0.96 ng L -1 ) were achieved under the optimal conditions. This study provides an important idea in the rational design of porous organic polymers for solid-phase microextraction or other adsorption applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Wood-Based Nanocomposite Derived by in Situ Formation of Organic-Inorganic Hybrid Polymer within Wood via a Sol-Gel Method.

PubMed

Dong, Xiaoying; Zhuo, Xiao; Wei, Jie; Zhang, Gang; Li, Yongfeng

2017-03-15

Solid wood materials and wood-plastic composites as two kinds of lightweight materials are attracting great interest from academia and industry due to their green and recycling nature. However, the relatively lower specific strength limits their wider applications. In particular, solid wood is vulnerable to moisture and decay fungi in nature, resulting in its poor durability for effectively long-term utilization. Inspired from the porous structure of wood, we propose a new design to build a wood-based nanocomposite with higher specific strength and satisfactory durability by in situ generation of organic-inorganic hybrid polymer within wood via a sol-gel method. The derived composite has 50-1200% improvement of impact toughness, 56-192% improvement of tensile strength, and 110-291% improvement of flexural strength over those of typical wood-plastic composites, respectively; and even 34% improvement of specific tensile strength than that of 36A steel; 208% enhancement of hardness; and 156% enhancement of compression strength than those of compared solid wood, respectively; as well as significantly improved dimensional stability and decay resistance over those of untreated natural wood. Such materials could be potentially utilized as lightweight and high-strength materials for applications in construction and automotive industries. This method could be extended to constitute other inorganic nanomaterials for novel organic-inorganic hybrid polymer within wood.

New, national bottom-up estimate for tree-based biological ...

EPA Pesticide Factsheets

Nitrogen is a limiting nutrient in many ecosystems, but is also a chief pollutant from human activity. Quantifying human impacts on the nitrogen cycle and investigating natural ecosystem nitrogen cycling both require an understanding of the magnitude of nitrogen inputs from biological nitrogen fixation (BNF). A bottom-up approach to estimating BNF—scaling rates up from measurements to broader scales—is attractive because it is rooted in actual BNF measurements. However, bottom-up approaches have been hindered by scaling difficulties, and a recent top-down approach suggested that the previous bottom-up estimate was much too large. Here, we used a bottom-up approach for tree-based BNF, overcoming scaling difficulties with the systematic, immense (>70,000 N-fixing trees) Forest Inventory and Analysis (FIA) database. We employed two approaches to estimate species-specific BNF rates: published ecosystem-scale rates (kg N ha-1 yr-1) and published estimates of the percent of N derived from the atmosphere (%Ndfa) combined with FIA-derived growth rates. Species-specific rates can vary for a variety of reasons, so for each approach we examined how different assumptions influenced our results. Specifically, we allowed BNF rates to vary with stand age, N-fixer density, and canopy position (since N-fixation is known to require substantial light).Our estimates from this bottom-up technique are several orders of magnitude lower than previous estimates indicating

Target-induced proximity ligation triggers recombinase polymerase amplification and transcription-mediated amplification to detect tumor-derived exosomes in nasopharyngeal carcinoma with high sensitivity.

PubMed

Liu, Wanli; Li, Jianpei; Wu, Yixian; Xing, Shan; Lai, Yanzhen; Zhang, Ge

2018-04-15

Tumor-derived exosomes (TEXs) are extracellular vesicles that are continuously released into the blood by tumor cells and carry specific surface markers of the original tumor cells. Substantial evidence has implicated TEXs as attractive diagnostic markers for cancer. However, the detection of TEXs in blood at an early tumor stage is challenging due to their very low concentration. Here, we established a method called PLA-RPA-TMA assay that allows TEXs to be detected with high sensitivity and specificity. Based on two proximity ligation assay (PLA) probes that recognize a biomarker on a TEX, we generated a unique surrogate DNA signal for the specific biomarker, which was synchronously amplified twice by recombinase polymerase amplification (RPA) coupled with transcription-mediated amplification (TMA), and then the products of the RPA-TMA reaction were quantitatively detected using a gold nanoparticle-based colorimetric assay. We established proof-of-concept evidence for this approach using TEXs from nasopharyngeal carcinoma (NPC) cells, with a detection limit of 10 2 particles/mL, and reported the measurement of plasma Epstein-Barr virus latent membrane protein 1 (LPM1)-positive (LMP1 + , accuracy: 0.956) and epidermal growth factor receptor (EGFR)-positive (EGFR + , accuracy: 0.906) TEXs as potent early diagnostic biomarkers for NPC. Copyright © 2017 Elsevier B.V. All rights reserved.

Spiral-Based Phononic Plates: From Wave Beaming to Topological Insulators

NASA Astrophysics Data System (ADS)

Foehr, André; Bilal, Osama R.; Huber, Sebastian D.; Daraio, Chiara

2018-05-01

Phononic crystals and metamaterials can sculpt elastic waves, controlling their dispersion using different mechanisms. These mechanisms are mostly Bragg scattering, local resonances, and inertial amplification, derived from ad hoc, often problem-specific geometries of the materials' building blocks. Here, we present a platform that ultilizes a lattice of spiraling unit cells to create phononic materials encompassing Bragg scattering, local resonances, and inertial amplification. We present two examples of phononic materials that can control waves with wavelengths much larger than the lattice's periodicity. (1) A wave beaming plate, which can beam waves at arbitrary angles, independent of the lattice vectors. We show that the beaming trajectory can be continuously tuned, by varying the driving frequency or the spirals' orientation. (2) A topological insulator plate, which derives its properties from a resonance-based Dirac cone below the Bragg limit of the structured lattice of spirals.

Radiation Protection Using Single-Wall Carbon Nanotube Derivatives

NASA Technical Reports Server (NTRS)

Tour, James M.; Lu, Meng; Lucente-Schultz, Rebecca; Leonard, Ashley; Doyle, Condell Dewayne; Kosynkin, Dimitry V.; Price, Brandi Katherine

2011-01-01

This invention is a means of radiation protection, or cellular oxidative stress mitigation, via a sequence of quenching radical species using nano-engineered scaffolds, specifically single-wall carbon nanotubes (SWNTs) and their derivatives. The material can be used as a means of radiation protection by reducing the number of free radicals within, or nearby, organelles, cells, tissue, organs, or living organisms, thereby reducing the risk of damage to DNA and other cellular components (i.e., RNA, mitochondria, membranes, etc.) that can lead to chronic and/or acute pathologies, including but not limited to cancer, cardiovascular disease, immuno-suppression, and disorders of the central nervous system. In addition, this innovation could be used as a prophylactic or antidote for accidental radiation exposure, during high-altitude or space travel where exposure to radiation is anticipated, or to protect from exposure from deliberate terrorist or wartime use of radiation- containing weapons.

Validation of a simple liquid chromatographic method for determination and quantitation of residual ivermectin and doramectin in pig liver.

PubMed

Knold, Lone; Reitov, Marianne; Mortensen, Anna Birthe; Hansen-Møller, Jens

2002-01-01

A rapid and quantitative method for the extraction, derivatization, and liquid chromatography with fluorescence detection of ivermectin (IVM) and doramectin (DOM) residues in porcine liver was developed and validated. IVM and DOM were extracted from the liver samples with acetonitrile, the supernatant was evaporated to dryness at 37 degrees C under nitrogen, and the residue was reconstituted in 1-methylimidazole solution. After 2 min at room temperature, IVM and DOM were converted to a fluorescent derivative and then separated on a Hypersil ODS column. The derivatives of IVM and DOM were detected and quantitated with high specificity by fluorescence (excitation: 365 nm, emission: 475 nm). Abamectin was used as an internal standard. The mean extraction efficiencies from fortified samples (15 ng/g) were 75% for IVM and 70% for DOM. The limit of detection was 0.8 ng/g for both IVM and DOM.

Application of wavelet and Fuorier transforms as powerful alternatives for derivative spectrophotometry in analysis of binary mixtures: A comparative study

NASA Astrophysics Data System (ADS)

Hassan, Said A.; Abdel-Gawad, Sherif A.

2018-02-01

Two signal processing methods, namely, Continuous Wavelet Transform (CWT) and the second was Discrete Fourier Transform (DFT) were introduced as alternatives to the classical Derivative Spectrophotometry (DS) in analysis of binary mixtures. To show the advantages of these methods, a comparative study was performed on a binary mixture of Naltrexone (NTX) and Bupropion (BUP). The methods were compared by analyzing laboratory prepared mixtures of the two drugs. By comparing performance of the three methods, it was proved that CWT and DFT methods are more efficient and advantageous in analysis of mixtures with overlapped spectra than DS. The three signal processing methods were adopted for the quantification of NTX and BUP in pure and tablet forms. The adopted methods were validated according to the ICH guideline where accuracy, precision and specificity were found to be within appropriate limits.

Induced pluripotent stem cells for the treatment of stroke: the potential and the pitfalls.

PubMed

Yu, Fenggang; Li, Yingying; Morshead, Cindi M

2013-09-01

The extraordinary discovery of induced pluripotent stem cells (iPSCs) has led to the very real possibility that patient-specific cell therapy can be realized. The potential to develop cell replacement therapies outside the ethical and legal limitations, has initiated a new era of hope for regenerative strategies to treat human neurological disease including stroke. In this article, we will review and compare the current approaches to derive iPSCs from different somatic cells, and the induction into neuronal phenotypes, considering the advantages and disadvantages to the methodologies of derivation. We will highlight the work relating to the use of iPSC-based therapies in models of stroke and their potential use in clinical trials. Finally, we will consider future directions and areas of exploration which may promote the realization of iPSC-based cell replacement strategies for the treatment of stroke.

Transformation of cell-derived microparticles into quantum-dot-labeled nanovectors for antitumor siRNA delivery.

PubMed

Chen, Gang; Zhu, Jun-Yi; Zhang, Zhi-Ling; Zhang, Wei; Ren, Jian-Gang; Wu, Min; Hong, Zheng-Yuan; Lv, Cheng; Pang, Dai-Wen; Zhao, Yi-Fang

2015-01-12

Cell-derived microparticles (MPs) have been recently recognized as critical intercellular information conveyors. However, further understanding of their biological behavior and potential application has been hampered by the limitations of current labeling techniques. Herein, a universal donor-cell-assisted membrane biotinylation strategy was proposed for labeling MPs by skillfully utilizing the natural membrane phospholipid exchange of their donor cells. This innovative strategy conveniently led to specific, efficient, reproducible, and biocompatible quantum dot (QD) labeling of MPs, thereby reliably conferring valuable traceability on MPs. By further loading with small interference RNA, QD-labeled MPs that had inherent cell-targeting and biomolecule-conveying ability were successfully employed for combined bioimaging and tumor-targeted therapy. This study provides the first reliable and biofriendly strategy for transforming biogenic MPs into functionalized nanovectors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Spectrofluorimetric determination of tobramycin in human serum and pharmaceutical preparations by derivatization with fluorescamine.

PubMed

Tekkeli, Serife Evrim Kepekci; Önal, Armağan; Sağırlı, A Olcay

2014-02-01

A simple, sensitive and selective spectrofluorimetric method has been developed for the determination of tobramycin (TOB) in human serum and pharmaceutical preparations. The method is based on the reaction between the primary amino group of TOB and fluorescamine in borate buffer, pH 8.5, to give a highly fluorescent derivative which is measured at 469 nm after excitation at 388 nm. The fluorescence intensity was directly proportional to the concentration over the range 300-1500 ng/mL, with a limit of detection of 65 ng/mL and limit of quantitation of 215 ng/mL. All variables were investigated to optimize the reaction conditions. The method was validated according to International Conference on Harmonization guidelines in terms of specificity, linearity, limit of detection, limit of quantification, accuracy, precision and robustness. Good recoveries were obtained ranging from 97.4 to 100.64%, indicating that no interference was observed from concomitants usually present in pharmaceutical dosage forms. The method was successfully, applied for the analysis of the drug substance in its pharmaceutical preparations and spiked serum samples. Copyright © 2013 John Wiley & Sons, Ltd.

Research Diagnostic Criteria for Temporomandibular Disorders: Validity of Axis I Diagnoses

PubMed Central

Truelove, Edmond; Pan, Wei; Look, John O.; Mancl, Lloyd A.; Ohrbach, Richard K.; Velly, Ana; Huggins, Kimberly; Lenton, Patricia; Schiffman, Eric L.

2011-01-01

AIMS To estimate the criterion validity of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis I TMD diagnoses. METHODS A combined total of 614 TMD community and clinic cases and 91 controls were examined at 3 study sites. RDC/TMD Axis I diagnoses were algorithmically derived from an examination performed by calibrated dental hygienists. Reference standards (Gold Standards) were established by means of consensus diagnoses rendered by 2 TMD experts using all available clinical data, including imaging studies. Validity of the RDC/TMD Axis I TMD diagnoses was estimated relative to reference-standard diagnoses (gold standard diagnoses). Target sensitivity and specificity were set a priori at ≥ 0.70 and ≥ 0.95, respectively. RESULTS Target sensitivity and specificity were not observed for any of the 8 RDC/TMD diagnoses. The highest validity was achieved for Group Ia myofascial pain (sensitivity 0.65, specificity 0.92) and Group Ib myofascial pain with limited opening (sensitivity 0.79, specificity 0.92). Target sensitivity and specificity were observed only when both Group I diagnoses were combined (0.87 and 0.98, respectively). For Group II (disc displacements) and Group III (arthralgia, arthritis, arthrosis) diagnoses, all estimates for sensitivity were below target (0.03 to 0.53), and specificity ranged from below to on target (0.86 to 0.99). CONCLUSION The RDC/TMD Axis I TMD diagnoses did not reach the targets set at sensitivity of ≥ 0.70 and specificity of ≥ 0.95. Target validity was obtained only for myofascial pain without differentiation between normal and limited opening. Revision of the current Axis I TMD diagnostic algorithms is warranted to improve their validity. PMID:20213030

Opportunities for Cost Effective Disposal of Radioactively Contaminated Solid Waste on the Oak Ridge Reservation, Oak Ridge, TN - 13045

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

DeMonia, Brian; Dunning, Don; Hampshire John

2013-07-01

Department of Energy (DOE) requirements for the release of non-real property, including solid waste, containing low levels of residual radioactive materials are specified in DOE Order 458.1 and associated guidance. Authorized limits have been approved under the requirements of DOE Order 5400.5, predecessor to DOE Order 458.1, to permit disposal of solid waste containing low levels of residual radioactive materials at solid waste landfills located within the DOE Oak Ridge Reservation (ORR). Specifically, volumetric concentration limits for disposal of solid waste at Industrial Landfill V and at Construction/Demolition Landfill VII were established in 2003 and 2007, respectively, based on themore » requirements in effect at that time, which included: an evaluation to ensure that radiation doses to the public would not exceed 25 mrem/year and would be as low as reasonably achievable (ALARA), with a goal of a few mrem/year or less (in fact, these authorized limits actually were derived to meet a dose constraint of 1 mrem/year); an evaluation of compliance with groundwater protection requirements; and reasonable assurance that the proposed disposal is not likely to result in a future requirement for remediation of the landfill. Prior to approval as DOE authorized limits, these volumetric concentration limits were coordinated with the Tennessee Department of Environment and Conservation (TDEC) and documented in a Memorandum of Understanding (MOU) between the TDEC Division of Radiological Health and the TDEC Division of Solid Waste Management. These limits apply to the disposal of soil and debris waste generated from construction, maintenance, environmental restoration, and decontamination and decommissioning (D and D) activities on the DOE Oak Ridge Reservation. The approved site-specific authorized limits were incorporated in the URS/CH2M Oak Ridge LLC (UCOR) waste profile system that authorizes disposal of special wastes at either of the RCRA Subtitle D landfills. However, a recent DOE assessment found that implementation of the site-specific authorized limits for volumetrically contaminated waste was potentially limited due in part to confusion regarding the applicability of volumetric concentration limits and/or surface activity limits to specific wastes. This paper describes recent efforts to update the authorized limits for Industrial Landfill V and Construction/Demolition Landfill VII and to improve the procedures for implementation of these criteria. The approved authorized limits have been evaluated and confirmed to meet the current requirements of DOE Order 458.1, which superseded DOE Order 5400.5 in February 2011. In addition, volumetric concentration limits have been developed for additional radionuclides, and site-specific authorized limits for wastes with surface contamination have been developed. Implementing procedures have been revised to clarify the applicability of volumetric concentration limits and surface activity limits, and to allow the use of non-destructive waste characterization methods. These changes have been designed to promote improved utilization of available disposal capacity of the onsite disposal facilities within the DOE Oak Ridge Reservation. In addition, these changes serve to bring the waste acceptance requirements at these DOE onsite landfills into greater consistency with the requirements for commercial/ public landfills under the TDEC Bulk Survey for Release (BSFR) program, including two public RCRA Subtitle D landfills in close proximity to the DOE Oak Ridge Reservation. (authors)« less

A New Approach in Force-Limited Vibration Testing of Flight Hardware

NASA Technical Reports Server (NTRS)

Kolaini, Ali R.; Kern, Dennis L.

2012-01-01

The force-limited vibration test approaches discussed in NASA-7004C were developed to reduce overtesting associated with base shake vibration tests of aerospace hardware where the interface responses are excited coherently. This handbook outlines several different methods of specifying the force limits. The rationale for force limiting is based on the disparity between the impedances of typical aerospace mounting structures and the large impedances of vibration test shakers when the interfaces in general are coherently excited. Among these approaches, the semi-empirical method is presently the most widely used method to derive the force limits. The inclusion of the incoherent excitation of the aerospace structures at mounting interfaces has not been accounted for in the past and provides the basis for more realistic force limits for qualifying the hardware using shaker testing. In this paper current methods for defining the force limiting specifications discussed in the NASA handbook are reviewed using data from a series of acoustic and vibration tests. A new approach based on considering the incoherent excitation of the structural mounting interfaces using acoustic test data is also discussed. It is believed that the new approach provides much more realistic force limits that may further remove conservatism inherent in shaker vibration testing not accounted for by methods discussed in the NASA handbook. A discussion on using FEM/BEM analysis to obtain realistic force limits for flight hardware is provided.

Characterizing amino-acid biosignatures amongst individuals with schizophrenia: a case-control study.

PubMed

Cao, Bing; Wang, Dongfang; Brietzke, Elisa; McIntyre, Roger S; Pan, Zihang; Cha, Danielle; Rosenblat, Joshua D; Zuckerman, Hannah; Liu, Yaqiong; Xie, Qing; Wang, Jingyu

2018-05-23

Amino acids and derivatives participate in the biosynthesis and downstream effects of numerous neurotransmitters. Variations in specific amino acids have been implicated in the pathophysiology of schizophrenia. Herein, we sought to compare levels of amino acids and derivatives between subjects with schizophrenia and healthy controls (HC). Two hundred and eight subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria (DSM-IV)-defined schizophrenia and 175 age- and sex-matched HC were enrolled. The levels of twenty-five amino acids and seven related derivatives were measured in plasma samples using hydrophilic interaction liquid chromatography (HILIC) liquid chromatography-tandem mass spectrometry (LC-MS). After controlling for age, sex and body mass index (BMI), four amino acids and derivatives (i.e., cysteine, GABA, glutamine and sarcosine) were observed to be higher in the schizophrenia group when compared with HC; seven amino acids and derivatives were lower in the schizophrenia group (i.e., arginine, L-ornithine, threonine, taurine, tryptophan, methylcysteine, and kynurenine). Statistically significant differences in plasma amino-acid profiles between subjects with first-episode vs. recurrent schizophrenia for aspartate and glutamine were also demonstrated using generalized linear models controlling for age, sex, and BMI. The differences in amino acids and derivatives among individuals with schizophrenia when compared to HC may represent underlying pathophysiology, including but not limited to dysfunctional proteinogenic processes, alterations in excitatory and inhibitory neurotransmission, changes in ammonia metabolism and the urea cycle. Taken together, amino-acid profiling may provide a novel stratification approach among individuals with schizophrenia.

A Comparison Between Gravity Wave Momentum Fluxes in Observations and Climate Models

NASA Technical Reports Server (NTRS)

Geller, Marvin A.; Alexadner, M. Joan; Love, Peter T.; Bacmeister, Julio; Ern, Manfred; Hertzog, Albert; Manzini, Elisa; Preusse, Peter; Sato, Kaoru; Scaife, Adam A.;

Genetically engineered oncolytic Newcastle disease virus mediates cytolysis of prostate cancer stem like cells.

PubMed

Raghunath, Shobana; Pudupakam, Raghavendra Sumanth; Allen, Adria; Biswas, Moanaro; Sriranganathan, Nammalwar

2017-10-20

Oncolytic virotherapy is a promising novel approach that overcomes the limitations posed by radiation and chemotherapy. In this study, the oncolytic efficacy of a recombinant Newcastle disease virus (rNDV) BC-KLQL-GFP, against prostate cancer stem-like/tumor initiating cells was evaluated. Xenograft derived prostaspheres (XPS) induced tumor more efficiently than monolayer cell derived prostaspheres (MCPS) in nude mice. Primary and secondary XPS show enhanced self-renewal and clonogenic potential compared to MCPS. XPS also expressed embryonic stem cell markers, such as Nanog, CD44 and Nestin. Further, prostate specific antigen (PSA) activated recombinant Newcastle Disease Virus (rNDV) was selectively cytotoxic to tumor derived DU145 prostaspheres. An effective concentration (EC 50 ) of 0.11-0.14 multiplicity of infection was sufficient to cause prostasphere cell death in serum free culture. DU145 tumor xenograft derived prostaspheres were used as tumor surrogates as they were enriched for a putative tumor initiating cell population. PSA activated rNDV was efficient in inducing cell death of cells and prostaspheres derived from primary xenografts ex-vivo, thus signifying a potential in vivo efficacy. The EC 50 (∼0.1 MOI) for cytolysis of tumor initiating cells was slightly higher than that was required for the parental cell line, but within the therapeutic margin for safety and efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

Enhancing coronary Wave Intensity Analysis robustness by high order central finite differences.

PubMed

Rivolo, Simone; Asrress, Kaleab N; Chiribiri, Amedeo; Sammut, Eva; Wesolowski, Roman; Bloch, Lars Ø; Grøndal, Anne K; Hønge, Jesper L; Kim, Won Y; Marber, Michael; Redwood, Simon; Nagel, Eike; Smith, Nicolas P; Lee, Jack

2014-09-01

Coronary Wave Intensity Analysis (cWIA) is a technique capable of separating the effects of proximal arterial haemodynamics from cardiac mechanics. Studies have identified WIA-derived indices that are closely correlated with several disease processes and predictive of functional recovery following myocardial infarction. The cWIA clinical application has, however, been limited by technical challenges including a lack of standardization across different studies and the derived indices' sensitivity to the processing parameters. Specifically, a critical step in WIA is the noise removal for evaluation of derivatives of the acquired signals, typically performed by applying a Savitzky-Golay filter, to reduce the high frequency acquisition noise. The impact of the filter parameter selection on cWIA output, and on the derived clinical metrics (integral areas and peaks of the major waves), is first analysed. The sensitivity analysis is performed either by using the filter as a differentiator to calculate the signals' time derivative or by applying the filter to smooth the ensemble-averaged waveforms. Furthermore, the power-spectrum of the ensemble-averaged waveforms contains little high-frequency components, which motivated us to propose an alternative approach to compute the time derivatives of the acquired waveforms using a central finite difference scheme. The cWIA output and consequently the derived clinical metrics are significantly affected by the filter parameters, irrespective of its use as a smoothing filter or a differentiator. The proposed approach is parameter-free and, when applied to the 10 in-vivo human datasets and the 50 in-vivo animal datasets, enhances the cWIA robustness by significantly reducing the outcome variability (by 60%).

Phonetic Spelling Filter for Keyword Selection in Drug Mention Mining from Social Media

PubMed Central

Pimpalkhute, Pranoti; Patki, Apurv; Nikfarjam, Azadeh; Gonzalez, Graciela

2014-01-01

Social media postings are rich in information that often remain hidden and inaccessible for automatic extraction due to inherent limitations of the site’s APIs, which mostly limit access via specific keyword-based searches (and limit both the number of keywords and the number of postings that are returned). When mining social media for drug mentions, one of the first problems to solve is how to derive a list of variants of the drug name (common misspellings) that can capture a sufficient number of postings. We present here an approach that filters the potential variants based on the intuition that, faced with the task of writing an unfamiliar, complex word (the drug name), users will tend to revert to phonetic spelling, and we thus give preference to variants that reflect the phonemes of the correct spelling. The algorithm allowed us to capture 50.4 – 56.0 % of the user comments using only about 18% of the variants. PMID:25717407

High-Throughput Lectin Microarray-Based Analysis of Live Cell Surface Glycosylation

PubMed Central

Li, Yu; Tao, Sheng-ce; Zhu, Heng; Schneck, Jonathan P.

2011-01-01

Lectins, plant-derived glycan-binding proteins, have long been used to detect glycans on cell surfaces. However, the techniques used to characterize serum or cells have largely been limited to mass spectrometry, blots, flow cytometry, and immunohistochemistry. While these lectin-based approaches are well established and they can discriminate a limited number of sugar isomers by concurrently using a limited number of lectins, they are not amenable for adaptation to a high-throughput platform. Fortunately, given the commercial availability of lectins with a variety of glycan specificities, lectins can be printed on a glass substrate in a microarray format to profile accessible cell-surface glycans. This method is an inviting alternative for analysis of a broad range of glycans in a high-throughput fashion and has been demonstrated to be a feasible method of identifying binding-accessible cell surface glycosylation on living cells. The current unit presents a lectin-based microarray approach for analyzing cell surface glycosylation in a high-throughput fashion. PMID:21400689

A phase transition in energy-filtered RNA secondary structures.

PubMed

Han, Hillary S W; Reidys, Christian M

2012-10-01

In this article we study the effect of energy parameters on minimum free energy (mfe) RNA secondary structures. Employing a simplified combinatorial energy model that is only dependent on the diagram representation and is not sequence-specific, we prove the following dichotomy result. Mfe structures derived via the Turner energy parameters contain only finitely many complex irreducible substructures, and just minor parameter changes produce a class of mfe structures that contain a large number of small irreducibles. We localize the exact point at which the distribution of irreducibles experiences this phase transition from a discrete limit to a central limit distribution and, subsequently, put our result into the context of quantifying the effect of sparsification of the folding of these respective mfe structures. We show that the sparsification of realistic mfe structures leads to a constant time and space reduction, and that the sparsification of the folding of structures with modified parameters leads to a linear time and space reduction. We, furthermore, identify the limit distribution at the phase transition as a Rayleigh distribution.

Phonetic spelling filter for keyword selection in drug mention mining from social media.

PubMed

Pimpalkhute, Pranoti; Patki, Apurv; Nikfarjam, Azadeh; Gonzalez, Graciela

2014-01-01

Social media postings are rich in information that often remain hidden and inaccessible for automatic extraction due to inherent limitations of the site's APIs, which mostly limit access via specific keyword-based searches (and limit both the number of keywords and the number of postings that are returned). When mining social media for drug mentions, one of the first problems to solve is how to derive a list of variants of the drug name (common misspellings) that can capture a sufficient number of postings. We present here an approach that filters the potential variants based on the intuition that, faced with the task of writing an unfamiliar, complex word (the drug name), users will tend to revert to phonetic spelling, and we thus give preference to variants that reflect the phonemes of the correct spelling. The algorithm allowed us to capture 50.4 - 56.0 % of the user comments using only about 18% of the variants.

Extreme value theory applied to the definition of bathing water quality discounting limits.

PubMed

Haggarty, R A; Ferguson, C A; Scott, E M; Iroegbu, C; Stidson, R

2010-02-01

The European Community Bathing Water Directive (European Parliament, 2006) set compliance standards for bathing waters across Europe, with minimum standards for microbiological indicators to be attained at all locations by 2015. The Directive allows up to 15% of samples affected by short-term pollution episodes to be disregarded from the figures used to classify bathing waters, provided certain management criteria have been met, including informing the public of short-term water pollution episodes. Therefore, a scientifically justifiable discounting limit is required which could be used as a management tool to determine the samples that should be removed. This paper investigates different methods of obtaining discounting limits, focusing in particular on extreme value methodology applied to data from Scottish bathing waters. Return level based limits derived from threshold models applied at a site-specific level improved the percentage of sites which met at least the minimum required standard. This approach provides a method of obtaining limits which identify the samples that should be removed from compliance calculations, although care has to be taken in terms of the quantity of data which is removed. (c) 2009 Elsevier Ltd. All rights reserved.

Issues in characterizing resting energy expenditure in obesity and after weight loss

PubMed Central

Bosy-Westphal, Anja; Braun, Wiebke; Schautz, Britta; Müller, Manfred J.

2013-01-01

Limitations of current methods: Normalization of resting energy expenditure (REE) for body composition using the 2-compartment model fat mass (FM), and fat-free mass (FFM) has inherent limitations for the interpretation of REE and may lead to erroneous conclusions when comparing people with a wide range of adiposity as well as before and after substantial weight loss. Experimental objectives: We compared different methods of REE normalization: (1) for FFM and FM (2) by the inclusion of %FM as a measure of adiposity and (3) based on organ and tissue masses. Results were compared between healthy subjects with different degrees of adiposity as well as within subject before and after weight loss. Results: Normalizing REE from an “REE vs. FFM and FM equation” that (1) was derived in obese participants and applied to lean people or (2) was derived before weight loss and applied after weight loss leads to the erroneous conclusion of a lower metabolic rate (i) in lean persons and (ii) after weight loss. This is revealed by the normalization of REE for organ and tissue masses that was not significantly different between lean and obese or between baseline and after weight loss. There is evidence for an increasing specific metabolic rate of FFM with increasing %FM that could be explained by a higher contribution of liver, kidney and heart mass to FFM in obesity. Using “REE vs. FFM and FM equations” specific for different levels of adiposity (%FM) eliminated differences in REE before and after weight loss in women. Conclusion: The most established method for normalization of REE based on FFM and FM may lead to spurious conclusions about metabolic rate in obesity and the phenomenon of weight loss-associated adaptive thermogenesis. Using %FM-specific REE prediction from FFM and FM in kg may improve the normalization of REE when subjects with wide differences in %FM are investigated. PMID:23532370

Real-time RT-PCR assays to differentiate wild-type group A rotavirus strains from Rotarix(®) and RotaTeq(®) vaccine strains in stool samples.

PubMed

Gautam, Rashi; Esona, Mathew D; Mijatovic-Rustempasic, Slavica; Ian Tam, Ka; Gentsch, Jon R; Bowen, Michael D

2014-01-01

Group A rotaviruses (RVA) are the leading cause of severe diarrhea in young children worldwide. Two live-attenuated RVA vaccines, Rotarix(®) and RotaTeq(®) are recommended by World Health Organization (WHO) for routine immunization of all infants. Rotarix(®) and RotaTeq(®) vaccines have substantially reduced RVA associated mortality but occasionally have been associated with acute gastroenteritis (AGE) cases identified in vaccinees and their contacts. High-throughput assays are needed to monitor the prevalence of vaccine strains in AGE cases and emergence of new vaccine-derived strains following RVA vaccine introduction. In this study, we have developed quantitative real-time RT-PCR (qRT-PCR) assays for detection of Rotarix(®) and RotaTeq(®) vaccine components in stool samples. Real-time RT-PCR assays were designed for vaccine specific targets in the genomes of Rotarix(®) (NSP2, VP4) and RotaTeq(®) (VP6, VP3-WC3, VP3-human) and validated on sequence confirmed stool samples containing vaccine strains, wild-type RVA strains, and RVA-negative stools. For quantification, standard curves were generated using dsRNA transcripts derived from RVA gene segments. Rotarix(®) NSP2 and VP4 qRT-PCR assays exhibited 92-100% sensitivity, 99-100% specificity, 94-105% efficiency, and a limit of detection of 2-3 copies per reaction. RotaTeq(®) VP6, VP3-WC3, and VP3-human qRT-PCR assays displayed 100% sensitivity, 94-100% specificity, 91-102% efficiency and limits of detection of 1 copy, 2 copies, and 140 copies, respectively. These assays permit rapid identification of Rotarix(®) and RotaTeq(®) vaccine components in stool samples from clinical and surveillance studies and will be helpful in determining the frequency of vaccine strain-associated AGE.

Real-time RT-PCR assays to differentiate wild-type group A rotavirus strains from Rotarix® and RotaTeq® vaccine strains in stool samples

PubMed Central

Gautam, Rashi; Esona, Mathew D; Mijatovic-Rustempasic, Slavica; Ian Tam, Ka; Gentsch, Jon R; Bowen, Michael D

2014-01-01

Group A rotaviruses (RVA) are the leading cause of severe diarrhea in young children worldwide. Two live-attenuated RVA vaccines, Rotarix® and RotaTeq® are recommended by World Health Organization (WHO) for routine immunization of all infants. Rotarix® and RotaTeq® vaccines have substantially reduced RVA associated mortality but occasionally have been associated with acute gastroenteritis (AGE) cases identified in vaccinees and their contacts. High-throughput assays are needed to monitor the prevalence of vaccine strains in AGE cases and emergence of new vaccine-derived strains following RVA vaccine introduction. In this study, we have developed quantitative real-time RT-PCR (qRT-PCR) assays for detection of Rotarix® and RotaTeq® vaccine components in stool samples. Real-time RT-PCR assays were designed for vaccine specific targets in the genomes of Rotarix® (NSP2, VP4) and RotaTeq® (VP6, VP3-WC3, VP3-human) and validated on sequence confirmed stool samples containing vaccine strains, wild-type RVA strains, and RVA-negative stools. For quantification, standard curves were generated using dsRNA transcripts derived from RVA gene segments. Rotarix® NSP2 and VP4 qRT-PCR assays exhibited 92–100% sensitivity, 99–100% specificity, 94–105% efficiency, and a limit of detection of 2–3 copies per reaction. RotaTeq® VP6, VP3-WC3, and VP3-human qRT-PCR assays displayed 100% sensitivity, 94–100% specificity, 91–102% efficiency and limits of detection of 1 copy, 2 copies, and 140 copies, respectively. These assays permit rapid identification of Rotarix® and RotaTeq® vaccine components in stool samples from clinical and surveillance studies and will be helpful in determining the frequency of vaccine strain-associated AGE. PMID:24342877

Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry.

PubMed

Hauck, Stefanie M; Dietter, Johannes; Kramer, Roxane L; Hofmaier, Florian; Zipplies, Johanna K; Amann, Barbara; Feuchtinger, Annette; Deeg, Cornelia A; Ueffing, Marius

2010-10-01

Autoimmune uveitis is a blinding disease presenting with autoantibodies against eye-specific proteins as well as autoagressive T cells invading and attacking the immune-privileged target tissue retina. The molecular events enabling T cells to invade and attack the tissue have remained elusive. Changes in membrane protein expression patterns between diseased and healthy stages are especially interesting because initiating events of disease will most likely occur at membranes. Since disease progression is accompanied with a break-down of the blood-retinal barrier, serum-derived proteins mask the potential target tissue-related changes. To overcome this limitation, we used membrane-enriched fractions derived from retinas of the only available spontaneous animal model for the disease equine recurrent uveitis, and compared expression levels by a label-free LC-MSMS-based strategy to healthy control samples. We could readily identify a total of 893 equine proteins with 57% attributed to the Gene Ontology project term "membrane." Of these, 179 proteins were found differentially expressed in equine recurrent uveitis tissue. Pathway enrichment analyses indicated an increase in proteins related to antigen processing and presentation, TNF receptor signaling, integrin cell surface interactions and focal adhesions. Additionally, loss of retina-specific proteins reflecting decrease of vision was observed as well as an increase in Müller glial cell-specific proteins indicating glial reactivity. Selected protein candidates (caveolin 1, integrin alpha 1 and focal adhesion kinase) were validated by immunohistochemistry and tissue staining pattern pointed to a significant increase of these proteins at the level of the outer limiting membrane which is part of the outer blood-retinal barrier. Taken together, the membrane enrichment in combination with LC-MSMS-based label-free quantification greatly increased the sensitivity of the comparative tissue profiling and resulted in detection of novel molecular pathways related to equine recurrent uveitis.

Hydrogels for engineering: normalization of swelling due to arbitrary stimulus

NASA Astrophysics Data System (ADS)

Ehrenhofer, Adrian; Wallmersperger, Thomas

2017-04-01

In engineering, materials are chosen from databases: Engineers orient on specific parameters such as Young's modulus, yield stress or thermal expansion coefficients for a desired application. For hydrogels, the choice of materials is rather tedious since no generalized material parameters are currently available to quantify the swelling behavior. The normalization of swelling, which we present in the current work, allows an easy comparison of different hydrogel materials. Thus, for a specific application like a sensor or an actuator, an adequate material can be chosen. In the current work, we present the process of normalization and provide a course of action for the data analysis. Special challenges for hydrogels like hysteresis, conditional multi-sensitivity and anisotropic swelling are addressed. Then, the Temperature Expansion Model is shortly described and applied. Using the derived normalized swelling curves, a nonlinear expansion coefficient ß(F) is derived. The derived material behavior is used in an analytical model to predict the bending behavior of a beam made of thermo-responsive hydrogel material under an anisotropic temperature load. A bending behavior of the beam can be observed and the impact of other geometry and material parameters can be investigated. To overcome the limitations of the one-dimensional beam theory, the material behavior and geometry can be implemented in Finite Element analysis tools. Thus, novel applications for hydrogels in various fields can be envisioned, designed and tested. This can lead to a wider use of smart materials in sensor or actuator devices even by engineers without chemical background.

Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice

PubMed Central

Yu, Cunzhi; Li, Yu; Liu, Mingxia; Gao, Man; Li, Chenggang; Yan, Hong; Li, Chunzhu; Sun, Lihan; Mo, Liying; Wu, Chunyong; Qi, Xinming; Ren, Jin

2017-01-01

Low solubility, tissue accumulation, and toxicity are chief obstacles to developing triptolide derivatives, so a better understanding of the pharmacokinetics and toxicity of triptolide derivatives will help with these limitations. To address this, we studied pharmacokinetics and toxicity of (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative immunosuppressant in a conditional knockout (KO) mouse model with liver-specific deletion of CYP450 reductase. Compared to wild type (WT) mice, after LLDT-8 treatment, KO mice suffered severe testicular toxicity (decreased testicular weight, spermatocytes apoptosis) unlike WT mice. Moreover, KO mice had greater LLDT-8 exposure as confirmed with elevated AUC and Cmax, increased drug half-life, and greater tissue distribution. γ-H2AX, a marker of meiosis process, its localization and protein level in testis showed a distinct meiosis block induced by LLDT-8. RNA polymerase II (Pol II), an essential factor for RNA storage and synapsis in spermatogenesis, decreased in testes of KO mice after LLDT-8 treatment. Germ-cell line based assays confirmed that LLDT-8 selectively inhibited Pol II in spermatocyte-like cells. Importantly, the analysis of androgen receptor (AR) related genes showed that LLDT-8 did not change AR-related signaling in testes. Thus, hepatic CYP450s were responsible for in vivo metabolism and clearance of LLDT-8 and aggravated testicular injury may be due to increased LLDT-8 exposure in testis and subsequent Pol II reduction. PMID:29209210

Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new antischistosomal drugs

PubMed Central

Johann, Laure; Belorgey, Didier; Huang, Hsin-Hung; Day, Latasha; Chessé, Matthieu; Becker, Katja; Williams, David L.; Davioud-Charvet, Elisabeth

2016-01-01

Investigations on the chemistry and mechanism of action of 2-methyl-1,4-naphthoquinone (or menadione) derivatives, revealed 3-phenoxymethyl menadiones as a novel antischistosomal series. These newly synthesized compounds 1–7 and their difluoromethylmenadione counterparts 8–9 were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR) identified as a potential target. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. the glutathione reductase (hGR) and the selenium-dependent human thioredoxin reductase (hTrxR) to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively versus hGR and hTrxR enzymes, in particular those bearing α-fluorophenol methyl ether moieties to improve antischistosomal action. In particular, the (substituted phenoxy)methyl menadione derivative 7 displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox-cycling of SmTGR, and potent antischistosomal action in ex vivo worms. In contrast, the difluoromethylmenadione analogue 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in cultured ex vivo worms. Because none of the compounds tested in vivo was active, a limited bioavailability might compromise compound activity and future studies will be directed toward improving pharmacokinetics properties. PMID:26111549

Proposed minimal panel of antibodies for cost-effectiveness and accuracy in acute leukemias immunophenotyping: Prospective study at a tertiary care center.

PubMed

Singh, Neha; Pati, Hara Prasad P; Tyagi, Seema; Deka, Roopam; Sharma, Rahul; Saxena, Renu

2016-07-01

Flowcytometry has an essential role in the diagnosis and classification of acute leukemias. However, there exists a great degree of inter-laboratory variability on issues like panel selection, antibody combinations, gating strategies, fluorochromes, and clonal selection. The primary aim of this study was to derive a minimal panel of antibodies and evaluate its diagnostic usefulness in acute leukemias by flowcytometry by using the detailed immune-phenotype of different lineage-specific or non-specific markers. This prospective observational study involved 400 newly diagnosed cases of acute leukemias. Bone marrow aspirate samples were subjected to morphological evaluation, cytogenetics and flow cytometric immunophenotyping. A minimal panel of eight antibodies comprising of CD45/CD34/CD19/MPO/cytoCD3/CD64/CD117/CD79a was derived by applying different permutations and combinations with a diagnostic yield of 97.5%. The minimal panel was further validated by testing in an independent cohort of patients with similar demographic characteristics, where it showed a high diagnostic yield of 98% in comparison with the screening panels proposed by other recently published studies. It may be concluded that the diagnostic performance of the eight antibody panel is better than most other panels used across the different laboratories in terms of yield, number of antibodies used and the scientific approach used to derive and validate the results and so henceforth may be applied in any setting with limited resources for better diagnostic accuracy.

TALEN-mediated functional correction of human iPSC-derived macrophages in context of hereditary pulmonary alveolar proteinosis.

PubMed

Kuhn, Alexandra; Ackermann, Mania; Mussolino, Claudio; Cathomen, Toni; Lachmann, Nico; Moritz, Thomas

2017-11-09

Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator-like effector nucleases (TALENs). Targeted insertion of a codon-optimized CSF2RA-cDNA driven by the hybrid cytomegalovirus (CMV) early enhancer/chicken beta actin (CAG) promoter into the AAVS1 locus resulted in robust expression of the CSF2RA gene in gene-edited herPAP-iPSCs as well as thereof derived macrophages. These macrophages displayed typical morphology, surface phenotype, phagocytic and secretory activity, as well as functional CSF2RA expression verified by STAT5 phosphorylation and GM-CSF uptake studies. Thus, our study provides a proof-of-concept, that TALEN-mediated integration of the CSF2RA gene into the AAVS1 safe harbor locus in patient-specific iPSCs represents an efficient strategy to generate functionally corrected monocytes/macrophages, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of herPAP.

A Deterministic Transport Code for Space Environment Electrons

NASA Technical Reports Server (NTRS)

Nealy, John E.; Chang, C. K.; Norman, Ryan B.; Blattnig, Steve R.; Badavi, Francis F.; Adamczyk, Anne M.

2010-01-01

A deterministic computational procedure has been developed to describe transport of space environment electrons in various shield media. This code is an upgrade and extension of an earlier electron code. Whereas the former code was formulated on the basis of parametric functions derived from limited laboratory data, the present code utilizes well established theoretical representations to describe the relevant interactions and transport processes. The shield material specification has been made more general, as have the pertinent cross sections. A combined mean free path and average trajectory approach has been used in the transport formalism. Comparisons with Monte Carlo calculations are presented.

[Presurgical orthodontics for facial asymmetry].

PubMed

Labarrère, H

2003-03-01

As with the treatment of all facial deformities, orthodontic pre-surgical preparation for facial asymmetry should aim at correcting severe occlusal discrepancies not solely on the basis of a narrow occlusal analysis but also in a way that will not disturb the proposed surgical protocol. In addition, facial asymmetries require specific adjustments, difficult to derive and to apply because of their inherent atypical morphological orientation of both alveolar and basal bony support. Three treated cases illustrate different solutions to problems posed by pathological torque: this torque must be considered with respect to proposed surgical changes, within the framework of their limitations and their possible contra-indications.

When the Cop Is the Victim: A Test of Target Congruence Theory on Intimate Partner Violence Victimization Experienced by Police Officers.

PubMed

Zavala, Egbert

2017-05-01

This study analyzed data from the Police Stress and Domestic Violence in Police Families in Baltimore, Maryland, 1997-1999 ( N = 753) to examine propositions derived from target congruence theory in the context of intimate partner violence (IPV) victimization experienced by police officers. Specifically, this study tested the influence of target vulnerability, target gratifiability, and target antagonism on IPV victimization. Results from logistic regression models showed that all three theoretical constructs positively and significantly predicted IPV victimization. Results, as well as the study's limitations and directions for future research, are discussed.

Biogelx: Cell Culture on Self-Assembling Peptide Gels.

PubMed

Harper, Mhairi M; Connolly, Michael L; Goldie, Laura; Irvine, Eleanore J; Shaw, Joshua E; Jayawarna, Vineetha; Richardson, Stephen M; Dalby, Matthew J; Lightbody, David; Ulijn, Rein V

2018-01-01

Aromatic peptide amphiphiles can form self-supporting nanostructured hydrogels with tunable mechanical properties and chemical compositions. These hydrogels are increasingly applied in two-dimensional (2D) and three-dimensional (3D) cell culture, where there is a rapidly growing need to store, grow, proliferate, and manipulate naturally derived cells within a hydrated, 3D matrix. Biogelx Limited is a biomaterials company, created to commercialize these bio-inspired hydrogels to cell biologists for a range of cell culture applications. This chapter describes methods of various characterization and cell culture techniques specifically optimized for compatibility with Biogelx products.

Hematoporphyrin derivative induced photodamage to brain tumor cells: Alterations in subcellular membranes

NASA Astrophysics Data System (ADS)

Sreenivasan, Rajesh; Joshi, Preeti G.; Joshi, Nanda B.

1997-01-01

Photoinduced structural and functional changes were studied in the subcellular membranes isolated from HpD treated cells. Changes in the limiting anisotropy of lipid specific probes 1,6,Diphenyl-1,3,5,hexatriene (DPH) and 1-(4-Trimethyl ammonium 1,6 diphenyl)-1,3,5,hexatriene toulene sulphonate (TMA-DPH) incorporated into the membrane were used to assess the structural alterations while changes in the activity of the marker enzymes were used to assess the functional alterations. Our results suggest that damage to the endoplasmic reticulum may play an important role in the photosensitization of brain tumor cells.

On Global Optimal Sailplane Flight Strategy

NASA Technical Reports Server (NTRS)

Sander, G. J.; Litt, F. X.

1979-01-01

The derivation and interpretation of the necessary conditions that a sailplane cross-country flight has to satisfy to achieve the maximum global flight speed is considered. Simple rules are obtained for two specific meteorological models. The first one uses concentrated lifts of various strengths and unequal distance. The second one takes into account finite, nonuniform space amplitudes for the lifts and allows, therefore, for dolphin style flight. In both models, altitude constraints consisting of upper and lower limits are shown to be essential to model realistic problems. Numerical examples illustrate the difference with existing techniques based on local optimality conditions.

Computerized method for automatic evaluation of lean body mass from PET/CT: comparison with predictive equations.

PubMed

Chan, Tao

2012-01-01

CT has become an established method for calculating body composition, but it requires data from the whole body, which are not typically obtained in routine PET/CT examinations. A computerized scheme that evaluates whole-body lean body mass (LBM) based on CT data from limited-whole-body coverage was developed. The LBM so obtained was compared with results from conventional predictive equations. LBM can be obtained automatically from limited-whole-body CT data by 3 means: quantification of body composition from CT images in the limited-whole-body scan, based on thresholding of CT attenuation; determination of the range of coverage based on a characteristic trend of changing composition across different levels and pattern recognition of specific features at strategic positions; and estimation of the LBM of the whole body on the basis of a predetermined relationship between proportion of fat mass and extent of coverage. This scheme was validated using 18 whole-body PET/CT examinations truncated at different lengths to emulate limited-whole-body data. LBM was also calculated using predictive equations that had been reported for use in SUV normalization. LBM derived from limited-whole-body data using the proposed method correlated strongly with LBM derived from whole-body CT data, with correlation coefficients ranging from 0.991 (shorter coverage) to 0.998 (longer coverage) and SEMs of LBM ranging from 0.14 to 0.33 kg. These were more accurate than results from different predictive equations, which ranged in correlation coefficient from 0.635 to 0.970 and in SEM from 0.64 to 2.40 kg. LBM of the whole body could be automatically estimated from CT data of limited-whole-body coverage typically acquired in PET/CT examinations. This estimation allows more accurate and consistent quantification of metabolic activity of tumors based on LBM-normalized standardized uptake value.

Beating the odds: The poisson distribution of all input cells during limiting dilution grossly underestimates whether a cell line is clonally-derived or not.

PubMed

Zhou, Yizhou; Shaw, David; Lam, Cynthia; Tsukuda, Joni; Yim, Mandy; Tang, Danming; Louie, Salina; Laird, Michael W; Snedecor, Brad; Misaghi, Shahram

2017-09-23

Establishing that a cell line was derived from a single cell progenitor and defined as clonally-derived for the production of clinical and commercial therapeutic protein drugs has been the subject of increased emphasis in cell line development (CLD). Several regulatory agencies have expressed that the prospective probability of clonality for CHO cell lines is assumed to follow the Poisson distribution based on the input cell count. The probability of obtaining monoclonal progenitors based on the Poisson distribution of all cells suggests that one round of limiting dilution may not be sufficient to assure the resulting cell lines are clonally-derived. We experimentally analyzed clonal derivatives originating from single cell cloning (SCC) via one round of limiting dilution, following our standard legacy cell line development practice. Two cell populations with stably integrated DNA spacers were mixed and subjected to SCC via limiting dilution. Cells were cultured in the presence of selection agent, screened, and ranked based on product titer. Post-SCC, the growing cell lines were screened by PCR analysis for the presence of identifying spacers. We observed that the percentage of nonclonal populations was below 9%, which is considerably lower than the determined probability based on the Poisson distribution of all cells. These results were further confirmed using fluorescence imaging of clonal derivatives originating from SCC via limiting dilution of mixed cell populations expressing GFP or RFP. Our results demonstrate that in the presence of selection agent, the Poisson distribution of all cells clearly underestimates the probability of obtaining clonally-derived cell lines. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 2017. © 2017 American Institute of Chemical Engineers.

Integrated cell and process engineering for improved transient production of a "difficult-to-express" fusion protein by CHO cells.

PubMed

Johari, Yusuf B; Estes, Scott D; Alves, Christina S; Sinacore, Marty S; James, David C

2015-12-01

Based on an optimized electroporation protocol, we designed a rapid, milliliter-scale diagnostic transient production assay to identify limitations in the ability of Chinese hamster ovary (CHO) cells to produce a model "difficult-to-express" homodimeric Fc-fusion protein, Sp35Fc, that exhibited very low volumetric titer and intracellular formation of disulfide-bonded oligomeric aggregates post-transfection. As expression of Sp35Fc induced an unfolded protein response in transfected host cells, we utilized the transient assay to compare, in parallel, multiple functionally diverse strategies to engineer intracellular processing of Sp35Fc in order to increase production and reduce aggregation as two discrete design objectives. Specifically, we compared the effect of (i) co-expression of ER-resident molecular chaperones (BiP, PDI, CypB) or active forms of UPR transactivators (ATF6c, XBP1s) at varying recombinant gene load, (ii) addition of small molecules known to act as chemical chaperones (PBA, DMSO, glycerol, betaine, TMAO) or modulate UPR signaling (PERK inhibitor GSK2606414) at varying concentration, (iii) a reduction in culture temperature to 32°C. Using this information, we designed a biphasic, Sp35Fc-specific transient manufacturing process mediated by lipofection that utilized CypB co-expression at an optimal Sp35Fc:CypB gene ratio of 5:1 to initially maximize transfected cell proliferation, followed by addition of a combination of PBA (0.5 mM) and glycerol (1% v/v) at the onset of stationary phase to maximize cell specific production and eliminate Sp35Fc aggregation. Using this optimal, engineered process transient Sp35Fc production was significantly increased sixfold over a 12 day production process with no evidence of disulfide-bonded aggregates. Finally, transient production in clonally derived sub-populations (derived from parental CHO host) screened for a heritably improved capability to produce Sp35Fc was also significantly improved by the optimized process, showing that protein-specific cell/process engineering can provide a solution that exceeds the limits of genetic/functional diversity within heterogeneous host cell populations. . © 2015 Wiley Periodicals, Inc.

Limitations of the isotopic composition of nitrates as a tracer of their origin

NASA Astrophysics Data System (ADS)

Kloppmann, Wolfram; Mayer, Bernhard; Otero, Neus; Sebilo, Mathieu; Gooddy, Daren; Lapworth, Dan; Surridge, Ben; Petelet Giraud, Emmanuelle; Flehoc, Christine; Baran, Nicole

2017-04-01

Nitrogen and oxygen isotopes are traditionally considered and frequently used as tracers of nitrate sources in watersheds used for drinking water production. The enrichment of synthetic nitrate-containing fertilizers in 18O due to the contribution of atmospheric oxygen in the production process confers a specific isotopic fingerprint to mineral fertilizers. In spite of the still widespread use on nitrate-containing synthetic fertilizers, their characteristic N and O isotope signatures are rarely unambiguously observed in nitrate-contaminated groundwater. We postulate, in line with Mengis et al. (2001), that fertilizer-derived nitrate is not directly and rapidly transferred to groundwater but rather retained in the soil-plant system as organic N and then mineralized and re-oxidized (termed the mineralization-immobilization turnover, MIT) thereby re-setting the oxygen isotope composition of nitrate and also changing its N isotope ratios. We show examples from watersheds on diverse alluvial/clastic and carbonate aquifers in eastern and northern France where, in spite of the use of mineral fertilizers, evidenced also through other isotopic tracers (boron isotopes), both N and O-isotope ratios are very homogeneous and compatible with nitrification of ammonium where 2/3 of oxygen is derived from soil water and 1/3 from atmospheric O2. These field data are corroborated by lysimeter data from Canada. Even if in areas where ammonium is derived from chemical fertilizers, N values still tend to be lower than in areas where ammonium is derived from manure/sewage, this is clearly a limitation to the dual isotope method (N, O) for nitrate source identification, but has important implications for the nitrogen mobility and residence time in soils amended with synthetic fertilizers (Sebilo et al., 2013). Mengis M., Walther U., Bernasconi S. M., Wehrli B. (2001) Limitations of Using δ18O for the Source Identification of Nitrate in Agricultural Soils. Environmental Science & Technology, 35, 1840-1844. Sebilo M., Mayer B., Nicolardot B., Pinay G., Mariotti A. (2013) Long-term fate of nitrate fertilizer in agricultural soils. Proceedings of the National Academy of Sciences of the United States of America, 110, 18185-18189.

Isoprene emission potentials from European oak forests derived from canopy flux measurements: an assessment of uncertainties and inter-algorithm variability

NASA Astrophysics Data System (ADS)

Langford, Ben; Cash, James; Acton, W. Joe F.; Valach, Amy C.; Hewitt, C. Nicholas; Fares, Silvano; Goded, Ignacio; Gruening, Carsten; House, Emily; Kalogridis, Athina-Cerise; Gros, Valérie; Schafers, Richard; Thomas, Rick; Broadmeadow, Mark; Nemitz, Eiko

2017-12-01

Biogenic emission algorithms predict that oak forests account for ˜ 70 % of the total European isoprene budget. Yet the isoprene emission potentials (IEPs) that underpin these model estimates are calculated from a very limited number of leaf-level observations and hence are highly uncertain. Increasingly, micrometeorological techniques such as eddy covariance are used to measure whole-canopy fluxes directly, from which isoprene emission potentials can be calculated. Here, we review five observational datasets of isoprene fluxes from a range of oak forests in the UK, Italy and France. We outline procedures to correct the measured net fluxes for losses from deposition and chemical flux divergence, which were found to be on the order of 5-8 and 4-5 %, respectively. The corrected observational data were used to derive isoprene emission potentials at each site in a two-step process. Firstly, six commonly used emission algorithms were inverted to back out time series of isoprene emission potential, and then an average isoprene emission potential was calculated for each site with an associated uncertainty. We used these data to assess how the derived emission potentials change depending upon the specific emission algorithm used and, importantly, on the particular approach adopted to derive an average site-specific emission potential. Our results show that isoprene emission potentials can vary by up to a factor of 4 depending on the specific algorithm used and whether or not it is used in a big-leaf or canopy environment (CE) model format. When using the same algorithm, the calculated average isoprene emission potential was found to vary by as much as 34 % depending on how the average was derived. Using a consistent approach with version 2.1 of the Model for Emissions of Gases and Aerosols from Nature (MEGAN), we derive new ecosystem-scale isoprene emission potentials for the five measurement sites: Alice Holt, UK (10 500 ± 2500 µg m-2 h-1); Bosco Fontana, Italy (1610 ± 420 µg m-2 h-1); Castelporziano, Italy (121 ± 15 µg m-2 h-1); Ispra, Italy (7590 ± 1070 µg m-2 h-1); and the Observatoire de Haute Provence, France (7990 ± 1010 µg m-2 h-1). Ecosystem-scale isoprene emission potentials were then extrapolated to the leaf-level and compared to previous leaf-level measurements for Quercus robur and Quercus pubescens, two species thought to account for 50 % of the total European isoprene budget. The literature values agreed closely with emission potentials calculated using the G93 algorithm, which were 85 ± 75 and 78 ± 25 µg g-1 h-1 for Q. robur and Q. pubescens, respectively. By contrast, emission potentials calculated using the G06 algorithm, the same algorithm used in a previous study to derive the European budget, were significantly lower, which we attribute to the influence of past light and temperature conditions. Adopting these new G06 specific emission potentials for Q. robur (55 ± 24 µg g-1 h-1) and Q. pubescens (47 ± 16 µg g-1 h-1) reduced the projected European budget by ˜ 17 %. Our findings demonstrate that calculated isoprene emission potentials vary considerably depending upon the specific approach used in their calculation. Therefore, it is our recommendation that the community now adopt a standardised approach to the way in which micrometeorological flux measurements are corrected and used to derive isoprene, and other biogenic volatile organic compounds, emission potentials.

Performance of electrolyte measurements assessed by a trueness verification program.

PubMed

Ge, Menglei; Zhao, Haijian; Yan, Ying; Zhang, Tianjiao; Zeng, Jie; Zhou, Weiyan; Wang, Yufei; Meng, Qinghui; Zhang, Chuanbao

2016-08-01

In this study, we analyzed frozen sera with known commutabilities for standardization of serum electrolyte measurements in China. Fresh frozen sera were sent to 187 clinical laboratories in China for measurement of four electrolytes (sodium, potassium, calcium, and magnesium). Target values were assigned by two reference laboratories. Precision (CV), trueness (bias), and accuracy [total error (TEa)] were used to evaluate measurement performance, and the tolerance limit derived from the biological variation was used as the evaluation criterion. About half of the laboratories used a homogeneous system (same manufacturer for instrument, reagent and calibrator) for calcium and magnesium measurement, and more than 80% of laboratories used a homogeneous system for sodium and potassium measurement. More laboratories met the tolerance limit of imprecision (coefficient of variation [CVa]) than the tolerance limits of trueness (biasa) and TEa. For sodium, calcium, and magnesium, the minimal performance criterion derived from biological variation was used, and the pass rates for total error were approximately equal to the bias (<50%). For potassium, the pass rates for CV and TE were more than 90%. Compared with the non homogeneous system, the homogeneous system was superior for all three quality specifications. The use of commutable proficiency testing/external quality assessment (PT/EQA) samples with values assigned by reference methods can monitor performance and provide reliable data for improving the performance of laboratory electrolyte measurement. The homogeneous systems were superior to the non homogeneous systems, whereas accuracy of assigned values of calibrators and assay stability remained challenges.

Localization of premature ventricular contractions from the papillary muscles using the standard 12-lead electrocardiogram: a feasibility study using a novel cardiac isochrone positioning system.

PubMed

van Dam, Peter M; Boyle, Noel G; Laks, Michael M; Tung, Roderick

2016-12-01

The precise localization of the site of origin of a premature ventricular contraction (PVC) prior to ablation can facilitate the planning and execution of the electrophysiological procedure. In clinical practice, the targeted ablation site is estimated from the standard 12-lead ECG. The accuracy of this qualitative estimation has limitations, particularly in the localization of PVCs originating from the papillary muscles. Clinical available electrocardiographic imaging (ECGi) techniques that incorporate patient-specific anatomy may improve the localization of these PVCs, but require body surface maps with greater specificity for the epicardium. The purpose of this report is to demonstrate that a novel cardiac isochrone positioning system (CIPS) program can accurately detect the specific location of the PVC on the papillary muscle using only a 12-lead ECG. Cardiac isochrone positioning system uses three components: (i) endocardial and epicardial cardiac anatomy and torso geometry derived from MRI, (ii) the patient-specific electrode positions derived from an MRI model registered 3D image, and (iii) the 12-lead ECG. CIPS localizes the PVC origin by matching the anatomical isochrone vector with the ECG vector. The predicted PVC origin was compared with the site of successful ablation or stimulation. Three patients who underwent electrophysiological mapping and ablation of PVCs originating from the papillary muscles were studied. CIPS localized the PVC origin for all three patients to the correct papillary muscle and specifically to the base, mid, or apical region. A simplified form of ECGi utilizing only 12 standard electrocardiographic leads may facilitate accurate localization of the origin of papillary muscle PVCs. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

Development of a qualitative, multiplex real-time PCR kit for screening of genetically modified organisms (GMOs).

PubMed

Dörries, Hans-Henno; Remus, Ivonne; Grönewald, Astrid; Grönewald, Cordt; Berghof-Jäger, Kornelia

2010-03-01

The number of commercially available genetically modified organisms (GMOs) and therefore the diversity of possible target sequences for molecular detection techniques are constantly increasing. As a result, GMO laboratories and the food production industry currently are forced to apply many different methods to reliably test raw material and complex processed food products. Screening methods have become more and more relevant to minimize the analytical effort and to make a preselection for further analysis (e.g., specific identification or quantification of the GMO). A multiplex real-time PCR kit was developed to detect the 35S promoter of the cauliflower mosaic virus, the terminator of the nopaline synthase gene of Agrobacterium tumefaciens, the 35S promoter from the figwort mosaic virus, and the bar gene of the soil bacterium Streptomyces hygroscopicus as the most widely used sequences in GMOs. The kit contains a second assay for the detection of plant-derived DNA to control the quality of the often processed and refined sample material. Additionally, the plant-specific assay comprises a homologous internal amplification control for inhibition control. The determined limits of detection for the five assays were 10 target copies/reaction. No amplification products were observed with DNAs of 26 bacterial species, 25 yeasts, 13 molds, and 41 not genetically modified plants. The specificity of the assays was further demonstrated to be 100% by the specific amplification of DNA derived from reference material from 22 genetically modified crops. The applicability of the kit in routine laboratory use was verified by testing of 50 spiked and unspiked food products. The herein described kit represents a simple and sensitive GMO screening method for the reliable detection of multiple GMO-specific target sequences in a multiplex real-time PCR reaction.

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

Cao, Xiao-Feng; Yu, Yun-Wei; Dai, Zi-Gao, E-mail: yuyw@mail.ccnu.edu.cn

The similarity of the host galaxy of FRB 121102 with those of long gamma-ray bursts and Type I superluminous supernovae suggests that this fast radio burst (FRB) could be associated with a young magnetar. By assuming the FRB emission is produced within the magnetosphere, we derive a lower limit on the age of the magnetar, after which GHz emission is able to escape freely from the dense relativistic wind of the magnetar. Another lower limit is obtained by requiring the dispersion measure contributed by the electron/positron pair wind to be consistent with the observations of the host galaxy. Furthermore, wemore » also derive some upper limits on the magnetar age with discussions on possible energy sources of the FRB emission and the recently discovered persistent radio counterpart. As a result, some constraints on model parameters are addressed by reconciling the lower limits with the possible upper limits that are derived with an assumption of the rotational energy source.« less

EPIC-Simulated and MODIS-Derived Leaf Area Index (LAI) ...

EPA Pesticide Factsheets

Leaf Area Index (LAI) is an important parameter in assessing vegetation structure for characterizing forest canopies over large areas at broad spatial scales using satellite remote sensing data. However, satellite-derived LAI products can be limited by obstructed atmospheric conditions yielding sub-optimal values, or complete non-returns. The United States Environmental Protection Agency’s Exposure Methods and Measurements and Computational Exposure Divisions are investigating the viability of supplemental modelled LAI inputs into satellite-derived data streams to support various regional and local scale air quality models for retrospective and future climate assessments. In this present study, one-year (2002) of plot level stand characteristics at four study sites located in Virginia and North Carolina are used to calibrate species-specific plant parameters in a semi-empirical biogeochemical model. The Environmental Policy Integrated Climate (EPIC) model was designed primarily for managed agricultural field crop ecosystems, but also includes managed woody species that span both xeric and mesic sites (e.g., mesquite, pine, oak, etc.). LAI was simulated using EPIC at a 4 km2 and 12 km2 grid coincident with the regional Community Multiscale Air Quality Model (CMAQ) grid. LAI comparisons were made between model-simulated and MODIS-derived LAI. Field/satellite-upscaled LAI was also compared to the corresponding MODIS LAI value. Preliminary results show field/satel

Ikaros-Notch axis in host hematopoietic cells regulates experimental graft-versus-host disease

PubMed Central

Toubai, Tomomi; Sun, Yaping; Tawara, Isao; Friedman, Ann; Liu, Chen; Evers, Rebecca; Nieves, Evelyn; Malter, Chelsea; Chockley, Peter; Maillard, Ivan; Winandy, Susan

2011-01-01

Host hematopoietically derived APCs play a vital role in the initiation of GVH responses. However, the APC autonomous molecular mechanisms that are critical for the induction of GVHD are not known. We report here that the Ikaros-Notch axis in host hematopoietically derived APCs regulates the severity of acute GVHD across multiple clinically relevant murine models of experimental bone marrow transplantation. In the present study, Ikaros deficiency (Ik−/−) limited to host hematopoietically derived APCs enhanced donor T-cell expansion and intensified acute GVHD, as determined by survival and other GVHD-specific parameters. The Ik−/− conventional CD8+ and CD8−CD11c+ dendritic cells (DCs), the most potent APCs, showed no increase in the expression of activation markers or in response to TLR stimulation compared with wild-type controls. However, Ik−/− DCs demonstrated an enhanced stimulation of allogeneic T cells. Deficiency of Ikaros in the conventional CD8+ and CD8−CD11c+ DCs was associated with an increase in Notch signaling, the blockade of which mitigated the enhanced in vitro and in vivo allostimulatory capacity. Therefore, the Ikaros-Notch axis is a novel pathway that modulates DC biology in general, and targeting this pathway in host hematopoietically derived APCs may reduce GVHD. PMID:21471527

Exploiting science? A systematic analysis of complementary and alternative medicine clinic websites’ marketing of stem cell therapies

PubMed Central

Murdoch, Blake; Zarzeczny, Amy; Caulfield, Timothy

2018-01-01

Objective To identify the frequency and qualitative characteristics of stem cell-related marketing claims made on websites of clinics featuring common types of complementary and alternative medicine practitioners. The involvement of complementary and alternative medicine practitioners in the marketing of stem cell therapies and stem cell-related interventions is understudied. This research explores the extent to which they are involved and collaborate with medical professionals. This knowledge will help with identifying and evaluating potential policy responses to this growing market. Design Systematic website analysis. Setting Global. US and English-language bias due to methodology. Main outcome measures Representations made on clinic websites in relation to practitioner types, stem cell therapies and their targets, stem cell-related interventions. Statements about stem cell therapies relating to evidence of inefficacy, limited evidence of efficacy, general procedural risks, risks specific to the mode of therapy, regulatory status, experimental or unproven nature of therapy. Use of hype language (eg, language that exaggerates potential benefits). Results 243 websites offered stem cell therapies. Many websites advertised stem cell transplantation from multiple sources, such as adipose-derived (112), bone marrow-derived (100), blood-derived (28), umbilical cord-derived (26) and others. Plant stem cell-based treatments and products (20) were also advertised. Purposes for and targets of treatment included pain, physical injury, a wide range of diseases and illnesses, cosmetic concerns, non-cosmetic ageing, sexual enhancement and others. Medical doctors (130), chiropractors (53) and naturopaths (44) commonly work in the clinics we found to be offering stem cell therapies. Few clinic websites advertising stem cell therapies included important additional information, including statements about evidence of inefficacy (present on only 12.76% of websites), statements about limited evidence of efficacy (18.93%), statements of general risks (24.69%), statements of risks specific to the mode(s) of therapy (5.76%), statements as to the regulatory status of the therapies (30.86%) and statements that the therapy is experimental or unproven (33.33%). Hype language was noted (31.69%). Conclusions Stem cell therapies and related interventions are marketed for a wide breadth of conditions and are being offered by complementary and alternative practitioners, often in conjunction with medical doctors. Consumer protection and truth-in-advertising regulation could play important roles in addressing misleading marketing practices in this area. PMID:29490963

Preparation and Characterization of Fluorescent Derivatives of Lysozyme

NASA Technical Reports Server (NTRS)

Smith, Lori; Pusey, Marc

1998-01-01

Fluorescence is one of the most versatile and powerful tools for the study of macromolecules. However, its use in macromolecular crystal growth studies is hampered by the necessity of preparing fluorescent derivatives where the probe does not markedly affect the crystal packing. Alternatively, one can prepare derivatives of limited utility if it is known that they will not affect the specific goals of a given study. We have prepared a number of fluorescent derivatives of chicken egg white lysozyme, covalently attaching fluorescent probes to two different sites on the protein molecule. The first site is the side chain carboxyl group of ASP 101. Amine containing probes such as lucifer yellow, cascade blue, and 5- (2-aminoethyl) aminonapthalene-l-sulfonic acid (EDANS) have been attached using a carbodiimide coupling procedure. ASP 101 lies within the active site cleft, and it is believed that the probes are "buried" within that cleft. This is supported by the fact that all such derivatives have been found to crystallize, with the crystals being fluorescent. Tetragonal crystals of the lucifer yellow derivative have been found to diffract to at least 1.9 A resolution. X-ray diffraction data has been acquired and we are now working on the structure of this derivative. The second group of derivatives is to the N-terminal amine group. The derivatization reaction is performed by using a succinimidyl ester of the probe to be attached. Fluorescent probes such as pyrene acetic acid, 5-carboxyfluorescein, and Oregon green have been attached to this site. We have had little success in crystallizing these derivatives, probably because this site is part of the contact region between the 43 helix chains. However, these sites do not interfere with formation of the 43 helices and the derivatives are suitable for study of their formation in solution. The derivatives are being characterized by steady state and lifetime fluorescence methods, and the presentation will discuss these results.

Thermodynamic limit for coherence-limited solar power conversion

NASA Astrophysics Data System (ADS)

Mashaal, Heylal; Gordon, Jeffrey M.

2014-09-01

The spatial coherence of solar beam radiation is a key constraint in solar rectenna conversion. Here, we present a derivation of the thermodynamic limit for coherence-limited solar power conversion - an expansion of Landsberg's elegant basic bound, originally limited to incoherent converters at maximum flux concentration. First, we generalize Landsberg's work to arbitrary concentration and angular confinement. Then we derive how the values are further lowered for coherence-limited converters. The results do not depend on a particular conversion strategy. As such, they pertain to systems that span geometric to physical optics, as well as classical to quantum physics. Our findings indicate promising potential for solar rectenna conversion.

A human performance modelling approach to intelligent decision support systems

NASA Technical Reports Server (NTRS)

Mccoy, Michael S.; Boys, Randy M.

1987-01-01

Manned space operations require that the many automated subsystems of a space platform be controllable by a limited number of personnel. To minimize the interaction required of these operators, artificial intelligence techniques may be applied to embed a human performance model within the automated, or semi-automated, systems, thereby allowing the derivation of operator intent. A similar application has previously been proposed in the domain of fighter piloting, where the demand for pilot intent derivation is primarily a function of limited time and high workload rather than limited operators. The derivation and propagation of pilot intent is presented as it might be applied to some programs.

The limits of hamiltonian structures in three-dimensional elasticity, shells, and rods

NASA Astrophysics Data System (ADS)

Ge, Z.; Kruse, H. P.; Marsden, J. E.

1996-01-01

This paper uses Hamiltonian structures to study the problem of the limit of three-dimensional (3D) elastic models to shell and rod models. In the case of shells, we show that the Hamiltonian structure for a three-dimensional elastic body converges, in a sense made precise, to that for a shell model described by a one-director Cosserat surface as the thickness goes to zero. We study limiting procedures that give rise to unconstrained as well as constrained Cosserat director models. The case of a rod is also considered and similar convergence results are established, with the limiting model being a geometrically exact director rod model (in the framework developed by Antman, Simo, and coworkers). The resulting model may or may not have constraints, depending on the nature of the constitutive relations and their behavior under the limiting procedure. The closeness of Hamiltonian structures is measured by the closeness of Poisson brackets on certain classes of functions, as well as the Hamiltonians. This provides one way of justifying the dynamic one-director model for shells. Another way of stating the convergence result is that there is an almost-Poisson embedding from the phase space of the shell to the phase space of the 3D elastic body, which implies that, in the sense of Hamiltonian structures, the dynamics of the elastic body is close to that of the shell. The constitutive equations of the 3D model and their behavior as the thickness tends to zero dictates whether the limiting 2D model is a constrained or an unconstrained director model. We apply our theory in the specific case of a 3D Saint Venant-Kirchhoff material and derive the corresponding limiting shell and rod theories. The limiting shell model is an interesting Kirchhoff-like shell model in which the stored energy function is explicitly derived in terms of the shell curvature. For rods, one gets (with an additional inextensibility constraint) a one-director Kirchhoff elastic rod model, which reduces to the well-known Euler elastica if one adds an additional single constraint that the director lines up with the Frenet frame.

Redirecting T-Cell Specificity to EGFR Using mRNA to Self-limit Expression of Chimeric Antigen Receptor.

PubMed

Caruso, Hillary G; Torikai, Hiroki; Zhang, Ling; Maiti, Sourindra; Dai, Jianliang; Do, Kim-Anh; Singh, Harjeet; Huls, Helen; Lee, Dean A; Champlin, Richard E; Heimberger, Amy B; Cooper, Laurence J N

2016-06-01

Potential for on-target, but off-tissue toxicity limits therapeutic application of genetically modified T cells constitutively expressing chimeric antigen receptors (CARs) from tumor-associated antigens expressed in normal tissue, such as epidermal growth factor receptor (EGFR). Curtailing expression of CAR through modification of T cells by in vitro-transcribed mRNA species is one strategy to mitigate such toxicity. We evaluated expression of an EGFR-specific CAR coded from introduced mRNA in human T cells numerically expanded ex vivo to clinically significant numbers through coculture with activating and propagating cells (AaPC) derived from K562 preloaded with anti-CD3 antibody. The density of AaPC could be adjusted to affect phenotype of T cells such that reduced ratio of AaPC resulted in higher proportion of CD8 and central memory T cells that were more conducive to electrotransfer of mRNA than T cells expanded with high ratios of AaPC. RNA-modified CAR T cells produced less cytokine, but demonstrated similar cytolytic capacity as DNA-modified CAR T cells in response to EGFR-expressing glioblastoma cells. Expression of CAR by mRNA transfer was transient and accelerated by stimulation with cytokine and antigen. Loss of CAR abrogated T-cell function in response to tumor and normal cells expressing EGFR. We describe a clinically applicable method to propagate and modify T cells to transiently express EGFR-specific CAR to target EGFR-expressing tumor cells that may be used to limit on-target, off-tissue toxicity to normal tissue.

Generalized Geometric Quantum Speed Limits

NASA Astrophysics Data System (ADS)

Pires, Diego Paiva; Cianciaruso, Marco; Céleri, Lucas C.; Adesso, Gerardo; Soares-Pinto, Diogo O.

2016-04-01

The attempt to gain a theoretical understanding of the concept of time in quantum mechanics has triggered significant progress towards the search for faster and more efficient quantum technologies. One of such advances consists in the interpretation of the time-energy uncertainty relations as lower bounds for the minimal evolution time between two distinguishable states of a quantum system, also known as quantum speed limits. We investigate how the nonuniqueness of a bona fide measure of distinguishability defined on the quantum-state space affects the quantum speed limits and can be exploited in order to derive improved bounds. Specifically, we establish an infinite family of quantum speed limits valid for unitary and nonunitary evolutions, based on an elegant information geometric formalism. Our work unifies and generalizes existing results on quantum speed limits and provides instances of novel bounds that are tighter than any established one based on the conventional quantum Fisher information. We illustrate our findings with relevant examples, demonstrating the importance of choosing different information metrics for open system dynamics, as well as clarifying the roles of classical populations versus quantum coherences, in the determination and saturation of the speed limits. Our results can find applications in the optimization and control of quantum technologies such as quantum computation and metrology, and might provide new insights in fundamental investigations of quantum thermodynamics.

Tumour-derived exosomes as a signature of pancreatic cancer - liquid biopsies as indicators of tumour progression

PubMed Central

Nuzhat, Zarin; Kinhal, Vyjayanthi; Sharma, Shayna; Rice, Gregory E.; Joshi, Virendra; Salomon, Carlos

2017-01-01

Pancreatic cancer is the fourth most common cause of death due to cancer in the world. It is known to have a poor prognosis, mostly because early stages of the disease are generally asymptomatic. Progress in pancreatic cancer research has been slow, leaving several fundamental questions pertaining to diagnosis and treatment unanswered. Recent studies highlight the putative utility of tissue-specific vesicles (i.e. extracellular vesicles) in the diagnosis of disease onset and treatment monitoring in pancreatic cancer. Extracellular vesicles are membrane-limited structures derived from the cell membrane. They contain specific molecules including proteins, mRNA, microRNAs and non-coding RNAs that are secreted in the extracellular space. Extracellular vesicles can be classified according to their size and/or origin into microvesicles (∼150-1000 nm) and exosomes (∼40-120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosomes are released via the endocytic pathway by fusion of multivesicular bodies with the plasmatic membrane. This endosomal origin means that exosomes contain an abundance of cell-specific biomolecules which may act as a fingerprint of the cell of origin. In this review, we discuss our current knowledge in the diagnosis and treatment of pancreatic cancer, particularly the potential role of EVs in these facets of disease management. In particular, we suggest that as exosomes contain cellular protein and RNA molecules in a cell type-specific manner, they may provide extensive information about the signature of the tumour and pancreatic cancer progression. PMID:27999198

Developing Extracellular Matrix Technology to Treat Retinal or Optic Nerve Injury

PubMed Central

van der Merwe, Yolandi

2015-01-01

Abstract Adult mammalian CNS neurons often degenerate after injury, leading to lost neurologic functions. In the visual system, retinal or optic nerve injury often leads to retinal ganglion cell axon degeneration and irreversible vision loss. CNS axon degeneration is increasingly linked to the innate immune response to injury, which leads to tissue-destructive inflammation and scarring. Extracellular matrix (ECM) technology can reduce inflammation, while increasing functional tissue remodeling, over scarring, in various tissues and organs, including the peripheral nervous system. However, applying ECM technology to CNS injuries has been limited and virtually unstudied in the visual system. Here we discuss advances in deriving fetal CNS-specific ECMs, like fetal porcine brain, retina, and optic nerve, and fetal non-CNS-specific ECMs, like fetal urinary bladder, and the potential for using tissue-specific ECMs to treat retinal or optic nerve injuries in two platforms. The first platform is an ECM hydrogel that can be administered as a retrobulbar, periocular, or even intraocular injection. The second platform is an ECM hydrogel and polymer “biohybrid” sheet that can be readily shaped and wrapped around a nerve. Both platforms can be tuned mechanically and biochemically to deliver factors like neurotrophins, immunotherapeutics, or stem cells. Since clinical CNS therapies often use general anti-inflammatory agents, which can reduce tissue-destructive inflammation but also suppress tissue-reparative immune system functions, tissue-specific, ECM-based devices may fill an important need by providing naturally derived, biocompatible, and highly translatable platforms that can modulate the innate immune response to promote a positive functional outcome. PMID:26478910

Place specificity of monopolar and tripolar stimuli in cochlear implants: the influence of residual masking.

PubMed

Fielden, Claire A; Kluk, Karolina; McKay, Colette M

2013-06-01

This experiment investigated whether place specificity of neural activity evoked by cochlear implant stimulation is improved in tripolar compared to monopolar mode using a forward masking protocol addressing some limitations of previous methods of measurement and analysis. The amount of residual masking (masking remaining at long masker-probe delays) was also measured, and its potential influence on the specificity measures was evaluated. The masker stimulus comprised equally loud interleaved mono- or tripolar stimulation on two electrodes equidistant from a central probe electrode in an apical and basal direction, reducing the influence of off-site listening. The effect of masker-probe distance on the threshold shift of the tripolar probe was analyzed to derive a measure of place specificity. On average, tripolar maskers were more place specific than monopolar maskers, although the mean effect was small. There was no significant effect of masker level on specificity or on the differences observed between modes. The mean influence of residual masking on normalized masking functions was similar for the two modes and, therefore, did not influence the comparison of specificity between the modes. However, variability in amount of residual masking was observed between subjects, and therefore should be considered in forward masking studies that compare place specificity across subjects.

Receptor-mediated gene transfer vectors: progress towards genetic pharmaceuticals.

PubMed

Molas, M; Gómez-Valadés, A G; Vidal-Alabró, A; Miguel-Turu, M; Bermudez, J; Bartrons, R; Perales, J C

2003-10-01

Although specific delivery to tissues and unique cell types in vivo has been demonstrated for many non-viral vectors, current methods are still inadequate for human applications, mainly because of limitations on their efficiencies. All the steps required for an efficient receptor-mediated gene transfer process may in principle be exploited to enhance targeted gene delivery. These steps are: DNA/vector binding, internalization, subcellular trafficking, vesicular escape, nuclear import, and unpacking either for transcription or other functions (i.e., antisense, RNA interference, etc.). The large variety of vector designs that are currently available, usually aimed at improving the efficiency of these steps, has complicated the evaluation of data obtained from specific derivatives of such vectors. The importance of the structure of the final vector and the consequences of design decisions at specific steps on the overall efficiency of the vector will be discussed in detail. We emphasize in this review that stability in serum and thus, proper bioavailability of vectors to their specific receptors may be the single greatest limiting factor on the overall gene transfer efficiency in vivo. We discuss current approaches to overcome the intrinsic instability of synthetic vectors in the blood. In this regard, a summary of the structural features of the vectors obtained from current protocols will be presented and their functional characteristics evaluated. Dissecting information on molecular conjugates obtained by such methodologies, when carefully evaluated, should provide important guidelines for the creation of effective, targeted and safe DNA therapeutics.

Ultimate Limit State Assessment of Timber Bolt Connection Subjected to Double Unequal Shears

NASA Astrophysics Data System (ADS)

Musilek, Josef; Plachy, Jan

2017-10-01

Nowadays the problems occur when a structure engineer need to assess the ultimate limit state of timber bolt connection which is subjected to double unequal shears. This assessment of ultimate limit state shows the reliability of these connections. In assessing the reliability of this connection in ultimate limit state is a problem, because the formulas and equations that are currently available in design standards and available literature, describing only connections loaded symmetrically - this mean that they describe the timber bolt connection subjected to double equal shears. This fact causes problems because structural engineers have no available support, according to which they could assess reliability of the connection in terms of the ultimate limit state. They must therefore often report following an asymmetrically loaded connections carry about using formulas, which are primarily designed for checking connections loaded symmetrically. This leads logically to the fact that it is not respected by the actual behaviour of the connection in the ultimate limit state. Formulas derived in this paper provide the possibility to assess the ultimate limit state for such connection. The formulas derived in this article allow to carry out a reliability assessment of the ultimate limit state of timber bolt connection subjected to double shear. The using of the formulas derived in this paper leads to better description of the behaviour of this type of connection and also to the more economic design. An example of using these derived formulas is shown. There is shown in this example, how to assess the reliability of timber bolt connection subjected to double unequal shears in terms of ultimate limit states.

The field theory of specific heat

NASA Astrophysics Data System (ADS)

Gusev, Yu. V.

2016-01-01

Finite temperature quantum field theory in the heat kernel method is used to study the heat capacity of condensed matter. The lattice heat is treated à la P. Debye as energy of the elastic (sound) waves. The dimensionless functional of free energy is re-derived with a cut-off parameter and used to obtain the specific heat of crystal lattices. The new dimensionless thermodynamical variable is formed as Planck's inverse temperature divided by the lattice constant. The dimensionless constant, universal for the class of crystal lattices, which determines the low temperature region of molar specific heat, is introduced and tested with the data for diamond lattice crystals. The low temperature asymptotics of specific heat is found to be the fourth power in temperature instead of the cubic power law of the Debye theory. Experimental data for the carbon group elements (silicon, germanium) and other materials decisively confirm the quartic law. The true low temperature regime of specific heat is defined by the surface heat, therefore, it depends on the geometrical characteristics of the body, while the absolute zero temperature limit is geometrically forbidden. The limit on the growth of specific heat at temperatures close to critical points, known as the Dulong-Petit law, appears from the lattice constant cut-off. Its value depends on the lattice type and it is the same for materials with the same crystal lattice. The Dulong-Petit values of compounds are equal to those of elements with the same crystal lattice type, if one mole of solid state matter were taken as the Avogadro number of the composing atoms. Thus, the Neumann-Kopp law is valid only in some special cases.

A nucleic acid strand displacement system for the multiplexed detection of tuberculosis-specific mRNA using quantum dots

NASA Astrophysics Data System (ADS)

Gliddon, H. D.; Howes, P. D.; Kaforou, M.; Levin, M.; Stevens, M. M.

2016-05-01

The development of rapid, robust and high performance point-of-care diagnostics relies on the advancement and combination of various areas of research. We have developed an assay for the detection of multiple mRNA molecules that combines DNA nanotechnology with fluorescent nanomaterials. The core switching mechanism is toehold-mediated strand displacement. We have used fluorescent quantum dots (QDs) as signal transducers in this assay, as they bring many benefits including bright fluorescence and multiplexing abilities. The resulting assay is capable of multiplexed detection of long RNA targets against a high concentration of background non-target RNA, with high sensitivity and specificity and limits of detection in the nanomolar range using only a standard laboratory plate reader. We demonstrate the utility of our QD-based system for the detection of two genes selected from a microarray-derived tuberculosis-specific gene expression signature. Levels of up- and downregulated gene transcripts comprising this signature can be combined to give a disease risk score, making the signature more amenable for use as a diagnostic marker. Our QD-based approach to detect these transcripts could pave the way for novel diagnostic assays for tuberculosis.The development of rapid, robust and high performance point-of-care diagnostics relies on the advancement and combination of various areas of research. We have developed an assay for the detection of multiple mRNA molecules that combines DNA nanotechnology with fluorescent nanomaterials. The core switching mechanism is toehold-mediated strand displacement. We have used fluorescent quantum dots (QDs) as signal transducers in this assay, as they bring many benefits including bright fluorescence and multiplexing abilities. The resulting assay is capable of multiplexed detection of long RNA targets against a high concentration of background non-target RNA, with high sensitivity and specificity and limits of detection in the nanomolar range using only a standard laboratory plate reader. We demonstrate the utility of our QD-based system for the detection of two genes selected from a microarray-derived tuberculosis-specific gene expression signature. Levels of up- and downregulated gene transcripts comprising this signature can be combined to give a disease risk score, making the signature more amenable for use as a diagnostic marker. Our QD-based approach to detect these transcripts could pave the way for novel diagnostic assays for tuberculosis. Electronic supplementary information (ESI) available: Base pair mismatch tuning of CProbes. Binding capacity of the QDs. Theoretical limit of detection (LOD) for the monoplex systems. Kinetics of strand displacement. Kinetics of QProbe-CProbe binding. LOD and saturation point calculations. See DOI: 10.1039/c6nr00484a

Evaluating and enhancing quantum capacitance in graphene-based electrodes from first principles

NASA Astrophysics Data System (ADS)

Ogitsu, Tadashi; Otani, Minoru; Lee, Jonathan; Bagge-Hansen, Michael; Biener, Juergen; Wood, Brandon

2013-03-01

Graphene derivatives are attractive as supercapacitor electrodes because they are lightweight, chemically inert, have high surface area and conductivity, and are stable in electrolyte solutions. Nevertheless, devising reliable strategies for improving energy density relies on an understanding of the specific factors that control electrode performance. We use density-functional theory calculations of pristine and defective graphene to extract quantum capacitance, as well as to identify specific limiting factors. The effect of structural point defects and strain-related morphological changes on the density of states is also evaluated. The results are combined with predicted and measured in situ X-ray absorption spectra in order to give insight into the structural and chemical features present in synthesized carbon aerogel samples. Performed under the auspices of the U.S. DOE by LLNL under Contract DE-AC52-07NA27344.

Human lactoferricin derived di-peptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine.

PubMed

Riedl, Sabrina; Leber, Regina; Rinner, Beate; Schaider, Helmut; Lohner, Karl; Zweytick, Dagmar

2015-11-01

Host defense-derived peptides have emerged as a novel strategy for the development of alternative anticancer therapies. In this study we report on characteristic features of human lactoferricin (hLFcin) derivatives which facilitate specific killing of cancer cells of melanoma, glioblastoma and rhabdomyosarcoma compared with non-specific derivatives and the synthetic peptide RW-AH. Changes in amino acid sequence of hLFcin providing 9-11 amino acids stretched derivatives LF11-316, -318 and -322 only yielded low antitumor activity. However, the addition of the repeat (di-peptide) and the retro-repeat (di-retro-peptide) sequences highly improved cancer cell toxicity up to 100% at 20 μM peptide concentration. Compared to the complete parent sequence hLFcin the derivatives showed toxicity on the melanoma cell line A375 increased by 10-fold and on the glioblastoma cell line U-87mg by 2-3-fold. Reduced killing velocity, apoptotic blebbing, activation of caspase 3/7 and formation of apoptotic DNA fragments proved that the active and cancer selective peptides, e.g. R-DIM-P-LF11-322, trigger apoptosis, whereas highly active, though non-selective peptides, such as DIM-LF11-318 and RW-AH seem to kill rapidly via necrosis inducing membrane lyses. Structural studies revealed specific toxicity on cancer cells by peptide derivatives with loop structures, whereas non-specific peptides comprised α-helical structures without loop. Model studies with the cancer membrane mimic phosphatidylserine (PS) gave strong evidence that PS only exposed by cancer cells is an important target for specific hLFcin derivatives. Other negatively charged membrane exposed molecules as sialic acid, heparan and chondroitin sulfate were shown to have minor impact on peptide activity. Copyright © 2015. Published by Elsevier B.V.

Statistical correction of lidar-derived digital elevation models with multispectral airborne imagery in tidal marshes

USGS Publications Warehouse

Buffington, Kevin J.; Dugger, Bruce D.; Thorne, Karen M.; Takekawa, John Y.

2016-01-01

Airborne light detection and ranging (lidar) is a valuable tool for collecting large amounts of elevation data across large areas; however, the limited ability to penetrate dense vegetation with lidar hinders its usefulness for measuring tidal marsh platforms. Methods to correct lidar elevation data are available, but a reliable method that requires limited field work and maintains spatial resolution is lacking. We present a novel method, the Lidar Elevation Adjustment with NDVI (LEAN), to correct lidar digital elevation models (DEMs) with vegetation indices from readily available multispectral airborne imagery (NAIP) and RTK-GPS surveys. Using 17 study sites along the Pacific coast of the U.S., we achieved an average root mean squared error (RMSE) of 0.072 m, with a 40–75% improvement in accuracy from the lidar bare earth DEM. Results from our method compared favorably with results from three other methods (minimum-bin gridding, mean error correction, and vegetation correction factors), and a power analysis applying our extensive RTK-GPS dataset showed that on average 118 points were necessary to calibrate a site-specific correction model for tidal marshes along the Pacific coast. By using available imagery and with minimal field surveys, we showed that lidar-derived DEMs can be adjusted for greater accuracy while maintaining high (1 m) resolution.

Differentiation of hepatocytes from induced pluripotent stem cells derived from human hair follicle mesenchymal stem cells.

PubMed

Shi, Xu; Lv, Shuang; He, Xia; Liu, Xiaomei; Sun, Meiyu; Li, Meiying; Chi, Guangfan; Li, Yulin

2016-10-01

Due to the limitations of organ donors and immune rejection in severe liver diseases, stem cell-based therapy presents a promising application for tissue repair and regeneration. As a novel cell source, mesenchymal stem cells separated from human hair follicles (HF-MSCs) are convenient to obtain and have no age limit. To date, the differentiation of HF-MSCs into hepatocytes has not been reported. In this study, we explored whether HF-MSCs and HF-MSC-derived-induced pluripotent stem cells (HF-iPS) could differentiate into hepatocytes in vitro. Flow cytometry, Oil Red O stain and Alizarin Red stain were used to identify the characteristics of HF-MSCs. The expression of liver-specific gene was detected by immunofluorescence and Quantitative Polymerase Chain Reaction. Periodic Acid-Schiff stain, Indocyanine Green stain and Low-Density Lipoprotein stain were performed to evaluate the functions of induced hepatocyte-like cells (HLCs). HF-MSCs were unable to differentiate into HLCs using previously reported procedures for MSCs from other tissues. However, HF-iPS efficiently induced the generation of HLCs that expressed hepatocyte markers and drug metabolism-related genes. HF-iPS can be used as novel and alternative cellular tools for inducing hepatocytes in vitro, simultaneously benefiting from utilizing HF-MSCs as a noninvasive and convenient cell source for reprogramming.

Fluctuation relation based continuum model for thermoviscoplasticity in metals

NASA Astrophysics Data System (ADS)

Roy Chowdhury, Shubhankar; Roy, Debasish; Reddy, J. N.; Srinivasa, Arun

2016-11-01

A continuum plasticity model for metals is presented from considerations of non-equilibrium thermodynamics. Of specific interest is the application of a fluctuation relation that subsumes the second law of thermodynamics en route to deriving the evolution equations for the internal state variables. The modelling itself is accomplished in a two-temperature framework that appears naturally by considering the thermodynamic system to be composed of two weakly interacting subsystems, viz. a kinetic vibrational subsystem corresponding to the atomic lattice vibrations and a configurational subsystem of the slower degrees of freedom describing the motion of defects in a plastically deforming metal. An apparently physical nature of the present model derives upon considering the dislocation density, which characterizes the configurational subsystem, as a state variable. Unlike the usual constitutive modelling aided by the second law of thermodynamics that merely provides a guideline to select the admissible (though possibly non-unique) processes, the present formalism strictly determines the process or the evolution equations for the thermodynamic states while including the effect of fluctuations. The continuum model accommodates finite deformation and describes plastic deformation in a yield-free setup. The theory here is essentially limited to face-centered cubic metals modelled with a single dislocation density as the internal variable. Limited numerical simulations are presented with validation against relevant experimental data.

Properties of an entropy-based signal receiver with an application to ultrasonic molecular imaging.

PubMed

Hughes, M S; McCarthy, J E; Marsh, J N; Arbeit, J M; Neumann, R G; Fuhrhop, R W; Wallace, K D; Znidersic, D R; Maurizi, B N; Baldwin, S L; Lanza, G M; Wickline, S A

2007-06-01

Qualitative and quantitative properties of the finite part, H(f), of the Shannon entropy of a continuous waveform f(t) in the continuum limit are derived in order to illuminate its use for waveform characterization. Simple upper and lower bounds on H(f), based on features of f(t), are defined. Quantitative criteria for a priori estimation of the average-case variation of H(f) and log E(f), where E(f) is the signal energy of f(t) are also derived. These provide relative sensitivity estimates that could be used to prospectively choose optimal imaging strategies in real-time ultrasonic imaging machines, where system bandwidth is often pushed to its limits. To demonstrate the utility of these sensitivity relations for this application, a study designed to assess the feasibility of identification of angiogenic neovasculature targeted with perfluorocarbon nanoparticles that specifically bind to alpha(v)beta3-integrin expression in tumors was performed. The outcome of this study agrees with the prospective sensitivity estimates that were used for the two receivers. Moreover, these data demonstrate the ability of entropy-based signal receivers when used in conjunction with targeted nanoparticles to elucidate the presence of alpha(v)beta3 integrins in primordial neovasculature, particularly in acoustically unfavorable environments.

Dementia Prevention: optimizing the use of observational data for personal, clinical, and public health decision-making.

PubMed

Dacks, Penny A; Andrieu, Sandrine; Blacker, Deborah; Carman, Aaron J; Green, Allan M; Grodstein, Francine; Henderson, Victor W; James, Bryan D; Lane, Rachel F; Lau, Joseph; Lin, Pei-Jung; Reeves, Barnaby C; Shah, Raj C; Vellas, Bruno; Yaffe, Kristine; Yurko-Mauro, Karin; Shineman, Diana W; Bennett, David A; Fillit, Howard M

2014-02-01

Worldwide, over 35 million people suffer from Alzheimer's disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.

Propagation of prion strains through specific conformers of the prion protein.

PubMed Central

Scott, M R; Groth, D; Tatzelt, J; Torchia, M; Tremblay, P; DeArmond, S J; Prusiner, S B

1997-01-01

Two prion strains with identical incubation periods in mice exhibited distinct incubation periods and different neuropathological profiles upon serial transmission to transgenic mice expressing chimeric Syrian hamster/mouse (MH2M) prion protein (PrP) genes [Tg(MH2M) mice] and subsequent transmission to Syrian hamsters. After transmission to Syrian hamsters, the Me7 strain was indistinguishable from the previously established Syrian hamster strain Sc237, despite having been derived from an independent ancestral source. This apparent convergence suggests that prion diversity may be limited. The Me7 mouse strain could also be transmitted directly to Syrian hamsters, but when derived in this way, its properties were distinct from those of Me7 passaged through Tg(MH2M) mice. The Me7 strain did not appear permanently altered in either case, since the original incubation period could be restored by effectively reversing the series of passages. Prion diversity enciphered in the conformation of the scrapie isoform of PrP (PrP(Sc)) (G. C. Telling et al., Science 274:2079-2082, 1996) seems to be limited by the sequence of the PrP substrates serially converted into PrP(Sc), while prions are propagated through interactions between the cellular and scrapie isoforms of PrP. PMID:9371560

Deriving a Set of Privacy Specific Heuristics for the Assessment of PHRs (Personal Health Records).

PubMed

Furano, Riccardo F; Kushniruk, Andre; Barnett, Jeff

2017-01-01

With the emergence of personal health record (PHR) platforms becoming more widely available, this research focused on the development of privacy heuristics to assess PHRs regarding privacy. Existing sets of heuristics are typically not application specific and do not address patient-centric privacy as a main concern prior to undergoing PHR procurement. A set of privacy specific heuristics were developed based on a scoping review of the literature. An internet-based commercially available, vendor specific PHR application was evaluated using the derived set of privacy specific heuristics. The proposed set of privacy specific derived heuristics is explored in detail in relation to ISO 29100. The assessment of the internet-based commercially available, vendor specific PHR application indicated numerous violations. These violations were noted within the study. It is argued that the new derived privacy heuristics should be used in addition to Nielsen's well-established set of heuristics. Privacy specific heuristics could be used to assess PHR portal system-level privacy mechanisms in the procurement process of a PHR application and may prove to be a beneficial form of assessment to prevent the selection of a PHR platform with a poor privacy specific interface design.

Detection of Mycobacterium tuberculosis based on H37R(v) binding peptides using surface functionalized magnetic microspheres coupled with quantum dots – a nano detection method for Mycobacterium tuberculosis.

PubMed

Yang, Hua; Qin, Lianhua; Wang, Yilong; Zhang, Bingbo; Liu, Zhonghua; Ma, Hui; Lu, Junmei; Huang, Xiaochen; Shi, Donglu; Hu, Zhongyi

2015-01-01

Despite suffering from the major disadvantage of low sensitivity, microscopy of direct smear with the Ziehl-Neelsen stain is still broadly used for detection of acid-fast bacilli and diagnosis of tuberculosis. Here, we present a unique detection method of Mycobacterium tuberculosis (MTB) using surface functionalized magnetic microspheres (MMSs) coupled with quantum dots (QDs), conjugated with various antibodies and phage display-derived peptides. The principle is based upon the conformation of the sandwich complex composed of bacterial cells, MMSs, and QDs. The complex system is tagged with QDs for providing the fluorescent signal as part of the detection while magnetic separation is achieved by MMSs. The peptide ligand H8 derived from the phage display library Ph.D.-7 is developed for MTB cells. Using the combinations of MMS-polyclonal antibody+QD-H8 and MMS-H8+QD-H8, a strong signal of 10(3) colony forming units (CFU)/mL H37R(v) was obtained with improved specificity. MS-H8+QD-H8 combination was further optimized by adjusting the concentrations of MMSs, QDs, and incubation time for the maximum detection signal. The limit of detection for MTB was found to reach 10(3) CFU/mL even for the sputum matrices. Positive sputum samples could be distinguished from control. Thus, this novel method is shown to improve the detection limit and specificity of MTB from the sputum samples, and to reduce the testing time for accurate diagnosis of tuberculosis, which needs further confirmation of more clinical samples.

Detection of Mycobacterium tuberculosis based on H37Rv binding peptides using surface functionalized magnetic microspheres coupled with quantum dots – a nano detection method for Mycobacterium tuberculosis

PubMed Central

Yang, Hua; Qin, Lianhua; Wang, Yilong; Zhang, Bingbo; Liu, Zhonghua; Ma, Hui; Lu, Junmei; Huang, Xiaochen; Shi, Donglu; Hu, Zhongyi

2015-01-01

Despite suffering from the major disadvantage of low sensitivity, microscopy of direct smear with the Ziehl–Neelsen stain is still broadly used for detection of acid-fast bacilli and diagnosis of tuberculosis. Here, we present a unique detection method of Mycobacterium tuberculosis (MTB) using surface functionalized magnetic microspheres (MMSs) coupled with quantum dots (QDs), conjugated with various antibodies and phage display-derived peptides. The principle is based upon the conformation of the sandwich complex composed of bacterial cells, MMSs, and QDs. The complex system is tagged with QDs for providing the fluorescent signal as part of the detection while magnetic separation is achieved by MMSs. The peptide ligand H8 derived from the phage display library Ph.D.-7 is developed for MTB cells. Using the combinations of MMS-polyclonal antibody+QD-H8 and MMS-H8+QD-H8, a strong signal of 103 colony forming units (CFU)/mL H37Rv was obtained with improved specificity. MS-H8+QD-H8 combination was further optimized by adjusting the concentrations of MMSs, QDs, and incubation time for the maximum detection signal. The limit of detection for MTB was found to reach 103 CFU/mL even for the sputum matrices. Positive sputum samples could be distinguished from control. Thus, this novel method is shown to improve the detection limit and specificity of MTB from the sputum samples, and to reduce the testing time for accurate diagnosis of tuberculosis, which needs further confirmation of more clinical samples. PMID:25565805

Site-specific antibody-liposome conjugation through copper-free click chemistry: a molecular biology approach for targeted photodynamic therapy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Obaid, Girgis; Wang, Yucheng; Kuriakose, Jerrin; Broekgaarden, Mans; Alkhateeb, Ahmed; Bulin, Anne-Laure; Hui, James; Tsourkas, Andrew; Hasan, Tayyaba

2016-03-01

Nanocarriers, such as liposomes, have the ability to potentiate photodynamic therapy (PDT) treatment regimens by the encapsulation of high payloads of photosensitizers and enhance their passive delivery to tumors through the enhanced permeability and retention effect. By conjugating targeting moieties to the surface of the liposomal nanoconstructs, cellular selectivity is imparted on them and PDT-based therapies can be performed with significantly higher dose tolerances, as off-target toxicity is simultaneously reduced.1 However, the maximal benefits of conventional targeted nanocarriers, including liposomes, are hindered by practical limitations including chemical instability, non-selective conjugation chemistry, poor control over ligand orientation, and loss of ligand functionality following conjugation, amongst others.2 We have developed a robust, physically and chemically stable liposomal nanoplatform containing benzoporphyrin derivative photosensitizer molecules within the phospholipid bilayer and an optimized surface density of strained cyclooctyne moieties for `click' conjugation to azido-functionalized antibodies.3 The clinical chimeric anti-EGFR antibody Cetuximab is site-specifically photocrosslinked to a recombinant bioengineered that recognizes the antibody's Fc region, containing a terminal azide.4 The copper-free click conjugation of the bioengineered Cetuximab derivative to the optimized photosensitizing liposome provides exceptional control over the antibody's optimal orientation for cellular antigen binding. Importantly, the reaction occurs rapidly under physiological conditions, bioorthogonally (selectively in the presence of other biomolecules) and without the need for toxic copper catalysis.3 Such state-of-the-art conjugation strategies push the boundaries of targeted photodynamic therapy beyond the limitations of traditional chemical coupling techniques to produce more robust and effective targeted therapeutics with applications beyond conventional treatments.

Development of Performance-Related Specification for Fresh Emulsions Used for Surface Treatments and Performance Study of Chip Seals and Microsurfacing

NASA Astrophysics Data System (ADS)

Ilias, Mohammad

Pavement preservation is a rapidly growing strategy for prolonging pavement service life. Pavement preservation consists of applying a thin layer of asphalt binder or emulsion with or without aggregate to the surface of an existing pavement. Preservation treatments do not provide any structural strength to the pavement but restores skid resistance, seals existing cracks, protects the underlying pavement from intrusion of water, and reduces further oxidative aging of the underlying pavement. In recent years, significant research has been dedicated to improving design of pavement preservation treatments. In pavement preservation treatments, asphalt emulsion is the predominant binding material used because of its low viscosity compared to asphalt cement which allows for production at greatly reduced temperatures, leading to energy efficiency, and potential cost savings. Currently, specifications for emulsions used in pavement preservation treatments are empirical and lack of direct relationship to performance. This study seeks to improve specifications for emulsions used in preservation treatments by developing performancerelated specifications (PRS) for (a) fresh emulsion properties, (b) microsurfacing emulsion residue, and (c) low-temperature raveling of chip seal emulsion residues. Fresh emulsion properties dictate constructability and stability, and consequently the resultant performance of a preservation treatment once placed. Specification test methods are proposed for chip seals, microsurfacings, and spray seals that reflect storage and construction conditions of the emulsions. Performance is quantified using viscosity measurements. Specification limits are determined based on a prior knowledge of emulsion performance coupled with statistical analyses. Microsurfacings are a preservation treatment consisting of application of a thin layer of asphalt emulsion -- fine aggregate mixture. Presently, mixture design and performances of microsurfacing mixtures are appraised using the procedure specified by the International Slurry Surfacing Association (ISSA) with no provision for quantifying microsurfacing residue performance. In this study, residue performance is quantified using the Multiple Stress Creep and Recovery (MSCR) test for rutting and bleeding, the Bitumen Bond Strength Test (BBS) for raveling, Low Temperature Frequency (LTF) test for low temperature Bending Beam Rheometer (BBR) properties prediction, and Single Edge Notched Bend (SENB) fracture test developed under this work. Microsurfacing mixture performance is quantified using the Wet Track Abrasion Test (WTAT) for raveling, Model Mobile Load Simulator (MMLS3) for rutting and bleeding, and SENB test developed for low-temperature cracking. Microsurfacing mixture performance is correlated to residue properties in order to identify critical emulsion residue properties in determining performance and to derive specification limits. Results indicate rutting and thermal cracking are the distresses most directly related to the emulsion residue performance. Correspondingly, specifications are proposed to address rutting at high temperature and thermal cracking at low temperature based on the relationship between residue and mixture results coupled. In addition, test methods and specification criteria are developed to address lowtemperature raveling resistance of emulsion residues used in chip seals. The SENB test is used to quantify residue resistance to thermal cracking under the assumption that lowtemperature raveling occurs primarily by cohesive fracture of the residue in the chip seal. The Vialit test is modified and employed for quantifying raveling resistance of chip seals mixture for determining if the SENB test captures binder contribution to mixture raveling. The correlation between residue and mixture properties have been used to assess applicability of the residue tests and to derive specification limits.

Assessing endotoxins in equine-derived snake antivenoms: Comparison of the USP pyrogen test and the Limulus Amoebocyte Lysate assay (LAL).

PubMed

Solano, Gabriela; Gómez, Aarón; León, Guillermo

2015-10-01

Snake antivenoms are parenterally administered; therefore, endotoxin content must be strictly controlled. Following international indications to calculate endotoxin limits, it was determined that antivenom doses between 20 mL and 120 mL should not exceed 17.5 Endotoxin Units per milliliter (EU/mL) and 2.9 EU/mL, respectively. The rabbit pyrogen test (RPT) has been used to evaluate endotoxin contamination in antivenoms, but some laboratories have recently implemented the LAL assay. We compared the capability of both tests to evaluate endotoxin contamination in antivenoms, and we found that both methods can detect all endotoxin concentrations in the range of the antivenom specifications. The acceptance criteria of RPT and LAL must be harmonized by calculating the endotoxin limit as the quotient of the threshold pyrogenic dose and the therapeutic dose and the dose administered to rabbits as the quotient of the threshold pyrogenic dose and the endotoxin limit. Since endotoxins from Gram-negative bacteria exert different pyrogenicity, if contamination occurred, antivenom batches that induce pyrogenic reactions may be found in spite of passing LAL specifications. Although LAL assay can be used to assess endotoxin content throughout the antivenom manufacturing process, we recommend that the release of final products be based on the results of both methods. Copyright © 2015 Elsevier Ltd. All rights reserved.

Regulation of non-relevant metabolites of plant protection products in drinking and groundwater in the EU: Current status and way forward.

PubMed

Laabs, V; Leake, C; Botham, P; Melching-Kollmuß, S

2015-10-01

Non-relevant metabolites are defined in the EU regulation for plant protection product authorization and a detailed definition of non-relevant metabolites is given in an EU Commission DG Sanco (now DG SANTE - Health and Food Safety) guidance document. However, in water legislation at EU and member state level non-relevant metabolites of pesticides are either not specifically regulated or diverse threshold values are applied. Based on their inherent properties, non-relevant metabolites should be regulated based on substance-specific and toxicity-based limit values in drinking and groundwater like other anthropogenic chemicals. Yet, if a general limit value for non-relevant metabolites in drinking and groundwater is favored, an application of a Threshold of Toxicological Concern (TTC) concept for Cramer class III compounds leads to a threshold value of 4.5 μg L(-1). This general value is exemplarily shown to be protective for non-relevant metabolites, based on individual drinking water limit values derived for a set of 56 non-relevant metabolites. A consistent definition of non-relevant metabolites of plant protection products, as well as their uniform regulation in drinking and groundwater in the EU, is important to achieve legal clarity for all stakeholders and to establish planning security for development of plant protection products for the European market. Copyright © 2015 Elsevier Inc. All rights reserved.

Edible Ginger-Derived Nanoparticles: A Novel Therapeutic Approach for the Prevention and Treatment of Inflammatory Bowel Disease and Colitis-Associated Cancer

PubMed Central

Zhang, Mingzhen; Viennois, Emilie; Prasad, Meena; Zhang, Yunchen; Wang, Lixin; Zhang, Zhan; Han, Moon Kwon; Xiao, Bo; Xu, Changlong; Srinivasan, Shanthi; Merlin, Didier

2016-01-01

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. In this study, we characterized a specific population of nanoparticles derived from edible ginger (GDNPs 2) and demonstrated their efficient colon targeting following oral administration. GDNPs 2 had an average size of ~230 nm and exhibited a negative zeta potential. These nanoparticles contained high levels of lipids, a few proteins, ~125 microRNAs (miRNAs), and large amounts of ginger bioactive constituents (6-gingerol and 6-shogaol). We also demonstrated that GDNPs 2 were mainly taken up by intestinal epithelial cells (IECs) and macrophages, and were nontoxic. Using different mouse colitis models, we showed that GDNPs 2 reduced acute colitis, enhanced intestinal repair, and prevented chronic colitis and colitis-associated cancer (CAC). 2D-DIGE/MS analyses further identified molecular target candidates of GDNPs 2 involved in these mouse models. Oral administration of GDNPs 2 increased the survival and proliferation of IECs and reduced the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), and increased the anti-inflammatory cytokines (IL-10 and IL-22) in colitis models, suggesting that GDNPs 2 has the potential to attenuate damaging factors while promoting the healing effect. In conclusion, GDNPs 2, nanoparticles derived from edible ginger, represent a novel, natural delivery mechanism for improving IBD prevention and treatment with an added benefit of overcoming limitations such as potential toxicity and limited production scale that are common with synthetic nanoparticles. PMID:27318094

Anterior pituitary cells defective in the cell-autonomous factor, df, undergo cell lineage specification but not expansion.

PubMed

Gage, P J; Roller, M L; Saunders, T L; Scarlett, L M; Camper, S A

1996-01-01

The Ames dwarf mouse transmits a recessive mutation (df) resulting in a profound anterior pituitary hypocellularity due to a general lack of thyrotropes, somatotropes and lactotropes. These cell types are also dependent on the pituitary-specific transcription factor, Pit-1. We present evidence that expression of Pit-1 and limited commitment to these cells lineages occurs in df/df pituitaries. Thus, the crucial role of df may be in lineage-specific proliferation, rather than cytodifferentiation. The presence of all three Pit-1-dependent cell types in clonally derived clusters provides compelling evidence that these three lineages share a common, pluripotent precursor cell. Clusters containing different combinations of Pit-1-dependent cell types suggests that the Pit-1+ precursor cells choose from multiple developmental options during ontogeny. Characterization of df/df<-->+/+ chimeric mice demonstrated that df functions by a cell-autonomous mechanism. Therefore, df and Pit-1 are both cell-autonomous factors required for thyrotrope, somatotrope and lactotrope ontogeny, but their relative roles are different.

Cluster analysis reveals subclinical subgroups with shared autistic and schizotypal traits.

PubMed

Ford, Talitha C; Apputhurai, Pragalathan; Meyer, Denny; Crewther, David P

2018-07-01

Autism and schizophrenia spectrum research is typically based on coarse diagnostic classification, which overlooks individual variation within clinical groups. This method limits the identification of underlying cognitive, genetic and neural correlates of specific symptom dimensions. This study, therefore, aimed to identify homogenous subclinical subgroups of specific autistic and schizotypal traits dimensions, that may be utilised to establish more effective diagnostic and treatment practices. Latent profile analysis of subscale scores derived from an autism-schizotypy questionnaire, completed by 1678 subclinical adults aged 18-40 years (1250 females), identified a local optimum of eight population clusters: High, Moderate and Low Psychosocial Difficulties; High, Moderate and Low Autism-Schizotypy; High Psychosis-Proneness; and Moderate Schizotypy. These subgroups represent the convergent and discriminant dimensions of autism and schizotypy in the subclinical population, and highlight the importance of examining subgroups of specific symptom characteristics across these spectra in order to identify the underlying genetic and neural correlates that can be utilised to advance diagnostic and treatment practices. Copyright © 2018 Elsevier B.V. All rights reserved.

Metal-organic gel enhanced fluorescence anisotropy for sensitive detection of prostate specific antigen

NASA Astrophysics Data System (ADS)

Zhao, Ting Ting; Peng, Zhe Wei; Yuan, Dan; Zhen, Shu Jun; Huang, Cheng Zhi; Li, Yuan Fang

2018-03-01

In this contribution, we demonstrated that Cu-based metal-organic gel (Cu-MOG) was able to serve as a novel amplification platform for fluorescence anisotropy (FA) assay for the first time, which was confirmed by the sensitive detection of a common cancer biomarker, prostate specific antigen (PSA). The dye-labeled probe aptamer (PA) product was adsorbed onto the benzimidazole derivative-containing Cu-MOG via electrostatic incorporation and strong π-π stacking interactions, which significantly increased the FA value due to the enlargement of the molecular volume of the PA/Cu-MOG complex. With the introduction of target PSA, the FA value was obviously decreased on account of the specific recognition between PSA and PA which resulted in the detachment of PA from the surface of MOG. The linear range was from 0.5-8 ng/mL, with a detection limit of 0.33 ng/mL. Our work has thus helped to demonstrate promising application of MOG material in the fields of biomolecules analysis and disease diagnosis.

Vascular-mediated signalling involved in early phosphate stress response in plants.

PubMed

Zhang, Zhaoliang; Zheng, Yi; Ham, Byung-Kook; Chen, Jieyu; Yoshida, Akiko; Kochian, Leon V; Fei, Zhangjun; Lucas, William J

2016-04-04

Depletion of finite global rock phosphate (Pi) reserves will impose major limitations on future agricultural productivity and food security. Hence, modern breeding programmes seek to develop Pi-efficient crops with sustainable yields under reduced Pi fertilizer inputs. In this regard, although the long-term responses of plants to Pi stress are well documented, the early signalling events have yet to be elucidated. Here, we show plant tissue-specific responses to early Pi stress at the transcription level and a predominant role of the plant vascular system in this process. Specifically, imposition of Pi stress induces rapid and major changes in the mRNA population in the phloem translocation stream, and grafting studies have revealed that many hundreds of phloem-mobile mRNAs are delivered to specific sink tissues. We propose that the shoot vascular system acts as the site of root-derived Pi stress perception, and the phloem serves to deliver a cascade of signals to various sinks, presumably to coordinate whole-plant Pi homeostasis.

Similarities in Photodegradation of Cyanobacteria-Derived and Marine Fluorescent Dissolved Organic Matter

NASA Astrophysics Data System (ADS)

Ianiri, H. L.; Timko, S.; Gonsior, M.

2016-02-01

Marine dissolved organic matter (DOM) is one of the largest reduced carbon reservoirs on Earth, yet we only have a limited understanding of its production, cycling, degradation, and overall structure. It was previously believed that a significant portion of refractory dissolved organic carbon (RDOC) in the ocean was derived from terrestrial sources, however recent studies indicated that the majority of marine DOM might be produced in situ by marine biota. Previous research has found that terrestrial and microbial DOM fluorescent signatures are similar, complicating the identification of the origins of marine fluorescent DOM (FDOM). However, photodegradation kinetics of terrestrial and microbial-derived DOM are expected to be different due to their assumed different chemical compositions. In this study we analyzed for the first time the photodegradation kinetics of microbial-derived DOM originating from different cyanobacteria strains. Cyanobacterial-derived DOM were exposed to simulated sunlight for a total of 20 hours while recording excitation emission matrix (EEM) fluorescence every twenty minutes to observe the photodegradation of this specific FDOM. Parallel Factor Analysis (PARAFAC) was applied to deconvolute the EEM matrices into six separate components. The photodegradation kinetics was then calculated for each component and compared with previously obtained photodegradation data of marine and terrestrial FDOM. This six component PARAFAC model was similar to those generated from open ocean data and global DOM data sets. The "humic-like" FDOM was also found in cyanobacteria FDOM and showed similar fluorescence intensities and percent fluorescence loss when compared to marine DOM. The degradation kinetics of the "humic-like" component of microbial-derived DOM was faster than that of terrestrial-derived DOM, and marine FDOM samples showed degradation kinetics more similar to microbial-derived FDOM. This indicates marine FDOM is more similar in chemical composition to microbial-derived FDOM than terrestrial-derived FDOM, supporting the hypothesis that the majority of marine FDOM is produced in situ.

Limits on estimating the width of thin tubular structures in 3D images.

PubMed

Wörz, Stefan; Rohr, Karl

2006-01-01

This work studies limits on estimating the width of thin tubular structures in 3D images. Based on nonlinear estimation theory we analyze the minimal stochastic error of estimating the width. Given a 3D analytic model of the image intensities of tubular structures, we derive a closed-form expression for the Cramér-Rao bound of the width estimate under image noise. We use the derived lower bound as a benchmark and compare it with three previously proposed accuracy limits for vessel width estimation. Moreover, by experimental investigations we demonstrate that the derived lower bound can be achieved by fitting a 3D parametric intensity model directly to the image data.

Responsiveness to Change of Functional Limitation Reporting: Cross-sectional Study Using the Intermountain ROMS Scale in Outpatient Rehabilitation.

PubMed

Brennan, Gerard P; Hunter, Stephen J; Snow, Greg; Minick, Kate I

2017-12-01

The Centers for Medicare and Medicaid Services (CMS) require physical therapists document patients' functional limitations. The process is not standardized. 
A systematic approach to determine a patient's functional limitations and responsiveness to change is needed. The purpose of this study is to compare patient-reported outcomes (PROs) responsiveness to change using 7-level severity/complexity modifier scale proposed by Medicare to a derived scale implemented by Intermountain Healthcare's Rehabilitation Outcomes Management System (ROMS). This was a retrospective, observational cohort design. 165,183 PROs prior to July 1, 2013, were compared to 46,334 records from July 1, 2013, to December 31, 2015. Histograms and ribbon plots illustrate distribution and change of patients' scores. ROMS raw score ranges were calculated and compared to CMS' severity/complexity levels based on score percentage. Distribution of the population was compared based on the 2 methods. Sensitivity and specificity were compared for responsiveness to change based on minimal clinically important difference (MCID). Histograms demonstrated few patient scores placed in CMS scale levels at the extremes, whereas the majority of scores placed in 2 middle levels (CJ, CK). ROMS distributed scores more evenly across levels. Ribbon plots illustrated advantage of ROMS' using narrower score ranges. Greater chance for patients to change levels was observed with ROMS when an MCID was achieved. ROMS narrower scale levels resulted in greater sensitivity and good specificity. Geographic representation for the United States was limited. Without patients' global rating of change, a reference standard to gauge validation of improvement could not be provided. ROMS provides a standard approach to identify accurately functional limitation modifier levels and to detect improvement more accurately than a straight across transposition using the CMS scale. © 2017 American Physical Therapy Association

Toxicity of ammonia, cadmium, and nitrobenzene to four local fishes in the Liao River, China and the derivation of site-specific water quality criteria.

PubMed

Liu, Zhihong; Li, Xiaojun; Tai, Peidong; Sun, Lizong; Yuan, Honghong; Yang, Xiaonan

2018-01-01

Water quality criteria (WQC) are considered to be an effective management tool for protecting aquatic environments. To derive site-specific WQC for an area, local data based on local species are essential to improve the applicability of WQC derived. Due to the paucity of local fish data available for the development of site-specific WQC for the Liao River, China, four local and widespread fishes (Pseudorasbora parva， Abbottina liaoningensis, Ctenogobius giurinus, and Misgurnus anguillicaudatus) were chosen to test their sensitivities to ammonia, cadmium and nitrobenzene. These compounds are common and regularly-measured pollutants in Chinese rivers. In addition to the published data for species resident in the Liao River, site-specific WQC for the three chemicals were derived using both a log-logistic species sensitivity distribution (SSD) and the method recommended by the USEPA, in line with current best practice, which were then compared with Chinese national WQC. It was found that A. liaoningensis was the most sensitive, followed, in order, by P. parva, C. giurinus and M. anguillicaudatus was the least sensitive, and this trend was the same to all three chemicals tested. When comparing the SSD derived solely from previously-published data with that including our data on local fish, there were significant differences identified among parameters describing the SSD curves for ammonia and nitrobenzene and significant differences were detected for site-specific WQC derived for all of the three chemicals. Based on the dataset with local fish data taxa, site-specific WQC of Liao River for ammonia, cadmium, and nitrobenzene were derived to be 20.53mg/L (at a pH of 7.0 and temperature of 20°C), 3.76μg/L (at a hardness of 100mg/L CaCO 3 ), and 0.49mg/L, respectively. Using the same deriving method for each chemical, the national Chinese WQC were higher than site-specific WQC derived in this study for ammonia (national WQC of 25.16mg/L) and nitrobenzene (national WQC of 0.57mg/L), while the national WQC for cadmium was lower (national WQC of 1.81μg/L). These results indicated that published data can be helpful for use when deriving site-specific WQC but that there were differences between site-specific and national WQC which may lead to either over- or under-protection depending on the pollutant if national WQC were used as the basis for the water management of specific river systems, like the Liao River. Copyright © 2017. Published by Elsevier Inc.

Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity.

PubMed

Jais, Alexander; Solas, Maite; Backes, Heiko; Chaurasia, Bhagirath; Kleinridders, André; Theurich, Sebastian; Mauer, Jan; Steculorum, Sophie M; Hampel, Brigitte; Goldau, Julia; Alber, Jens; Förster, Carola Y; Eming, Sabine A; Schwaninger, Markus; Ferrara, Napoleone; Karsenty, Gerard; Brüning, Jens C

2016-05-05

High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGF(Δmyel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associated macrophage activation a homeostatic role to restore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

Mesenchymal stem cell therapy for attenuation of scar formation during wound healing.

PubMed

Jackson, Wesley M; Nesti, Leon J; Tuan, Rocky S

2012-05-31

Scars are a consequence of cutaneous wound healing that can be both unsightly and detrimental to the function of the tissue. Scar tissue is generated by excessive deposition of extracellular matrix tissue by wound healing fibroblasts and myofibroblasts, and although it is inferior to the uninjured skin, it is able to restore integrity to the boundary between the body and its environment. Scarring is not a necessary process to repair the dermal tissues. Rather, scar tissue forms due to specific mechanisms that occur during the adult wound healing process and are modulated primarily by the inflammatory response at the site of injury. Adult tissue-derived mesenchymal stem cells, which participate in normal wound healing, are trophic mediators of tissue repair. These cells participate in attenuating inflammation in the wound and reprogramming the resident immune and wound healing cells to favor tissue regeneration and inhibit fibrotic tissue formation. As a result, these cells have been considered and tested as a likely candidate for a cellular therapy to promote scar-less wound healing. This review identifies specific mechanisms by which mesenchymal stem cells can limit tissue fibrosis and summarizes recent in vivo studies where these cells have been used successfully to limit scar formation.

Generation of high-yield insulin producing cells from human bone marrow mesenchymal stem cells.

PubMed

Jafarian, Arefeh; Taghikhani, Mohammad; Abroun, Saeid; Pourpak, Zahra; Allahverdi, Amir; Soleimani, Masoud

2014-07-01

Allogenic islet transplantation is a most efficient approach for treatment of diabetes mellitus. However, the scarcity of islets and long term need for an immunosuppressant limits its application. Recently, cell replacement therapies that generate of unlimited sources of β cells have been developed to overcome these limitations. In this study we have described a stage specific differentiation protocol for the generation of insulin producing islet-like clusters from human bone marrow mesenchymal stem cells (hBM-MSCs). This specific stepwise protocol induced differentiation of hMSCs into definitive endoderm, pancreatic endoderm and pancreatic endocrine cells that expressed of sox17, foxa2, pdx1, ngn3, nkx2.2, insulin, glucagon, somatostatin, pancreatic polypeptide, and glut2 transcripts respectively. In addition, immunocytochemical analysis confirmed protein expression of the above mentioned genes. Western blot analysis discriminated insulin from proinsulin in the final differentiated cells. In derived insulin producing cells (IPCs), secreted insulin and C-peptide was in a glucose dependent manner. We have developed a protocol that generates effective high-yield human IPCs from hBM-MSCs in vitro. These finding suggest that functional IPCs generated by this procedure can be used as a cell-based approach for insulin dependent diabetes mellitus.

Enhancing coronary Wave Intensity Analysis robustness by high order central finite differences

PubMed Central

Rivolo, Simone; Asrress, Kaleab N.; Chiribiri, Amedeo; Sammut, Eva; Wesolowski, Roman; Bloch, Lars Ø.; Grøndal, Anne K.; Hønge, Jesper L.; Kim, Won Y.; Marber, Michael; Redwood, Simon; Nagel, Eike; Smith, Nicolas P.; Lee, Jack

2014-01-01

Background Coronary Wave Intensity Analysis (cWIA) is a technique capable of separating the effects of proximal arterial haemodynamics from cardiac mechanics. Studies have identified WIA-derived indices that are closely correlated with several disease processes and predictive of functional recovery following myocardial infarction. The cWIA clinical application has, however, been limited by technical challenges including a lack of standardization across different studies and the derived indices' sensitivity to the processing parameters. Specifically, a critical step in WIA is the noise removal for evaluation of derivatives of the acquired signals, typically performed by applying a Savitzky–Golay filter, to reduce the high frequency acquisition noise. Methods The impact of the filter parameter selection on cWIA output, and on the derived clinical metrics (integral areas and peaks of the major waves), is first analysed. The sensitivity analysis is performed either by using the filter as a differentiator to calculate the signals' time derivative or by applying the filter to smooth the ensemble-averaged waveforms. Furthermore, the power-spectrum of the ensemble-averaged waveforms contains little high-frequency components, which motivated us to propose an alternative approach to compute the time derivatives of the acquired waveforms using a central finite difference scheme. Results and Conclusion The cWIA output and consequently the derived clinical metrics are significantly affected by the filter parameters, irrespective of its use as a smoothing filter or a differentiator. The proposed approach is parameter-free and, when applied to the 10 in-vivo human datasets and the 50 in-vivo animal datasets, enhances the cWIA robustness by significantly reducing the outcome variability (by 60%). PMID:25187852

Derivation of site-specific relationships between hydraulic parameters and p-wave velocities based on hydraulic and seismic tomography

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

Brauchler, R.; Doetsch, J.; Dietrich, P.

2012-01-10

In this study, hydraulic and seismic tomographic measurements were used to derive a site-specific relationship between the geophysical parameter p-wave velocity and the hydraulic parameters, diffusivity and specific storage. Our field study includes diffusivity tomograms derived from hydraulic travel time tomography, specific storage tomograms, derived from hydraulic attenuation tomography, and p-wave velocity tomograms, derived from seismic tomography. The tomographic inversion was performed in all three cases with the SIRT (Simultaneous Iterative Reconstruction Technique) algorithm, using a ray tracing technique with curved trajectories. The experimental set-up was designed such that the p-wave velocity tomogram overlaps the hydraulic tomograms by half. Themore » experiments were performed at a wellcharacterized sand and gravel aquifer, located in the Leine River valley near Göttingen, Germany. Access to the shallow subsurface was provided by direct-push technology. The high spatial resolution of hydraulic and seismic tomography was exploited to derive representative site-specific relationships between the hydraulic and geophysical parameters, based on the area where geophysical and hydraulic tests were performed. The transformation of the p-wave velocities into hydraulic properties was undertaken using a k-means cluster analysis. Results demonstrate that the combination of hydraulic and geophysical tomographic data is a promising approach to improve hydrogeophysical site characterization.« less

Environmental and Genetic Contributors to Hypospadias: A Review of the Epidemiologic Evidence

PubMed Central

Carmichael, Suzan L.; Shaw, Gary M.; Lammer, Edward J.

2012-01-01

This review evaluates current knowledge related to trends in the prevalence of hypospadias, the association of hypospadias with endocrine-disrupting exposures, and the potential contribution of genetic susceptibility to its etiology. The review focuses on epidemiologic evidence. Increasing prevalence of hypospadias has been observed, but such increases tend to be localized to specific regions or time periods. Thus, generalized statements that hypospadias is increasing are unsupported. Due to limitations of study designs and inconsistent results, firm conclusions cannot be made regarding the association of endocrine-disrupting exposures with hypospadias. Studies with more rigorous study designs (e.g., larger and more detailed phenotypes) and exposure assessment that encompasses more breadth as well as depth (e.g., specific endocrine-related chemicals) will be critical to make better inferences about these important environmental exposures. Many candidate genes for hypospadias have been identified, but few of them have been examined to an extent that enables solid conclusions. Further studies are needed that include larger sample sizes, comparison groups that are more representative of the populations from which the cases were derived, phenotype-specific analyses, and more extensive exploration of variants. In conclusion, examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited. PMID:22678668

Assessment of exposure to radio frequency electromagnetic fields from smart utility meters in GB; part II) numerical assessment of induced SAR within the human body.

PubMed

Qureshi, Muhammad R A; Alfadhl, Yasir; Chen, Xiaodong; Peyman, Azadeh; Maslanyj, Myron; Mann, Simon

2018-04-01

Human body exposure to radiofrequency electromagnetic waves emitted from smart meters was assessed using various exposure configurations. Specific energy absorption rate distributions were determined using three anatomically realistic human models. Each model was assigned with age- and frequency-dependent dielectric properties representing a collection of age groups. Generalized exposure conditions involving standing and sleeping postures were assessed for a home area network operating at 868 and 2,450 MHz. The smart meter antenna was fed with 1 W power input which is an overestimation of what real devices typically emit (15 mW max limit). The highest observed whole body specific energy absorption rate value was 1.87 mW kg -1 , within the child model at a distance of 15 cm from a 2,450 MHz device. The higher values were attributed to differences in dimension and dielectric properties within the model. Specific absorption rate (SAR) values were also estimated based on power density levels derived from electric field strength measurements made at various distances from smart meter devices. All the calculated SAR values were found to be very small in comparison to International Commission on Non-Ionizing Radiation Protection limits for public exposure. Bioelectromagnetics. 39:200-216, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Thorough specification of the neurophysiologic processes underlying behavior and of their manifestation in EEG - demonstration with the go/no-go task.

PubMed

Shahaf, Goded; Pratt, Hillel

2013-01-01

In this work we demonstrate the principles of a systematic modeling approach of the neurophysiologic processes underlying a behavioral function. The modeling is based upon a flexible simulation tool, which enables parametric specification of the underlying neurophysiologic characteristics. While the impact of selecting specific parameters is of interest, in this work we focus on the insights, which emerge from rather accepted assumptions regarding neuronal representation. We show that harnessing of even such simple assumptions enables the derivation of significant insights regarding the nature of the neurophysiologic processes underlying behavior. We demonstrate our approach in some detail by modeling the behavioral go/no-go task. We further demonstrate the practical significance of this simplified modeling approach in interpreting experimental data - the manifestation of these processes in the EEG and ERP literature of normal and abnormal (ADHD) function, as well as with comprehensive relevant ERP data analysis. In-fact we show that from the model-based spatiotemporal segregation of the processes, it is possible to derive simple and yet effective and theory-based EEG markers differentiating normal and ADHD subjects. We summarize by claiming that the neurophysiologic processes modeled for the go/no-go task are part of a limited set of neurophysiologic processes which underlie, in a variety of combinations, any behavioral function with measurable operational definition. Such neurophysiologic processes could be sampled directly from EEG on the basis of model-based spatiotemporal segregation.

Tlx-1 and Tlx-3 homeobox gene expression in cranial sensory ganglia and hindbrain of the chick embryo: markers of patterned connectivity.

PubMed

Logan, C; Wingate, R J; McKay, I J; Lumsden, A

1998-07-15

Recent evidence suggests that in vertebrates the formation of distinct neuronal cell types is controlled by specific families of homeodomain transcription factors. Furthermore, the expression domains of a number of these genes correlates with functionally integrated neuronal populations. We have isolated two members of the divergent T-cell leukemia translocation (HOX11/Tlx) homeobox gene family from chick, Tlx-1 and Tlx-3, and show that they are expressed in differentiating neurons of both the peripheral and central nervous systems. In the peripheral nervous system, Tlx-1 and Tlx-3 are expressed in overlapping domains within the placodally derived components of a number of cranial sensory ganglia. Tlx-3, unlike Tlx-1, is also expressed in neural crest-derived dorsal root and sympathetic ganglia. In the CNS, both genes are expressed in longitudinal columns of neurons at specific dorsoventral levels of the hindbrain. Each column has distinct anterior and/or posterior limits that respect inter-rhombomeric boundaries. Tlx-3 is also expressed in D2 and D3 neurons of the spinal cord. Tlx-1 and Tlx-3 expression patterns within the peripheral and central nervous systems suggest that Tlx proteins may be involved not only in the differentiation and/or survival of specific neuronal populations but also in the establishment of neuronal circuitry. Furthermore, by analogy with the LIM genes, Tlx family members potentially define sensory columns early within the developing hindbrain in a combinatorial manner.

Closed medical negligence claims can drive patient safety and reduce litigation.

PubMed

Pegalis, Steven E; Bal, B Sonny

2012-05-01

Medical liability reform is viewed by many physician groups as a means of reducing medical malpractice litigation and lowering healthcare costs. However, alternative approaches such as closed medical negligence claims data may also achieve these goals. We asked whether information gleaned from closed claims related to medical negligence could promote patient safety and reduce costs related to medical liability. Specifically, we investigated whether physician groups have examined such data to identify error patterns and to then institute specific patient treatment protocols. We searched for medical societies that have systematically examined closed medical negligence claims in their specialty to develop specific standards of physician conduct. We then searched the medical literature for published evidence of the efficacy, if any, related to the patient safety measures thus developed. Anesthesia and obstetric physician societies have successfully targeted costs and related concerns arising from medical malpractice lawsuits by using data from closed claims to develop patient safety and treatment guidelines. In both specialties, after institution of safety measures derived from closed medical negligence claims, the incidence and costs related to medical malpractice decreased and physician satisfaction improved. Tort reform, in the form of legislatively prescribed limits on damages arising from lawsuits, is not the only means of addressing the incidence and costs related to medical malpractice litigation. As the experience of anesthesia and obstetric physicians has demonstrated, safety guidelines derived from analyzing past medical malpractice litigation can achieve the same goals while also promoting patient safety.

VITAL NMR: Using Chemical Shift Derived Secondary Structure Information for a Limited Set of Amino Acids to Assess Homology Model Accuracy

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

Brothers, Michael C; Nesbitt, Anna E; Hallock, Michael J

2011-01-01

Homology modeling is a powerful tool for predicting protein structures, whose success depends on obtaining a reasonable alignment between a given structural template and the protein sequence being analyzed. In order to leverage greater predictive power for proteins with few structural templates, we have developed a method to rank homology models based upon their compliance to secondary structure derived from experimental solid-state NMR (SSNMR) data. Such data is obtainable in a rapid manner by simple SSNMR experiments (e.g., (13)C-(13)C 2D correlation spectra). To test our homology model scoring procedure for various amino acid labeling schemes, we generated a library ofmore » 7,474 homology models for 22 protein targets culled from the TALOS+/SPARTA+ training set of protein structures. Using subsets of amino acids that are plausibly assigned by SSNMR, we discovered that pairs of the residues Val, Ile, Thr, Ala and Leu (VITAL) emulate an ideal dataset where all residues are site specifically assigned. Scoring the models with a predicted VITAL site-specific dataset and calculating secondary structure with the Chemical Shift Index resulted in a Pearson correlation coefficient (-0.75) commensurate to the control (-0.77), where secondary structure was scored site specifically for all amino acids (ALL 20) using STRIDE. This method promises to accelerate structure procurement by SSNMR for proteins with unknown folds through guiding the selection of remotely homologous protein templates and assessing model quality.« less

17 CFR Appendix B to Part 36 - Guidance on, and Acceptable Practices in, Compliance With Core Principles

Code of Federal Regulations, 2012 CFR

2012-04-01

... spot-month positions. Spot-month limits should be adopted for significant price discovery contracts to... market or derivatives transaction execution facility should set the spot-month limit for its significant... designated contract market or derivatives transaction execution facility. In this case, the spot-month...

Improving smoothing efficiency of rigid conformal polishing tool using time-dependent smoothing evaluation model

NASA Astrophysics Data System (ADS)

Song, Chi; Zhang, Xuejun; Zhang, Xin; Hu, Haifei; Zeng, Xuefeng

2017-06-01

A rigid conformal (RC) lap can smooth mid-spatial-frequency (MSF) errors, which are naturally smaller than the tool size, while still removing large-scale errors in a short time. However, the RC-lap smoothing efficiency performance is poorer than expected, and existing smoothing models cannot explicitly specify the methods to improve this efficiency. We presented an explicit time-dependent smoothing evaluation model that contained specific smoothing parameters directly derived from the parametric smoothing model and the Preston equation. Based on the time-dependent model, we proposed a strategy to improve the RC-lap smoothing efficiency, which incorporated the theoretical model, tool optimization, and efficiency limit determination. Two sets of smoothing experiments were performed to demonstrate the smoothing efficiency achieved using the time-dependent smoothing model. A high, theory-like tool influence function and a limiting tool speed of 300 RPM were o

Competition among memes in a world with limited attention

NASA Astrophysics Data System (ADS)

Weng, L.; Flammini, A.; Vespignani, A.; Menczer, F.

2012-03-01

The wide adoption of social media has increased the competition among ideas for our finite attention. We employ a parsimonious agent-based model to study whether such a competition may affect the popularity of different memes, the diversity of information we are exposed to, and the fading of our collective interests for specific topics. Agents share messages on a social network but can only pay attention to a portion of the information they receive. In the emerging dynamics of information diffusion, a few memes go viral while most do not. The predictions of our model are consistent with empirical data from Twitter, a popular microblogging platform. Surprisingly, we can explain the massive heterogeneity in the popularity and persistence of memes as deriving from a combination of the competition for our limited attention and the structure of the social network, without the need to assume different intrinsic values among ideas.

Competition among memes in a world with limited attention.

PubMed

Weng, L; Flammini, A; Vespignani, A; Menczer, F

2012-01-01

The wide adoption of social media has increased the competition among ideas for our finite attention. We employ a parsimonious agent-based model to study whether such a competition may affect the popularity of different memes, the diversity of information we are exposed to, and the fading of our collective interests for specific topics. Agents share messages on a social network but can only pay attention to a portion of the information they receive. In the emerging dynamics of information diffusion, a few memes go viral while most do not. The predictions of our model are consistent with empirical data from Twitter, a popular microblogging platform. Surprisingly, we can explain the massive heterogeneity in the popularity and persistence of memes as deriving from a combination of the competition for our limited attention and the structure of the social network, without the need to assume different intrinsic values among ideas.

A Distributed Amplifier System for Bilayer Lipid Membrane (BLM) Arrays With Noise and Individual Offset Cancellation.

PubMed

Crescentini, Marco; Thei, Frederico; Bennati, Marco; Saha, Shimul; de Planque, Maurits R R; Morgan, Hywel; Tartagni, Marco

2015-06-01

Lipid bilayer membrane (BLM) arrays are required for high throughput analysis, for example drug screening or advanced DNA sequencing. Complex microfluidic devices are being developed but these are restricted in terms of array size and structure or have integrated electronic sensing with limited noise performance. We present a compact and scalable multichannel electrophysiology platform based on a hybrid approach that combines integrated state-of-the-art microelectronics with low-cost disposable fluidics providing a platform for high-quality parallel single ion channel recording. Specifically, we have developed a new integrated circuit amplifier based on a novel noise cancellation scheme that eliminates flicker noise derived from devices under test and amplifiers. The system is demonstrated through the simultaneous recording of ion channel activity from eight bilayer membranes. The platform is scalable and could be extended to much larger array sizes, limited only by electronic data decimation and communication capabilities.

Single pulse two photon fluorescence lifetime imaging (SP-FLIM) with MHz pixel rate.

PubMed

Eibl, Matthias; Karpf, Sebastian; Weng, Daniel; Hakert, Hubertus; Pfeiffer, Tom; Kolb, Jan Philip; Huber, Robert

2017-07-01

Two-photon-excited fluorescence lifetime imaging microscopy (FLIM) is a chemically specific 3-D sensing modality providing valuable information about the microstructure, composition and function of a sample. However, a more widespread application of this technique is hindered by the need for a sophisticated ultra-short pulse laser source and by speed limitations of current FLIM detection systems. To overcome these limitations, we combined a robust sub-nanosecond fiber laser as the excitation source with high analog bandwidth detection. Due to the long pulse length in our configuration, more fluorescence photons are generated per pulse, which allows us to derive the lifetime with a single excitation pulse only. In this paper, we show high quality FLIM images acquired at a pixel rate of 1 MHz. This approach is a promising candidate for an easy-to-use and benchtop FLIM system to make this technique available to a wider research community.

Dose Assessment of Los Alamos National Laboratory-Derived Residual Radionuclides in Soils within Tract A-18-2 for Land Conveyance and Transfer Decisions

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

Ruedig, Elizabeth; Whicker, Jeffrey Jay

In 2017, soil sampling for radiological materials was conducted within Tract A-18-2 specifically for land conveyance decisions. Measurements of radionuclides in soil samples were evaluated against a recreational use scenario, and all measurements were below screening action levels for each radionuclide. The total estimated dose was less than 1 mrem/y (< 10 μSv/y) for a hypothetical recreational user (compared to a dose limit of 25 mrem/y (250 μSv/y)). Dose estimates were based on the 95% upper confidence limits for radionuclide concentrations within the Tract. Additionally, dose estimates less than 3 mrem/y are considered to be As Low As Reasonably Achievable,more » so no follow-up analysis was conducted. Release of this property is consistent with the requirements of DOE Order 458.1 and Policy 412.« less

Competition among memes in a world with limited attention

PubMed Central

Weng, L.; Flammini, A.; Vespignani, A.; Menczer, F.

2012-01-01

The wide adoption of social media has increased the competition among ideas for our finite attention. We employ a parsimonious agent-based model to study whether such a competition may affect the popularity of different memes, the diversity of information we are exposed to, and the fading of our collective interests for specific topics. Agents share messages on a social network but can only pay attention to a portion of the information they receive. In the emerging dynamics of information diffusion, a few memes go viral while most do not. The predictions of our model are consistent with empirical data from Twitter, a popular microblogging platform. Surprisingly, we can explain the massive heterogeneity in the popularity and persistence of memes as deriving from a combination of the competition for our limited attention and the structure of the social network, without the need to assume different intrinsic values among ideas. PMID:22461971

Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia

PubMed Central

Patel, Mayankbhai; Palani, Santhosh; Chakravarty, Arijit; Yang, Johnny; Shyu, Wen Chyi; Mettetal, Jerome T.

2014-01-01

Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection. PMID:25360756

Development of NIRS method for quality control of drug combination artesunate–azithromycin for the treatment of severe malaria

PubMed Central

Boyer, Chantal; Gaudin, Karen; Kauss, Tina; Gaubert, Alexandra; Boudis, Abdelhakim; Verschelden, Justine; Franc, Mickaël; Roussille, Julie; Boucher, Jacques; Olliaro, Piero; White, Nicholas J.; Millet, Pascal; Dubost, Jean-Pierre

2012-01-01

Near infrared spectroscopy (NIRS) methods were developed for the determination of analytical content of an antimalarial-antibiotic (artesunate and azithromycin) co-formulation in hard gelatin capsule (HGC). The NIRS consists of pre-processing treatment of spectra (raw spectra and first-derivation of two spectral zones), a unique principal component analysis model to ensure the specificity and then two partial least-squares regression models for the determination content of each active pharmaceutical ingredient. The NIRS methods were developed and validated with no reference method, since the manufacturing process of HGC is basically mixed excipients with active pharmaceutical ingredients. The accuracy profiles showed β-expectation tolerance limits within the acceptance limits (±5%). The analytical control approach performed by reversed phase (HPLC) required two different methods involving two different preparation and chromatographic methods. NIRS offers advantages in terms of lower costs of equipment and procedures, time saving, environmentally friendly. PMID:22579599

Tissue-Specific Regulation of Chromatin Insulator Function

PubMed Central

Matzat, Leah H.; Dale, Ryan K.; Moshkovich, Nellie; Lei, Elissa P.

2012-01-01

Chromatin insulators organize the genome into distinct transcriptional domains and contribute to cell type–specific chromatin organization. However, factors regulating tissue-specific insulator function have not yet been discovered. Here we identify the RNA recognition motif-containing protein Shep as a direct interactor of two individual components of the gypsy insulator complex in Drosophila. Mutation of shep improves gypsy-dependent enhancer blocking, indicating a role as a negative regulator of insulator activity. Unlike ubiquitously expressed core gypsy insulator proteins, Shep is highly expressed in the central nervous system (CNS) with lower expression in other tissues. We developed a novel, quantitative tissue-specific barrier assay to demonstrate that Shep functions as a negative regulator of insulator activity in the CNS but not in muscle tissue. Additionally, mutation of shep alters insulator complex nuclear localization in the CNS but has no effect in other tissues. Consistent with negative regulatory activity, ChIP–seq analysis of Shep in a CNS-derived cell line indicates substantial genome-wide colocalization with a single gypsy insulator component but limited overlap with intact insulator complexes. Taken together, these data reveal a novel, tissue-specific mode of regulation of a chromatin insulator. PMID:23209434

Automating Traceability for Generated Software Artifacts

NASA Technical Reports Server (NTRS)

Richardson, Julian; Green, Jeffrey

2004-01-01

Program synthesis automatically derives programs from specifications of their behavior. One advantage of program synthesis, as opposed to manual coding, is that there is a direct link between the specification and the derived program. This link is, however, not very fine-grained: it can be best characterized as Program is-derived- from Specification. When the generated program needs to be understood or modified, more $ne-grained linking is useful. In this paper, we present a novel technique for automatically deriving traceability relations between parts of a specification and parts of the synthesized program. The technique is very lightweight and works -- with varying degrees of success - for any process in which one artifact is automatically derived from another. We illustrate the generality of the technique by applying it to two kinds of automatic generation: synthesis of Kalman Filter programs from speci3cations using the Aut- oFilter program synthesis system, and generation of assembly language programs from C source code using the GCC C compilel: We evaluate the effectiveness of the technique in the latter application.

Bioelectronic Nose Using Odorant Binding Protein-Derived Peptide and Carbon Nanotube Field-Effect Transistor for the Assessment of Salmonella Contamination in Food.

PubMed

Son, Manki; Kim, Daesan; Kang, Jinkyung; Lim, Jong Hyun; Lee, Seung Hwan; Ko, Hwi Jin; Hong, Seunghun; Park, Tai Hyun

2016-12-06

Salmonella infection is the one of the major causes of food borne illnesses including fever, abdominal pain, diarrhea, and nausea. Thus, early detection of Salmonella contamination is important for our healthy life. Conventional detection methods for the food contamination have limitations in sensitivity and rapidity; thus, the early detection has been difficult. Herein, we developed a bioelectronic nose using a carbon nanotube (CNT) field-effect transistor (FET) functionalized with Drosophila odorant binding protein (OBP)-derived peptide for easy and rapid detection of Salmonella contamination in ham. 3-Methyl-1-butanol is known as a specific volatile organic compound, generated from the ham contaminated with Salmonella. We designed and synthesized the peptide based on the sequence of the Drosophila OBP, LUSH, which specifically binds to alcohols. The C-terminus of the synthetic peptide was modified with three phenylalanine residues and directly immobilized onto CNT channels using the π-π interaction. The p-type properties of FET were clearly maintained after the functionalization using the peptide. The biosensor detected 1 fM of 3-methyl-1-butanol with high selectivity and successfully assessed Salmonella contamination in ham. These results indicate that the bioelectronic nose can be used for the rapid detection of Salmonella contamination in food.

Measuring body structures and body functions from the International Classification of Functioning, Disability, and Health perspective: considerations for biomedical parameters in spinal cord injury research.

PubMed

Eriks-Hoogland, Inge E; Brinkhof, Martin W G; Al-Khodairy, Abdul; Baumberger, Michael; Brechbühl, Jörg; Curt, Armin; Mäder, Mark; Stucki, Gerold; Post, Marcel W M

2011-11-01

The aims of this study were to provide a selection of biomedical domains based on the comprehensive International Classification of Functioning, Disability, and Health (ICF) core sets for spinal cord injury (SCI) and to present an overview of the corresponding measurement instruments. Based on the Biomedical Domain Set, the SCI literature, the International Spinal Cord Society international data sets, and the Spinal Cord Injury Rehabilitation Evidence project publications were used to derive category specifications for use in SCI research. Expert opinion was used to derive a priority selection. The same sources were used to determine candidate measurement instruments for the specification of body functions and body structures using an example, and guiding principles were applied to select the most appropriate biomedical measurement instrument(s) for use in an SCI research project. Literature searches were performed for 41 second-level ICF body functions categories and for four second-level ICF body structures categories. For some of these categories, only a few candidate measurement instruments were found with limited variation in the type of measurement instruments. An ICF-based measurement set for biomedical aspects of functioning with SCI was established. For some categories of the ICF core sets for SCI, there is a need to develop measurement instruments.

Amine-functionalized diatom frustules: a platform for specific and sensitive detection of nitroaromatic explosive derivative.

PubMed

Selvaraj, Viji; Thomas, Neethi; Anthuvan, Allen Joseph; Nagamony, Ponpandian; Chinnuswamy, Viswanathan

2017-12-14

In the present study, an attempt was made to develop a proof of concept for the detection of nitroaromatic explosive derivatives through the photoluminescence (PL) quenching process using functionalized diatom frustules as a sensing platform. The diatom frustules are composed of nanostructured, highly porous biogenic silica material and emit strong, visible blue PL upon UV excitation. PL-active biosilica was isolated from the marine diatom Nitzschia sp. and was amine-functionalized to develop a sensing platform. Functionalized diatom frustules were further characterized using field emission scanning electron microscope and a series of spectroscopic methods. When nitroaromatic compounds were bound to the functionalized diatom frustules biosilica, the PL intensity from the functionalized biosilica was partially quenched due to the electrophilic nature of the nitro (-NO) groups. The quenching process confirmed the Meisenheimer complex formation and was investigated by using Fourier transform infrared spectroscopy and time-resolved photoluminescence studies. The developed platform was further evaluated for its sensitivity and specificity, and the limit of detection (LOD) of the assay was determined as 1 μM for a series of nitroaromatic explosive compounds. In conclusion, the developed sensing platform will have great utility in the development of on-site detection platforms for sensitive detection of warfare explosive nitroaromatic compounds from the environment.

Statistical adjustment of culture-independent diagnostic tests for trend analysis in the Foodborne Diseases Active Surveillance Network (FoodNet), USA.

PubMed

Gu, Weidong; Dutta, Vikrant; Patrick, Mary; Bruce, Beau B; Geissler, Aimee; Huang, Jennifer; Fitzgerald, Collette; Henao, Olga

2018-03-19

Culture-independent diagnostic tests (CIDTs) are increasingly used to diagnose Campylobacter infection in the Foodborne Diseases Active Surveillance Network (FoodNet). Because CIDTs have different performance characteristics compared with culture, which has been used historically and is still used to diagnose campylobacteriosis, adjustment of cases diagnosed by CIDT is needed to compare with culture-confirmed cases for monitoring incidence trends. We identified the necessary parameters for CIDT adjustment using culture as the gold standard, and derived formulas to calculate positive predictive values (PPVs). We conducted a literature review and meta-analysis to examine the variability in CIDT performance and Campylobacter prevalence applicable to FoodNet sites. We then developed a Monte Carlo method to estimate test-type and site-specific PPVs with their associated uncertainties. The uncertainty in our estimated PPVs was largely derived from uncertainty about the specificity of CIDTs and low prevalence of Campylobacter in tested samples. Stable CIDT-adjusted incidences of Campylobacter cases from 2012 to 2015 were observed compared with a decline in culture-confirmed incidence. We highlight the lack of data on the total numbers of tested samples as one of main limitations for CIDT adjustment. Our results demonstrate the importance of adjusting CIDTs for understanding trends in Campylobacter incidence in FoodNet.

Antigen-activated dendritic cells ameliorate influenza A infections

PubMed Central

Boonnak, Kobporn; Vogel, Leatrice; Orandle, Marlene; Zimmerman, Daniel; Talor, Eyal; Subbarao, Kanta

2013-01-01

Influenza A viruses cause significant morbidity and mortality worldwide. There is a need for alternative or adjunct therapies, as resistance to currently used antiviral drugs is emerging rapidly. We tested ligand epitope antigen presentation system (LEAPS) technology as a new immune-based treatment for influenza virus infection in a mouse model. Influenza-J-LEAPS peptides were synthesized by conjugating the binding ligand derived from the β2-microglobulin chain of the human MHC class I molecule (J-LEAPS) with 15 to 30 amino acid–long peptides derived from influenza virus NP, M, or HA proteins. DCs were stimulated with influenza-J-LEAPS peptides (influenza-J-LEAPS) and injected intravenously into infected mice. Antigen-specific LEAPS-stimulated DCs were effective in reducing influenza virus replication in the lungs and enhancing survival of infected animals. Additionally, they augmented influenza-specific T cell responses in the lungs and reduced the severity of disease by limiting excessive cytokine responses, which are known to contribute to morbidity and mortality following influenza virus infection. Our data demonstrate that influenza-J-LEAPS–pulsed DCs reduce virus replication in the lungs, enhance survival, and modulate the protective immune responses that eliminate the virus while preventing excessive cytokines that could injure the host. This approach shows promise as an adjunct to antiviral treatment of influenza virus infections. PMID:23934125

Inactivated recombinant plant virus protects dogs from a lethal challenge with canine parvovirus.

PubMed

Langeveld, J P; Brennan, F R; Martínez-Torrecuadrada, J L; Jones, T D; Boshuizen, R S; Vela, C; Casal, J I; Kamstrup, S; Dalsgaard, K; Meloen, R H; Bendig, M M; Hamilton, W D

2001-06-14

A vaccine based upon a recombinant plant virus (CPMV-PARVO1), displaying a peptide derived from the VP2 capsid protein of canine parvovirus (CPV), has previously been described. To date, studies with the vaccine have utilized viable plant chimaeric particles (CVPs). In this study, CPMV-PARVO1 was inactivated by UV treatment to remove the possibility of replication of the recombinant plant virus in a plant host after manufacture of the vaccine. We show that the inactivated CVP is able to protect dogs from a lethal challenge with CPV following parenteral immunization with the vaccine. Dogs immunized with the inactivated CPMV-PARVO1 in adjuvant displayed no clinical signs of disease and shedding of CPV in faeces was limited following CPV challenge. All immunized dogs elicited high titres of peptide-specific antibody, which neutralized CPV in vitro. Levels of protection, virus shedding and VP2-specific antibody were comparable to those seen in dogs immunized with the same VP2- peptide coupled to keyhole limpet hemocyanin (KLH). Since plant virus-derived vaccines have the potential for cost-effective manufacture and are not known to replicate in mammalian cells, they represent a viable alternative to current replicating vaccine vectors for development of both human and veterinary vaccines.

Image-derived arterial input function for quantitative fluorescence imaging of receptor-drug binding in vivo

PubMed Central

Elliott, Jonathan T.; Samkoe, Kimberley S.; Davis, Scott C.; Gunn, Jason R.; Paulsen, Keith D.; Roberts, David W.; Pogue, Brian W.

2017-01-01

Receptor concentration imaging (RCI) with targeted-untargeted optical dye pairs has enabled in vivo immunohistochemistry analysis in preclinical subcutaneous tumors. Successful application of RCI to fluorescence guided resection (FGR), so that quantitative molecular imaging of tumor-specific receptors could be performed in situ, would have a high impact. However, assumptions of pharmacokinetics, permeability and retention, as well as the lack of a suitable reference region limit the potential for RCI in human neurosurgery. In this study, an arterial input graphic analysis (AIGA) method is presented which is enabled by independent component analysis (ICA). The percent difference in arterial concentration between the image-derived arterial input function (AIFICA) and that obtained by an invasive method (ICACAR) was 2.0 ± 2.7% during the first hour of circulation of a targeted-untargeted dye pair in mice. Estimates of distribution volume and receptor concentration in tumor bearing mice (n = 5) recovered using the AIGA technique did not differ significantly from values obtained using invasive AIF measurements (p=0.12). The AIGA method, enabled by the subject-specific AIFICA, was also applied in a rat orthotopic model of U-251 glioblastoma to obtain the first reported receptor concentration and distribution volume maps during open craniotomy. PMID:26349671

Characterizing and modeling protein-surface interactions in lab-on-chip devices

NASA Astrophysics Data System (ADS)

Katira, Parag

Protein adsorption on surfaces determines the response of other biological species present in the surrounding solution. This phenomenon plays a major role in the design of biomedical and biotechnological devices. While specific protein adsorption is essential for device function, non-specific protein adsorption leads to the loss of device function. For example, non-specific protein adsorption on bioimplants triggers foreign body response, in biosensors it leads to reduced signal to noise ratios, and in hybrid bionanodevices it results in the loss of confinement and directionality of molecular shuttles. Novel surface coatings are being developed to reduce or completely prevent the non-specific adsorption of proteins to surfaces. A novel quantification technique for extremely low protein coverage on surfaces has been developed. This technique utilizes measurement of the landing rate of microtubule filaments on kinesin proteins adsorbed on a surface to determine the kinesin density. Ultra-low limits of detection, dynamic range, ease of detection and availability of a ready-made kinesin-microtubule kit makes this technique highly suitable for detecting protein adsorption below the detection limits of standard techniques. Secondly, a random sequential adsorption model is presented for protein adsorption to PEO-coated surfaces. The derived analytical expressions accurately predict the observed experimental results from various research groups, suggesting that PEO chains act as almost perfect steric barriers to protein adsorption. These expressions can be used to predict the performance of a variety of systems towards resisting protein adsorption and can help in the design of better non-fouling surface coatings. Finally, in biosensing systems, target analytes are captured and concentrated on specifically adsorbed proteins for detection. Non-specific adsorption of proteins results in the loss of signal, and an increase in the background. The use of nanoscale transducers as receptors is beneficial from the point of view of signal enhancement, but has a strong mass transport limitation. To overcome this, the use of molecular shuttles has been proposed that can selectively capture analytes and actively transport them to the nanoreceptors. The effect of employing such a two-stage capture process on biosensor sensitivity is theoretically investigated and an optimum design for a kinesin-microtubule-driven hybrid biosensor is proposed.

FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor

PubMed Central

Vaden, Rachel M.; Oswald, Nathaniel W.; Potts, Malia B.; MacMillan, John B.; White, Michael A.

2017-01-01

Chemicals found in nature have evolved over geological time scales to productively interact with biological molecules, and thus represent an effective resource for pharmaceutical development. Marine-derived bacteria are rich sources of chemically diverse, bioactive secondary metabolites, but harnessing this diversity for biomedical benefit is limited by challenges associated with natural product purification and determination of biochemical mechanism. Using Functional Signature Ontology (FUSION), we report the parallel isolation and characterization of a marine-derived natural product, N6,N6-dimethyladenosine, that robustly inhibits AKT signaling in a variety of non-small cell lung cancer cell lines. Upon validation of the elucidated structure by comparison with a commercially available sample, experiments were initiated to understand the small molecule’s breadth of effect in a biological setting. One such experiment, a reverse phase protein array (RPPA) analysis of >50 kinases, indicated a specific cellular response to treatment. In all, leveraging the FUSION platform allowed for the rapid generation and validation of a biological mechanism of action hypothesis for an unknown natural product and permitted accelerated purification of the bioactive component from a chemically complex fraction. PMID:28294973

Thiazolidine-2,4-dione derivatives: programmed chemical weapons for key protein targets of various pathological conditions.

PubMed

Chadha, Navriti; Bahia, Malkeet Singh; Kaur, Maninder; Silakari, Om

2015-07-01

Thiazolidine-2,4-dione is an extensively explored heterocyclic nucleus for designing of novel agents implicated for a wide variety of pathophysiological conditions, that is, diabetes, diabetic complications, cancer, arthritis, inflammation, microbial infection, and melanoma, etc. The current paradigm of drug development has shifted to the structure-based drug design, since high-throughput screenings have continued to generate disappointing results. The gap between hit generation and drug establishment can be narrowed down by investigation of ligand interactions with its receptor protein. Therefore, it would always be highly beneficial to gain knowledge of molecular level interactions between specific protein target and developed ligands; since this information can be maneuvered to design new molecules with improved protein fitting. Thus, considering this aspect, we have corroborated the information about molecular (target) level implementations of thiazolidine-2,4-diones (TZD) derivatives having therapeutic implementations such as, but not limited to, anti-diabetic (glitazones), anti-cancer, anti-arthritic, anti-inflammatory, anti-oxidant and anti-microbial, etc. The structure based SAR of TZD derivatives for various protein targets would serve as a benchmark for the alteration of existing ligands to design new ones with better binding interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

Towards a Unified Quark-Hadron-Matter Equation of State for Applications in Astrophysics and Heavy-Ion Collisions

NASA Astrophysics Data System (ADS)

Bastian, Niels-Uwe; Blaschke, David; Fischer, Tobias; Röpke, Gerd

2018-05-01

We outline an approach to a unified equation of state for quark-hadron matter on the basis of a $\\Phi-$derivable approach to the generalized Beth-Uhlenbeck equation of state for a cluster decomposition of thermodynamic quantities like the density. To this end we summarize the cluster virial expansion for nuclear matter and demonstrate the equivalence of the Green's function approach and the $\\Phi-$derivable formulation. For an example, the formation and dissociation of deuterons in nuclear matter is discussed. We formulate the cluster $\\Phi-$derivable approach to quark-hadron matter which allows to take into account the specifics of chiral symmetry restoration and deconfinement in triggering the Mott-dissociation of hadrons. This approach unifies the description of a strongly coupled quark-gluon plasma with that of a medium-modified hadron resonance gas description which are contained as limiting cases. The developed formalism shall replace the common two-phase approach to the description of the deconfinement and chiral phase transition that requires a phase transition construction between separately developed equations of state for hadronic and quark matter phases. Applications to the phenomenology of heavy-ion collisions and astrophysics are outlined.

Norovirus Narita 104 Virus-Like Particles Expressed in Nicotiana benthamiana Induce Serum and Mucosal Immune Responses

PubMed Central

Mathew, Lolita George; Herbst-Kralovetz, Melissa M.; Mason, Hugh S.

2014-01-01

Narita 104 virus is a human pathogen belonging to the norovirus (family Caliciviridae) genogroup II. Noroviruses cause epidemic gastroenteritis worldwide. To explore the potential of developing a plant-based vaccine, a plant optimized gene encoding Narita 104 virus capsid protein (NaVCP) was expressed transiently in Nicotiana benthamiana using a tobacco mosaic virus expression system. NaVCP accumulated up to approximately 0.3 mg/g fresh weight of leaf at 4 days postinfection. Initiation of hypersensitive response-like symptoms followed by tissue necrosis necessitated a brief infection time and was a significant factor limiting expression. Transmission electron microscopy of plant-derived NaVCP confirmed the presence of fully assembled virus-like particles (VLPs). In this study, an optimized method to express and partially purify NaVCP is described. Further, partially purified NaVCP was used to immunize mice by intranasal delivery and generated significant mucosal and serum antibody responses. Thus, plant-derived Narita 104 VLPs have potential for use as a candidate subunit vaccine or as a component of a multivalent subunit vaccine, along with other genotype-specific plant-derived VLPs. PMID:24949472

Ff-nano, short functionalized nanorods derived from Ff (f1, fd, or M13) filamentous bacteriophage

PubMed Central

Sattar, Sadia; Bennett, Nicholas J.; Wen, Wesley X.; Guthrie, Jenness M.; Blackwell, Len F.; Conway, James F.; Rakonjac, Jasna

2015-01-01

F-specific filamentous phage of Escherichia coli (Ff: f1, M13, or fd) are long thin filaments (860 nm × 6 nm). They have been a major workhorse in display technologies and bionanotechnology; however, some applications are limited by the high length-to-diameter ratio of Ff. Furthermore, use of functionalized Ff outside of laboratory containment is in part hampered by the fact that they are genetically modified viruses. We have now developed a system for production and purification of very short functionalized Ff-phage-derived nanorods, named Ff-nano, that are only 50 nm in length. In contrast to standard Ff-derived vectors that replicate in E. coli and contain antibiotic-resistance genes, Ff-nano are protein-DNA complexes that cannot replicate on their own and do not contain any coding sequences. These nanorods show an increased resistance to heating at 70∘C in 1% SDS in comparison to the full-length Ff phage of the same coat composition. We demonstrate that functionalized Ff-nano particles are suitable for application as detection particles in sensitive and quantitative “dipstick” lateral flow diagnostic assay for human plasma fibronectin. PMID:25941520

BHR equations re-derived with immiscible particle effects

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

Schwarzkopf, John Dennis; Horwitz, Jeremy A.

2015-05-01

Compressible and variable density turbulent flows with dispersed phase effects are found in many applications ranging from combustion to cloud formation. These types of flows are among the most challenging to simulate. While the exact equations governing a system of particles and fluid are known, computational resources limit the scale and detail that can be simulated in this type of problem. Therefore, a common method is to simulate averaged versions of the flow equations, which still capture salient physics and is relatively less computationally expensive. Besnard developed such a model for variable density miscible turbulence, where ensemble-averaging was applied tomore » the flow equations to yield a set of filtered equations. Besnard further derived transport equations for the Reynolds stresses, the turbulent mass flux, and the density-specific volume covariance, to help close the filtered momentum and continuity equations. We re-derive the exact BHR closure equations which include integral terms owing to immiscible effects. Physical interpretations of the additional terms are proposed along with simple models. The goal of this work is to extend the BHR model to allow for the simulation of turbulent flows where an immiscible dispersed phase is non-trivially coupled with the carrier phase.« less

Differential Effects of Small Molecule WNT Agonists on the Multilineage Differentiation Capacity of Human Mesenchymal Stem Cells.

PubMed

Narcisi, Roberto; Arikan, Ozan H; Lehmann, Johannes; Ten Berge, Derk; van Osch, Gerjo J V M

2016-11-01

Human bone marrow-derived mesenchymal stem cells (MSCs) are promising candidates for cell-based therapies, but loss of expansion and differentiation potential in vitro limits their applicability. Recently we showed that WNT3A protein promoted MSC proliferation and enhanced their chondrogenic potential, while simultaneously suppressing the propensity of the cartilage to undergo hypertrophic maturation. Since WNT3A protein is costly and rapidly loses its activity in culture, we investigated the possibility of replacing it with cheaper commercially available WNT agonists, specifically lithium chloride (LiCl), CHIR99021 (CHIR), SKL2001, and AMBMP. Of these, we found that only CHIR and LiCl stimulated MSC proliferation. Moreover, CHIR enhanced the chondrogenic capacity of MSCs, whereas LiCl predominantly increased the osteo- and adipogenic capacity. The different WNT agonists also differentially impacted the surface marker profile of the MSCs, possibly explaining the observed differences. Moreover, CHIR suppressed the hypertrophic propensity of the MSC-derived cartilage after in vivo implantation to an extent approaching that of WNT3A protein. These results indicate that CHIR may be a promising alternative for WNT3A protein for certain applications of human bone marrow-derived MSCs.

Ff-nano, short functionalized nanorods derived from Ff (f1, fd, or M13) filamentous bacteriophage.

PubMed

Sattar, Sadia; Bennett, Nicholas J; Wen, Wesley X; Guthrie, Jenness M; Blackwell, Len F; Conway, James F; Rakonjac, Jasna

2015-01-01

F-specific filamentous phage of Escherichia coli (Ff: f1, M13, or fd) are long thin filaments (860 nm × 6 nm). They have been a major workhorse in display technologies and bionanotechnology; however, some applications are limited by the high length-to-diameter ratio of Ff. Furthermore, use of functionalized Ff outside of laboratory containment is in part hampered by the fact that they are genetically modified viruses. We have now developed a system for production and purification of very short functionalized Ff-phage-derived nanorods, named Ff-nano, that are only 50 nm in length. In contrast to standard Ff-derived vectors that replicate in E. coli and contain antibiotic-resistance genes, Ff-nano are protein-DNA complexes that cannot replicate on their own and do not contain any coding sequences. These nanorods show an increased resistance to heating at 70(∘)C in 1% SDS in comparison to the full-length Ff phage of the same coat composition. We demonstrate that functionalized Ff-nano particles are suitable for application as detection particles in sensitive and quantitative "dipstick" lateral flow diagnostic assay for human plasma fibronectin.

In utero transplantation of human bone marrow-derived multipotent mesenchymal stem cells in mice.

PubMed

Chou, Shiu-Huey; Kuo, Tom K; Liu, Ming; Lee, Oscar K

2006-03-01

Mesenchymal stem cells (MSCs) are multipotent cells that can be isolated from human bone marrow and possess the potential to differentiate into progenies of embryonic mesoderm. However, current evidence is based predominantly on in vitro experiments. We used a murine model of in utero transplantation (IUT) to study the engraftment capabilities of human MSCs. MSCs were obtained from bone marrow by negative immunoselection and limiting dilution, and were characterized by flow cytometry and by in vitro differentiation into osteoblasts, chondrocytes, and adipocytes. MSCs were transplanted into fetal mice at a gestational age of 14 days. Engraftment of human MSCs was determined by flow cytometry, polymerase chain reaction, and fluorescence in situ hybridization (FISH). MSCs engrafted into tissues originating from all three germ layers and persisted for up to 4 months or more after delivery, as evidenced by the expression of the human-specific beta-2 microglobulin gene and by FISH for donor-derived cells. Donor-derived CD45+ cells were detectable in the peripheral blood of recipients, suggesting the participation of MSCs in hematopoiesis at the fetal stage. This model can further serve to evaluate possible applications of MSCs. Copyright 2006 Orthopaedic Research Society.

Cellular Models: HD Patient-Derived Pluripotent Stem Cells.

PubMed

Geater, Charlene; Hernandez, Sarah; Thompson, Leslie; Mattis, Virginia B

2018-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded polyglutamine (polyQ)-encoding repeats in the Huntingtin (HTT) gene. Traditionally, HD cellular models consisted of either patient cells not affected by disease or rodent neurons expressing expanded polyQ repeats in HTT. As these models can be limited in their disease manifestation or proper genetic context, respectively, human HD pluripotent stem cells (PSCs) are currently under investigation as a way to model disease in patient-derived neurons and other neural cell types. This chapter reviews embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) models of disease, including published differentiation paradigms for neurons and their associated phenotypes, as well as current challenges to the field such as validation of the PSCs and PSC-derived cells. Highlighted are potential future technical advances to HD PSC modeling, including transdifferentiation, complex in vitro multiorgan/system reconstruction, and personalized medicine. Using a human HD patient model of the central nervous system, hopefully one day researchers can tease out the consequences of mutant HTT (mHTT) expression on specific cell types within the brain in order to identify and test novel therapies for disease.

17 CFR 240.36a1-2 - Exemption from SIPA for OTC derivatives dealers.

Code of Federal Regulations, 2011 CFR

2011-04-01

... derivatives dealers. 240.36a1-2 Section 240.36a1-2 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... § 240.36a1-2 Exemption from SIPA for OTC derivatives dealers. Preliminary Note: OTC derivatives dealers... derivative dealers are subject to special requirements, including limitations on the scope of their...

A sensitive and rapid assay for 4-aminophenol in paracetamol drug and tablet formulation, by flow injection analysis with spectrophotometric detection.

PubMed

Bloomfield, M S

2002-12-06

4-Aminophenol (4AP) is the primary degradation product of paracetamol which is limited at a low level (50 ppm or 0.005% w/w) in the drug substance by the European, United States, British and German Pharmacopoeias, employing a manual colourimetric limit test. The 4AP limit is widened to 1000 ppm or 0.1% w/w for the tablet product monographs, which quote the use of a less sensitive automated HPLC method. The lower drug substance specification limit is applied to our products, (50 ppm, equivalent to 25 mug 4AP in a tablet containing 500-mg paracetamol) and the pharmacopoeial HPLC assay was not suitable at this low level due to matrix interference. For routine analysis a rapid, automated assay was required. This paper presents a highly sensitive, precise and automated method employing the technique of Flow Injection (FI) analysis to quantitatively assay low levels of this degradant. A solution of the drug substance, or an extract of the tablets, containing 4AP and paracetamol is injected into a solvent carrier stream and merged on-line with alkaline sodium nitroprusside reagent, to form a specific blue derivative which is detected spectrophotometrically at 710 nm. Standard HPLC equipment is used throughout. The procedure is fully quantitative and has been optimised for sensitivity and robustness using a multivariate experimental design (multi-level 'Central Composite' response surface) model. The method has been fully validated and is linear down to 0.01 mug ml(-1). The approach should be applicable to a range of paracetamol products.

Toward Personalized Medicine: Using Cardiomyocytes Differentiated From Urine-Derived Pluripotent Stem Cells to Recapitulate Electrophysiological Characteristics of Type 2 Long QT Syndrome.

PubMed

Jouni, Mariam; Si-Tayeb, Karim; Es-Salah-Lamoureux, Zeineb; Latypova, Xenia; Champon, Benoite; Caillaud, Amandine; Rungoat, Anais; Charpentier, Flavien; Loussouarn, Gildas; Baró, Isabelle; Zibara, Kazem; Lemarchand, Patricia; Gaborit, Nathalie

2015-09-01

Human genetically inherited cardiac diseases have been studied mainly in heterologous systems or animal models, independent of patients' genetic backgrounds. Because sources of human cardiomyocytes (CMs) are extremely limited, the use of urine samples to generate induced pluripotent stem cell-derived CMs would be a noninvasive method to identify cardiac dysfunctions that lead to pathologies within patients' specific genetic backgrounds. The objective was to validate the use of CMs differentiated from urine-derived human induced pluripotent stem (UhiPS) cells as a new cellular model for studying patients' specific arrhythmia mechanisms. Cells obtained from urine samples of a patient with long QT syndrome who harbored the HERG A561P gene mutation and his asymptomatic noncarrier mother were reprogrammed using the episomal-based method. UhiPS cells were then differentiated into CMs using the matrix sandwich method.UhiPS-CMs showed proper expression of atrial and ventricular myofilament proteins and ion channels. They were electrically functional, with nodal-, atrial- and ventricular-like action potentials recorded using high-throughput optical and patch-clamp techniques. Comparison of HERG expression from the patient's UhiPS-CMs to the mother's UhiPS-CMs showed that the mutation led to a trafficking defect that resulted in reduced delayed rectifier K(+) current (IKr). This phenotype gave rise to action potential prolongation and arrhythmias. UhiPS cells from patients carrying ion channel mutations can be used as novel tools to differentiate functional CMs that recapitulate cardiac arrhythmia phenotypes. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Radiosynthesis binding affinity and biodistribution of 3-[F-18]fluoro-N-({alpha},{alpha},{alpha}-trifluoro-m-tolyl)piperazine (FTFMPP), a radioligand for the Serotonin system

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

Mishani, E.; Cristel, M.E.; McCarthy, T.J.

1996-05-01

The serotonin agonist N({alpha},{alpha},{alpha}-trifluoro-m-tolyl)piperazine (TFMPP) is a potent ligand for the serotonin system. Angelini and co-workers previously synthesized the c.a [F-18]TFMPP but the low specific activity (less than 0.2GBq/mmol) limited the application of this ligand. We have recently reported the formation of phenylpiperazines by a novel alumina supported bis-alkylation. We report the application of this method and biological evaluation of 3-[F-18]FTFMPP, a fluoro derivative of TFMPP. Reaction of [F-18]fluoride with 3,5-dinitrobenzotrifluoride gave the 3-[F-18]fluoro-5-nitrobenzotrifluoride in 70% yield. Reduction of the nitro group with Raney nickel and hydrazine hydrate gave the [F-18]aniline derivative in 70% yield. Finally, the phenylpiperazine was constructedmore » by reaction of the [F-18]aniline derivative with bis-2-bromoethyl-N-(ethoxy carbonyl)amine on basic alumina (pH=9) as a solid support. After extraction of the activity with basic MeOH and HPLC purification on normal phase the final product- [F-18]FTFMPP was obtained in 50% yield (98% radiochemical purity). The specific activity of the final product was 100GBq/mmol. The binding affinity of FTFMPP to 5-HT receptor was determined (Ki = 80-100 nM) and found to be similar to the binding affinity of the TFMPP (160-180 nM). The biodistribution of [F-18]FTFMPP was performed in rats.« less

Isolation and characterization of ventricular-like cells derived from NKX2-5eGFP/w and MLC2vmCherry/w double knock-in human pluripotent stem cells.

PubMed

Yamauchi, Kaori; Li, Junjun; Morikawa, Kumi; Liu, Li; Shirayoshi, Yasuaki; Nakatsuji, Norio; Elliott, David A; Hisatome, Ichiro; Suemori, Hirofumi

2018-01-01

Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) are a promising source for cell transplantation into the damaged heart, which has limited regenerative ability. Many methods have been developed to obtain large amounts of functional CMs from hPSCs for therapeutic applications. However, during the differentiation process, a mixed population of various cardiac cells, including ventricular, atrial, and pacemaker cells, is generated, which hampers the proper functional analysis and evaluation of cell properties. Here, we established NKX2-5 eGFP/w and MLC2v mCherry/w hPSC double knock-ins that allow for labeling, tracing, purification, and analysis of the development of ventricular cells from early to late stages. As with the endogenous transcriptional activities of these genes, MLC2v-mCherry expression following NKX2-5-eGFP expression was observed under previously established culture conditions, which mimic the in vivo cardiac developmental process. Patch-clamp and microelectrode array electrophysiological analyses showed that the NKX2-5 and MLC2v double-positive cells possess ventricular-like properties. The results demonstrate that the NKX2-5 eGFP/w and MLC2v mCherry/w hPSCs provide a powerful model system to capture region-specific cardiac differentiation from early to late stages. Our study would facilitate subtype-specific cardiac development and functional analysis using the hPSC-derived sources. Copyright © 2017 Elsevier Inc. All rights reserved.

Cranberry-derived proanthocyanidins prevent formation of Candida albicans biofilms in artificial urine through biofilm- and adherence-specific mechanisms

PubMed Central

Rane, Hallie S.; Bernardo, Stella M.; Howell, Amy B.; Lee, Samuel A.

2014-01-01

Objectives Candida albicans is a common cause of nosocomial urinary tract infections (UTIs) and is responsible for increased morbidity and healthcare costs. Moreover, the US Centers for Medicare & Medicaid Services no longer reimburse for hospital-acquired catheter-associated UTIs. Thus, development of specific approaches for the prevention of Candida urinary infections is needed. Cranberry juice-derived proanthocyanidins (PACs) have efficacy in the prevention of bacterial UTIs, partially due to anti-adherence properties, but there are limited data on their use for the prevention and/or treatment of Candida UTIs. Therefore, we sought to systematically assess the in vitro effect of cranberry-derived PACs on C. albicans biofilm formation in artificial urine. Methods C. albicans biofilms in artificial urine were coincubated with cranberry PACs at serially increasing concentrations and biofilm metabolic activity was assessed using the XTT assay in static microplate and silicone disc models. Results Cranberry PAC concentrations of ≥16 mg/L significantly reduced biofilm formation in all C. albicans strains tested, with a paradoxical effect observed at high concentrations in two clinical isolates. Further, cranberry PACs were additive in combination with traditional antifungals. Cranberry PACs reduced C. albicans adherence to both polystyrene and silicone. Supplementation of the medium with iron reduced the efficacy of cranberry PACs against biofilms. Conclusions These findings indicate that cranberry PACs have excellent in vitro activity against C. albicans biofilm formation in artificial urine. We present preliminary evidence that cranberry PAC activity against C. albicans biofilm formation is due to anti-adherence properties and/or iron chelation. PMID:24114570

Improved HCP Reduction Using a New, All-Synthetic Depth Filtration Media Within an Antibody Purification Process.

PubMed

Nguyen, Hoang C; Langland, Amie L; Amara, John P; Dullen, Michael; Kahn, David S; Costanzo, Joseph A

2018-04-30

Biologic manufacturing processes typically employ clarification technologies like depth filtration to remove insoluble and soluble impurities. Conventional depth filtration media used in these processes contain naturally-derived components like diatomaceous earth and cellulose. These components may introduce performance variability and contribute extractable/leachable components like beta-glucans that could interfere with limulus amebocyte lysate endotoxin assays. Recently a novel, all-synthetic depth filtration media is developed (Millistak+ ® HC Pro X0SP) that may improve process consistency, efficiency, and drug substance product quality by reducing soluble process impurities. This new media is evaluated against commercially available benchmark filters containing naturally-derived components (Millistak+ ® HC X0HC and B1HC). Using model proteins, the synthetic media demonstrates increased binding capacity of positively charged proteins (72-126 mg g -1 media) compared to conventional media (0.3-8.6 mg g -1 media); and similar values for negatively charged species (1.3-5.6 mg g -1 media). Several CHO-derived monoclonal antibodies (mAbs) or mAb-like molecules are also evaluated. The X0SP filtration performance behaves similarly to benchmarks, and exhibits improved HCP reduction (at least 50% in 55% of cases tested). X0SP filtrates contained increased silicon extractables relative to benchmarks, but these were readily removed downstream. Finally, the X0SP devices demonstrates suitable lot-to-lot robustness when specific media components are altered intentionally to manufacturing specification limits. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new anti-schistosomal drugs.

PubMed

Johann, Laure; Belorgey, Didier; Huang, Hsin-Hung; Day, Latasha; Chessé, Matthieu; Becker, Katja; Williams, David L; Davioud-Charvet, Elisabeth

2015-08-01

Investigations regarding the chemistry and mechanism of action of 2-methyl-1,4-naphthoquinone (or menadione) derivatives revealed 3-phenoxymethyl menadiones as a novel anti-schistosomal chemical series. These newly synthesized compounds (1-7) and their difluoromethylmenadione counterparts (8, 9) were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR), which has been identified as a potential target for anti-schistosomal drugs. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. glutathione reductase (hGR) and selenium-dependent human thioredoxin reductase (hTrxR), to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively compared to hGR and hTrxR enzymes, in particular those bearing an α-fluorophenol methyl ether moiety, which improves anti-schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (7) displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox cycling of SmTGR, and potent anti-schistosomal action in worms cultured ex vivo. In contrast, the difluoromethylmenadione analog 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in worms cultured ex vivo. Despite ex vivo activity, none of the compounds tested was active in vivo, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability. © 2015 FEBS.

CHAM: weak signals detection through a new multivariate algorithm for process control

NASA Astrophysics Data System (ADS)

Bergeret, François; Soual, Carole; Le Gratiet, B.

2016-10-01

Derivatives technologies based on core CMOS processes are significantly aggressive in term of design rules and process control requirements. Process control plan is a derived from Process Assumption (PA) calculations which result in a design rule based on known process variability capabilities, taking into account enough margin to be safe not only for yield but especially for reliability. Even though process assumptions are calculated with a 4 sigma known process capability margin, efficient and competitive designs are challenging the process especially for derivatives technologies in 40 and 28nm nodes. For wafer fab process control, PA are declined in monovariate (layer1 CD, layer2 CD, layer2 to layer1 overlay, layer3 CD etc….) control charts with appropriated specifications and control limits which all together are securing the silicon. This is so far working fine but such system is not really sensitive to weak signals coming from interactions of multiple key parameters (high layer2 CD combined with high layer3 CD as an example). CHAM is a software using an advanced statistical algorithm specifically designed to detect small signals, especially when there are many parameters to control and when the parameters can interact to create yield issues. In this presentation we will first present the CHAM algorithm, then the case-study on critical dimensions, with the results, and we will conclude on future work. This partnership between Ippon and STM is part of E450LMDAP, European project dedicated to metrology and lithography development for future technology nodes, especially 10nm.

Cranberry-derived proanthocyanidins prevent formation of Candida albicans biofilms in artificial urine through biofilm- and adherence-specific mechanisms.

PubMed

Rane, Hallie S; Bernardo, Stella M; Howell, Amy B; Lee, Samuel A

2014-02-01

Candida albicans is a common cause of nosocomial urinary tract infections (UTIs) and is responsible for increased morbidity and healthcare costs. Moreover, the US Centers for Medicare & Medicaid Services no longer reimburse for hospital-acquired catheter-associated UTIs. Thus, development of specific approaches for the prevention of Candida urinary infections is needed. Cranberry juice-derived proanthocyanidins (PACs) have efficacy in the prevention of bacterial UTIs, partially due to anti-adherence properties, but there are limited data on their use for the prevention and/or treatment of Candida UTIs. Therefore, we sought to systematically assess the in vitro effect of cranberry-derived PACs on C. albicans biofilm formation in artificial urine. C. albicans biofilms in artificial urine were coincubated with cranberry PACs at serially increasing concentrations and biofilm metabolic activity was assessed using the XTT assay in static microplate and silicone disc models. Cranberry PAC concentrations of ≥16 mg/L significantly reduced biofilm formation in all C. albicans strains tested, with a paradoxical effect observed at high concentrations in two clinical isolates. Further, cranberry PACs were additive in combination with traditional antifungals. Cranberry PACs reduced C. albicans adherence to both polystyrene and silicone. Supplementation of the medium with iron reduced the efficacy of cranberry PACs against biofilms. These findings indicate that cranberry PACs have excellent in vitro activity against C. albicans biofilm formation in artificial urine. We present preliminary evidence that cranberry PAC activity against C. albicans biofilm formation is due to anti-adherence properties and/or iron chelation.

Empirische Verfahren zur Ableitung verschiedener Porositätsarten aus Durchlässigkeitsbeiwert und Ungleichkörnigkeitszahl - ein Überblick

NASA Astrophysics Data System (ADS)

Fuchs, Sven; Ziesche, Michael; Nillert, Peter

2017-06-01

This paper comprises a review of the 13 studies that have been proposed for the derivation of porosity, effective porosity and/or specific yield from grain size distributions (Lejbenson 1947; Istomina 1957; Beyer 1964; Hennig 1966; Golf 1966; Marotz 1968; Beyer und Schweiger 1969; Seiler 1973; Bureau of Reclamation 1984; Helmbold 1988; Beims und Luckner 1999; Balke et al. 2000; Helmbold 2002). Experimental design, limitations and application boundaries are discussed and methods are compared against each other. The quality of the predictive methods strongly depends on the experimental design and the sample type.

Epigenomics of autoimmune diseases.

PubMed

Gupta, Bhawna; Hawkins, R David

2015-03-01

Autoimmune diseases are complex disorders of largely unknown etiology. Genetic studies have identified a limited number of causal genes from a marginal number of individuals, and demonstrated a high degree of discordance in monozygotic twins. Studies have begun to reveal epigenetic contributions to these diseases, primarily through the study of DNA methylation, but chromatin and non-coding RNA changes are also emerging. Moving forward an integrative analysis of genomic, transcriptomic and epigenomic data, with the latter two coming from specific cell types, will provide an understanding that has been missed from genetics alone. We provide an overview of the current state of the field and vision for deriving the epigenomics of autoimmunity.

Postpartum smoking relapse and becoming a mother.

PubMed

Gaffney, Kathleen F

2006-01-01

To propose an innovative, theoretically-derived conceptual framework for studies of postpartum smoking relapse including concepts of smoking abstinence self-efficacy and becoming a mother. Presentation of an existing research paradigm followed by evidence from intervention research and studies of factors associated with postpartum smoking behavior, leading to a new approach to postpartum smoking relapse. Effectiveness of current interventions to prevent relapse is limited. Variables associated with becoming a mother are missing from studies of postpartum smoking relapse. Context-specific variables that influence a woman's progression through the stages of becoming a mother might include protective or risk factors that should be incorporated into the design of postpartum smoking relapse studies.

Quantum estimation of parameters of classical spacetimes

NASA Astrophysics Data System (ADS)

Downes, T. G.; van Meter, J. R.; Knill, E.; Milburn, G. J.; Caves, C. M.

2017-11-01

We describe a quantum limit to the measurement of classical spacetimes. Specifically, we formulate a quantum Cramér-Rao lower bound for estimating the single parameter in any one-parameter family of spacetime metrics. We employ the locally covariant formulation of quantum field theory in curved spacetime, which allows for a manifestly background-independent derivation. The result is an uncertainty relation that applies to all globally hyperbolic spacetimes. Among other examples, we apply our method to the detection of gravitational waves with the electromagnetic field as a probe, as in laser-interferometric gravitational-wave detectors. Other applications are discussed, from terrestrial gravimetry to cosmology.

The impact of initial and recurrent cockpit resource management training on attitudes

NASA Technical Reports Server (NTRS)

Irwin, Cheryl M.

1991-01-01

It is noted that previous analyses of the boomerang effect (attitude change as a result of training in the direction opposite of that intended) in aviation training environments were limited in that each subscale of the cockpit management attitudes questionnaire (CMAQ) was examined independently. This study develops and utilizes a new algorithm for grouping subjects such that a global attitude change score is derived from the attitude change scores on each CMAQ subscale. By evaluating global attitude change in addition to the more specific attitude change on each subscale, it might be possible to better comprehend the effects of crew resource management training on pilot attitudes.

Methodologies for Root Locus and Loop Shaping Control Design with Comparisons

NASA Technical Reports Server (NTRS)

Kopasakis, George

2017-01-01

This paper describes some basics for the root locus controls design method as well as for loop shaping, and establishes approaches to expedite the application of these two design methodologies to easily obtain control designs that meet requirements with superior performance. The two design approaches are compared for their ability to meet control design specifications and for ease of application using control design examples. These approaches are also compared with traditional Proportional Integral Derivative (PID) control in order to demonstrate the limitations of PID control. Robustness of these designs is covered as it pertains to these control methodologies and for the example problems.

Computing Instantaneous Frequency by normalizing Hilbert Transform

NASA Technical Reports Server (NTRS)

Huang, Norden E. (Inventor)

2005-01-01

This invention presents Normalized Amplitude Hilbert Transform (NAHT) and Normalized Hilbert Transform(NHT), both of which are new methods for computing Instantaneous Frequency. This method is designed specifically to circumvent the limitation set by the Bedorsian and Nuttal Theorems, and to provide a sharp local measure of error when the quadrature and the Hilbert Transform do not agree. Motivation for this method is that straightforward application of the Hilbert Transform followed by taking the derivative of the phase-angle as the Instantaneous Frequency (IF) leads to a common mistake made up to this date. In order to make the Hilbert Transform method work, the data has to obey certain restrictions.

Computing Instantaneous Frequency by normalizing Hilbert Transform

DOEpatents

Huang, Norden E.

2005-05-31

This invention presents Normalized Amplitude Hilbert Transform (NAHT) and Normalized Hilbert Transform(NHT), both of which are new methods for computing Instantaneous Frequency. This method is designed specifically to circumvent the limitation set by the Bedorsian and Nuttal Theorems, and to provide a sharp local measure of error when the quadrature and the Hilbert Transform do not agree. Motivation for this method is that straightforward application of the Hilbert Transform followed by taking the derivative of the phase-angle as the Instantaneous Frequency (IF) leads to a common mistake made up to this date. In order to make the Hilbert Transform method work, the data has to obey certain restrictions.

Bizarre and scary ECG in yew leaves poisoning: Report of successful treatment.

PubMed

Cerrato, Natascia; Calzolari, Gilberto; Tizzani, Pietro; Actis Perinetto, Emma; Dellavalle, Antonio; Aluffi, Enzo

2018-02-28

Yew leaves poisoning is a rare life-threatening intoxication, whose diagnosis can be difficult. Initial symptoms are nausea, vomiting, abdominal pain, dizziness, tachycardia, muscle weakness, confusion, beginning within 1 hr from ingestion and followed by bradycardia, ventricular arrhythmias, ventricular fibrillation, severe hypotension, and death. Taxine-derived alkaloids are responsible for the toxicity of the yew leaves, blocking sodium and calcium channels, and causing conduction abnormalities. Because of lack of a specific antidote and limited efficacy of common antiarrhythmic drugs, prompt diagnosis, detoxification measures, and immediate hemodynamic support (also with transvenous cardiac stimulation) are essential. © 2018 Wiley Periodicals, Inc.

Equations of Motion for the g-LIMIT Microgravity Vibration Isolation System

NASA Technical Reports Server (NTRS)

Kim, Y. K.; Whorton, M. S.

2001-01-01

A desirable microgravity environment for experimental science payloads may require an active vibration isolation control system. A vibration isolation system named g-LIMIT (GLovebox Integrated Microgravity Isolation Technology) is being developed by NASA Marshall Space Flight Center to support microgravity science experiments using the microgravity science glovebox. In this technical memorandum, the full six-degree-of-freedom nonlinear equations of motion for g-LIMIT are derived. Although the motivation for this model development is control design and analysis of g-LIMIT, the equations are derived for a general configuration and may be used for other isolation systems as well.

Tempered fractional calculus

NASA Astrophysics Data System (ADS)

Sabzikar, Farzad; Meerschaert, Mark M.; Chen, Jinghua

2015-07-01

Fractional derivatives and integrals are convolutions with a power law. Multiplying by an exponential factor leads to tempered fractional derivatives and integrals. Tempered fractional diffusion equations, where the usual second derivative in space is replaced by a tempered fractional derivative, govern the limits of random walk models with an exponentially tempered power law jump distribution. The limiting tempered stable probability densities exhibit semi-heavy tails, which are commonly observed in finance. Tempered power law waiting times lead to tempered fractional time derivatives, which have proven useful in geophysics. The tempered fractional derivative or integral of a Brownian motion, called a tempered fractional Brownian motion, can exhibit semi-long range dependence. The increments of this process, called tempered fractional Gaussian noise, provide a useful new stochastic model for wind speed data. A tempered fractional difference forms the basis for numerical methods to solve tempered fractional diffusion equations, and it also provides a useful new correlation model in time series.

TEMPERED FRACTIONAL CALCULUS.

PubMed

Meerschaert, Mark M; Sabzikar, Farzad; Chen, Jinghua

2015-07-15

Fractional derivatives and integrals are convolutions with a power law. Multiplying by an exponential factor leads to tempered fractional derivatives and integrals. Tempered fractional diffusion equations, where the usual second derivative in space is replaced by a tempered fractional derivative, govern the limits of random walk models with an exponentially tempered power law jump distribution. The limiting tempered stable probability densities exhibit semi-heavy tails, which are commonly observed in finance. Tempered power law waiting times lead to tempered fractional time derivatives, which have proven useful in geophysics. The tempered fractional derivative or integral of a Brownian motion, called a tempered fractional Brownian motion, can exhibit semi-long range dependence. The increments of this process, called tempered fractional Gaussian noise, provide a useful new stochastic model for wind speed data. A tempered difference forms the basis for numerical methods to solve tempered fractional diffusion equations, and it also provides a useful new correlation model in time series.

TEMPERED FRACTIONAL CALCULUS

PubMed Central

MEERSCHAERT, MARK M.; SABZIKAR, FARZAD; CHEN, JINGHUA

2014-01-01

Fractional derivatives and integrals are convolutions with a power law. Multiplying by an exponential factor leads to tempered fractional derivatives and integrals. Tempered fractional diffusion equations, where the usual second derivative in space is replaced by a tempered fractional derivative, govern the limits of random walk models with an exponentially tempered power law jump distribution. The limiting tempered stable probability densities exhibit semi-heavy tails, which are commonly observed in finance. Tempered power law waiting times lead to tempered fractional time derivatives, which have proven useful in geophysics. The tempered fractional derivative or integral of a Brownian motion, called a tempered fractional Brownian motion, can exhibit semi-long range dependence. The increments of this process, called tempered fractional Gaussian noise, provide a useful new stochastic model for wind speed data. A tempered difference forms the basis for numerical methods to solve tempered fractional diffusion equations, and it also provides a useful new correlation model in time series. PMID:26085690

Tempered fractional calculus

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

Sabzikar, Farzad, E-mail: sabzika2@stt.msu.edu; Meerschaert, Mark M., E-mail: mcubed@stt.msu.edu; Chen, Jinghua, E-mail: cjhdzdz@163.com

2015-07-15

Fractional derivatives and integrals are convolutions with a power law. Multiplying by an exponential factor leads to tempered fractional derivatives and integrals. Tempered fractional diffusion equations, where the usual second derivative in space is replaced by a tempered fractional derivative, govern the limits of random walk models with an exponentially tempered power law jump distribution. The limiting tempered stable probability densities exhibit semi-heavy tails, which are commonly observed in finance. Tempered power law waiting times lead to tempered fractional time derivatives, which have proven useful in geophysics. The tempered fractional derivative or integral of a Brownian motion, called a temperedmore » fractional Brownian motion, can exhibit semi-long range dependence. The increments of this process, called tempered fractional Gaussian noise, provide a useful new stochastic model for wind speed data. A tempered fractional difference forms the basis for numerical methods to solve tempered fractional diffusion equations, and it also provides a useful new correlation model in time series.« less

Experimentally-Derived Fibroblast Gene Signatures Identify Molecular Pathways Associated with Distinct Subsets of Systemic Sclerosis Patients in Three Independent Cohorts

PubMed Central

Johnson, Michael E.; Mahoney, J. Matthew; Taroni, Jaclyn; Sargent, Jennifer L.; Marmarelis, Eleni; Wu, Ming-Ru; Varga, John; Hinchcliff, Monique E.; Whitfield, Michael L.

2015-01-01

Genome-wide expression profiling in systemic sclerosis (SSc) has identified four ‘intrinsic’ subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling. PMID:25607805

Self-forces on static bodies in arbitrary dimensions

NASA Astrophysics Data System (ADS)

Harte, Abraham I.; Flanagan, Éanna É.; Taylor, Peter

2016-06-01

We derive exact expressions for the scalar and electromagnetic self-forces and self-torques acting on arbitrary static extended bodies in arbitrary static spacetimes with any number of dimensions. Nonperturbatively, our results are identical in all dimensions. Meaningful point particle limits are quite different in different dimensions, however. These limits are defined and evaluated, resulting in simple "regularization algorithms" which can be used in concrete calculations. In these limits, self-interaction is shown to be progressively less important in higher numbers of dimensions; it generically competes in magnitude with increasingly high-order extended-body effects. Conversely, we show that self-interaction effects can be relatively large in 1 +1 and 2 +1 dimensions. Our motivations for this work are twofold: First, no previous derivation of the self-force has been provided in arbitrary dimensions, and heuristic arguments presented by different authors have resulted in conflicting conclusions. Second, the static self-force problem in arbitrary dimensions provides a valuable test bed with which to continue the development of general, nonperturbative methods in the theory of motion. Several new insights are obtained in this direction, including a significantly improved understanding of the renormalization process. We also show that there is considerable freedom to use different "effective fields" in the laws of motion—a freedom which can be exploited to optimally simplify specific problems. Different choices give rise to different inertias, gravitational forces, and electromagnetic or scalar self-forces, but there is a sense in which none of these quantities are individually accessible to experiment. Certain combinations are observable, however, and these remain invariant under all possible field redefinitions.

The association between tax structure and cigarette price variability: findings from the ITC Project.

PubMed

Shang, Ce; Chaloupka, Frank J; Fong, Geoffrey T; Thompson, Mary; O'Connor, Richard J

2015-07-01

Recent studies have shown that more opportunities exist for tax avoidance when cigarette excise tax structure departs from a uniform specific structure. However, the association between tax structure and cigarette price variability has not been thoroughly studied in the existing literature. To examine how cigarette tax structure is associated with price variability. The variability of self-reported prices is measured using the ratios of differences between higher and lower prices to the median price such as the IQR-to-median ratio. We used survey data taken from the International Tobacco Control Policy Evaluation (ITC) Project in 17 countries to conduct the analysis. Cigarette prices were derived using individual purchase information and aggregated to price variability measures for each surveyed country and wave. The effect of tax structures on price variability was estimated using Generalised Estimating Equations after adjusting for year and country attributes. Our study provides empirical evidence of a relationship between tax structure and cigarette price variability. We find that, compared to the specific uniform tax structure, mixed uniform and tiered (specific, ad valorem or mixed) structures are associated with greater price variability (p≤0.01). Moreover, while a greater share of the specific component in total excise taxes is associated with lower price variability (p≤0.05), a tiered tax structure is associated with greater price variability (p≤0.01). The results suggest that a uniform and specific tax structure is the most effective tax structure for reducing tobacco consumption and prevalence by limiting price variability and decreasing opportunities for tax avoidance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Targeted Quantitation of Proteins by Mass Spectrometry

PubMed Central

2013-01-01

Quantitative measurement of proteins is one of the most fundamental analytical tasks in a biochemistry laboratory, but widely used immunochemical methods often have limited specificity and high measurement variation. In this review, we discuss applications of multiple-reaction monitoring (MRM) mass spectrometry, which allows sensitive, precise quantitative analyses of peptides and the proteins from which they are derived. Systematic development of MRM assays is permitted by databases of peptide mass spectra and sequences, software tools for analysis design and data analysis, and rapid evolution of tandem mass spectrometer technology. Key advantages of MRM assays are the ability to target specific peptide sequences, including variants and modified forms, and the capacity for multiplexing that allows analysis of dozens to hundreds of peptides. Different quantitative standardization methods provide options that balance precision, sensitivity, and assay cost. Targeted protein quantitation by MRM and related mass spectrometry methods can advance biochemistry by transforming approaches to protein measurement. PMID:23517332

Targeting the microbiota in the management of gastrointestinal and liver disease.

PubMed

Quigley, Eamonn M M; Monsour, Howard P

2013-01-01

Thanks to rapid advances in technology the details of the human microbiome and its functions in health and disease are being progressively revealed. Though many reports have linked various disease states with an altered microbiome and while some associations between the microbiome and disease states are well established, many of these studies are largely descriptive and the changes reported in the microbiome have yet to be shown to be causative. A number of strategies are available to modify the microbiota; some such as the use of antibiotics for specific indications, are well established, others such as the use of probiotics and prebiotics in a variety of disease states are supported by more limited data. Fecal transplantation has emerged as an exciting, albeit rather drastic, intervention for intestinal and, perhaps, other disorders. Other approaches, such as the isolation, purification and formulation of small molecules with specific biological actions, derived from the microbiota look very promising.

Bovine apolipoprotein B-100 is a dominant immunogen in therapeutic cell populations cultured in fetal calf serum in mice and humans

PubMed Central

Sakamoto, Norihisa; Tsuji, Kazuhide; Muul, Linda M.; Lawler, Ann M.; Petricoin, Emanuel F.; Candotti, Fabio; Metcalf, Julia A.; Tavel, Jorge A.; Lane, H. Clifford; Urba, Walter J.; Fox, Bernard A.; Varki, Ajit; Lunney, Joan K.

2007-01-01

Recent studies have demonstrated that cell populations intended for therapeutic purposes that are cultured in heterologous animal products can acquire xenoantigens, potentially limiting their utility. In investigations of the immune response to murine embryonic stem cells, we found that a strong antibody response was generated after the second infusion. Both polyclonal and monoclonal antibody responses, derived from immunized mice, were found to be specific for bovine apolipoprotein B-100, which binds to abundant low-density lipoprotein receptors on the cell surface and is internalized. Here we show that in the majority of patients administered 3 different types of cell-based therapies using cells grown in fetal calf serum-containing media, an antibody response to bovine apolipoprotein B-100 develops after the second infusion and is the dominant specificity. The known and potential clinical effects of such antibodies are discussed. PMID:17395779

Objectivity in a Noisy Photonic Environment through Quantum State Information Broadcasting

NASA Astrophysics Data System (ADS)

Korbicz, J. K.; Horodecki, P.; Horodecki, R.

2014-03-01

Recently, the emergence of classical objectivity as a property of a quantum state has been explicitly derived for a small object embedded in a photonic environment in terms of a spectrum broadcast form—a specific classically correlated state, redundantly encoding information about the preferred states of the object in the environment. However, the environment was in a pure state and the fundamental problem was how generic and robust is the conclusion. Here, we prove that despite the initial environmental noise, the emergence of the broadcast structure still holds, leading to the perceived objectivity of the state of the object. We also show how this leads to a quantum Darwinism-type condition, reflecting the classicality of proliferated information in terms of a limit behavior of the mutual information. Quite surprisingly, we find "singular points" of the decoherence, which can be used to faithfully broadcast a specific classical message through the noisy environment.

Quantum annealing versus classical machine learning applied to a simplified computational biology problem

PubMed Central

Li, Richard Y.; Di Felice, Rosa; Rohs, Remo; Lidar, Daniel A.

2018-01-01

Transcription factors regulate gene expression, but how these proteins recognize and specifically bind to their DNA targets is still debated. Machine learning models are effective means to reveal interaction mechanisms. Here we studied the ability of a quantum machine learning approach to predict binding specificity. Using simplified datasets of a small number of DNA sequences derived from actual binding affinity experiments, we trained a commercially available quantum annealer to classify and rank transcription factor binding. The results were compared to state-of-the-art classical approaches for the same simplified datasets, including simulated annealing, simulated quantum annealing, multiple linear regression, LASSO, and extreme gradient boosting. Despite technological limitations, we find a slight advantage in classification performance and nearly equal ranking performance using the quantum annealer for these fairly small training data sets. Thus, we propose that quantum annealing might be an effective method to implement machine learning for certain computational biology problems. PMID:29652405

Implementation of two new resource management information systems in Australia

NASA Astrophysics Data System (ADS)

Kessell, Stephen R.; Good, Roger B.; Hopkins, Angas J. M.

1984-05-01

This paper describes the development and implementation of PREPLAN, A Pristine Environment Planning Language and Simulator, for two conservation areas in Australia, Kosciusko National Park (New South Wales) and Tutanning Nature Reserve (Western Australia). PREPLAN was derived from the North American gradient modeling systems and the Forest Planning Language and Simulator (FORPLAN), but includes unique characteristics not previously available. PREPLAN includes an integrated resource management data base, modules for predicting site-specific vegetation, fuels, animals, fire behavior, and fire effects, and an English language instruction set. PREPLAN was developed specifically to provide available information and understanding of ecosystems to managers in a readily accessible and usable form, and to provide the motivation to conduct additional required research projects. An evaluation of the system's advantages and limitations is presented, and the way the utilization of such systems is improving natural area decision making throughout Australia is discussed.

Targeted quantitation of proteins by mass spectrometry.

PubMed

Liebler, Daniel C; Zimmerman, Lisa J

2013-06-04

Quantitative measurement of proteins is one of the most fundamental analytical tasks in a biochemistry laboratory, but widely used immunochemical methods often have limited specificity and high measurement variation. In this review, we discuss applications of multiple-reaction monitoring (MRM) mass spectrometry, which allows sensitive, precise quantitative analyses of peptides and the proteins from which they are derived. Systematic development of MRM assays is permitted by databases of peptide mass spectra and sequences, software tools for analysis design and data analysis, and rapid evolution of tandem mass spectrometer technology. Key advantages of MRM assays are the ability to target specific peptide sequences, including variants and modified forms, and the capacity for multiplexing that allows analysis of dozens to hundreds of peptides. Different quantitative standardization methods provide options that balance precision, sensitivity, and assay cost. Targeted protein quantitation by MRM and related mass spectrometry methods can advance biochemistry by transforming approaches to protein measurement.

A Quantitative PCR-Electrochemical Genosensor Test for the Screening of Biotech Crops

PubMed Central

Moura-Melo, Suely; Miranda-Castro, Rebeca; de-los-Santos-Álvarez, Noemí; Miranda-Ordieres, Arturo J.; dos Santos Junior, José Ribeiro; da Silva Fonseca, Rosana A.; Lobo-Castañón, María Jesús

2017-01-01

The design of screening methods for the detection of genetically modified organisms (GMOs) in food would improve the efficiency in their control. We report here a PCR amplification method combined with a sequence-specific electrochemical genosensor for the quantification of a DNA sequence characteristic of the 35S promoter derived from the cauliflower mosaic virus (CaMV). Specifically, we employ a genosensor constructed by chemisorption of a thiolated capture probe and p-aminothiophenol gold surfaces to entrap on the sensing layer the unpurified PCR amplicons, together with a signaling probe labeled with fluorescein. The proposed test allows for the determination of a transgene copy number in both hemizygous (maize MON810 trait) and homozygous (soybean GTS40-3-2) transformed plants, and exhibits a limit of quantification of at least 0.25% for both kinds of GMO lines. PMID:28420193

Autonomous urban reconnaissance ingress system (AURIS): providing a tactically relevant autonomous door-opening kit for unmanned ground vehicles

NASA Astrophysics Data System (ADS)

Shane, David J.; Rufo, Michael A.; Berkemeier, Matthew D.; Alberts, Joel A.

2012-06-01

The Autonomous Urban Reconnaissance Ingress System (AURIS™) addresses a significant limitation of current military and first responder robotics technology: the inability of reconnaissance robots to open doors. Leveraging user testing as a baseline, the program has derived specifications necessary for military personnel to open doors with fielded UGVs (Unmanned Ground Vehicles), and evaluates the technology's impact on operational mission areas: duration, timing, and user patience in developing a tactically relevant, safe, and effective system. Funding is provided through the US ARMY Tank Automotive Research, Development and Engineering Center (TARDEC) and the project represents a leap forward in perception, autonomy, robotic implements, and coordinated payload operation in UGVs. This paper describes high level details of specification generation, status of the last phase of development, an advanced view of the system autonomy capability, and a short look ahead towards the ongoing work on this compelling and important technology.

Persuasive Dialogue Based on a Narrative Theory: An ECA Implementation

NASA Astrophysics Data System (ADS)

Cavazza, Marc; Smith, Cameron; Charlton, Daniel; Crook, Nigel; Boye, Johan; Pulman, Stephen; Moilanen, Karo; Pizzi, David; de La Camara, Raul Santos; Turunen, Markku

Embodied Conversational Agents (ECA) are poised to constitute a specific category within persuasive systems, in particular through their ability to support affective dialogue. One possible approach consists in using ECA as virtual coaches or personal assistants and to make persuasion part of a dialogue game implementing specific argumentation or negotiation features. In this paper, we explore an alternative framework, which emerges from the long-term development of ECA as "Companions" supporting free conversation with the user, rather than task-oriented dialogue. Our system aims at influencing user attitudes as part of free conversation, albeit on a limited set of topics. We describe the implementation of a Companion ECA to which the user reports on his working day, and which can assess the user's emotional attitude towards daily events in the office, trying to influence such attitude using affective strategies derived from a narrative model. This discussion is illustrated through examples from a first fully-implemented prototype.

Leadership for health improvement--implementation and evaluation.

PubMed

Carr, Susan M; Carr, Sue; Lhussier, Monique; Reynolds, Joanna; Hunter, David J; Hannaway, Catherine

2009-01-01

The purpose of this paper is to present a co-authored reflection on the health improvement leadership development programme and the key evaluation messages derived from piloting in an English National Health Service region. It highlights the specific attributes of this approach to health improvement leadership development and clarifies health improvement development issues. Appreciative inquiry and soft systems methodology are combined in an evaluation approach designed to capture individual as well as organisation learning and how it impacts on leadership in specific contexts. The evaluation exposes the health improvement leadership needs of a multi-organisation cohort, offers some explanations for successful achievement of learning needs while also exposing of the challenges and paradoxes faced in this endeavour. There are limited reported templates of how to develop leadership for health improvement. This paper details a whole systems approach, acknowledging the impact of context on leadership and an approach to evaluating such complex initiatives.

Development of a qualitative real-time PCR method to detect 19 targets for identification of genetically modified organisms.

PubMed

Peng, Cheng; Wang, Pengfei; Xu, Xiaoli; Wang, Xiaofu; Wei, Wei; Chen, Xiaoyun; Xu, Junfeng

2016-01-01

As the amount of commercially available genetically modified organisms (GMOs) grows recent years, the diversity of target sequences for molecular detection techniques are eagerly needed. Considered as the gold standard for GMO analysis, the real-time PCR technology was optimized to produce a high-throughput GMO screening method. With this method we can detect 19 transgenic targets. The specificity of the assays was demonstrated to be 100 % by the specific amplification of DNA derived from reference material from 20 genetically modified crops and 4 non modified crops. Furthermore, most assays showed a very sensitive detection, reaching the limit of ten copies. The 19 assays are the most frequently used genetic elements present in GM crops and theoretically enable the screening of the known GMO described in Chinese markets. Easy to use, fast and cost efficient, this method approach fits the purpose of GMO testing laboratories.

A new CFD based non-invasive method for functional diagnosis of coronary stenosis.

PubMed

Xie, Xinzhou; Zheng, Minwen; Wen, Didi; Li, Yabing; Xie, Songyun

2018-03-22

Accurate functional diagnosis of coronary stenosis is vital for decision making in coronary revascularization. With recent advances in computational fluid dynamics (CFD), fractional flow reserve (FFR) can be derived non-invasively from coronary computed tomography angiography images (FFR CT ) for functional measurement of stenosis. However, the accuracy of FFR CT is limited due to the approximate modeling approach of maximal hyperemia conditions. To overcome this problem, a new CFD based non-invasive method is proposed. Instead of modeling maximal hyperemia condition, a series of boundary conditions are specified and those simulated results are combined to provide a pressure-flow curve for a stenosis. Then, functional diagnosis of stenosis is assessed based on parameters derived from the obtained pressure-flow curve. The proposed method is applied to both idealized and patient-specific models, and validated with invasive FFR in six patients. Results show that additional hemodynamic information about the flow resistances of a stenosis is provided, which cannot be directly obtained from anatomy information. Parameters derived from the simulated pressure-flow curve show a linear and significant correlations with invasive FFR (r > 0.95, P < 0.05). The proposed method can assess flow resistances by the pressure-flow curve derived parameters without modeling of maximal hyperemia condition, which is a new promising approach for non-invasive functional assessment of coronary stenosis.

Clinical performance of serum [-2]proPSA derivatives, %p2PSA and PHI, in the detection and management of prostate cancer.

PubMed

Huang, Ya-Qiang; Sun, Tong; Zhong, Wei-De; Wu, Chin-Lee

2014-01-01

Prostate-specific antigen (PSA) has been widely used as a serum marker for prostate cancer (PCa) screening or progression monitoring, which dramatically increased rate of early detection while significantly reduced PCa-specific mortality. However, a number of limitations of PSA have been noticed. Low specificity of PSA may lead to overtreatment in men who presenting with a total PSA (tPSA) level of < 10 ng/mL. As a type of free PSA (fPSA), [-2]proPSA is differentially expressed in peripheral zone of prostate gland and found to be elevated in serum of men with PCa. Two p2PSA-based derivatives, prostate health index (PHI) and %p2PSA, which were defined as [(p2PSA/fPSA) × √ tPSA] and [(p2PSA/fPSA) × 100] respectively, have been suggested to be increased in PCa and can better distinguish PCa from benign prostatic diseases than tPSA or fPSA. We performed a systematic review of the available scientific evidences to evaluate the potentials of %p2PSA and PHI in clinical application. Mounting evidences suggested that both %p2PSA and PHI possess higher area under the ROC curve (AUC) and better specificity at a high sensitivity for PCa detection when compare with tPSA and %fPSA. It indicated that measurements of %p2PSA and PHI significantly improved the accuracy of PCa detection and diminished unnecessary biopsies. Furthermore, elevations of %p2PSA and PHI are related to more aggressive diseases. %p2PSA and PHI might be helpful in reducing overtreatment on indolent cases or assessing the progression of PCa in men who undergo active surveillance. Further studies are needed before being applied in routine clinical practice.

Development of a propidium monoazide-polymerase chain reaction assay for detection of viable Lactobacillus brevis in beer.

PubMed

Ma, Yanlin; Deng, Yang; Xu, Zhenbo; Liu, Junyan; Dong, Jianjun; Yin, Hua; Yu, Junhong; Chang, Zongming; Wang, Dongfeng

The spoilage of beer by bacteria is of great concern to the brewer as this can lead to turbidity and abnormal flavors. The polymerase chain reaction (PCR) method for detection of beer-spoilage bacteria is highly specific and provides results much faster than traditional microbiology techniques. However, one of the drawbacks is the inability to differentiate between live and dead cells. In this paper, the combination of propidium monoazide (PMA) pretreatment and conventional PCR had been described. The established PMA-PCR identified beer spoilage Lactobacillus brevis based not on their identity, but on the presence of horA gene which we show to be highly correlated with the ability of beer spoilage LAB to grow in beer. The results suggested that the use of 30μg/mL or less of PMA did not inhibit the PCR amplification of DNA derived from viable L. brevis cells. The minimum amount of PMA to completely inhibit the PCR amplification of DNA derived from dead L. brevis cells was 2.0μg/mL. The detection limit of PMA-PCR assay described here was found to be 10 colony forming units (CFU)/reaction for the horA gene. Moreover, the horA-specific PMA-PCR assays were subjected to 18 reference isolates, representing 100% specificity with no false positive amplification observed. Overall the use of horA-specific PMA-PCR allows for a substantial reduction in the time required for detection of potential beer spoilage L. brevis and efficiently differentiates between viable and nonviable cells. Copyright © 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Predicting Heart Rate at the Ventilatory Threshold for Aerobic Exercise Prescription in Persons With Chronic Stroke.

PubMed

Boyne, Pierce; Buhr, Sarah; Rockwell, Bradley; Khoury, Jane; Carl, Daniel; Gerson, Myron; Kissela, Brett; Dunning, Kari

2015-10-01

Treadmill aerobic exercise improves gait, aerobic capacity, and cardiovascular health after stroke, but a lack of specificity in current guidelines could lead to underdosing or overdosing of aerobic intensity. The ventilatory threshold (VT) has been recommended as an optimal, specific starting point for continuous aerobic exercise. However, VT measurement is not available in clinical stroke settings. Therefore, the purpose of this study was to identify an accurate method to predict heart rate at the VT (HRVT) for use as a surrogate for VT. A cross-sectional design was employed. Using symptom-limited graded exercise test (GXT) data from 17 subjects more than 6 months poststroke, prediction methods for HRVT were derived by traditional target HR calculations (percentage of HRpeak achieved during GXT, percentage of peak HR reserve [HRRpeak], percentage of age-predicted maximal HR, and percentage of age-predicted maximal HR reserve) and by regression analysis. The validity of the prediction methods was then tested among 8 additional subjects. All prediction methods were validated by the second sample, so data were pooled to calculate refined prediction equations. HRVT was accurately predicted by 80% HRpeak (R, 0.62; standard deviation of error [SDerror], 7 bpm), 62% HRRpeak (R, 0.66; SDerror, 7 bpm), and regression models that included HRpeak (R, 0.62-0.75; SDerror, 5-6 bpm). Derived regression equations, 80% HRpeak and 62% HRRpeak, provide a specific target intensity for initial aerobic exercise prescription that should minimize underdosing and overdosing for persons with chronic stroke. The specificity of these methods may lead to more efficient and effective treatment for poststroke deconditioning.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A114).

Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA–peptide tetramers

PubMed Central

Cobbold, Mark; Khan, Naeem; Pourgheysari, Batoul; Tauro, Sudhir; McDonald, Dorothy; Osman, Husam; Assenmacher, Mario; Billingham, Lucinda; Steward, Colin; Crawley, Charles; Olavarria, Eduardo; Goldman, John; Chakraverty, Ronjon; Mahendra, Premini; Craddock, Charles; Moss, Paul A.H.

2005-01-01

Stem cell transplantation is used widely in the management of a range of diseases of the hemopoietic system. Patients are immunosuppressed profoundly in the early posttransplant period, and reactivation of cytomegalovirus (CMV) remains a significant cause of morbidity and mortality. Adoptive transfer of donor-derived CMV-specific CD8+ T cell clones has been shown to reduce the rate of viral reactivation; however, the complexity of this approach severely limits its clinical application. We have purified CMV-specific CD8+ T cells from the blood of stem cell transplant donors using staining with HLA–peptide tetramers followed by selection with magnetic beads. CMV-specific CD8+ cells were infused directly into nine patients within 4 h of selection. Median cell dosage was 8.6 × 103/kg with a purity of 98% of all T cells. CMV-specific CD8+ T cells became detectable in all patients within 10 d of infusion, and TCR clonotype analysis showed persistence of infused cells in two patients studied. CMV viremia was reduced in every case and eight patients cleared the infection, including one patient who had a prolonged history of CMV infection that was refractory to antiviral therapy. This novel approach to adoptive transfer has considerable potential for antigen-specific T cell therapy. PMID:16061727

Development of Strain-Specific Primers for Identification of Bifidobacterium bifidum BGN4.

PubMed

Youn, So Youn; Ji, Geun Eog; Han, Yoo Ri; Park, Myeong Soo

2017-05-28

Bifidobacterium bifidum BGN4 (BGN4) has many proven beneficial effects, including antiallergy and anticancer properties. It has been commercialized and used in several probiotic products, and thus strain-specific identification of this strain is very valuable for further strain-dependent physiological study. For this purpose, we developed novel multiplex polymerase chain reaction (PCR) primer sets for strain-specific detection of BGN4 in commercial products and fecal samples of animal models. The primer set was tested on seven strains of B. bifidum and 75 strains of the other Bifidobacterium species. The BGN4-specific regions were derived using megaBLAST against genome sequences of various B. bifidum databases and four sets of primers were designed. As a result, only BGN4 produced four PCR products simultaneously whereas the other strains did not. The PCR detection limit using BGN4-specific primer sets was 2.8 × 10 1 CFU/ml of BGN4. Those primer sets also detected and identified BGN4 in the probiotic products containing BNG4 and fecal samples from a BGN4-fed animal model with high specificity. Our results indicate that the PCR assay from this study is an efficient tool for the simple, rapid, and reliable identification of BGN4, for which probiotic strains are known.

A transient laboratory method for determining the hydraulic properties of 'tight' rocks-I. Theory

USGS Publications Warehouse

Hsieh, P.A.; Tracy, J.V.; Neuzil, C.E.; Bredehoeft, J.D.; Silliman, Stephen E.

1981-01-01

Transient pulse testing has been employed increasingly in the laboratory to measure the hydraulic properties of rock samples with low permeability. Several investigators have proposed a mathematical model in terms of an initial-boundary value problem to describe fluid flow in a transient pulse test. However, the solution of this problem has not been available. In analyzing data from the transient pulse test, previous investigators have either employed analytical solutions that are derived with the use of additional, restrictive assumptions, or have resorted to numerical methods. In Part I of this paper, a general, analytical solution for the transient pulse test is presented. This solution is graphically illustrated by plots of dimensionless variables for several cases of interest. The solution is shown to contain, as limiting cases, the more restrictive analytical solutions that the previous investigators have derived. A method of computing both the permeability and specific storage of the test sample from experimental data will be presented in Part II. ?? 1981.

A pear-derived kairomone with pheromonal potency that attracts male and female codling moth, Cydia pomonella (L.)

NASA Astrophysics Data System (ADS)

Light, Douglas M.; Knight, Alan L.; Henrick, Clive A.; Rajapaska, Dayananda; Lingren, Bill; Dickens, Joseph C.; Reynolds, Katherine M.; Buttery, Ronald G.; Merrill, Gloria; Roitman, James; Campbell, Bruce C.

2001-08-01

Ethyl (2 E, 4 Z)-2,4-decadienoate, a pear-derived volatile, is a species-specific, durable, and highly potent attractant to the codling moth (CM), Cydia pomonella (L.), a serious pest of walnuts, apples, and pears worldwide. This kairomone attracts both CM males and virgin and mated females. It is highly attractive to CM in both walnut and apple orchard contexts, but has shown limited effectiveness in a pear orchard context. Rubber septa lures loaded with ethyl (2 E, 4 Z)-2,4-decadienoate remained attractive for several months under field conditions. At the same low microgram load rates on septa, the combined gender capture of CM in kairomone-baited traps was similar to the capture rate of males in traps baited with codlemone, the major sex pheromone component. The particular attribute of attracting CM females renders this kairomone a novel tool for monitoring population flight and mating-ovipositional status, and potentially a major new weapon for directly controlling CM populations.

Development and Characterization of a 3D Printed, Keratin-Based Hydrogel.

PubMed

Placone, Jesse K; Navarro, Javier; Laslo, Gregory W; Lerman, Max J; Gabard, Alexis R; Herendeen, Gregory J; Falco, Erin E; Tomblyn, Seth; Burnett, Luke; Fisher, John P

2017-01-01

Keratin, a naturally-derived polymer derived from human hair, is physiologically biodegradable, provides adequate cell support, and can self-assemble or be crosslinked to form hydrogels. Nevertheless, it has had limited use in tissue engineering and has been mainly used as casted scaffolds for drug or growth factor delivery applications. Here, we present and assess a novel method for the printed, sequential production of 3D keratin scaffolds. Using a riboflavin-SPS-hydroquinone (initiator-catalyst-inhibitor) photosensitive solution we produced 3D keratin constructs via UV crosslinking in a lithography-based 3D printer. The hydrogels obtained have adequate printing resolution and result in compressive and dynamic mechanical properties, uptake and swelling capacities, cytotoxicity, and microstructural characteristics that are comparable or superior to those of casted keratin scaffolds previously reported. The novel keratin-based printing resin and printing methodology presented have the potential to impact future research by providing an avenue to rapidly and reproducibly manufacture patient-specific hydrogels for tissue engineering and regenerative medicine applications.

Generating community-built tools for data sharing and analysis in environmental networks

USGS Publications Warehouse

Read, Jordan S.; Gries, Corinna; Read, Emily K.; Klug, Jennifer; Hanson, Paul C.; Hipsey, Matthew R.; Jennings, Eleanor; O'Reilley, Catherine; Winslow, Luke A.; Pierson, Don; McBride, Christopher G.; Hamilton, David

2016-01-01

Rapid data growth in many environmental sectors has necessitated tools to manage and analyze these data. The development of tools often lags behind the proliferation of data, however, which may slow exploratory opportunities and scientific progress. The Global Lake Ecological Observatory Network (GLEON) collaborative model supports an efficient and comprehensive data–analysis–insight life cycle, including implementations of data quality control checks, statistical calculations/derivations, models, and data visualizations. These tools are community-built and openly shared. We discuss the network structure that enables tool development and a culture of sharing, leading to optimized output from limited resources. Specifically, data sharing and a flat collaborative structure encourage the development of tools that enable scientific insights from these data. Here we provide a cross-section of scientific advances derived from global-scale analyses in GLEON. We document enhancements to science capabilities made possible by the development of analytical tools and highlight opportunities to expand this framework to benefit other environmental networks.