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Sample records for successful target clearance

  1. Clearance Pathways and Tumor Targeting of Imaging Nanoparticles

    PubMed Central

    Yu, Mengxiao; Zheng, Jie

    2016-01-01

    A basic understanding of how imaging nanoparticles are removed from the normal organs/tissues but retained in the tumors is important for their future clinical applications in early cancer diagnosis and therapy. In this review, we discuss current understandings of clearance pathways and tumor targeting of small-molecule- and inorganic-nanoparticle-based imaging probes with an emphasis on molecular nanoprobes, a class of inorganic nanoprobes that can escape reticuloendothelial system (RES) uptake and be rapidly eliminated from the normal tissues/organs via kidneys but can still passively target the tumor with high efficiency through the enhanced permeability permeability and retention (EPR) effect. The impact of nanoparticle design (size, shape, and surface chemistry) on their excretion, pharmacokinetics, and passive tumor targeting were quantitatively discussed. Synergetic integration of effective renal clearance and EPR effect offers a promising pathway to design low-toxicity and high-contrast-enhancement imaging nanoparticles that could meet with the clinical translational requirements of regulatory agencies. PMID:26149184

  2. Clearance Prediction of Targeted Covalent Inhibitors by In Vitro-In Vivo Extrapolation of Hepatic and Extrahepatic Clearance Mechanisms.

    PubMed

    Leung, Louis; Yang, Xin; Strelevitz, Timothy J; Montgomery, Justin; Brown, Matthew F; Zientek, Michael A; Banfield, Christopher; Gilbert, Adam M; Thorarensen, Atli; Dowty, Martin E

    2017-01-01

    The concept of target-specific covalent enzyme inhibitors appears attractive from both an efficacy and a selectivity viewpoint considering the potential for enhanced biochemical efficiency associated with an irreversible mechanism. Aside from potential safety concerns, clearance prediction of covalent inhibitors represents a unique challenge due to the inclusion of nontraditional metabolic pathways of direct conjugation with glutathione (GSH) or via GSH S-transferase-mediated processes. In this article, a novel pharmacokinetic algorithm was developed using a series of Pfizer kinase selective acrylamide covalent inhibitors based on their in vitro-in vivo extrapolation of systemic clearance in rats. The algorithm encompasses the use of hepatocytes as an in vitro model for hepatic clearance due to oxidative metabolism and GSH conjugation, and the use of whole blood as an in vitro surrogate for GSH conjugation in extrahepatic tissues. Initial evaluations with clinical covalent inhibitors suggested that the scaling algorithm developed from rats may also be useful for human clearance prediction when species-specific parameters, such as hepatocyte and blood stability and blood binding, were considered. With careful consideration of clearance mechanisms, the described in vitro-in vivo extrapolation approach may be useful to facilitate candidate optimization, selection, and prediction of human pharmacokinetic clearance during the discovery and development of targeted covalent inhibitors.

  3. Rapid clearance of Giardia lamblia DNA from the gut after successful treatment.

    PubMed

    van den Bijllaardt, W; Overdevest, I T; Buiting, A G; Verweij, J J

    2014-11-01

    To assess the time it takes for a real-time PCR to become negative after treatment of a Giardia lamblia infection, we evaluated two consecutive follow-up samples from 75 infected patients. Approximately 1 week after treatment all samples tested negative, indicating rapid clearance of parasitic DNA after successful treatment.

  4. Targeted Fcγ Receptor (FcγR)-mediated Clearance by a Biparatopic Bispecific Antibody.

    PubMed

    Kasturirangan, Srinath; Rainey, G Jonah; Xu, Linda; Wang, Xinwei; Portnoff, Alyse; Chen, Tracy; Fazenbaker, Christine; Zhong, Helen; Bee, Jared; Zeng, Zhutian; Jenne, Craig; Wu, Herren; Gao, Changshou

    2017-03-10

    Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. Although monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6-mediated signaling. The BiSAb formed large immune complexes with IL-6 that can bind Fcγ receptors on phagocytic cells and are rapidly internalized. In addition, rapid clearance of the BiSAb·IL-6 complex was observed in mice while the parental antibodies prolonged the serum half-life of IL-6. Intravital imaging of the liver in mice confirmed that the rapid clearance of these large immune complexes was associated with Fcγ receptor-dependent binding to Kupffer cells in the liver. The approach described here provides a general strategy for therapeutic antibodies with the ability to not only neutralize but also actively drive clearance of their soluble antigens.

  5. Targeted Fcγ Receptor (FcγR)-mediated Clearance by a Biparatopic Bispecific Antibody*

    PubMed Central

    Kasturirangan, Srinath; Rainey, G. Jonah; Xu, Linda; Wang, Xinwei; Portnoff, Alyse; Chen, Tracy; Fazenbaker, Christine; Zhong, Helen; Bee, Jared; Zeng, Zhutian; Jenne, Craig; Wu, Herren; Gao, Changshou

    2017-01-01

    Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. Although monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6-mediated signaling. The BiSAb formed large immune complexes with IL-6 that can bind Fcγ receptors on phagocytic cells and are rapidly internalized. In addition, rapid clearance of the BiSAb·IL-6 complex was observed in mice while the parental antibodies prolonged the serum half-life of IL-6. Intravital imaging of the liver in mice confirmed that the rapid clearance of these large immune complexes was associated with Fcγ receptor-dependent binding to Kupffer cells in the liver. The approach described here provides a general strategy for therapeutic antibodies with the ability to not only neutralize but also actively drive clearance of their soluble antigens. PMID:28100773

  6. Effects of skeleton structure on necrosis targeting and clearance properties of radioiodinated dianthrones.

    PubMed

    Zhang, Dongjian; Jiang, Cuihua; Yang, Shengwei; Gao, Meng; Huang, Dejian; Wang, Xiaoning; Shao, Haibo; Feng, Yuanbo; Sun, Ziping; Ni, Yicheng; Zhang, Jian; Yin, Zhiqi

    2016-01-01

    Necrosis avid agents (NAAs) can be used for diagnose of necrosis-related diseases, evaluation of therapeutic responses and targeted therapeutics of tumor. In order to probe into the effects of molecular skeleton structure on necrosis targeting and clearance properties of radioiodinated dianthrones, four dianthrone compounds with the same substituents but different skeletal structures, namely Hypericin (Hyp), protohypericin (ProHyp), emodin dianthrone mesomer (ED-1) and emodin dianthrone raceme (ED-2) were synthesized and radioiodinated. Then radioiodinated dianthrones were evaluated in vitro for their necrosis avidity in A549 lung cancer cells untreated and treated with H2O2. Their biodistribution and pharmacokinetic properties were determined in rat models of induced necrosis. In vitro cell assay revealed that destruction of rigid skeleton structure dramatically reduced their necrosis targeting ability. Animal studies demonstrated that destruction of rigid skeleton structure dramatically reduced the necrotic tissue uptake and speed up the clearance from the most normal tissues for the studied compounds. Among these (131)I-dianthrones, (131)I-Hyp exhibited the highest uptake and persistent retention in necrotic tissues. Hepatic infarction could be clearly visualized by SPECT/CT using (131)I-Hyp as an imaging probe. The results suggest that the skeleton structure of Hyp is the lead structure for further structure optimization of this class of NAAs.

  7. Succession Planning and Targeted Leadership Development

    ERIC Educational Resources Information Center

    Wallin, Desna; Cameron, Don W.; Sharples, Kent

    2005-01-01

    A growing number of colleges and boards of trustees are looking to the future by embracing succession planning as the key to assuring college sustainability in an environment that requires global thinking, strategic planning and political savvy. Once confined to the corporate world or to family businesses, and limited to the CEO, succession…

  8. TARGETING DEVELOPMENTAL PATHWAYS IN CHILDREN WITH CANCER: WHAT PRICE SUCCESS?

    PubMed Central

    Gore, Lia; DeGregori, James; Porter, Christopher C.

    2013-01-01

    Much of current cancer research is aimed at exploiting cancers’ molecular addictions with targeted therapeutics, with notable successes documented in clinical trials. By their nature, these agents have different side effect profiles than conventional chemotherapeutics. While very few targeted agents have attained regulatory approval for use in children, pediatric oncologists are gaining experience with these drugs, which may have unique effects, both short- and long-term, on the developing child, unrecognized in adults. This Review summarizes the rationale for targeted therapy, challenges in pediatric drug development, unique side effect profiles of targeted agents, limited data from children treated with targeted agents, as well as implications of the current knowledge and gaps thereof. The demonstrated and potential impacts of targeted therapies on normal tissue development and function are discussed. We conclude that future clinical trial design should include carefully considered assessment of developmental effects of targeted therapy, as well as informed supportive care recommendations. PMID:23369685

  9. Serum Human Chorionic Gonadotropin (β- hCG) Clearance Curves in Women with Successfully Expectantly Managed Tubal Ectopic Pregnancies: A Retrospective Cohort Study

    PubMed Central

    Helmy, Samir; Mavrelos, Dimitrios; Sawyer, Elinor; Ben-Nagi, Jara; Koch, Marianne; Day, Andrea; Jurkovic, Davor

    2015-01-01

    Objective To establish clearance curves for serum β -hCG in women with successfully expectantly managed tubal ectopic pregnancies. Design Retrospective cohort study. Non- viable tubal ectopic pregnancy was diagnosed on transvaginal ultrasound. If initial serum β hCG was less than 5000 IU/L and patients were asymptomatic, expectant management was offered. Patients underwent serial β hCG measurements until serum β hCG was less than 20 IU/l, or the urine pregnancy test was negative. Setting Early Pregnancy and Gynaecology Assessment Unit, Kings College Hospital, London (December 1998 to July 2006). Patients We included 161 women with diagnosed non-viable tubal ectopic pregnancy who underwent successful expectant management. Main outcome measure Serum β hCG level. Results Mean initial serum β- hCG was 488 IU/L (41 - 4883) and median serum β hCG clearance time was 19 days (5 - 82). The average half-life of β hCG clearance was 82.5 hours (±SD 50.2) in patients with steadily declining serum β- hCG levels compared to 106.7 hours (±SD 72.0) in patients with primarily plateauing β-hCG levels in the declining phase. However, these differences were not significant (p>0.05). Conclusion We identified a median follow-up of 19 days until serum β hCG clearance in women with tubal ectopic pregnancy and successful expectant management. Although non- significant, women with initially plateauing serum β hCG showed a longer follow-up time until clearance compared to women with steadily declining β hCG levels. This information may serve as a guideline enabling clinicians to predict the length of follow-up for women with tubal ectopic pregnancy and expectant management. PMID:26135923

  10. Targeting STAT3 in cancer: how successful are we?

    PubMed Central

    Yue, Peibin; Turkson, James

    2008-01-01

    Background Aberrant activation of the signal transducer and activator of transcription (STAT)3 occurs in many human tumors. Moreover, studies utilizing genetic and pharmacological approaches to modulate constitutive STAT3 activity have provided compelling evidence for the critical role of aberrant STAT3 activity in malignant transformation and tumor progression, and thereby validated STAT3 as a novel cancer drug target. Objective This review is intended to be a full coverage of the efforts to develop direct STAT3 inhibitors and will provide a discussion on the inhibitory modalities developed to date. Methods Review of the literature focused on the modalities and mechanisms that directly target and inhibit the STAT protein or its functions. Results/conclusion While a variety of STAT3 inhibitors have been identified that induce antitumor cell effects in vitro and in vivo, the landscape remains murky. With a few exceptions, most of the STAT3 inhibitors reported to date have not undergone an in vivo efficacy, pharmacology or toxicity testing. Also, there is no evidence, per the published literature of an impending clinical development for the few agents that were reported to exhibit in vivo efficacy. Overall, there is the need for a reassessment of the ongoing strategies to target STAT3 intended not only for refinement, but also for incorporating some new technologies to strengthen our efforts and ensure the success – sooner, rather than later – of identifying suitable anti-STAT3 agents for development into clinically useful anticancer therapeutics. PMID:19053881

  11. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model.

    PubMed

    Harvey, Christopher J; Thimmulappa, Rajesh K; Sethi, Sanjay; Kong, Xiaoni; Yarmus, Lonny; Brown, Robert H; Feller-Kopman, David; Wise, Robert; Biswal, Shyam

    2011-04-13

    Patients with chronic obstructive pulmonary disease (COPD) have innate immune dysfunction in the lung largely due to defective macrophage phagocytosis. This deficiency results in periodic bacterial infections that cause acute exacerbations of COPD, a major source of morbidity and mortality. Recent studies indicate that a decrease in Nrf2 (nuclear erythroid-related factor 2) signaling in patients with COPD may hamper their ability to defend against oxidative stress, although the role of Nrf2 in COPD exacerbations has not been determined. Here, we test whether activation of Nrf2 by the phytochemical sulforaphane restores phagocytosis of clinical isolates of nontypeable Haemophilus influenza (NTHI) and Pseudomonas aeruginosa (PA) by alveolar macrophages from patients with COPD. Sulforaphane treatment restored bacteria recognition and phagocytosis in alveolar macrophages from COPD patients. Furthermore, sulforaphane treatment enhanced pulmonary bacterial clearance by alveolar macrophages and reduced inflammation in wild-type mice but not in Nrf2-deficient mice exposed to cigarette smoke for 6 months. Gene expression and promoter analysis revealed that Nrf2 increased phagocytic ability of macrophages by direct transcriptional up-regulation of the scavenger receptor MARCO. Disruption of Nrf2 or MARCO abrogated sulforaphane-mediated bacterial phagocytosis by COPD alveolar macrophages. Our findings demonstrate the importance of Nrf2 and its downstream target MARCO in improving antibacterial defenses and provide a rationale for targeting this pathway, via pharmacological agents such as sulforaphane, to prevent exacerbations of COPD caused by bacterial infection.

  12. miR-155 suppresses bacterial clearance in Pseudomonas aeruginosa-induced keratitis by targeting Rheb.

    PubMed

    Yang, Kun; Wu, Minhao; Li, Meiyu; Li, Dandan; Peng, Anping; Nie, Xinxin; Sun, Mingxia; Wang, Jinli; Wu, Yongjian; Deng, Qiuchan; Zhu, Min; Chen, Kang; Yuan, Jin; Huang, Xi

    2014-07-01

    miR-155 (microRNA-155) is an important noncoding RNA in regulating host inflammatory responses. However, its regulatory role in ocular infection remains unclear. Our study first explored the function of miR-155 in Pseudomonas aeruginosa-induced keratitis, one of the most common sight-threatening ocular diseases. We found that miR-155 expression was enhanced in human and mouse corneas after P. aeruginosa infection and was mainly expressed in macrophages but not neutrophils. In vivo studies demonstrated that miR-155 knockout mice displayed more resistance to P. aeruginosa keratitis, with a higher inducible nitric oxide synthase level and a lower bacterial burden. More importantly, in vitro data indicated that miR-155 suppressed the macrophage-mediated bacterial phagocytosis and intracellular killing of P. aeruginosa by targeting Rheb (Ras homolog enriched in brain). To the best of our knowledge, this is the first study to explore the role of miR-155 in bacterial keratitis, which may provide a promising target for clinical treatment of P. aeruginosa keratitis and other infectious diseases.

  13. Development of a successive targeting liposome with multi-ligand for efficient targeting gene delivery

    PubMed Central

    Ma, Kun; Shen, Haijun; Shen, Song; Xie, Men; Mao, Chuanbin; Qiu, Liyan; Jin, Yi

    2012-01-01

    Background A successful gene delivery system needs to breakthrough several barriers to allow efficient transgenic expression. In the present study, successive targeting liposomes (STL) were constructed by integrating various targeting groups into a nanoparticle to address this issue. Methods Polyethylenimine (PEI) 1800-triamcinolone acetonide (TA) with nuclear targeting capability was synthesized by a two-step reaction. Lactobionic acid was connected with cholesterol to obtain a compound of [(2-lactoylamido) ethylamino]formic acid cholesterol ester (CHEDLA) with hepatocyte-targeting capability. The liposome was modified with PEI 1800-TA and CHEDLA to prepare successive targeting liposome (STL). Its physicochemical properties and transfection efficiency were investigated both in vitro and in vivo. Results The diameter of STL was approximately 100 nm with 20 mV of potential. The confocal microscopy observation and potential assay verified that lipid bilayer of STL was decorated with PEI 1800-TA. Cytotoxicity of STL was significantly lower than that of PEI 1800-TA and PEI 25K. The transfection efficiency of 10% CHEDLA STL in HepG2 cells was the higher than of the latter two with serum. Its transfection efficiency was greatly reduced with excessive free galactose, indicating that STL was absorbed via galactose receptor-mediated endocytosis. The in vivo study in mice showed that 10% CHEDLA STL had better transgenic expression in liver than the other carriers. Conclusions STL with multi-ligand was able to overcome the various barriers to target nucleus and special cells and present distinctive transgenic expression. Therefore, it has a great potential for gene therapy as a nonviral carrier. PMID:21574214

  14. Biodistribution and Renal Clearance of Biocompatible Lung Targeted Poly(ethylene glycol) (PEG) Nanogel Aggregates

    PubMed Central

    Deshmukh, Manjeet; Kutscher, Hilliard L.; Gao, Dayuan; Sunil, Vasanthi R.; Malaviya, Rama; Vayas, Kinal; Stein, Stanley; Laskin, Jeffrey D.; Laskin, Debra L.; Sinko, Patrick J.

    2013-01-01

    A novel stabilized aggregated nanogel particle (SANP) drug delivery system was prepared for injectable passive lung targeting. Gel nanoparticles (GNPs) were synthesized by irreversibly cross-linking 8 Arm PEG thiol with 1,6-Hexane-bis-vinylsulfone (HBVS) in phosphate buffer (PB, pH 7.4) containing 0.1% v/v Tween™ 80. Aggregated nanogel particles (ANPs) were generated by aggregating GNPs to micron-size, which were then stabilized (i.e., SANPs) using a PEG thiol polymer to prevent further growth-aggregation. The size of SANPs, ANPs and GNPs was analyzed using a Coulter counter and transmission electron microscopy (TEM). Stability studies of SANPs were performed at 37 °C in rat plasma, phosphate buffered saline (PBS, pH 7.4) and PB (pH 7.4). SANPs were stable in rat plasma, PBS and PB over 7 days. SANPs were covalently labeled with HiLyteFluor™750 (DYE-SANPs) to facilitate ex vivo imaging. Biodistribution of intravenous DYE-SANPs (30 μm, 4 mg in 500 μL PBS) in male Sprague-Dawley rats was compared to free HiLyteFluor™750 DYE alone (1 mg in 500 μL PBS) and determined using a Xenogen IVIS®100 Imaging System. Biodistribution studies demonstrated that free DYE was rapidly eliminated from the body by renal filtration, whereas DYE-SANPs accumulated in the lung within 30 minutes and persisted for 48 h. DYE-SANPs were enzymatically degraded to their original principle components (i.e., DYE-PEG-thiol and PEG-VS polymer) and were then eliminated from the body by renal filtration. Histological evaluation using H & E staining and broncho alveolar lavage (BAL) confirmed that these flexible SANPs were not toxic. This suggests that because of their flexible and non-toxic nature, SANPs may be a useful alternative for treating pulmonary diseases such as asthma, pneumonia, tuberculosis and disseminated lung cancer. PMID:23041417

  15. ICP-MS analysis of lanthanide-doped nanoparticles: A quantitative and multiplexing approach to investigate biodistribution, blood clearance, and targeting

    NASA Astrophysics Data System (ADS)

    Crayton, Samuel

    The rapidly progressing field of nanotechnology promises to revolutionize healthcare in the 21st century, with applications in the prevention, diagnosis, and treatment of a wide range of diseases. However, before nanoparticulate agents can be brought into clinical use, they must first be developed, optimized, and evaluated in animal models. In the typical pre-clinical paradigm, almost all of the optimization is done at the in vitro level, with only a few select agents reaching the level of animal studies. Since only one experimental nanoparticle formulation can be investigated in a single animal, and in vivo experiments have relatively higher complexity, cost, and time requirements, it is not feasible to evaluate a very large number of agents at the in vivo stage. A major drawback of this approach, however, is that in vitro assays do not always accurately predict how a nanoparticle will perform in animal studies. Therefore, a method that allows many agents to be evaluated in a single animal subject would allow for much more efficient and predictive optimization of nanoparticles. We have found that by incorporating lanthanide tracer metals into nanoparticle formulations, we are successfully able to use inductively coupled plasma mass spectrometry (ICP-MS) to quantitatively determine a nanoparticle's blood clearance kinetics, biodistribution, and tumor delivery. This approach was applied to evaluate both passive and active tumor targeting, as well as metabolically directed targeting of nanoparticles to low pH tumor microenvironments. Importantly, we found that these in vivo measurements could be made for many nanoparticle formulations simultaneously, in single animals, due to the high-order multiplexing capability of mass spectrometry. This approach allowed for efficient and reproducible comparison of performance between different nanoparticle formulations, by eliminating the effects of subject-to-subject variability. In the future, we envision that this "higher

  16. Novel antibacterial compounds and their drug targets - successes and challenges.

    PubMed

    Kaczor, Agnieszka A; Polski, Andrzej; Sobótka-Polska, Karolina; Pachuta-Stec, Anna; Makarska-Bialokoz, Magdalena; Pitucha, Monika

    2016-12-12

    Infectious diseases are one of the most important and urgent health problems in the world. According to the World Health Organization (WHO) statistics, infectious and parasitic diseases are a cause of about 16% of all deaths worldwide and over 40% of deaths in Africa. A considerable progress that has been made during last hundred years in the fight against infectious diseases, in particular bacterial infections, can be attributed mainly to three factors: (1) the general improvement of living conditions, in particular sanitation; (2) development of vaccines and (3) development of efficient antibacterial drugs. Although considerable progress in reduction of the number of cases of bacterial infections, especially in lethal cases, has been made, continued cases and outbreaks of these diseases persist, which is caused by different contributing factors. Indeed, during last sixty years antibacterial drugs were used against various infectious diseases caused by bacterial pathogens with an undoubtable success. The most fruitful period for antibiotic development lasted from 40's to 60's of the last century and resulted in the majority of antibiotics currently on the market, which were obtained by screening actinomycetes derived from soil. Although the market for antibacterial drugs is nowadays greater than 25 billion US dollars per year, novel antibacterial drugs are still demanded due to developed resistance of many pathogenic bacteria against current antibiotics. In last five years one can observe a dramatic increase in cases of resistant bacteria strains (eg. Klebsiella pneumoniae and E. coli) which are responsible for difficult to treat pneumonia and infections of urinary tract. The development of resistant bacteria strains is a side effect of antibiotic application for treatment: the infections become untreatable as a result of the existence of antibiotic-tolerant persisters. In this review, we discuss the challenges in antibacterial drug discovery, including the

  17. Successful clearance of human parainfluenza virus type 2 viraemia with intravenous ribavirin and immunoglobulin in a patient with acute myocarditis.

    PubMed

    Kalimuddin, Shirin; Sessions, October M; Hou, Yan'An; Ooi, Eng Eong; Sim, David; Cumaraswamy, Sivathasan; Tan, Teing Ee; Lai, Siang Hui; Low, Chian Yong

    2013-01-01

    Human parainfluenza virus (HPIV) infection as an aetiology of acute viral myocarditis is rare, with only few cases reported in the literature to date. Here we report a case of fulminant HPIV-2 myocarditis in a 47 year-old man with viraemia who was successfully treated with intravenous ribavirin and intravenous immunoglobulin (IVIG). There are currently no recommendations on the treatment of HPIV myocarditis. We are, to our knowledge, the first to report a patient with a documented HPIV-2 viraemia that subsequently cleared after the initiation of antiviral therapy. Although it is difficult to definitively attribute the patient's clinical improvement to ribavirin or IVIG alone, our case does suggest that clinicians may wish to consider initiating ribavirin and IVIG in patients with HPIV myocarditis and persistent viraemia not responding to supportive measures alone.

  18. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    PubMed

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-07

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

  19. Modeling the impact of hepatitis C viral clearance on end-stage liver disease in an HIV co-infected cohort with Targeted Maximum Likelihood Estimation

    PubMed Central

    Schnitzer, Mireille E; Moodie, Erica EM; van der Laan, Mark J; Platt, Robert W; Klein, Marina B

    2013-01-01

    Summary Despite modern effective HIV treatment, hepatitis C virus (HCV) co-infection is associated with a high risk of progression to end-stage liver disease (ESLD) which has emerged as the primary cause of death in this population. Clinical interest lies in determining the impact of clearance of HCV on risk for ESLD. In this case study, we examine whether HCV clearance affects risk of ESLD using data from the multicenter Canadian Co-infection Cohort Study. Complications in this survival analysis arise from the time-dependent nature of the data, the presence of baseline confounders, loss to follow-up, and confounders that change over time, all of which can obscure the causal effect of interest. Additional challenges included non-censoring variable missingness and event sparsity. In order to efficiently estimate the ESLD-free survival probabilities under a specific history of HCV clearance, we demonstrate the doubly-robust and semiparametric efficient method of Targeted Maximum Likelihood Estimation (TMLE). Marginal structural models (MSM) can be used to model the effect of viral clearance (expressed as a hazard ratio) on ESLD-free survival and we demonstrate a way to estimate the parameters of a logistic model for the hazard function with TMLE. We show the theoretical derivation of the efficient influence curves for the parameters of two different MSMs and how they can be used to produce variance approximations for parameter estimates. Finally, the data analysis evaluating the impact of HCV on ESLD was undertaken using multiple imputations to account for the non-monotone missing data. PMID:24571372

  20. Successful Targeted Treatment of Mast Cell Activation Syndrome with Tofacitinib.

    PubMed

    Afrin, Lawrence B; Fox, Roger W; Zito, Susan L; Choe, Leo; Glover, Sarah C

    2017-04-06

    Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. MCAS presents as chronic, generally inflammatory multisystem polymorbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients. Targeting commonly affected downstream effectors may yield clinical benefit independent of upstream mutational profile. For example, both activated KIT and numerous cytokine receptors activate the Janus kinases (JAKs). Thus, JAK-inhibiting therapies may be useful against the downstream inflammatory effects of MCAS. The oral JAK1/JAK3 inhibitor, tofacitinib, is currently approved for rheumatoid arthritis and is in clinical trials for other chronic inflammatory disorders. Herein, we report two MCAS patients who rapidly gained substantial symptomatic response to tofacitinib. Their improvement suggests need for further evaluation of this class of drugs in MCAS treatment. This article is protected by copyright. All rights reserved.

  1. Host-based Prophylaxis Successfully Targets Liver Stage Malaria Parasites

    PubMed Central

    Douglass, Alyse N; Kain, Heather S; Abdullahi, Marian; Arang, Nadia; Austin, Laura S; Mikolajczak, Sebastian A; Billman, Zachary P; Hume, Jen C C; Murphy, Sean C; Kappe, Stefan H I; Kaushansky, Alexis

    2015-01-01

    Eliminating malaria parasites during the asymptomatic but obligate liver stages (LSs) of infection would stop disease and subsequent transmission. Unfortunately, only a single licensed drug that targets all LSs, Primaquine, is available. Targeting host proteins might significantly expand the repertoire of prophylactic drugs against malaria. Here, we demonstrate that both Bcl-2 inhibitors and P53 agonists dramatically reduce LS burden in a mouse malaria model in vitro and in vivo by altering the activity of key hepatocyte factors on which the parasite relies. Bcl-2 inhibitors act primarily by inducing apoptosis in infected hepatocytes, whereas P53 agonists eliminate parasites in an apoptosis-independent fashion. In combination, Bcl-2 inhibitors and P53 agonists act synergistically to delay, and in some cases completely prevent, the onset of blood stage disease. Both families of drugs are highly effective at doses that do not cause substantial hepatocyte cell death in vitro or liver damage in vivo. P53 agonists and Bcl-2 inhibitors were also effective when administered to humanized mice infected with Plasmodium falciparum. Our data demonstrate that host-based prophylaxis could be developed into an effective intervention strategy that eliminates LS parasites before the onset of clinical disease and thus opens a new avenue to prevent malaria. PMID:25648263

  2. Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance

    PubMed Central

    Guo, Xiao-dan; Sun, Guang-long; Zhou, Ting-ting; Xu, Xin; Zhu, Zhi-yuan; Rukachaisirikul, Vatcharin; Hu, Li-hong; Shen, Xu

    2016-01-01

    Aim: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. Methods: Cell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APPsw and CHO-APP cells, and Aβ clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg−1·d−1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. Results: LX2343 (5–20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aβ clearance. Administration of LX2343 in APP

  3. Appropriately Targeting Group Interventions for Academic Success Adopting the Clinical Model and PAR Profiles

    ERIC Educational Resources Information Center

    Johnson, Craig W.; Johnson, Ronald; Steigman, Michael; Odo, Chioma; Vijayan, Suvendra; Tata, Devadatta V.

    2016-01-01

    Prevalence of academic risk (PAR) group profiles provide data enabling empirically based group-specialized prescriptions for targeted academic success interventions to increase student retention, completion, and graduation rates, while improving allocation of institutional resources. Postsecondary student attrition engenders student debt,…

  4. An Analytic Model for the Success Rate of a Robotic Actuator System in Hitting Random Targets

    PubMed Central

    Bradley, Stuart

    2015-01-01

    Autonomous robotic systems are increasingly being used in a wide range of applications such as precision agriculture, medicine, and the military. These systems have common features which often includes an action by an “actuator” interacting with a target. While simulations and measurements exist for the success rate of hitting targets by some systems, there is a dearth of analytic models which can give insight into, and guidance on optimization, of new robotic systems. The present paper develops a simple model for estimation of the success rate for hitting random targets from a moving platform. The model has two main dimensionless parameters: the ratio of actuator spacing to target diameter; and the ratio of platform distance moved (between actuator “firings”) to the target diameter. It is found that regions of parameter space having specified high success are described by simple equations, providing guidance on design. The role of a “cost function” is introduced which, when minimized, provides optimization of design, operating, and risk mitigation costs. PMID:26610500

  5. An Analytic Model for the Success Rate of a Robotic Actuator System in Hitting Random Targets.

    PubMed

    Bradley, Stuart

    2015-11-20

    Autonomous robotic systems are increasingly being used in a wide range of applications such as precision agriculture, medicine, and the military. These systems have common features which often includes an action by an "actuator" interacting with a target. While simulations and measurements exist for the success rate of hitting targets by some systems, there is a dearth of analytic models which can give insight into, and guidance on optimization, of new robotic systems. The present paper develops a simple model for estimation of the success rate for hitting random targets from a moving platform. The model has two main dimensionless parameters: the ratio of actuator spacing to target diameter; and the ratio of platform distance moved (between actuator "firings") to the target diameter. It is found that regions of parameter space having specified high success are described by simple equations, providing guidance on design. The role of a "cost function" is introduced which, when minimized, provides optimization of design, operating, and risk mitigation costs.

  6. siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene

    NASA Astrophysics Data System (ADS)

    Minami, Kosuke; Okamoto, Koji; Doi, Kent; Harano, Koji; Noiri, Eisei; Nakamura, Eiichi

    2014-05-01

    The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications.

  7. Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells

    SciTech Connect

    Witasp, Erika; Kupferschmidt, Natalia; Bengtsson, Linnea; Hultenby, Kjell; Smedman, Christian; Paulie, Staffan; Garcia-Bennett, Alfonso E.; Fadeel, Bengt

    2009-09-15

    Macrophage recognition and ingestion of apoptotic cell corpses, a process referred to as programmed cell clearance, is of considerable importance for the maintenance of tissue homeostasis and in the resolution of inflammation. Moreover, macrophages are the first line of defense against microorganisms and other foreign materials including particles. However, there is sparse information on the mode of uptake of engineered nanomaterials by primary macrophages. In this study, mesoporous silica particles with cubic pore geometries and covalently fluorescein-grafted particles were synthesized through a novel route, and their interactions with primary human monocyte-derived macrophages were assessed. Efficient and active internalization of mesoporous silica particles of different sizes was observed by transmission electron microscopic and flow cytometric analysis and studies using pharmacological inhibitors suggested that uptake occurred through a process of endocytosis. Moreover, uptake of silica particles was independent of serum factors. The silica particles with very high surface areas due to their porous structure did not impair cell viability or function of macrophages, including the ingestion of different classes of apoptotic or opsonized target cells. The current findings are relevant to the development of mesoporous materials for drug delivery and other biomedical applications.

  8. Clearance of Vancomycin-Resistant Enterococcus Concomitant With Administration of a Microbiota-Based Drug Targeted at Recurrent Clostridium difficile Infection

    PubMed Central

    Dubberke, Erik R.; Mullane, Kathleen M.; Gerding, Dale N.; Lee, Christine H.; Louie, Thomas J.; Guthertz, Harriet; Jones, Courtney

    2016-01-01

    Background. Vancomycin-resistant Enterococcus (VRE) is a major healthcare-associated pathogen and a well known complication among transplant and immunocompromised patients. We report on stool VRE clearance in a post hoc analysis of the Phase 2 PUNCH CD study assessing a microbiota-based drug for recurrent Clostridium difficile infection (CDI). Methods. A total of 34 patients enrolled in the PUNCH CD study received 1 or 2 doses of RBX2660 (microbiota suspension). Patients were requested to voluntarily submit stool samples at baseline and at 7, 30, and 60 days and 6 months after the last administration of RBX2660. Stool samples were tested for VRE using bile esculin azide agar with 6 µg/mL vancomycin and Gram staining. Vancomycin resistance was confirmed by Etest. Results. VRE status (at least 1 test result) was available for 30 patients. All stool samples for 19 patients (63.3%, mean age 61.7 years, 68% female) tested VRE negative. Eleven patients (36.7%, mean age 75.5 years, 64% female) were VRE positive at the first test (baseline or 7-day follow-up). Of these patients, 72.7%, n = 8 converted to negative as of the last available follow-up (30 or 60 days or 6 months). Of the other 3: 1 died (follow-up data not available); 1 patient remained positive at all follow-ups; 1 patient retested positive at 6 months with negative tests during the interim. Conclusions. Although based on a small sample size, this secondary analysis demonstrated the possibility of successfully converting a high percentage of VRE-positive patients to negative in a recurrent CDI population with RBX2660. PMID:27703995

  9. Effects of amino acids on melanoma targeting and clearance properties of Tc-99m-labeled Arg-X-Asp-conjugated α-melanocyte stimulating hormone peptides.

    PubMed

    Flook, Adam M; Yang, Jianquan; Miao, Yubin

    2013-11-14

    The purpose of this study was to examine the effects of amino acids on melanoma targeting and clearance properties of new (99m)Tc-labeled Arg-X-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-Lys-(Arg(11))CCMSH {c[Arg-Ser-Asp-DTyr-Asp]-Lys-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RNleD-Lys-(Arg(11))CCMSH, RPheD-Lys-(Arg(11))CCMSH, and RdPheD-Lys-(Arg(11))CCMSH peptides were synthesized and evaluated for their melanocortin-1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of (99m)Tc-RSD-Lys-(Arg(11))CCMSH, (99m)Tc-RFD-Lys-(Arg(11))CCMSH, and (99m)Tc-RfD-Lys-(Arg(11))CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The substitution of Gly with Ser, Phe, and dPhe increased the MC1 receptor binding affinities of the peptides, whereas the substitution of Gly with Nle decreased the MC1 receptor binding affinity of the peptide. (99m)Tc-RSD-Lys-(Arg(11))CCMSH exhibited the highest melanoma uptake (18.01 ± 4.22% ID/g) and the lowest kidney and liver uptake among these (99m)Tc-peptides. The B16/F1 melanoma lesions could be clearly visualized by SPECT/CT using (99m)Tc-RSD-Lys-(Arg(11))CCMSH as an imaging probe. It is desirable to reduce the renal uptake of (99m)Tc-RSD-Lys-(Arg(11))CCMSH to facilitate its potential therapeutic application.

  10. Hox gene Ultrabithorax regulates distinct sets of target genes at successive stages of Drosophila haltere morphogenesis.

    PubMed

    Pavlopoulos, Anastasios; Akam, Michael

    2011-02-15

    Hox genes encode highly conserved transcription factors that regionalize the animal body axis by controlling complex developmental processes. Although they are known to operate in multiple cell types and at different stages, we are still missing the batteries of genes targeted by any one Hox gene over the course of a single developmental process to achieve a particular cell and organ morphology. The transformation of wings into halteres by the Hox gene Ultrabithorax (Ubx) in Drosophila melanogaster presents an excellent model system to study the Hox control of transcriptional networks during successive stages of appendage morphogenesis and cell differentiation. We have used an inducible misexpression system to switch on Ubx in the wing epithelium at successive stages during metamorphosis--in the larva, prepupa, and pupa. We have then used extensive microarray expression profiling and quantitative RT-PCR to identify the primary transcriptional responses to Ubx. We find that Ubx targets range from regulatory genes like transcription factors and signaling components to terminal differentiation genes affecting a broad repertoire of cell behaviors and metabolic reactions. Ubx up- and down-regulates hundreds of downstream genes at each stage, mostly in a subtle manner. Strikingly, our analysis reveals that Ubx target genes are largely distinct at different stages of appendage morphogenesis, suggesting extensive interactions between Hox genes and hormone-controlled regulatory networks to orchestrate complex genetic programs during metamorphosis.

  11. Highly fluorescent resorcinarene cavitand nanocapsules with efficient renal clearance

    NASA Astrophysics Data System (ADS)

    Mahadevan, Kalpana; Patthipati, Venkata Suresh; Han, Sangbum; Swanson, R. James; Whelan, Eoin C.; Osgood, Christopher; Balasubramanian, Ramjee

    2016-08-01

    Nanomaterial based imaging approaches hold substantial promise in addressing current diagnostic and therapeutic challenges. One of the key requirements for the successful clinical translation of nanomaterials is their complete clearance from the body within a reasonable time period preferably via the renal filtration route. This article describes the synthesis of highly fluorescent, water soluble, resorcinarene cavitand nanocapsules and demonstrates their effective renal clearance in mice. The synthesis and functionalization of nanocapsules was accomplished in a one-pot operation via thiol-ene reactions without involving self-assembly, sacrificial templates or emulsions. Water soluble resorcinarene cavitand nanocapsules obtained by this approach were covalently functionalized with Alexa Fluor 750. Highly fluorescent nanocapsules with hydrodynamic diameters of 122 nm and 68 nm and extinction coefficients of 1.3 × 109 M-1 cm-1 and 1.5 × 108 M-1 cm-1 respectively were prepared by varying the reaction conditions. The in vivo biodistribution and clearance of these nanocapsules in mice followed by whole-body fluorescence imaging showed that they were both cleared renally within a few hours. Given the inherent encapsulation capabilities of nanocapsules, the renal clearance demonstrated in this work opens up new opportunities for their theranostic applications especially for targeting and treating the urinary tract.

  12. Highly fluorescent resorcinarene cavitand nanocapsules with efficient renal clearance.

    PubMed

    Mahadevan, Kalpana; Patthipati, Venkata Suresh; Han, Sangbum; Swanson, R James; Whelan, Eoin C; Osgood, Christopher; Balasubramanian, Ramjee

    2016-08-19

    Nanomaterial based imaging approaches hold substantial promise in addressing current diagnostic and therapeutic challenges. One of the key requirements for the successful clinical translation of nanomaterials is their complete clearance from the body within a reasonable time period preferably via the renal filtration route. This article describes the synthesis of highly fluorescent, water soluble, resorcinarene cavitand nanocapsules and demonstrates their effective renal clearance in mice. The synthesis and functionalization of nanocapsules was accomplished in a one-pot operation via thiol-ene reactions without involving self-assembly, sacrificial templates or emulsions. Water soluble resorcinarene cavitand nanocapsules obtained by this approach were covalently functionalized with Alexa Fluor 750. Highly fluorescent nanocapsules with hydrodynamic diameters of 122 nm and 68 nm and extinction coefficients of 1.3 × 10(9) M(-1) cm(-1) and 1.5 × 10(8) M(-1) cm(-1) respectively were prepared by varying the reaction conditions. The in vivo biodistribution and clearance of these nanocapsules in mice followed by whole-body fluorescence imaging showed that they were both cleared renally within a few hours. Given the inherent encapsulation capabilities of nanocapsules, the renal clearance demonstrated in this work opens up new opportunities for their theranostic applications especially for targeting and treating the urinary tract.

  13. 48 CFR 16.403-2 - Fixed-price incentive (successive targets) contracts.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) An initial target cost. (ii) An initial target profit. (iii) An initial profit adjustment formula to... target cost and firm target profit will be negotiated (usually before delivery or shop completion of the..., the parties negotiate the firm target cost, giving consideration to cost experience under the...

  14. 48 CFR 52.216-17 - Incentive Price Revision-Successive Targets.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... include an initial target profit of _ percent of the initial target cost. Any supplies or services that... profit, as follows: (1) The parties shall negotiate a total firm target cost, based upon the data submitted under paragraph (c) above. (2) If the total firm target cost is more than the total initial...

  15. Malaria parasite clearance.

    PubMed

    White, Nicholas J

    2017-02-23

    Following anti-malarial drug treatment asexual malaria parasite killing and clearance appear to be first order processes. Damaged malaria parasites in circulating erythrocytes are removed from the circulation mainly by the spleen. Splenic clearance functions increase markedly in acute malaria. Either the entire infected erythrocytes are removed because of their reduced deformability or increased antibody binding or, for the artemisinins which act on young ring stage parasites, splenic pitting of drug-damaged parasites is an important mechanism of clearance. The once-infected erythrocytes returned to the circulation have shortened survival. This contributes to post-artesunate haemolysis that may follow recovery in non-immune hyperparasitaemic patients. As the parasites mature Plasmodium vivax-infected erythrocytes become more deformable, whereas Plasmodium falciparum-infected erythrocytes become less deformable, but they escape splenic filtration by sequestering in venules and capillaries. Sequestered parasites are killed in situ by anti-malarial drugs and then disintegrate to be cleared by phagocytic leukocytes. After treatment with artemisinin derivatives some asexual parasites become temporarily dormant within their infected erythrocytes, and these may regrow after anti-malarial drug concentrations decline. Artemisinin resistance in P. falciparum reflects reduced ring stage susceptibility and manifests as slow parasite clearance. This is best assessed from the slope of the log-linear phase of parasitaemia reduction and is commonly measured as a parasite clearance half-life. Pharmacokinetic-pharmacodynamic modelling of anti-malarial drug effects on parasite clearance has proved useful in predicting therapeutic responses and in dose-optimization.

  16. Controls Considerations for Turbine Active Clearance Control

    NASA Technical Reports Server (NTRS)

    Melcher, Kevin J.

    2004-01-01

    This presentation discusses active control of turbine tip clearance from a control systems perspective. It is a subset of charts that were presented at the 2003 meeting of the International Society of Air Breathing Engines which was held August 31 through September 5 in Cleveland, Ohio. The associated reference paper is cited at the end of the presentation. The presentation describes active tip clearance control research being conducted by NASA to improve turbine engine systems. The target application for this effort is commercial aircraft engines. However, it is believed that the technologies developed as part of this research will benefit a broad spectrum of current and future turbomachinery. The first part of the presentation discusses the concept of tip clearance, problems associated with it, and the benefits of controlling it. It lays out a framework for implementing tip clearance controls that enables the implementation to progress from purely analytical to hardware-in-the-loop to fully experimental. And it briefly discusses how the technologies developed will be married to the previously described ACC Test Rig for hardware-in-the-loop demonstrations. The final portion of the presentation, describes one of the key technologies in some detail by presenting equations and results for a functional dynamic model of the tip clearance phenomena. As shown, the model exhibits many of the clearance dynamics found in commercial gas turbine engines. However, initial attempts to validate the model identified limitations that are being addressed to make the model more realistic.

  17. The remarkable success of adaptive cosine estimator in hyperspectral target detection

    NASA Astrophysics Data System (ADS)

    Manolakis, D.; Pieper, M.; Truslow, E.; Cooley, T.; Brueggeman, M.; Lipson, S.

    2013-05-01

    A challenging problem of major importance in hyperspectral imaging applications is the detection of subpixel targets of military and civilian interest. The background clutter surrounding the target, acts as an interference source that simultaneously distorts the target spectrum and reduces its strength. Two additional limiting factors are the spectral variability of the background clutter and the spectral variability of the target. Since a result in applied statistics is only as reliable as the assumptions from which it is derived, it is important to investigate whether the basic assumptions used for the derivation of matched filter and adaptive cosine estimator algorithms are a reasonable description of the physical situation. Careful examination of the linear signal model used to derive these algorithms and the replacement signal model, which is a more realistic model for subpixel targets, reveals a serious discrepancy between modeling assumptions and the physical world. Despite this discrepancy and additional mismatches between assumed and actual signal and clutter models, the adaptive cosine estimator shows an amazing effectiveness in practical target detection applications. The objective of this paper is an attempt to explain this unbelievable effectiveness using a combination of classical statistical detection theory, geometrical interpretations, and a novel realistic performance prediction model for the adaptive cosine estimator.

  18. Assessing the Effectiveness of Targeted Intrusive Advising and Student Success Using an Early Intervention Program

    ERIC Educational Resources Information Center

    Poole, Jesse

    2015-01-01

    The institution in this study is a medium size, public liberal arts institution located in a rural setting. At the beginning of Fall 2012 term, 5,366 undergraduate and 922 graduate students were enrolled in the university's ten-week quarter system. In an attempt to increase student success and retention, the institution implemented a student…

  19. Speaking Spontaneously in the Modern Foreign Languages Classroom: Tools for Supporting Successful Target Language Conversation

    ERIC Educational Resources Information Center

    Christie, Colin

    2016-01-01

    This article reports on the findings of a study into the conditions which promote spontaneous learner talk in the target language in the modern foreign languages (MFL) classroom. A qualitative case study approach was adopted. French lessons, with school students aged 11-16 years old, were observed and analysed with the aim of identifying tools and…

  20. Cimetidine impairs nitrazepam clearance.

    PubMed

    Ochs, H R; Greenblatt, D J; Gugler, R; Müntefering, G; Locniskar, A; Abernethy, D R

    1983-08-01

    The effect of cimetidine on hepatic clearance of the benzodiazepine derivative nitrazepam was evaluated in healthy subjects. Six received a single 5- or 10-mg oral nitrazepam dose in the drug-free state and again with therapeutic cimetidine doses. Nitrazepam kinetics were determined from multiple serum concentrations measured during the 72 hr after each dose. Cimetidine had no effect on nitrazepam absorption kinetics, since peak serum nitrazepam concentration and time of peak concentration were not altered. Cimetidine did not alter nitrazepam volume of distribution, but cimetidine consistently reduced nitrazepam clearance, from a mean of 1.41 ml/min/kg in the control state to 1.17 ml/min/kg during cimetidine treatment. This resulted in prolongation of nitrazepam elimination t1/2 from 22.2 to 27.8 hr. Thus the ability of cimetidine to impair drug oxidation in man extends to the capacity for clearance of nitrazepam, a compound biotransformed mainly by nitroreduction.

  1. Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

    PubMed Central

    Nunes, Renata Rachide; Costa, Marina dos Santos; Santos, Bianca dos Reis; da Fonseca, Amanda Luisa; Ferreira, Lorena Sales; Chagas, Rafael Cesar Russo; da Silva, Alisson Marques; Varotti, Fernando de Pilla; Taranto, Alex Gutterres

    2016-01-01

    The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays. PMID:27982302

  2. Targeted delivery as key for the success of small osteoinductive molecules.

    PubMed

    Balmayor, Elizabeth R

    2015-11-01

    Molecules such as growth factors, peptides and small molecules can guide cellular behavior and are thus important for tissue engineering. They are rapidly emerging as promising compounds for the regeneration of tissues of the musculoskeletal system. Growth factors have disadvantages such as high cost, short half-life, supraphysiological amounts needed, etc. Therefore, small molecules may be an alternative. These molecules have been discovered using high throughput screening. Small osteoinductive molecules exhibit several advantages over growth factors owing to their small sizes, such as high stability and non-immunogenicity. These molecules may stimulate directly signaling pathways that are important for osteogenesis. However, systemic application doesn't induce osteogenesis in most cases. Therefore, local administration is needed. This may be achieved by using a bone graft material providing additional osteoconductive properties. These graft materials can also act by themselves as a delivery matrix for targeted and local delivery. Furthermore, vascularization is necessary in the process of osteogenesis. Many of the small molecules are also capable of promoting vascularization of the tissue to be regenerated. Thus, in this review, special attention is given to molecules that are capable of inducing both angiogenesis and osteogenesis simultaneously. Finally, more recent preclinical and clinical uses in bone regeneration of those molecules are described, highlighting the needs for the clinical translation of these promising compounds.

  3. THE ELM SURVEY. III. A SUCCESSFUL TARGETED SURVEY FOR EXTREMELY LOW MASS WHITE DWARFS

    SciTech Connect

    Brown, Warren R.; Kenyon, Scott J.; Kilic, Mukremin; Allende Prieto, Carlos E-mail: skenyon@cfa.harvard.edu E-mail: callende@iac.es

    2012-01-10

    Extremely low mass (ELM) white dwarfs (WDs) with masses < 0.25 M{sub Sun} are rare objects that result from compact binary evolution. Here, we present a targeted spectroscopic survey of ELM WD candidates selected by color. The survey is 71% complete and has uncovered 18 new ELM WDs. Of the seven ELM WDs with follow-up observations, six are short-period binaries and four have merger times less than 5 Gyr. The most intriguing object, J1741+6526, likely has either a pulsar companion or a massive WD companion making the system a possible supernova Type Ia or an Ia progenitor. The overall ELM survey has now identified 19 double degenerate binaries with <10 Gyr merger times. The significant absence of short orbital period ELM WDs at cool temperatures suggests that common envelope evolution creates ELM WDs directly in short period systems. At least one-third of the merging systems are halo objects, thus ELM WD binaries continue to form and merge in both the disk and the halo.

  4. Advanced Thermal HPT Clearance Control

    NASA Technical Reports Server (NTRS)

    WojciechVoytek, Sak

    2006-01-01

    OBJECTIVE: Develop a fast acting HPT Active Clearance Control System to improve engine efficiency and reduce emissions CHALLENGE: Reduction of HPT blade clearance throughout engine operation System complexity, reliability and cost must remain comparable or surpass today s engines Reduced clearance may increase possibility of rubs

  5. Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities

    PubMed Central

    Blunt, Matthew D.; Ward, Stephen G.

    2012-01-01

    The predominant expression of the γ and δ isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some success in developing PI3Kδ inhibitors, progress in developing selective inhibitors of PI3Kγ has been rather disappointing. This has prompted the search for alternative targets with which to modulate PI3K signaling specifically in the immune system. One such target is the SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1) which de-phosphorylates PI(3,4,5)P3 at the D5 position of the inositol ring to create PI(3,4)P2. In this article, we first describe the current state of PI3K isoform-selective inhibitor development. We then focus on the structure of SHIP-1 and its function in the immune system. Finally, we consider the current state of development of small molecule compounds that potently and selectively modulate SHIP activity and which offer novel opportunities to manipulate PI3K mediated signaling in the immune system. PMID:22876243

  6. Rapid blood clearance of biotinylated IgG after infusion of avidin

    SciTech Connect

    Sinitsyn, V.V.; Mamontova, A.G.; Checkneva, Y.Y.; Shnyra, A.A.; Domogatsky, S.P.

    1989-01-01

    The techniques of immunotherapy and radioimmunoimaging suffer from the problem of background: intravenously injected antibodies remain in the circulation much longer than it is necessary for effective binding to the target. Various approaches, including the postinjection of second antibodies, were explored to overcome the problem with some success. The phenomenon of a 100-fold more rapid blood clearance of biotinylated immunoglobulins after postinjection of an equivalent dose of avidin is described. The concentration of /sup 125/I-labeled biotinylated IgG in the circulation of rats slowly decreased to 20% of initial in 24 hr. Avidin injection at any interval during this period induced 90-95% reduction of radioactivity in blood in 15 min. Up to 70% of the radioactivity was recovered in the liver. Avidin-induced blood clearance of biotinylated immunoglobulins may find applications in immunotherapy and radio- or nuclear magnetic resonance immunoimaging.

  7. Site clearance working group

    SciTech Connect

    1997-03-01

    The Gulf of Mexico and Louisiana continue to be areas with a high level of facility removal, and the pace of removal is projected to increase. Regulations were promulgated for the Gulf of Mexico and Louisiana requiring that abandoned sites be cleared of debris that could interfere with fishing and shrimping activities. The site clearance regulations also required verification that the sites were clear. Additionally, government programs were established to compensate fishermen for losses associated with snagging their equipment on oil and gas related objects that remained on the water bottoms in areas other than active producing sites and sites that had been verified as clear of obstructions and snags. The oil and gas industry funds the compensation programs. This paper reviews the regulations and evolving operating practices in the Gulf of Mexico and Louisiana where site clearance and fisherman`s gear compensation regulations have been in place for a number of years. Although regulations and guidelines may be in place elsewhere in the world, this paper focuses on the Gulf of Mexico and Louisiana. Workshop participants are encouraged to bring up international issues during the course of the workshop. Additionally, this paper raises questions and focuses on issues that are of concern to the various Gulf of Mexico and Louisiana water surface and water bottom stakeholders. This paper does not have answers to the questions or issues. During the workshop participants will debate the questions and issues in an attempt to develop consensus opinions and/or make suggestions that can be provided to the appropriate organizations, both private and government, for possible future research or policy adjustments. Site clearance and facility removal are different activities. Facility removal deals with removal of the structures used to produce oil and gas including platforms, wells, casing, piles, pipelines, well protection structures, etc.

  8. Toward a Fast-Response Active Turbine Tip Clearance Control

    NASA Technical Reports Server (NTRS)

    Melcher, Kevin J.; Kypuros, Javier A.

    2003-01-01

    This paper describes active tip clearance control research being conducted by NASA to improve turbine engine systems. The target application for this effort is commercial aircraft engines. However, technologies developed for clearance control can benefit a broad spectrum of current and future turbomachinery. The first portion of the paper addresses the research from a programmatic viewpoint. Recent studies that provide motivation for the work, identification of key technologies, and NASA's plan for addressing deficiencies in the technologies are discussed. The later portion of the paper drills down into one of the key technologies by presenting equations and results for a preliminary dynamic model of the tip clearance phenomena.

  9. Parallel computation safety analysis irradiation targets fission product molybdenum in neutronic aspect using the successive over-relaxation algorithm

    NASA Astrophysics Data System (ADS)

    Susmikanti, Mike; Dewayatna, Winter; Sulistyo, Yos

    2014-09-01

    One of the research activities in support of commercial radioisotope production program is a safety research on target FPM (Fission Product Molybdenum) irradiation. FPM targets form a tube made of stainless steel which contains nuclear-grade high-enrichment uranium. The FPM irradiation tube is intended to obtain fission products. Fission materials such as Mo99 used widely the form of kits in the medical world. The neutronics problem is solved using first-order perturbation theory derived from the diffusion equation for four groups. In contrast, Mo isotopes have longer half-lives, about 3 days (66 hours), so the delivery of radioisotopes to consumer centers and storage is possible though still limited. The production of this isotope potentially gives significant economic value. The criticality and flux in multigroup diffusion model was calculated for various irradiation positions and uranium contents. This model involves complex computation, with large and sparse matrix system. Several parallel algorithms have been developed for the sparse and large matrix solution. In this paper, a successive over-relaxation (SOR) algorithm was implemented for the calculation of reactivity coefficients which can be done in parallel. Previous works performed reactivity calculations serially with Gauss-Seidel iteratives. The parallel method can be used to solve multigroup diffusion equation system and calculate the criticality and reactivity coefficients. In this research a computer code was developed to exploit parallel processing to perform reactivity calculations which were to be used in safety analysis. The parallel processing in the multicore computer system allows the calculation to be performed more quickly. This code was applied for the safety limits calculation of irradiated FPM targets containing highly enriched uranium. The results of calculations neutron show that for uranium contents of 1.7676 g and 6.1866 g (× 106 cm-1) in a tube, their delta reactivities are the still

  10. Application of clearance automatic laser inspection system to clearance measurement of concrete waste

    SciTech Connect

    Sasaki, Michiya; Ogino, Haruyuki; Hattori, Takatoshi

    2007-07-01

    Recently, the Clearance Automatic Laser Inspection System (CLALIS) has been developed for the clearance measurement of metal scraps. It utilizes three-dimensional (3D) laser scanning, y-ray measurement and Monte Carlo calculation, and has outstanding detection ability. For the clearance measurement of concrete segments, the effect of background (BG) gamma rays from natural radionuclides in the measurement target, such as K-40 and the radioactive decay products of Th-232 and U-238, should be compensated for to ensure adequate waste management. Since NE102A plastic scintillation detectors are used for y-ray measurement in CLALIS, it is impossible to distinguish between count rates of natural radionuclides and contaminants on the basis of gamma-ray energy information. To apply CLALIS to the clearance measurement of concrete segments, the original activity evaluation method was improved by adding a new compensation procedure. In this procedure, BG count rate due to natural radionuclides is estimated by a Monte Carlo calculation with pre-analyzed data of a representative sample of the measurement target. The activity concentration of natural radionuclides in concrete differs markedly depending on the production location of its components, such as cement and aggregates. In this study, using six mock concrete waste samples, which were composed of cement and fine aggregate from various production locations, the accuracy of BG compensation was experimentally estimated. In addition, the accuracy of calibration for concrete waste was also estimated using a number of mock concrete segments of small and large triangular prisms. By considering the uncertainties of BG compensation and calibration, the detection limit of CLALIS for concrete waste was estimated. As a result, it was revealed that CLALIS could be applied to the clearance measurement of concrete segments when the mass of the measurement target is greater than approximately 1.1 kg and the key radionuclide is Co-60

  11. Turbomachinery Clearance Control

    NASA Technical Reports Server (NTRS)

    Chupp, Raymond E.; Hendricks, Robert C.; Lattime, Scott B.; Steinetz, Bruce M.; Aksit, Mahmut F.

    2007-01-01

    Controlling interface clearances is the most cost effective method of enhancing turbomachinery performance. Seals control turbomachinery leakages, coolant flows and contribute to overall system rotordynamic stability. In many instances, sealing interfaces and coatings are sacrificial, like lubricants, giving up their integrity for the benefit of the component. They are subjected to abrasion, erosion, oxidation, incursive rubs, foreign object damage (FOD) and deposits as well as extremes in thermal, mechanical, aerodynamic and impact loadings. Tribological pairing of materials control how well and how long these interfaces will be effective in controlling flow. A variety of seal types and materials are required to satisfy turbomachinery sealing demands. These seals must be properly designed to maintain the interface clearances. In some cases, this will mean machining adjacent surfaces, yet in many other applications, coatings are employed for optimum performance. Many seals are coating composites fabricated on superstructures or substrates that are coated with sacrificial materials which can be refurbished either in situ or by removal, stripping, recoating and replacing until substrate life is exceeded. For blade and knife tip sealing an important class of materials known as abradables permit blade or knife rubbing without significant damage or wear to the rotating element while maintaining an effective sealing interface. Most such tip interfaces are passive, yet some, as for the high-pressure turbine (HPT) case or shroud, are actively controlled. This work presents an overview of turbomachinery sealing. Areas covered include: characteristics of gas and steam turbine sealing applications and environments, benefits of sealing, types of standard static and dynamics seals, advanced seal designs, as well as life and limitations issues.

  12. Identifying Effective Enzyme Activity Targets for Recombinant Class I and Class II Collagenase for Successful Human Islet Isolation

    PubMed Central

    Balamurugan, Appakalai N.; Green, Michael L.; Breite, Andrew G.; Loganathan, Gopalakrishnan; Wilhelm, Joshua J.; Tweed, Benjamin; Vargova, Lenka; Lockridge, Amber; Kuriti, Manikya; Hughes, Michael G.; Williams, Stuart K.; Hering, Bernhard J.; Dwulet, Francis E.; McCarthy, Robert C.

    2016-01-01

    Background Isolation following a good manufacturing practice-compliant, human islet product requires development of a robust islet isolation procedure where effective limits of key reagents are known. The enzymes used for islet isolation are critical but little is known about the doses of class I and class II collagenase required for successful islet isolation. Methods We used a factorial approach to evaluate the effect of high and low target activities of recombinant class I (rC1) and class II (rC2) collagenase on human islet yield. Consequently, 4 different enzyme formulations with divergent C1:C2 collagenase mass ratios were assessed, each supplemented with the same dose of neutral protease. Both split pancreas and whole pancreas models were used to test enzyme targets (n = 20). Islet yield/g pancreas was compared with historical enzymes (n = 42). Results Varying the Wunsch (rC2) and collagen degradation activity (CDA, rC1) target dose, and consequently the C1:C2 mass ratio, had no significant effect on tissue digestion. Digestions using higher doses of Wunsch and CDA resulted in comparable islet yields to those obtained with 60% and 50% of those activities, respectively. Factorial analysis revealed no significant main effect of Wunsch activity or CDA for any parameter measured. Aggregate results from 4 different collagenase formulations gave 44% higher islet yield (>5000 islet equivalents/g) in the body/tail of the pancreas (n = 12) when compared with those from the same segment using a standard natural collagenase/protease mixture (n = 6). Additionally, islet yields greater than 5000 islet equivalents/g pancreas were also obtained in whole human pancreas. Conclusions A broader C1:C2 ratio can be used for human islet isolation than has been used in the past. Recombinant collagenase is an effective replacement for the natural enzyme and we have determined that high islet yield can be obtained even with low doses of rC1:rC2, which is beneficial for the survival

  13. Parallel computation safety analysis irradiation targets fission product molybdenum in neutronic aspect using the successive over-relaxation algorithm

    SciTech Connect

    Susmikanti, Mike; Dewayatna, Winter; Sulistyo, Yos

    2014-09-30

    One of the research activities in support of commercial radioisotope production program is a safety research on target FPM (Fission Product Molybdenum) irradiation. FPM targets form a tube made of stainless steel which contains nuclear-grade high-enrichment uranium. The FPM irradiation tube is intended to obtain fission products. Fission materials such as Mo{sup 99} used widely the form of kits in the medical world. The neutronics problem is solved using first-order perturbation theory derived from the diffusion equation for four groups. In contrast, Mo isotopes have longer half-lives, about 3 days (66 hours), so the delivery of radioisotopes to consumer centers and storage is possible though still limited. The production of this isotope potentially gives significant economic value. The criticality and flux in multigroup diffusion model was calculated for various irradiation positions and uranium contents. This model involves complex computation, with large and sparse matrix system. Several parallel algorithms have been developed for the sparse and large matrix solution. In this paper, a successive over-relaxation (SOR) algorithm was implemented for the calculation of reactivity coefficients which can be done in parallel. Previous works performed reactivity calculations serially with Gauss-Seidel iteratives. The parallel method can be used to solve multigroup diffusion equation system and calculate the criticality and reactivity coefficients. In this research a computer code was developed to exploit parallel processing to perform reactivity calculations which were to be used in safety analysis. The parallel processing in the multicore computer system allows the calculation to be performed more quickly. This code was applied for the safety limits calculation of irradiated FPM targets containing highly enriched uranium. The results of calculations neutron show that for uranium contents of 1.7676 g and 6.1866 g (× 10{sup 6} cm{sup −1}) in a tube, their delta

  14. 30 CFR 57.11010 - Stairstep clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Stairstep clearance. 57.11010 Section 57.11010... Escapeways Travelways-Surface and Underground § 57.11010 Stairstep clearance. Vertical clearance above stair... to indicate an impaired clearance....

  15. 30 CFR 57.11008 - Restricted clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Restricted clearance. 57.11008 Section 57.11008... Escapeways Travelways-Surface and Underground § 57.11008 Restricted clearance. Where restricted clearance creates a hazard to persons, the restricted clearance shall be conspicuously marked....

  16. 30 CFR 56.11010 - Stairstep clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Stairstep clearance. 56.11010 Section 56.11010... Stairstep clearance. Vertical clearance above stair steps shall be a minimum of seven feet, or suitable warning signs or similar devices shall be provided to indicate an impaired clearance....

  17. 28 CFR 524.74 - Activities clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Activities clearance. 524.74 Section 524... clearance. (a) Except as provided for in paragraph (b) of this section, the Warden is the clearance... Security cases. Central Office Inmate Monitoring Section staff shall be the clearance authority on...

  18. 30 CFR 56.11008 - Restricted clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Restricted clearance. 56.11008 Section 56.11008 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE... Restricted clearance. Where restricted clearance creates a hazard to persons, the restricted clearance...

  19. Success of the International Year of the Planet Earth through Targeted High-impact Programs at the American Geological Institute

    NASA Astrophysics Data System (ADS)

    Leahy, P.

    2007-12-01

    The American Geological Institute (AGI) is one of the 12 founding partners of the International Year of the Planet Earth (IYPE) and as such AGI serves on its governing board. AGI is a nonprofit federation of 44 geoscientific and professional associations that represents more than 120,000 geologists, geophysicists, and other earth scientists. AGI provides information services to geoscientists, serves as a voice of shared interests in our profession, plays a major role in strengthening geoscience education, and strives to increase public awareness of the vital role the geosciences play in society's use of resources, resilience to natural hazards, and the health of the environment. The outreach and educational opportunities afforded by IYPE provide AGI with an international venue to promote the role of the geosciences in the daily life of society. AGI's successful release of the 4-part television series entitled Faces of Earth done in partnership with the Discovery Communications is a hallmark example of an outreach product that is technically accurate but designed to engage the non-scientific audience in the wonderment of our science. The series focuses on building the planet, shaping the planet, assembling America, and the human world. Custom short cuts have been produced for special purposes and one of these may be used as part of an IYPE-launch event in Europe. AGI's news magazine, Geotimes will highlight appropriate IYPE events to increase the awareness of the American geoscience community. In addition, Geotimes will promote IYPE by using its logo routinely and through publishing advertisements reminding its professional and public readership of the importance of the IYPE triennium. Similarly, as part of AGI's K-12 educational efforts and teacher training and through its development of Earth Science Week materials, the goals, accomplishments, and importance of IYPE will be incorporated into the targeted educational audiences. IYPE activities will be highlighted

  20. Targeted irradiation of biological cells using an ion microprobe - Why a small beam spot is not sufficient for success

    NASA Astrophysics Data System (ADS)

    Fischer, B. E.; Voss, K.-O.; Du, G.

    2009-06-01

    When people plan to adapt their ion microprobe for the targeted irradiation of biological cells, they often claim that they expect a targeting accuracy in the range of their beam spot diameter, because they assume that reaching a sub-μm beam spot is the most difficult part of the job. Although many microprobes have now a beam spot diameter of some hundred nano-meters or less, nobody reached a targeting accuracy below 1 μm. Besides obvious reasons, like mechanical or thermal instabilities, there is a more difficult problem to overcome: one still needs a light microscope to locate both the microbeam and the cells to be irradiated, and there are various light-optical effects, which can give misleading information about the position of the beam and the cells.

  1. Tumor Presence Induces Global Immune Changes and Enhances Nanoparticle Clearance.

    PubMed

    Kai, Marc P; Brighton, Hailey E; Fromen, Catherine A; Shen, Tammy W; Luft, J Christopher; Luft, Yancey E; Keeler, Amanda W; Robbins, Gregory R; Ting, Jenny P Y; Zamboni, William C; Bear, James E; DeSimone, Joseph M

    2016-01-26

    Long-circulating nanoparticles are essential for increasing tumor accumulation to provide therapeutic efficacy. While it is known that tumor presence can alter the immune system, very few studies have explored this impact on nanoparticle circulation. In this report, we demonstrate how the presence of a tumor can change the local and global immune system, which dramatically increases particle clearance. We found that tumor presence significantly increased clearance of PRINT hydrogel nanoparticles from the circulation, resulting in increased accumulation in the liver and spleen, due to an increase in M2-like macrophages. Our findings highlight the need to better understand interactions between immune status and nanoparticle clearance, and suggest that further consideration of immune function is required for success in preclinical and clinical nanoparticle studies.

  2. The scoring bias in reverse docking and the score normalization strategy to improve success rate of target fishing

    PubMed Central

    Luo, Qiyao; Zhao, Liang; Hu, Jianxing; Jin, Hongwei; Liu, Zhenming; Zhang, Liangren

    2017-01-01

    Target fishing often relies on the use of reverse docking to identify potential target proteins of ligands from protein database. The limitation of reverse docking is the accuracy of current scoring funtions used to distinguish true target from non-target proteins. Many contemporary scoring functions are designed for the virtual screening of small molecules without special optimization for reverse docking, which would be easily influenced by the properties of protein pockets, resulting in scoring bias to the proteins with certain properties. This bias would cause lots of false positives in reverse docking, interferring the identification of true targets. In this paper, we have conducted a large-scale reverse docking (5000 molecules to 100 proteins) to study the scoring bias in reverse docking by DOCK, Glide, and AutoDock Vina. And we found that there were actually some frequency hits, namely interference proteins in all three docking procedures. After analyzing the differences of pocket properties between these interference proteins and the others, we speculated that the interference proteins have larger contact area (related to the size and shape of protein pockets) with ligands (for all three docking programs) or higher hydrophobicity (for Glide), which could be the causes of scoring bias. Then we applied the score normalization method to eliminate this scoring bias, which was effective to make docking score more balanced between different proteins in the reverse docking of benchmark dataset. Later, the Astex Diver Set was utilized to validate the effect of score normalization on actual cases of reverse docking, showing that the accuracy of target prediction significantly increased by 21.5% in the reverse docking by Glide after score normalization, though there was no obvious change in the reverse docking by DOCK and AutoDock Vina. Our results demonstrate the effectiveness of score normalization to eliminate the scoring bias and improve the accuracy of target

  3. Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency.

    PubMed

    Reddy, Kavya; Cusack, Corey L; Nnah, Israel C; Khayati, Khoosheh; Saqcena, Chaitali; Huynh, Tuong B; Noggle, Scott A; Ballabio, Andrea; Dobrowolski, Radek

    2016-03-08

    Attenuated auto-lysosomal system has been associated with Alzheimer disease (AD), yet all underlying molecular mechanisms leading to this impairment are unknown. We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1) is dysregulated in cells deficient in presenilin, a protein associated with AD. In these cells, mTORC1 is constitutively tethered to lysosomal membranes, unresponsive to starvation, and inhibitory to TFEB-mediated clearance due to a reduction in Sestrin2 expression. Normalization of Sestrin2 levels through overexpression or elevation of nuclear calcium rescued mTORC1 tethering and initiated clearance. While CLEAR network attenuation in vivo results in buildup of amyloid, phospho-Tau, and neurodegeneration, presenilin-knockout fibroblasts and iPSC-derived AD human neurons fail to effectively initiate autophagy. These results propose an altered mechanism for nutrient sensing in presenilin deficiency and underline an importance of clearance pathways in the onset of AD.

  4. Predictors of Success in Implementing HIV Prevention in Rural America: A State-Level Structural Factor Analysis of HIV Prevention Targeting Men who have Sex with Men

    PubMed Central

    Horvath, Keith J.

    2013-01-01

    Relatively few studies have examined the impact of modifying structural factors on HIV prevention efforts in the United States despite their high potential for lowering HIV prevalence rates. The aim of this study was to identify state-level characteristics of successful HIV prevention implementation. Structured interviews with 73 key informants in 13 rural states identified ‘more successful’ and ‘less successful’ states in HIV prevention. States were compared on demographic, religious, gay community, and funding variables. The 7 more successful states had both a wider variety and more MSM-targeted interventions. Overall funding, degree of epidemic, and “ruralness” were not significantly associated with success. Rather, successful states had less religious and Evangelical Protestant adherents and more ‘gay community’ infrastructure. They also spent a greater proportion of funds contracting community-based organizations and on MSMtargeted programming. Success in HIV prevention varies across rural states. Key demographic, social and economic indicators distinguish success in HIV prevention. PMID:17440806

  5. Clearance of von Willebrand factor.

    PubMed

    Denis, Cécile V; Christophe, Olivier D; Oortwijn, Beatrijs D; Lenting, Peter J

    2008-02-01

    The life cycle of von Willebrand factor (VWF) comprises a number of distinct steps, ranging from the controlled expression of the VWF gene in endothelial cells and megakaryocytes to the removal of VWF from the circulation. The various aspects of VWF clearance have been the objects of intense research in the last few years, stimulated by observations that VWF clearance is a relatively common component of the pathogenesis of type 1 von Willebrand disease (VWD). Moreover, improving the survival of VWF is now considered as a viable therapeutic strategy to prolong the half-life of factor VIII in order to optimise treatment of haemophilia A. The present review aims to provide an overview of recent findings with regard to the molecular basis of VWF clearance. A number of parameters have been identified that influence VWF clearance, including its glycosylation profile and a number of VWF missense mutations. In addition, in-vivo studies have been used to identify cells that contribute to the catabolism of VWF, providing a starting point for the identification of receptors that mediate the cellular uptake of VWF. Finally, we discuss recent data describing chemically modification of VWF as an approach to prolong the half-life of the VWF/FVIII complex.

  6. Aerial Refueling Clearance Initiation Request

    DTIC Science & Technology

    2016-07-14

    and receiver agencies. The AR Clearance Initiation Request document recognizes the requirement for definitive aerial refueling agreements between...include directions for the development or content of these contractual agreements. 15. –SUBJECT TERMS See Document Terms and Definitions , Page 8 16...7 Terms and Definitions

  7. Myeloid cell turnover and clearance

    PubMed Central

    Janssen, William J.; Bratton, Donna L.; Jakubzick, Claudia V.; Henson, Peter M.

    2016-01-01

    Given the dual and intrinsically contradictory roles for myeloid cells in both protective and yet also damaging effects of inflammatory and immunological processes we suggest that it is important to consider the mechanisms and circumstances by which these cells are removed, either in the normal unchallenged state or during inflammation or disease. In this essay we address these subjects from a conceptual perspective, focusing as examples on four main myeloid cell types (neutrophils, monocytes, macrophages and myeloid dendritic cells) and their clearance from the circulation or from naïve and inflamed tissues. While the primary clearance process appears to involve endocytic uptake into macrophages, various tissue cell types can also recognize and remove dying cells though their overall quantitative contribution is unclear. In fact, surprisingly, given the wealth of study in this area over the last 30 years, our conclusion is that we are still challenged with substantial lack of mechanistic and regulatory understanding of when, how and by what mechanisms migratory myeloid cells come to die, are recognized as needing to be removed and indeed the precise processes of uptake of either the intact or fragmented cells. This reflects the extreme complexity and inherent redundancy of the clearance processes and argues for substantial investigative effort in this arena. In addition, it leads us to a sense that approaches to significant therapeutic modulation of selective myeloid clearance is still a long way off. PMID:27837740

  8. Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients.

    PubMed

    Miyagawa, Maiko; Naito, Takehiko; Nishio, Shin-ya; Kamatani, Naoyuki; Usami, Shin-ichi

    2013-01-01

    Target exon resequencing using Massively Parallel DNA Sequencing (MPS) is a new powerful strategy to discover causative genes in rare Mendelian disorders such as deafness. We attempted to identify genomic variations responsible for deafness by massive sequencing of the exons of 112 target candidate genes. By the analysis of 216randomly selected Japanese deafness patients (120 early-onset and 96 late-detected), who had already been evaluated for common genes/mutations by Invader assay and of which 48 had already been diagnosed, we efficiently identified causative mutations and/or mutation candidates in 57 genes. Approximately 86.6% (187/216) of the patients had at least one mutation. Of the 187 patients, in 69 the etiology of the hearing loss was completely explained. To determine which genes have the greatest impact on deafness etiology, the number of mutations was counted, showing that those in GJB2 were exceptionally higher, followed by mutations in SLC26A4, USH2A, GPR98, MYO15A, COL4A5 and CDH23. The present data suggested that targeted exon sequencing of selected genes using the MPS technology followed by the appropriate filtering algorithm will be able to identify rare responsible genes including new candidate genes for individual patients with deafness, and improve molecular diagnosis. In addition, using a large number of patients, the present study clarified the molecular epidemiology of deafness in Japanese. GJB2 is the most prevalent causative gene, and the major (commonly found) gene mutations cause 30-40% of deafness while the remainder of hearing loss is the result of various rare genes/mutations that have been difficult to diagnose by the conventional one-by-one approach. In conclusion, target exon resequencing using MPS technology is a suitable method to discover common and rare causative genes for a highly heterogeneous monogenic disease like hearing loss.

  9. Lessons From HIV-1 Gene Therapy in Humanized Mice: Is Targeting Viral Entry the Road to Success?

    PubMed

    Petit, Nicolas; Marodon, Gilles

    2016-01-01

    Immunodeficient mice reconstituted with human CD4(+) T cells, which can be achieved either by transfer of mature cells or immature progenitors, represent the only animal model to study HIV-1 infection of human lymphocytes in vivo. However, the immunocompromised status of most of these models currently rule out their use for vaccine studies. Nevertheless, the model might be ideally suited for HIV-1 gene therapy studies since eliciting an efficient anti-viral immune response is not the primary end-point. Rather, HIV-1 gene therapy should protect CD4(+) T cells from HIV-1- induced deletion and/or reduced viral replication. Here, we describe recent advancements in the field of HIV-1 gene therapy, focusing on tools and targets validated in various models of humanized mice. From the analysis of this literature, it appears that strategies targeting viral entry, by means of neutralizing antibodies or fusion inhibitors, are the most promising so far. Indeed, strategies targeting viral entry have moved to the clinic with encouraging results. Thus, humanized mice should be considered as the prime model to devise the safer and most effective HIV-1 gene therapy strategy.

  10. Microwave Blade Tip Clearance System: An Update

    NASA Technical Reports Server (NTRS)

    Geisheimer, Jon

    2006-01-01

    Newer engines use compressor bleed air and a model to close clearances open loop. Measuring clearances and closing the control loop can add additional efficiencies. Tip clearance control has been identified as a key technology for future engines Additional benefits in prognostics, NSMS, and condition-based maintenance. In the HPT for every 1 mil improvement in clearance: a) SFC decreases 0.1%; and b) EGT margin increases 1 C.

  11. Simulation of bronchial mucociliary clearance of insoluble particles by computational fluid and particle dynamics methods.

    PubMed

    Farkas, Arpád; Szöke, István

    2013-08-01

    For a correct assessment of health consequences of inhaled aerosols as a function of dose, whether for environmental, occupational or therapeutic agents, knowledge of their deposition distribution in the respiratory tract and subsequent clearance is important. The objective of this study is to model particle clearance at bronchial airway bifurcation level and to analyze the combined effect of deposition and clearance. For this purpose, a numerical model has been implemented. Air and mucus flow fields were computed in a model bronchial airway bifurcation. Inhaled particles with 1 and 10 µm aerodynamic diameters were tracked to determine deposition and clearance patterns. Simulation results revealed the existence of a slow clearance zone around the peak of the airway bifurcation causing delayed clearance of the particles depositing or entering here. Particles clearing up from the deeper airways and crossing the studied bifurcation do not accumulate in this zone, because of their tendency to avoid it. The average residence time of these particles was around 20 min independently of particle size (whether it is 1 or 10 µm). However, as a result of the superposition of deposition and clearance mechanisms, the final spatial distribution of particles deposited primarily in the target bifurcation is size dependent, because deposition is size specific. Although deposition density of particles deposited in the slow clearance area is one-two orders of magnitude higher than the average deposition density, these values are reduced by clearance by the factors of 4-7, depending on the particle size and the surface area of the selected slow clearance zone. In conclusion, although particle deposition is inhomogeneous, clearance can significantly decrease the degree of spatial non-uniformity of the particles. Therefore, for a correct assessment of doses at local levels, it is important to consider both deposition and clearance. Although future research may overwrite some of

  12. 14 CFR 23.925 - Propeller clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ..., an airplane with an aft mounted propeller must be designed such that the propeller will not contact...) Structural clearance. There must be— (1) At least one inch radial clearance between the blade tips and the... least one-half inch longitudinal clearance between the propeller blades or cuffs and stationary parts...

  13. 14 CFR 23.925 - Propeller clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., an airplane with an aft mounted propeller must be designed such that the propeller will not contact...) Structural clearance. There must be— (1) At least one inch radial clearance between the blade tips and the... least one-half inch longitudinal clearance between the propeller blades or cuffs and stationary parts...

  14. 14 CFR 23.925 - Propeller clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ..., an airplane with an aft mounted propeller must be designed such that the propeller will not contact...) Structural clearance. There must be— (1) At least one inch radial clearance between the blade tips and the... least one-half inch longitudinal clearance between the propeller blades or cuffs and stationary parts...

  15. 14 CFR 23.925 - Propeller clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., an airplane with an aft mounted propeller must be designed such that the propeller will not contact...) Structural clearance. There must be— (1) At least one inch radial clearance between the blade tips and the... least one-half inch longitudinal clearance between the propeller blades or cuffs and stationary parts...

  16. 29 CFR 1917.113 - Clearance heights.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Clearance heights. 1917.113 Section 1917.113 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) MARINE TERMINALS Terminal Facilities § 1917.113 Clearance heights. Clearance heights shall...

  17. 22 CFR 16.6 - Security clearances.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Security clearances. 16.6 Section 16.6 Foreign Relations DEPARTMENT OF STATE PERSONNEL FOREIGN SERVICE GRIEVANCE SYSTEM § 16.6 Security clearances. The agencies shall use their best endeavors to expedite security clearances whenever necessary to ensure a...

  18. 22 CFR 16.6 - Security clearances.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Security clearances. 16.6 Section 16.6 Foreign Relations DEPARTMENT OF STATE PERSONNEL FOREIGN SERVICE GRIEVANCE SYSTEM § 16.6 Security clearances. The agencies shall use their best endeavors to expedite security clearances whenever necessary to ensure a...

  19. 22 CFR 16.6 - Security clearances.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Security clearances. 16.6 Section 16.6 Foreign Relations DEPARTMENT OF STATE PERSONNEL FOREIGN SERVICE GRIEVANCE SYSTEM § 16.6 Security clearances. The agencies shall use their best endeavors to expedite security clearances whenever necessary to ensure a...

  20. 22 CFR 16.6 - Security clearances.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Security clearances. 16.6 Section 16.6 Foreign Relations DEPARTMENT OF STATE PERSONNEL FOREIGN SERVICE GRIEVANCE SYSTEM § 16.6 Security clearances. The agencies shall use their best endeavors to expedite security clearances whenever necessary to ensure a...

  1. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  2. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  3. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  4. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  5. Security Clearances: Consideration of Sexual Orientation in the Clearance Process.

    DTIC Science & Technology

    1995-03-01

    Until about 1991, when agencies began to change their security policies and practices regarding sexual orientation , there were a number of documented...cases where defense civilian or contractor employees’ security clearances were denied or revoked because of their sexual orientation . However our...forward and discuss their cases. Notwithstanding these limitations, our work disclosed no evidence that sexual orientation has been used as a criterion

  6. Removal - An alternative to clearance

    SciTech Connect

    Feinhals, J.; Kelch, A.; Kunze, V.

    2007-07-01

    This presentation shows the differences between the application of clearance and removal, both being procedures for materials leaving radiation protection areas permanently. The differentiation will be done on the basis of the German legislation but may be also applicable for other national legislation. For clearance in Germany two basic requirements must be given, i.e. that the materials are activated or contaminated and that they result from the licensed use or can be assigned to the scope of the license. Clearance needs not to be applied to objects in Germany which are to be removed only temporarily from controlled areas with the purpose of repair or reuse in other controlled areas. In these cases only the requirements of contamination control apply. In the case of removal it must either be proved by measurements that the relevant materials are neither activated nor contaminated or that the materials result from areas where activation or contamination is impossible due to the operational history considering operational procedures and events. If the material is considered neither activated nor contaminated there is no need for a clearance procedure. Therefore, these materials can be removed from radiation protection areas and the removal is in the responsibility of the licensee. Nevertheless, the removal procedure and the measuring techniques to be applied for the different types of materials need an agreement from the competent authority. In Germany a maximum value of 10% of the clearance values has been established in different licenses as a criterion for the application of removal. As approximately 2/3 of the total mass of a nuclear power plant is not expected to be contaminated or activated there is a need for such a procedure of removal for this non contaminated material without any regulatory control especially in the case of decommissioning. A remarkable example is NPP Stade where in the last three years more than 8600 Mg were disposed of by removal and

  7. Successful Use of Targeted Temperature Management After Repair of Myocardial Rupture from Blunt Chest Trauma: A Case Report.

    PubMed

    Choi, Wook-Jin; Kim, Yun Seok; Hong, Jung Seok; Kim, Jeong Won

    2017-03-01

    Targeted temperature management (TTM) improves survival and neurological outcome after nontraumatic cardiac arrest. However, TTM is not used widely after traumatic cardiac arrest because of concerns that it might exacerbate bleeding. We report the use of postarrest TTM after repair of blunt myocardial rupture. A 48-year-old man was admitted after being rescued from a major traffic accident by the local emergency service. Focused sonography showed pericardial fluid without cardiac tamponade. Computed tomography showed a large hematoma in the anterior mediastinum associated with hemopericardium. The patient developed cardiac arrest during the operative preparations. Repeat bedside sonography revealed a large pericardial effusion and signs of cardiac tamponade. Spontaneous circulation was restored after ultrasound-guided pericardiocentesis. His Glasgow Coma Scale score was 3. The patient was transported promptly to the operating room and underwent median sternotomy without cardiopulmonary bypass. A rupture of the junction of the superior vena cava/right atrium and left atrial appendage was detected and was closed by direct suturing. Immediately after return to the intensive care unit, we performed TTM (target body temperature 34.5°C) using a surface-cooling device at 4 hours postarrest. TTM was maintained for 24 hours and controlled gradual rewarming was then initiated. He regained consciousness 36 hours postrewarming with limited speech ability. The patient recovered with no further cardiac events and was discharged 3 weeks after admission, with no other serious complications. The patient was neurologically intact (cerebral performance category 1) at 6 months of follow-up. This case demonstrates the potential benefit and applicability of postarrest TTM in patients after repair of blunt myocardial rupture.

  8. Integrated electromagnetic data investigation of a Mesozoic CO2 storage target reservoir-cap-rock succession, Svalbard

    NASA Astrophysics Data System (ADS)

    Beka, Thomas I.; Senger, Kim; Autio, Uula A.; Smirnov, Maxim; Birkelund, Yngve

    2017-01-01

    Recently acquired time-domain electromagnetic (TEM) and magnetotelluric (MT) data sets are utilized in the first electromagnetic (EM) characterization of a geological CO2 storage target site in Adventdalen, Arctic Norway. Combining the two EM data sets enabled to resolve the electrical resistivity structure of the target site better than either of the methods alone. 2D inverting the MT data in the audio period interval (0.003-1 s) with supporting input derived from the TEM data (0.01-10 ms) provided a geologically meaningful resistivity model that included information not previously evident from existing seismic and borehole data. The ca. 1.8 × 1 km 2D resistivity model displays a laterally constrained highly conductive anomaly (ca. 10 Ω m) at about 400-500 m depth, where reflectors of a parallel seismic section are concealed and core samples indicate a highly fractured décollement zone formed during Paleogene compression. The base of the permafrost is imaged at ca. 200 m depth. Synthetic inversion tests, however, suggest that this may be exaggerated by tens of meters, due to a thin conductive layer present approximately between 10 and 25 m depth. The resistivity model does not give indication for a fluid pathway we can connect to leakage, in line with water injection and leak-off tests in the reservoir and cap-rock, both of which indicate a sealing shale-dominated cap-rock separating an over-pressured compartment above the sealing shale from a severely under-pressured reservoir interval. The results we present indicate the advantage of integrating EM exploration techniques in a CO2 reservoir-cap-rock study to obtain a more complete picture.

  9. Aerial Refueling Clearance Process Guide

    DTIC Science & Technology

    2014-08-21

    08-2014 2. REPORT TYPE Guidance Document 3. DATES COVERED 2008-2014 4. TITLE AND SUBTITLE Aerial Refueling Clearance Process Guide Attachment: Aerial...ATP-3.3.4.2 covers general operational procedures for AR and national/organizational SRDs cover data and procedures specific to their AR platforms...Receptacle, Probe/Drogue, and BDA Kit. 3.1.3 The items for assessment consideration cover several areas of interface for both the tanker and the

  10. Patient Age, Ethnicity, Medical History, and Risk Factor Profile, but Not Drug Insurance Coverage, Predict Successful Attainment of Glycemic Targets

    PubMed Central

    Teoh, Hwee; Braga, Manoela F.B.; Casanova, Amparo; Drouin, Denis; Goodman, Shaun G.; Harris, Stewart B.; Langer, Anatoly; Tan, Mary K.; Ur, Ehud; Yan, Andrew T.; Zinman, Bernard; Leiter, Lawrence A.

    2010-01-01

    OBJECTIVE To identify factors in patients with type 2 diabetes and A1C >7.0% associated with attainment of A1C ≤7.0%. RESEARCH DESIGN AND METHODS We used a prospective registry of 5,280 Canadian patients in primary care settings enrolled in a 12-month glycemic pharmacotherapy optimization strategy based on national guidelines. RESULTS At close out, median A1C was 7.1% (vs. 7.8% at baseline) with 48% of subjects achieving A1C ≤7.0% (P < 0.0001). Older patients of Asian or black origin, those with longer diabetes duration, those with lower baseline A1C, BMI, LDL cholesterol, and blood pressure, and those on angiotensin receptor blockers and a lower number of antihyperglycemic agents, were more likely to achieve A1C ≤7.0% at some point during the study (all P < 0.0235). Access to private versus public drug coverage did not impact glycemic target realization. CONCLUSIONS Patient demography, cardiometabolic health, and ongoing pharmacotherapy, but not access to private drug insurance coverage, contribute to the care gap in type 2 diabetes. PMID:20823344

  11. Prediction of drug clearance in children.

    PubMed

    Foissac, Frantz; Bouazza, Naïm; Valade, Elodie; De Sousa Mendes, Mailys; Fauchet, Floris; Benaboud, Sihem; Hirt, Déborah; Tréluyer, Jean-Marc; Urien, Saïk

    2015-07-01

    The pediatric population is often exposed to drugs without sufficient knowledge about pharmacokinetics. The prediction of accurate clearance values in children, especially in neonates and infants, will improve the rational in dosing decisions. Drug clearances from birth to adulthood were compiled after a systematic review of pharmacokinetic reports. The analysis was performed using NONMEM. Clearance predictions were then evaluated by external validation. Prediction errors were also compared with those obtained from weight-based allometric scaling and physiologically based clearance (PBCL) models. For the analysis, 17 and 15 drugs were used for model building and external validation, respectively. A model based on the adult drug clearance value and taking into account both weight and age was retained. Age-related maturation of clearance reached 90% of the adult value within 1.5 years of life. For children less than 2 years old, allometric scaling alone systematically overestimated clearances. Accounting for age improved the clearance prediction in the 6 months-2 years age group (prediction error < 25%). Predictions obtained from the PBCL approach were close to our results. This analysis established a single equation using the adult clearance value as well as individual age and weight to predict drug clearance in children older than 6 months.

  12. Metabolism of nanomaterials in vivo: blood circulation and organ clearance.

    PubMed

    Wang, Bing; He, Xiao; Zhang, Zhiyong; Zhao, Yuliang; Feng, Weiyue

    2013-03-19

    Before researchers apply nanomaterials (NMs) in biomedicine, they need to understand the blood circulation and clearance profile of these materials in vivo. These qualities determine the balance between nanomaterial-induced activity and unwanted toxicity. NMs have heterogeneous characteristics: they combine the bulk properties of solids with the mobility of molecules, and their highly active contact interfaces exhibit diverse functionalities. Any new and unexpected circulation features and clearance patterns are of great concern in toxicological studies and pharmaceutical screens. A number of studies have reported that NMs can enter the bloodstream directly during their application or indirectly via inhalation, ingestion, and dermal exposure. Due to the small size of NMs, the blood can then transport them throughout the circulation and to many organs where they can be stored. In this Account, we discuss the blood circulation and organ clearance patterns of NMs in the lung, liver, and kidney. The circulation of NMs in bloodstream is critical for delivery of inhalable NMs to extrapulmonary organs, the delivery of injectable NMs, the dynamics of tissue redistribution, and the overall targeting of drug carriers to specific cells and organs. The lung, liver, and kidney are the major distribution sites and target organs for NMs exposure, and the clearance patterns of NMs in these organs are critical for understanding the in vivo fate of NMs. Current studies suggest that multiple factors control the circulation and organ clearance of NMs. The size, shape, surface charge, surface functional groups, and aspect ratio of NMs as well as tissue microstructures strongly influence the circulation of NMs in bloodstream, their site-specific extravasation, and their clearance profiles within organs. Therefore structure design and surface modification can improve biocompatibility, regulate the in vivo metabolism, and reduce the toxicity of NMs. The biophysicochemical interactions

  13. CRISPR-targeted genome editing of mesenchymal stem cell-derived therapies for type 1 diabetes: a path to clinical success?

    PubMed

    Gerace, Dario; Martiniello-Wilks, Rosetta; Nassif, Najah Therese; Lal, Sara; Steptoe, Raymond; Simpson, Ann Margaret

    2017-03-09

    Due to their ease of isolation, differentiation capabilities, and immunomodulatory properties, the therapeutic potential of mesenchymal stem cells (MSCs) has been assessed in numerous pre-clinical and clinical settings. Currently, whole pancreas or islet transplantation is the only cure for people with type 1 diabetes (T1D) and, due to the autoimmune nature of the disease, MSCs have been utilised either natively or transdifferentiated into insulin-producing cells (IPCs) as an alternative treatment. However, the initial success in pre-clinical animal models has not translated into successful clinical outcomes. Thus, this review will summarise the current state of MSC-derived therapies for the treatment of T1D in both the pre-clinical and clinical setting, in particular their use as an immunomodulatory therapy and targets for the generation of IPCs via gene modification. In this review, we highlight the limitations of current clinical trials of MSCs for the treatment of T1D, and suggest the novel clustered regularly interspaced short palindromic repeat (CRISPR) gene-editing technology and improved clinical trial design as strategies to translate pre-clinical success to the clinical setting.

  14. Elastic clearance change in axisymmetric shearing process

    NASA Astrophysics Data System (ADS)

    Yoshida, Yoshinori

    2016-10-01

    An axisymmetric shearing experiment is conducted for a sheet of low carbon steel and stainless steel. Elastic change in the clearance between punch and die is measured. The increase of the clearance in shearing is confirmed and the influence of sheared material's flow stress on the clearance change is shown. Finite element analysis (FEA) of shearing with Gurson-Tvergaard-Needlman model (GTN model) is conducted for shearing of the carbon steels with rigid tools as a numerical experiment. Burr height is predicted in the FEA and the result is compared with the experimental result. In addition, the influence of the clearance on stress state in the material is investigated.

  15. Intelligent Engine Systems: HPT Clearance Control

    NASA Technical Reports Server (NTRS)

    2008-01-01

    The Advanced Thermally Actuated Clearance Control System underwent several studies. Improved flow path isolation quantified what can be gained by making the HPT case nearly adiabatic. The best method of heat transfer was established, and finally two different borrowed air cooling circuits were evaluated to be used for the HPT Active Clearance Control System.

  16. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... following: (a) Ground clearance. There must be a clearance of at least seven inches (for each airplane with nose wheel landing gear) or nine inches (for each airplane with tail wheel landing gear) between each propeller and the ground with the landing gear statically deflected and in the level takeoff, or...

  17. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... following: (a) Ground clearance. There must be a clearance of at least seven inches (for each airplane with nose wheel landing gear) or nine inches (for each airplane with tail wheel landing gear) between each propeller and the ground with the landing gear statically deflected and in the level takeoff, or...

  18. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... following: (a) Ground clearance. There must be a clearance of at least seven inches (for each airplane with nose wheel landing gear) or nine inches (for each airplane with tail wheel landing gear) between each propeller and the ground with the landing gear statically deflected and in the level takeoff, or...

  19. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Clearance certificate. 122.77 Section 122.77 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Documents Required for Clearance and Permission To Depart;...

  20. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Clearance certificate. 122.77 Section 122.77 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Documents Required for Clearance and Permission To Depart;...

  1. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Clearance certificate. 122.77 Section 122.77 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Documents Required for Clearance and Permission To Depart;...

  2. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 1 2013-04-01 2013-04-01 false Clearance certificate. 122.77 Section 122.77 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Documents Required for Clearance and Permission To Depart;...

  3. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Clearance certificate. 122.77 Section 122.77 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Documents Required for Clearance and Permission To Depart;...

  4. 15 CFR 752.15 - Export clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Export clearance. 752.15 Section 752... OF INDUSTRY AND SECURITY, DEPARTMENT OF COMMERCE EXPORT ADMINISTRATION REGULATIONS SPECIAL COMPREHENSIVE LICENSE § 752.15 Export clearance. (a) Shipper's Export Declaration (SED) or Automated...

  5. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... nose wheel landing gear) or nine inches (for each airplane with tail wheel landing gear) between each propeller and the ground with the landing gear statically deflected and in the level takeoff, or taxiing... the corresponding landing gear strut bottomed. (b) Water clearance. There must be a clearance of...

  6. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  7. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  8. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  9. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  10. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  11. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  12. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  13. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  14. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  15. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  16. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  17. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  18. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  19. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  20. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  1. 30 CFR 56.11010 - Stairstep clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Stairstep clearance. 56.11010 Section 56.11010 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE... warning signs or similar devices shall be provided to indicate an impaired clearance....

  2. 30 CFR 56.11010 - Stairstep clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Stairstep clearance. 56.11010 Section 56.11010 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE... warning signs or similar devices shall be provided to indicate an impaired clearance....

  3. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves

    PubMed Central

    Gomez-Sanchez, Jose A.; Carty, Lucy; Iruarrizaga-Lejarreta, Marta; Palomo-Irigoyen, Marta; Varela-Rey, Marta; Griffith, Megan; Hantke, Janina; Macias-Camara, Nuria; Azkargorta, Mikel; Aurrekoetxea, Igor; De Juan, Virginia Gutiérrez; Jefferies, Harold B.J.; Aspichueta, Patricia; Elortza, Félix; Aransay, Ana M.; Martínez-Chantar, María L.; Baas, Frank; Mato, José M.; Mirsky, Rhona

    2015-01-01

    Although Schwann cell myelin breakdown is the universal outcome of a remarkably wide range of conditions that cause disease or injury to peripheral nerves, the cellular and molecular mechanisms that make Schwann cell–mediated myelin digestion possible have not been established. We report that Schwann cells degrade myelin after injury by a novel form of selective autophagy, myelinophagy. Autophagy was up-regulated by myelinating Schwann cells after nerve injury, myelin debris was present in autophagosomes, and pharmacological and genetic inhibition of autophagy impaired myelin clearance. Myelinophagy was positively regulated by the Schwann cell JNK/c-Jun pathway, a central regulator of the Schwann cell reprogramming induced by nerve injury. We also present evidence that myelinophagy is defective in the injured central nervous system. These results reveal an important role for inductive autophagy during Wallerian degeneration, and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease. PMID:26150392

  4. Experimental and Clinical Evaluation of Predilution and Postdilution Continuous Venovenous Hemofiltration on Clearance Characteristics.

    PubMed

    Chihara, Shinya; Masuda, Yoshiki; Yamakage, Michiaki

    We compared the clearance characteristics of low-to-high molecular weight substances during pre-and postdilution continuous venovenous hemofiltration (CVVH) in experimental and clinical conditions. Experimental circuits for pre- and postdilution CVVH were prepared using a test solution containing creatinine (110 Da), inulin (5,000 Da), interleukin (IL)-8 (8,000 Da), IL-6 (22,000 Da), and tumor necrosis factor (TNF)-α (51,000 Da). Quantity of test solution flow and filtration flow (QF) were set to 150 ml/min and 10, 20, and 35 ml/min, respectively. Clinical CVVH settings were blood flow (QB): 150 ml/min and QF: 35 ml/min. Samples were obtained from pre- and posthemofilters, and clearance of target substances was determined during pre- and postdilution CVVH in experimental and clinical conditions. Clearance changed according to QF during both pre- and postdilution CVVH in the experiment. Clearance of creatinine, inulin (experiment only), and IL-8 during postdilution CVVH was superior to that during predilution CVVH. Few differences were seen in clearance of IL-6 and TNF-α between dilution methods in the experiment and clinical practice. Clearance of IL-8 and IL-6 decreased during postdilution CVVH over 24 hr but did not change during predilution CVVH in clinical practice. Predilution CVVH is useful for stable cytokine clearance in septic patients with acute kidney injury.

  5. The kidneys play a central role in the clearance of rhGH in rats.

    PubMed

    Vestergaard, Bill; Thygesen, Peter; Kreilgaard, Mads; Fels, Johannes Josef; Lykkesfeldt, Jens; Agersø, Henrik

    2016-04-30

    The kidneys are thought to play an important role in the clearance of recombinant human growth hormone (rhGH), but the relative importance is not clear. Obtaining knowledge of clearance pathway is an important prerequisite for the development of new long acting growth hormone analogues targeted at treatment of patients with growth hormone disorders. The purpose of this study was to investigate the relative importance of the kidneys in the clearance of rhGH. The study employed a newly validated nephrectomy rat model and a population based pharmacokinetic approach to assess renal clearance of rhGH in non-anesthetized rats, anesthetized rats and in nephrectomized anesthetized rats. Clearance in non-anesthetized rats was 290 ml/h/kg. This was reduced to 185 ml/h/kg by anesthesia and further reduced to 18 ml/h/kg by nephrectomy. As nephrectomy was able to reduce clearance with 90%, we conclude that renal clearance plays a pivotal role in the elimination of rhGH in rats.

  6. Nasal mucociliary clearance after radiation therapy.

    PubMed

    Stringer, S P; Stiles, W; Slattery, W H; Krumerman, J; Parsons, J T; Mendenhall, W M; Cassisi, N J

    1995-04-01

    Irradiation has been demonstrated to cause decreased mucociliary clearance in animal models. We sought to verify this effect clinically by using the saccharin transport test to evaluate nasal mucociliary clearance in 9 patients previously treated with radiation therapy to the nasal cavity. The patients also completed a questionnaire examining the prevalence of nasal symptoms before and after radiation therapy. Patients who received radiation therapy had no clearance of saccharin from the nasal cavity at a minimum of 20 minutes. The controls had a median clearance time of 5 minutes. The patients noted a higher prevalence of nasal congestion, drainage, and facial pain after radiation therapy. This study demonstrates that radiation therapy to the nasal cavity causes a decrease in nasal mucociliary clearance. This alteration should be considered when selecting therapy for malignancies in the nasal area.

  7. 19 CFR 4.61 - Requirements for clearance.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... optional clearance locations. (b) When clearance required. Under certain circumstances, American vessels.... While American vessels transporting unentered foreign merchandise must fully comply with usual clearance procedures, American vessels carrying no unentered foreign merchandise but that have in-bond...

  8. 77 FR 21989 - Critical Infrastructure Private Sector Clearance Program Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-12

    ... SECURITY Critical Infrastructure Private Sector Clearance Program Request AGENCY: National Protection and... information provided. SUPPLEMENTARY INFORMATION: The Critical Infrastructure Private Sector Clearance Program (PSCP) sponsors clearances for private sector partners who are responsible for critical...

  9. Alternative Mechanisms of Respiratory Syncytial Virus Clearance in Perforin Knockout Mice Lead to Enhanced Disease

    PubMed Central

    Aung, Sandra; Rutigliano, John A.; Graham, Barney S.

    2001-01-01

    Virus-specific cytotoxic T lymphocytes are key effectors for the clearance of virus-infected cells and are required for the normal clearance of respiratory syncytial virus (RSV) in mice. Although perforin/granzyme-mediated lysis of infected cells is thought to be the major molecular mechanism used by CD8+ cytotoxic T lymphocytes for elimination of virus, its role in RSV has not been reported. Here, we show that viral clearance in perforin knockout (PKO) mice is slightly delayed but that both PKO and wild-type mice clear virus by day 10, suggesting an alternative mechanism of RSV clearance. Effector T cells from the lungs of both groups of mice were shown to lyse Fas (CD95)-overexpressing target cells in greater numbers than target cells expressing low levels of Fas, suggesting that Fas ligand (CD95L)-mediated target cell lysis was occurring in vivo. This cell lysis was associated with a delay in RSV-induced disease in PKO mice compared to the time of disease onset for wild-type controls, which correlated with increased and prolonged production of gamma interferon and tumor necrosis factor alpha levels in PKO mice. We conclude that while perforin is not necessary for the clearance of primary RSV infection, the use of alternative CTL target cell killing mechanisms is less efficient and can lead to enhanced disease. PMID:11559824

  10. Advanced optical blade tip clearance measurement system

    NASA Technical Reports Server (NTRS)

    Ford, M. J.; Honeycutt, R. E.; Nordlund, R. E.; Robinson, W. W.

    1978-01-01

    An advanced electro-optical system was developed to measure single blade tip clearances and average blade tip clearances between a rotor and its gas path seal in an operating gas turbine engine. This system is applicable to fan, compressor, and turbine blade tip clearance measurement requirements, and the system probe is particularly suitable for operation in the extreme turbine environment. A study of optical properties of blade tips was conducted to establish measurement system application limitations. A series of laboratory tests was conducted to determine the measurement system's operational performance characteristics and to demonstrate system capability under simulated operating gas turbine environmental conditions. Operational and environmental performance test data are presented.

  11. Autophagy enhances bacterial clearance during P. aeruginosa lung infection.

    PubMed

    Junkins, Robert D; Shen, Ann; Rosen, Kirill; McCormick, Craig; Lin, Tong-Jun

    2013-01-01

    Pseudomonas aeruginosa is an opportunistic bacterial pathogen which is the leading cause of morbidity and mortality among cystic fibrosis patients. Although P. aeruginosa is primarily considered an extacellular pathogen, recent reports have demonstrated that throughout the course of infection the bacterium acquires the ability to enter and reside within host cells. Normally intracellular pathogens are cleared through a process called autophagy which sequesters and degrades portions of the cytosol, including invading bacteria. However the role of autophagy in host defense against P. aeruginosa in vivo remains unknown. Understanding the role of autophagy during P. aeruginosa infection is of particular importance as mutations leading to cystic fibrosis have recently been shown to cause a blockade in the autophagy pathway, which could increase susceptibility to infection. Here we demonstrate that P. aeruginosa induces autophagy in mast cells, which have been recognized as sentinels in the host defense against bacterial infection. We further demonstrate that inhibition of autophagy through pharmacological means or protein knockdown inhibits clearance of intracellular P. aeruginosa in vitro, while pharmacologic induction of autophagy significantly increased bacterial clearance. Finally we find that pharmacological manipulation of autophagy in vivo effectively regulates bacterial clearance of P. aeruginosa from the lung. Together our results demonstrate that autophagy is required for an effective immune response against P. aeruginosa infection in vivo, and suggest that pharmacological interventions targeting the autophagy pathway could have considerable therapeutic potential in the treatment of P. aeruginosa lung infection.

  12. RAB24 facilitates clearance of autophagic compartments during basal conditions

    PubMed Central

    Ylä-Anttila, Päivi; Mikkonen, Elisa; Happonen, Kaisa E; Holland, Petter; Ueno, Takashi; Simonsen, Anne; Eskelinen, Eeva-Liisa

    2015-01-01

    RAB24 belongs to a family of small GTPases and has been implicated to function in autophagy. Here we confirm the intracellular localization of RAB24 to autophagic vacuoles with immuno electron microscopy and cell fractionation, and show that prenylation and guanine nucleotide binding are necessary for the targeting of RAB24 to autophagic compartments. Further, we show that RAB24 plays a role in the maturation and/or clearance of autophagic compartments under nutrient-rich conditions, but not during short amino acid starvation. Quantitative electron microscopy shows an increase in the numbers of late autophagic compartments in cells silenced for RAB24, and mRFP-GFP-LC3 probe and autophagy flux experiments indicate that this is due to a hindrance in their clearance. Formation of autophagosomes is shown to be unaffected by RAB24-silencing with siRNA. A defect in aggregate clearance in the absence of RAB24 is also shown in cells forming polyglutamine aggregates. This study places RAB24 function in the termination of the autophagic process under nutrient-rich conditions. PMID:26325487

  13. Comparison of Two Alternate Methods for Tracking Toe Clearance

    NASA Technical Reports Server (NTRS)

    Miller, Christopher A.; Feiveson, Alan H.; Bloomberg, Jacob J.

    2007-01-01

    Analyses of toe clearance during the swing phase of locomotion has often been utilized in determining a subject s propensity to trip while either walking or stepping over an obstacle. In the literature, toe clearance has been studied using a marker on the superior aspect of the second toe (rtoe), a marker on the lateral aspect of the fifth metatarsal head (mth5), or a virtual marker positioned at the anterior tip of the toe (vtoe). The purpose of this study was to compute toe clearance and associated parameters using a fifth metatarsal marker and a virtual toe marker, and compare the results with those of the standard toe marker. Subjects walked on a motorized treadmill at five different speeds while performing a visual acuity task at two separate target distances (ten 60-second trials). The minimum vertical height (TCl) was determined for each stride, along with its point of occurence in the gait cycle, and the angles of the foot and ankle at that time. A regression analysis was performed on the vtoe and mth5 results versus rtoe individually. For all TCl parameters, the mth5 marker did not correlate well with rtoe; the vtoe marker showed better agreement. Most importantly, the mth5 marker predicted a later occurence of TCl than rtoe and vtoe - thereby missing the most dangerous point in swing phase for a trip. From this analysis, the vtoe marker proved to be a better analog to rtoe than mth5, especially for determining a subject s propensity to trip.

  14. Design of ligand-targeted nanoparticles for enhanced cancer targeting

    NASA Astrophysics Data System (ADS)

    Stefanick, Jared F.

    Ligand-targeted nanoparticles are increasingly used as drug delivery vehicles for cancer therapy, yet have not consistently produced successful clinical outcomes. Although these inconsistencies may arise from differences in disease models and target receptors, nanoparticle design parameters can significantly influence therapeutic efficacy. By employing a multifaceted synthetic strategy to prepare peptide-targeted nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities, this work evaluates the roles of polyethylene glycol (PEG) coating, ethylene glycol (EG) peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size on tumor targeting in a systematic manner. These parameters were analyzed in multiple disease models by targeting human epidermal growth factor receptor 2 (HER2) in breast cancer and very late antigen-4 (VLA-4) in multiple myeloma to demonstrate the widespread applicability of this approach. By increasing the hydrophilicity of the targeting peptide sequence and simultaneously optimizing the EG peptide-linker length, the in vitro cellular uptake of targeted liposomes was significantly enhanced. Specifically, including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake ~80-fold using an EG6 peptide-linker compared to ~10-fold using an EG45 linker. In vivo, targeted liposomes prepared in a traditional manner lacking the oligolysine chain demonstrated similar biodistribution and tumor uptake to non-targeted liposomes. However, by including the oligolysine chain, targeted liposomes using an EG45 linker significantly improved tumor uptake ~8-fold over non-targeted liposomes, while the use of an EG6 linker decreased tumor accumulation and uptake, owing to differences in cellular uptake kinetics, clearance mechanisms, and binding site barrier effects. To further improve tumor targeting and enhance the selectivity of targeted

  15. Establishment and use of surgical rat models for assessment of organ specific in vivo clearance.

    PubMed

    Vestergaard, Bill

    2016-06-01

    nephrectomy model as a tool to investigate renal clearance was successful, but an in vivo rat model of hepatic clearance model was not successfully established.

  16. Effects of leakage through clearance seals on the performance of a 10 K Stirling-cycle refrigerator

    NASA Technical Reports Server (NTRS)

    Keung, C. S.; Lindale, E.

    1985-01-01

    The use of clearance seals is essential to achieve long life, wear free operation of Stirling cycle cryogenic refrigerators. The effect of leakage through clearance seals on the performance of such a refrigerator operating at temperatures ranging from 20 K down to 10 K was determined. The ability of a Stirling cycle refrigerator to achieve 10 K with clearance seals was successfully demonstrated. It is indicated that the leakage flow undergoes gap regeneration before reaching the cold expansion volume. A simple model of gap regeneration was used to estimate the regeneration loss due to the leakage flow. This regeneration process minimizes the loss in refrigerator performance caused by the clearance seal leakage. It is found that clearance seals remain effective down to a refrigeration temperature of 10 K.

  17. Plasma Creatinine Clearance in the Dog

    ERIC Educational Resources Information Center

    Frazier, Loy W.

    1977-01-01

    Lists materials and methods for an experiment that demonstrates the concept of glomerular filtration rate (GFR) using anesthesized dogs. In the dog, GFR is equivalent to the renal plasma clearance of exogenous creatinine. (CS)

  18. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... attitude, whichever is most critical. In addition, there must be positive clearance between the propeller and the ground when in the level takeoff attitude with the critical tire(s) completely deflated...

  19. Shear-Joint Capability Versus Bolt Clearance

    NASA Technical Reports Server (NTRS)

    Lee, H. M.

    1994-01-01

    NASA Technical Memorandum presents theoretical study of relationships between load-bearing capabilities of shear joints that comprise plates clamped together by multiple bolts and clearances between bolts and boltholes in those joints.

  20. Shear joint capability versus bolt clearance

    NASA Technical Reports Server (NTRS)

    Lee, H. M.

    1992-01-01

    The results of a conservative analysis approach into the determination of shear joint strength capability for typical space-flight hardware as a function of the bolt-hole clearance specified in the design are presented. These joints are comprised of high-strength steel fasteners and abutments constructed of aluminum alloys familiar to the aerospace industry. A general analytical expression was first arrived at which relates bolt-hole clearance to the bolt shear load required to place all joint fasteners into a shear transferring position. Extension of this work allowed the analytical development of joint load capability as a function of the number of fasteners, shear strength of the bolt, bolt-hole clearance, and the desired factor of safety. Analysis results clearly indicate that a typical space-flight hardware joint can withstand significant loading when less than ideal bolt hole clearances are used in the design.

  1. Compressor airfoil tip clearance optimization system

    DOEpatents

    Little, David A.; Pu, Zhengxiang

    2015-08-18

    A compressor airfoil tip clearance optimization system for reducing a gap between a tip of a compressor airfoil and a radially adjacent component of a turbine engine is disclosed. The turbine engine may include ID and OD flowpath boundaries configured to minimize compressor airfoil tip clearances during turbine engine operation in cooperation with one or more clearance reduction systems that are configured to move the rotor assembly axially to reduce tip clearance. The configurations of the ID and OD flowpath boundaries enhance the effectiveness of the axial movement of the rotor assembly, which includes movement of the ID flowpath boundary. During operation of the turbine engine, the rotor assembly may be moved axially to increase the efficiency of the turbine engine.

  2. Voltage-clearance recommendations for printed boards

    SciTech Connect

    Jennings, C W; Cave, G; Evans, A; Harrington, D J; Kirchenbaum, J; Martz, R E; Mierendorf, R C; Smith, G A

    1980-01-01

    Present and future trends in printed board designs point to higher circuit densities with narrower lines and closer spacings. Some designers are now laying out boards with 0.13 mm lines and spacings. The reduction of nominal spacing between conductive elements has raised questions concerning the adequacy of present voltage-clearance recommendations. The present recommendations are considered too conservative in that they are weighted with large safety factors, especially for small clearances, and are frequently disregarded by many designers. Published voltage breakdown measurements made on printed boards with comb patterns with their enhanced conductor test lengths show breakdowns occurring at much higher voltages than those specified for the clearances in existing documents. A Task Group was set up to review published breakdown measurements and to make any additional measurements necessary to provide voltage-clearance recommendations. These recommendations are reported.

  3. 2015 Annual Report on Security Clearance Determinations

    DTIC Science & Technology

    2016-06-28

    preceding fiscal year that resulted in a denial or revocation of a security clearance...and o more than 1 year. iii. Percentage of reviews during the preceding fiscal year that resulted in a denial or revocation of a security clearance...1,322 in FY 2014 to 2,526 in FY 20154. iii. The percentage of reviews during the preceding fiscal year that resulted in a denial or revocation of a

  4. Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms

    PubMed Central

    Mansilla Pareja, Maria Eugenia; Colombo, Maria I.

    2013-01-01

    Autophagy is involved in several physiological and pathological processes. One of the key roles of the autophagic pathway is to participate in the first line of defense against the invasion of pathogens, as part of the innate immune response. Targeting of intracellular bacteria by the autophagic machinery, either in the cytoplasm or within vacuolar compartments, helps to control bacterial proliferation in the host cell, controlling also the spreading of the infection. In this review we will describe the means used by diverse bacterial pathogens to survive intracellularly and how they are recognized by the autophagic molecular machinery, as well as the mechanisms used to avoid autophagic clearance. PMID:24137567

  5. Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms.

    PubMed

    Pareja, Maria Eugenia Mansilla; Colombo, Maria I

    2013-01-01

    Autophagy is involved in several physiological and pathological processes. One of the key roles of the autophagic pathway is to participate in the first line of defense against the invasion of pathogens, as part of the innate immune response. Targeting of intracellular bacteria by the autophagic machinery, either in the cytoplasm or within vacuolar compartments, helps to control bacterial proliferation in the host cell, controlling also the spreading of the infection. In this review we will describe the means used by diverse bacterial pathogens to survive intracellularly and how they are recognized by the autophagic molecular machinery, as well as the mechanisms used to avoid autophagic clearance.

  6. ADAPTIVE CLEARANCE CONTROL SYSTEMS FOR TURBINE ENGINES

    NASA Technical Reports Server (NTRS)

    Blackwell, Keith M.

    2004-01-01

    The Controls and Dynamics Technology Branch at NASA Glenn Research Center primarily deals in developing controls, dynamic models, and health management technologies for air and space propulsion systems. During the summer of 2004 I was granted the privilege of working alongside professionals who were developing an active clearance control system for commercial jet engines. Clearance, the gap between the turbine blade tip and the encompassing shroud, increases as a result of wear mechanisms and rubbing of the turbine blades on shroud. Increases in clearance cause larger specific fuel consumption (SFC) and loss of efficient air flow. This occurs because, as clearances increase, the engine must run hotter and bum more fuel to achieve the same thrust. In order to maintain efficiency, reduce fuel bum, and reduce exhaust gas temperature (EGT), the clearance must be accurately controlled to gap sizes no greater than a few hundredths of an inch. To address this problem, NASA Glenn researchers have developed a basic control system with actuators and sensors on each section of the shroud. Instead of having a large uniform metal casing, there would be sections of the shroud with individual sensors attached internally that would move slightly to reform and maintain clearance. The proposed method would ultimately save the airline industry millions of dollars.

  7. 48 CFR 945.603-70 - Plant clearance function.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Plant clearance function... Plant clearance function. If the plant clearance function has not been formally delegated to another Federal agency, the contracting officer shall assume all responsibilities of the plant clearance...

  8. 48 CFR 245.7203 - Assigning plant clearance case numbers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Assigning plant clearance....7203 Assigning plant clearance case numbers. (a) Use a three-part, 11-character number constructed as... clearance number on DD Form 1635, Plant Clearance Case Register, or mechanized equivalent....

  9. 48 CFR 245.7202 - Establishing a plant clearance case.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... clearance case. 245.7202 Section 245.7202 Federal Acquisition Regulations System DEFENSE ACQUISITION....7202 Establishing a plant clearance case. (a) Upon receipt of an acceptable inventory schedule or a DD Form 1342, DoD Property Record, the plant clearance officer shall establish a plant clearance case...

  10. 7 CFR 1927.55 - Title clearance services.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 12 2010-01-01 2010-01-01 false Title clearance services. 1927.55 Section 1927.55... REGULATIONS TITLE CLEARANCE AND LOAN CLOSING Real Estate Title Clearance and Loan Closing § 1927.55 Title clearance services. (a) Responsibilities of closing agents. Services to be provided to the agency and...

  11. 48 CFR 945.603-70 - Plant clearance function.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Plant clearance function... Plant clearance function. If the plant clearance function has not been formally delegated to another Federal agency, the contracting officer shall assume all responsibilities of the plant clearance...

  12. 48 CFR 945.603-70 - Plant clearance function.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Plant clearance function... Plant clearance function. If the plant clearance function has not been formally delegated to another Federal agency, the contracting officer shall assume all responsibilities of the plant clearance...

  13. 48 CFR 801.602-76 - Business clearance review.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Business clearance review... Authority, and Responsibilities 801.602-76 Business clearance review. (a) A business clearance review is a... obtain a business clearance review prior to award of any contract, task or delivery order, or...

  14. 48 CFR 801.602-76 - Business clearance review.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Business clearance review... Authority, and Responsibilities 801.602-76 Business clearance review. (a) A business clearance review is a... obtain a business clearance review prior to award of any contract, task or delivery order, or...

  15. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Clearance of Army lands. 644.517 Section 644.517... ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from Proposed Excess Land and Improvements § 644.517 Clearance of Army lands. The responsibility for performing clearance...

  16. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Clearance of Army lands. 644.517 Section 644.517... ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from Proposed Excess Land and Improvements § 644.517 Clearance of Army lands. The responsibility for performing clearance...

  17. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Clearance of Army lands. 644.517 Section 644.517... ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from Proposed Excess Land and Improvements § 644.517 Clearance of Army lands. The responsibility for performing clearance...

  18. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Clearance of Army lands. 644.517 Section 644.517... ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from Proposed Excess Land and Improvements § 644.517 Clearance of Army lands. The responsibility for performing clearance...

  19. Lower metabolic clearance of tizanidine in Japanese subjects.

    PubMed

    Momo, Kenji; Homma, Masato; Kohda, Yukinao

    2013-12-01

    Our aim was to determine whether metabolic clearance, renal clearance, or both elimination pathways contribute to ethnic differences in tizanidine clearance, which is ~ 2-fold higher in Caucasians than in Asians. The pharmacokinetic parameters of tizanidine in 9 healthy male Japanese subjects were compared with those of Caucasians in previous studies. Metabolic clearance of tizanidine was lower in Japanese than in Caucasian subjects (5.9 vs. 8.1 - 10.9 l/h/kg), although renal clearances were similar (0.040 vs. 0.047 - 0.055 l/h/kg). The results suggest that ethnic differences in tizanidine clearance are due to differences in metabolic clearance.

  20. The Role of Nucleotides and Purinergic Signaling in Apoptotic Cell Clearance – Implications for Chronic Inflammatory Diseases

    PubMed Central

    Chen, Jin; Zhao, Yi; Liu, Yi

    2014-01-01

    Billions of cells undergo apoptosis every day in healthy individuals. A prompt removal of dying cells prevents the release of pro-inflammatory intracellular content and progress to secondary necrosis. Thus, inappropriate clearance of apoptotic cells provokes autoimmunity and has been associated with many chronic inflammatory diseases. Recent studies have suggested that extracellular adenosine 5′-triphosphate and related nucleotides play an important role in the apoptotic clearance process. Here, we review the current understanding of nucleotides and purinergic receptors in apoptotic cell clearance and the potential therapeutic targets of purinergic receptor subtypes in inflammatory conditions. PMID:25566266

  1. E-Reserves Permissions and the Copyright Clearance Center: Process, Efficiency, and Cost

    ERIC Educational Resources Information Center

    Holobar, J. Christopher; Marshall, Andrew

    2011-01-01

    This study examines the process of requesting copyright permissions through the Copyright Clearance Center's (CCC) pay-per-use service for electronic course reserves at the Penn State University Libraries in 2008. The authors investigate the efficiency of this process as a function of the percentage of permission requests successfully mediated by…

  2. Effects of airborne pollutants on mucociliary clearance.

    PubMed Central

    Wolff, R K

    1986-01-01

    The mucociliary clearance system is a first line of defense against inhaled agents, and so its compromise can adversely affect health. The purpose of this paper is to provide a review of data on the effect of in vivo air pollutant exposures on the clearance of test particles from airways. Data from both animals and humans are compared whenever possible, so that estimates of human health effects may be made. Mechanisms of action are also discussed, presenting the view that for low level exposures, changes in secretions are probably responsible for most observed changes in clearance. The pollutants pertinent to this review are those that are common in the environment and most likely to have impacts on large numbers of people: sulfur oxides, sulfuric acid mist, O3, NO2, particulates, diesel exhaust, and cigarette smoke. Images FIGURE 1. FIGURE 2. a FIGURE 2. b FIGURE 4. PMID:3519203

  3. Effects of airborne pollutants on mucociliary clearance

    SciTech Connect

    Wolff, R.K.

    1986-04-01

    The mucociliary clearance system is a first line of defense against inhaled agents, and so its compromise can adversely affect health. The purpose of this paper is to provide a review of data on the effect of in vivo air pollutant exposures on the clearance of test particles from airways. Data from both animals and humans are compared whenever possible, so that estimates of human health effects may be made. Mechanisms of action are also discussed, presenting the view that for low level exposures, changes in secretions are probably responsible for most observed changes in clearance. The pollutants pertinent to this review are those that are common in the environment and most likely to have impacts on large numbers of people: sulfur oxides, sulfuric acid mist, O/sub 3/, NO/sub 2/, particulates, diesel exhaust, and cigarette smoke.149 references.

  4. Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS).

    PubMed

    Varma, Manthena V; Steyn, Stefanus J; Allerton, Charlotte; El-Kattan, Ayman F

    2015-12-01

    Early prediction of clearance mechanisms allows for the rapid progression of drug discovery and development programs, and facilitates risk assessment of the pharmacokinetic variability associated with drug interactions and pharmacogenomics. Here we propose a scientific framework--Extended Clearance Classification System (ECCS)--which can be used to predict the predominant clearance mechanism (rate-determining process) based on physicochemical properties and passive membrane permeability. Compounds are classified as: Class 1A--metabolism as primary systemic clearance mechanism (high permeability acids/zwitterions with molecular weight (MW) ≤400 Da), Class 1B--transporter-mediated hepatic uptake as primary systemic clearance mechanism (high permeability acids/zwitterions with MW >400 Da), Class 2--metabolism as primary clearance mechanism (high permeability bases/neutrals), Class 3A--renal clearance (low permeability acids/zwitterions with MW ≤400 Da), Class 3B--transporter mediated hepatic uptake or renal clearance (low permeability acids/zwitterions with MW >400 Da), and Class 4--renal clearance (low permeability bases/neutrals). The performance of the ECCS framework was validated using 307 compounds with single clearance mechanism contributing to ≥70% of systemic clearance. The apparent permeability across clonal cell line of Madin - Darby canine kidney cells, selected for low endogenous efflux transporter expression, with a cut-off of 5 × 10(-6) cm/s was used for permeability classification, and the ionization (at pH7) was assigned based on calculated pKa. The proposed scheme correctly predicted the rate-determining clearance mechanism to be either metabolism, hepatic uptake or renal for ~92% of total compounds. We discuss the general characteristics of each ECCS class, as well as compare and contrast the framework with the biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS

  5. New immunotherapies targeting the PD-1 pathway

    PubMed Central

    Chinai, Jordan M.; Janakiram, Murali; Chen, Fuxiang; Chen, Wantao; Kaplan, Mark; Zang, Xingxing

    2015-01-01

    Ligands from the B7 family bind to receptors of the CD28 family, which regulate early T cell activation in lymphoid organs and control inflammation and autoimmunity in peripheral tissues. PD-1, a member of the CD28 family, is an inhibitory receptor on T cells and is responsible for their dysfunction in infectious diseases and cancers. The complex mechanisms controlling expression and signaling of PD-1 and PD-L1 are emerging. Recently completed and ongoing clinical trials that target these molecules have shown remarkable success by generating durable clinical responses in some cancer patients. In chronic viral infections, preclinical data reveal that targeting PD-1 and its ligands can improve T cell responses and viral clearance. There is also promise in stimulating this pathway for the treatment of autoimmune and inflammatory disorders. PMID:26162965

  6. Pharmacologic agents for mucus clearance in bronchiectasis.

    PubMed

    Nair, Girish B; Ilowite, Jonathan S

    2012-06-01

    There are no approved pharmacologic agents to enhance mucus clearance in non-cystic fibrosis (CF) bronchiectasis. Evidence supports the use of hyperosmolar agents in CF, and studies with inhaled mannitol and hypertonic saline are ongoing in bronchiectasis. N-acetylcysteine may act more as an antioxidant than a mucolytic in other lung diseases. Dornase α is beneficial to patients with CF, but is not useful in patients with non-CF bronchiectasis. Mucokinetic agents such as β-agonists have the potential to improve mucociliary clearance in normals and many disease states, but have not been adequately studied in patients with bronchiectasis.

  7. Mucociliary clearance from the calf lung.

    PubMed Central

    Jones, C D

    1983-01-01

    Mucociliary clearance rate constants for ten calves were obtained using Technetium 99m-sulphur colloid complex. The mean rate constant measured at the lung for all calves was 0.012 (+/- 0.009) min-1 (half-life 58 minutes). The clearance rate constants obtained from measurements made at the larynx were higher (0.02 +/- 0.007 min-1), although not significantly higher, than those determined from measurements taken at the lung. The constants can be used to predict the particle burden on the lungs of calves kept under husbandry systems of varying air hygiene. Images Fig. 1. PMID:6640409

  8. Rapid clearance of bacteria and their toxins: development of therapeutic proteins.

    PubMed

    Kunkel, Meghan; Vuyisich, Momchilo; Gnanakaran, Gnana; Bruening, George E; Dandekar, Abhaya M; Civerolo, Edwin; Marchalonis, John J; Gupta, Goutam

    2007-01-01

    The emergence of pathogens and toxins with resistance against conventional drugs, vaccines, and host defense peptides and proteins warrants novel countermeasures that can efficiently capture and rapidly clear them. This article examines the utility of chimeric proteins with capture and clearance domains as a novel countermeasure against pathogens and their toxins. The capture and clearance domains are chosen from the large repertoire of host defense peptides and proteins. Although individual capture and clearance domains are rendered ineffective by pathogenic resistance mechanisms, chimeric scaffolds can be designed to retain their antimicrobial activity, even in the face of pathogenic resistance. Here, initial studies on the design of chimeric proteins targeted against (1) intact bacteria such as Xylella fastidiosa (plant pathogens), Salmonella spp. (food-borne pathogens), and Staphylococcus aureus (blood-borne pathogens); and (2) lethal toxins from Bacillus anthracis are described.

  9. Effects of Bearing Clearance on Turbopump Stability

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Effects of bearing clearances, or "dead bands," on bearing loads and rotor stability in turbopumps examined in a 194-page report. Relatively simple mathematical force model for analyzing effects highlighted. Report shows nonlinear characteristics resulting from bearing dead bands have significant effect on dynamics of turbomachinery and not ignored as in the past.

  10. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Security clearance. 154.16 Section 154.16 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE SECURITY DEPARTMENT OF DEFENSE PERSONNEL SECURITY PROGRAM REGULATION Personnel Security Investigative Requirements § 154.16...

  11. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 1 2014-07-01 2014-07-01 false Security clearance. 154.16 Section 154.16 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE SECURITY DEPARTMENT OF DEFENSE PERSONNEL SECURITY PROGRAM REGULATION Personnel Security Investigative Requirements § 154.16...

  12. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 false Security clearance. 154.16 Section 154.16 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE SECURITY DEPARTMENT OF DEFENSE PERSONNEL SECURITY PROGRAM REGULATION Personnel Security Investigative Requirements § 154.16...

  13. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Security clearance. 154.16 Section 154.16 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE SECURITY DEPARTMENT OF DEFENSE PERSONNEL SECURITY PROGRAM REGULATION Personnel Security Investigative Requirements § 154.16...

  14. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Electrical clearances. 18.24 Section 18.24 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR TESTING, EVALUATION, AND APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and...

  15. 30 CFR 57.11010 - Stairstep clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Stairstep clearance. 57.11010 Section 57.11010 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE... steps shall be a minimum of seven feet, or suitable warning signs or similar devices shall be...

  16. 30 CFR 57.11010 - Stairstep clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Stairstep clearance. 57.11010 Section 57.11010 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE... steps shall be a minimum of seven feet, or suitable warning signs or similar devices shall be...

  17. Clearance of seborrhoeic keratoses with topical dobesilate

    PubMed Central

    Cuevas, Pedro; Angulo, Javier; Salgüero, Irene; Giménez-Gallego, Guillermo

    2012-01-01

    A patient with two seborrhoeic keratoses in the face received a single daily application of dobesilate cream during 6 months. Dobesilate achieved complete clearance of the seborrhoeic keratosis lesions with good cosmoses, suggesting that this compound is a safe and efficient candidate in the treatment of seborrhoeic keratoses. PMID:22729328

  18. Quantitative Magnetic Particle Imaging Monitors the Transplantation, Biodistribution, and Clearance of Stem Cells In Vivo

    PubMed Central

    Zheng, Bo; von See, Marc P.; Yu, Elaine; Gunel, Beliz; Lu, Kuan; Vazin, Tandis; Schaffer, David V.; Goodwill, Patrick W.; Conolly, Steven M.

    2016-01-01

    Stem cell therapies have enormous potential for treating many debilitating diseases, including heart failure, stroke and traumatic brain injury. For maximal efficacy, these therapies require targeted cell delivery to specific tissues followed by successful cell engraftment. However, targeted delivery remains an open challenge. As one example, it is common for intravenous deliveries of mesenchymal stem cells (MSCs) to become entrapped in lung microvasculature instead of the target tissue. Hence, a robust, quantitative imaging method would be essential for developing efficacious cell therapies. Here we show that Magnetic Particle Imaging (MPI), a novel technique that directly images iron-oxide nanoparticle-tagged cells, can longitudinally monitor and quantify MSC administration in vivo. MPI offers near-ideal image contrast, depth penetration, and robustness; these properties make MPI both ultra-sensitive and linearly quantitative. Here, we imaged, for the first time, the dynamic trafficking of intravenous MSC administrations using MPI. Our results indicate that labeled MSC injections are immediately entrapped in lung tissue and then clear to the liver within one day, whereas standard iron oxide particle (Resovist) injections are immediately taken up by liver and spleen. Longitudinal MPI-CT imaging also indicated a clearance half-life of MSC iron oxide labels in the liver at 4.6 days. Finally, our ex vivo MPI biodistribution measurements of iron in liver, spleen, heart, and lungs after injection showed excellent agreement (R2 = 0.943) with measurements from induction coupled plasma spectrometry. These results demonstrate that MPI offers strong utility for noninvasively imaging and quantifying the systemic distribution of cell therapies and other therapeutic agents. PMID:26909106

  19. Quantitative Magnetic Particle Imaging Monitors the Transplantation, Biodistribution, and Clearance of Stem Cells In Vivo.

    PubMed

    Zheng, Bo; von See, Marc P; Yu, Elaine; Gunel, Beliz; Lu, Kuan; Vazin, Tandis; Schaffer, David V; Goodwill, Patrick W; Conolly, Steven M

    2016-01-01

    Stem cell therapies have enormous potential for treating many debilitating diseases, including heart failure, stroke and traumatic brain injury. For maximal efficacy, these therapies require targeted cell delivery to specific tissues followed by successful cell engraftment. However, targeted delivery remains an open challenge. As one example, it is common for intravenous deliveries of mesenchymal stem cells (MSCs) to become entrapped in lung microvasculature instead of the target tissue. Hence, a robust, quantitative imaging method would be essential for developing efficacious cell therapies. Here we show that Magnetic Particle Imaging (MPI), a novel technique that directly images iron-oxide nanoparticle-tagged cells, can longitudinally monitor and quantify MSC administration in vivo. MPI offers near-ideal image contrast, depth penetration, and robustness; these properties make MPI both ultra-sensitive and linearly quantitative. Here, we imaged, for the first time, the dynamic trafficking of intravenous MSC administrations using MPI. Our results indicate that labeled MSC injections are immediately entrapped in lung tissue and then clear to the liver within one day, whereas standard iron oxide particle (Resovist) injections are immediately taken up by liver and spleen. Longitudinal MPI-CT imaging also indicated a clearance half-life of MSC iron oxide labels in the liver at 4.6 days. Finally, our ex vivo MPI biodistribution measurements of iron in liver, spleen, heart, and lungs after injection showed excellent agreement (R(2) = 0.943) with measurements from induction coupled plasma spectrometry. These results demonstrate that MPI offers strong utility for noninvasively imaging and quantifying the systemic distribution of cell therapies and other therapeutic agents.

  20. Carbamazepine clearance and seizure stability during pregnancy.

    PubMed

    Johnson, Emily L; Stowe, Zachary N; Ritchie, James C; Newport, D Jeffrey; Newman, Melanee L; Knight, Bettina; Pennell, Page B

    2014-04-01

    The aims of this study were to characterize the alterations in total and free carbamazepine (CBZ) and in total and free carbamazepine-epoxide (CBZ-EPO) clearances during pregnancy, to calculate the change in free fractions of CBZ and CBZ-EPO during pregnancy, and to determine whether seizure worsening is associated with a low ratio to nonpregnant baseline concentration of total or free CBZ or CBZ-EPO. Women on CBZ were enrolled before conception or during pregnancy in this prospective, observational study. Concomitant medications and seizure frequency were recorded. Serum total and free CBZ and CBZ-EPO were collected at each visit. Changes in the clearance of all four compounds and free fractions of CBZ and CBZ-EPO were compared with nonpregnant baseline. During pregnancy, the ratios to baseline concentrations of total and free CBZ and CBZ-EPO were compared for months with and without increased seizure frequency. Total and free CBZ and CBZ-EPO clearances were calculated in 15 pregnancies in 12 women. Clearances did not change for any of these compounds during pregnancy. The free fraction of CBZ increased from 0.23 at baseline to a maximum of 0.32 in the third trimester (p=0.008). In the six women on CBZ monotherapy with adequate seizure diaries and blood sampling, seizure worsening did not correspond to a ratio to baseline concentration of less than 0.65 for total or free CBZ or CBZ-EPO. In conclusion, total and free CBZ and CBZ-EPO clearances did not change substantially during pregnancy, and seizure frequency worsening was not associated with decreased concentrations of total or free CBZ; therefore, therapeutic drug monitoring may not be necessary for all women on CBZ during pregnancy. Further studies with larger sample sizes are needed before definitive recommendations can be made. Carbamazepine monotherapy may be a relatively safe and cost effective treatment option for women with focal epilepsy syndromes during pregnancy.

  1. Clearance of refractory bile duct stones with extracorporeal shockwave lithotripsy

    PubMed Central

    Ellis, R; Jenkins, A; Thompson, R; Ede, R

    2000-01-01

    BACKGROUND—Extracorporeal shockwave lithotripsy (ESWL) has been used since the mid-1980s to fragment bile duct stones which cannot be removed endoscopically. Early machines required general anaesthesia and immersion in a waterbath.
AIMS—To investigate the effectiveness of the third generation Storz Modulith SL20 lithotriptor in fragmenting bile duct stones that could not be cleared by mechanical lithotripsy.
METHODS—Eighty three patients with retained bile duct stones were treated. All patients received intravenous benzodiazepine sedation and pethidine analgesia. Stones were targeted by fluoroscopy following injection of contrast via a nasobiliary drain or T tube. Residual fragments were cleared at endoscopic retrograde cholangiopancreatography.
RESULTS—Complete stone clearance was achieved in 69 (83%) patients and in 18 of 24 patients (75%) who required more than one ESWL treatment. Stone clearance was achieved in all nine patients (100%) with intrahepatic stones and also in nine patients (100%) referred following surgical exploration of the bile duct. Complications included six cases of cholangitis and one perinephric haematoma which resolved spontaneously.
CONCLUSION—Using the Storz Modulith, 83% of refractory bile duct calculi were cleared with a low rate of complications. These results confirm that ESWL is an excellent alternative to surgery in those patients in whom endoscopic techniques have failed.


Keywords: lithotripsy; bile duct calculi; extracorporeal lithotripsy PMID:11034593

  2. Relative importance of magnetic moments in UXO clearance applications

    USGS Publications Warehouse

    Sanchez, V.; Li, Y.; Nabighian, M.; Wright, D.

    2006-01-01

    Surface magnetic anomaly observed in UXO clearance is mainly dipolar and, as a result, the dipole is the only moment used regularly in UXO applications. The dipole moment contains intensity of magnetization information but lacks shape information. Unlike dipole, higher-order moments, such as quadrupole and octupole, encode asymmetry properties of magnetization distribution within buried targets. In order to improve our understanding of magnetization distribution within UXO and non-UXO objects and its potential utility in UXO clearance, we present results of a 3D numerical modeling study for highly susceptible metallic objects. The basis for modeling is the solution of a nonlinear integral equation, describing magnetization within isolated objects, allowing us to compute magnetic moments of the object, analyze their relationships, and provide a depiction of the surface anomaly produced by the different moments within the object. Our modeling results show significant high-order moments for more asymmetric objects situated at typical UXO burial depths, and suggest that the increased relative contribution to magnetic gradient data from these higher-order moments may provide a practical tool for improved UXO discrimination. ?? 2005 Society of Exploration Geophysicists.

  3. 19 CFR 122.26 - Entry and clearance.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... AIR COMMERCE REGULATIONS Private Aircraft § 122.26 Entry and clearance. Private aircraft, as defined... information as set forth in § 122.22(c), and grants electronic clearance via electronic mail or telephone....

  4. New IVIVE method for the prediction of total human clearance and relative elimination pathway contributions from in vitro hepatocyte and microsome data.

    PubMed

    Riede, Julia; Poller, Birk; Umehara, Ken-ichi; Huwyler, Jörg; Camenisch, Gian

    2016-04-30

    Total human clearance is a key determinant for the pharmacokinetic behavior of drug candidates. Our group recently introduced the Extended Clearance Model (ECM) as an accurate in vitro-in vivo extrapolation (IVIVE) method for the prediction of hepatic clearance. Yet, knowledge about relative elimination pathway contributions is needed in order to predict the total human clearance of drug candidates. In the present work, a training set of 18 drug compounds was used to describe the affiliations between in vitro sinusoidal uptake clearance and the fractional contributions of hepatic (metabolic and biliary) or renal clearance to overall in vivo elimination. By means of these quantitative relationships and using a validation set of 10 diverse drug molecules covering different (sub)classes of the Extended Clearance Concept Classification System (ECCCS), the relative contributions of elimination pathways were calculated and demonstrated to well correlate with human reference data. Likewise, ECM- and pathway-based predictions of total clearances from both data sets demonstrated a strong correlation with the observed clinical values with 26 out of 28 compounds within a three-fold deviation. Hence, total human clearance and relative contributions of elimination pathways were successfully predicted by the presented method using solely hepatocyte and microsome in vitro data.

  5. Age-Related Decline in Brain and Hepatic Clearance of Amyloid-Beta is Rectified by the Cholinesterase Inhibitors Donepezil and Rivastigmine in Rats.

    PubMed

    Mohamed, Loqman A; Qosa, Hisham; Kaddoumi, Amal

    2015-05-20

    In Alzheimer's disease (AD), accumulation of brain amyloid-β (Aβ) depends on imbalance between production and clearance of Aβ. Several pathways for Aβ clearance have been reported including transport across the blood-brain barrier (BBB) and hepatic clearance. The incidence of AD increases with age and failure of Aβ clearance correlates with AD. The cholinesterase inhibitors (ChEIs) donepezil and rivastigmine are used to ease the symptoms of dementia associated with AD. Besides, both drugs have been reported to provide neuroprotective and disease-modifying effects. Here, we investigated the effect of ChEIs on age-related reduced Aβ clearance. Findings from in vitro and in vivo studies demonstrated donepezil and rivastigmine to enhance (125)I-Aβ40 clearance. Also, the increase in brain and hepatic clearance of (125)I-Aβ40 was more pronounced in aged compared to young rats, and was associated with significant reduction in brain Aβ endogenous levels determined by ELISA. Furthermore, the enhanced clearance was concomitant with up-regulation in the expression of Aβ major transport proteins P-glycoprotein and LRP1. Collectively, our findings that donepezil and rivastigmine enhance Aβ clearance across the BBB and liver are novel and introduce an additional mechanism by which both drugs could affect AD pathology. Thus, optimizing their clinical use could help future drug development by providing new drug targets and possible mechanisms involved in AD pathology.

  6. WWW-based data entry for document clearance requests

    SciTech Connect

    Stasiak, D.M.

    1997-10-08

    All documents created at Argonne must be cleared before being published. The clearance process is coordinated by the Publications and Record Services. The Electronic Document Review and Clearance System (EDRC) consists of a Web-based system for submission of clearance requests, an electronic staging area for document awaiting review, and Web-based review and clearance of documents. This report covers the document clearing process, the EDRC system, expected benefits/costs, and a demonstration.

  7. Importance of bacterial replication and alveolar macrophage-independent clearance mechanisms during early lung infection with Streptococcus pneumoniae.

    PubMed

    Camberlein, Emilie; Cohen, Jonathan M; José, Ricardo; Hyams, Catherine J; Callard, Robin; Chimalapati, Suneeta; Yuste, Jose; Edwards, Lindsey A; Marshall, Helina; van Rooijen, Nico; Noursadeghi, Mahdad; Brown, Jeremy S

    2015-03-01

    Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae.

  8. 48 CFR 245.602-70 - Plant clearance procedures.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Plant clearance procedures... Disposal 245.602-70 Plant clearance procedures. Follow the procedures at PGI 245.602-70 for establishing and processing a plant clearance case....

  9. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Rotor blade clearance. 29.661 Section...

  10. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Rotor blade clearance. 27.661 Section...

  11. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Rotor blade clearance. 29.661 Section...

  12. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Rotor blade clearance. 29.661 Section...

  13. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Rotor blade clearance. 27.661 Section...

  14. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Rotor blade clearance. 27.661 Section...

  15. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Rotor blade clearance. 27.661 Section...

  16. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Rotor blade clearance. 29.661 Section...

  17. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Rotor blade clearance. 29.661 Section...

  18. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure to... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Rotor blade clearance. 27.661 Section...

  19. 48 CFR 2452.237-75 - Clearance of contractor personnel.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Clearance of contractor... Clauses 2452.237-75 Clearance of contractor personnel. As prescribed in 2437.110(e), insert the following clause in solicitations and contracts. Clearance of Contractor Personnel (OCT 1999) (a) General....

  20. 32 CFR 644.69 - Title Clearance-Easements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Title Clearance-Easements. 644.69 Section 644.69... ESTATE HANDBOOK Acquisition Procurement of Title Evidence, Title Clearance, and Closings § 644.69 Title Clearance—Easements. (a) Easements Costing in Excess of $1,000. Curative action and clearance of title...

  1. 10 CFR 706.31 - Clearance of conciliators and arbitrators.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Clearance of conciliators and arbitrators. 706.31 Section... RELATIONS Contract Negotiation and Administration § 706.31 Clearance of conciliators and arbitrators. Conciliators and arbitrators who are regularly assigned to DOE cases may be processed for “Q” clearance at...

  2. 30 CFR 56.19104 - Clearance at shaft stations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance at shaft stations. 56.19104 Section 56.19104 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND... Hoisting Shafts § 56.19104 Clearance at shaft stations. Suitable clearance at shaft stations shall...

  3. 14 CFR 375.24 - Entry and clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Entry and clearance. 375.24 Section 375.24 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL... Entry and clearance. All U.S. entry and clearance requirements for aircraft, passengers, crews,...

  4. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  5. 30 CFR 57.19104 - Clearance at shaft stations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance at shaft stations. 57.19104 Section 57.19104 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND... Hoisting Shafts § 57.19104 Clearance at shaft stations. Suitable clearance at shaft stations shall...

  6. 75 FR 70341 - Agency Information Collection Activities: Emergency Clearance Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-17

    ... ADMINISTRATION Agency Information Collection Activities: Emergency Clearance Request The Social Security Administration (SSA) publishes a list of information collection packages requiring clearance by the Office of... Desk Officer and SSA Reports Clearance Officer to the following addresses or fax numbers. (OMB),...

  7. 19 CFR 122.158 - Other entry and clearance requirements.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Other entry and clearance requirements. 122.158 Section 122.158 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY... clearance requirements. All other provisions of this part relating to entry and clearance of aircraft...

  8. 30 CFR 56.9103 - Clearance on adjacent tracks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance on adjacent tracks. 56.9103 Section..., Hauling, and Dumping Traffic Safety § 56.9103 Clearance on adjacent tracks. Railcars shall not be left on side tracks unless clearance is provided for traffic on adjacent tracks....

  9. 76 FR 17615 - Highway-Rail Grade Crossing; Safe Clearance

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-30

    ... Parts 177 and 392 RIN 2137-AE69 & 2126-AB04 Highway-Rail Grade Crossing; Safe Clearance AGENCY: Pipeline... that PHMSA and FMCSA extend the comment period for the Highway-Rail Grade Crossing; Safe Clearance... Crossing; Safe Clearance Notice of Proposed Rulemaking, which was published on January 28, 2011 (76 FR...

  10. 10 CFR 706.13 - Clearance of counsel.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Clearance of counsel. 706.13 Section 706.13 Energy... and Procedures in National Labor Relations Board Proceedings § 706.13 Clearance of counsel. It is recognized that clearance of counsel for the parties is sometimes desirable for proper preparation of a...

  11. 8 CFR 1280.6 - Bond to obtain clearance; form.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Bond to obtain clearance; form. 1280.6... IMMIGRATION REGULATIONS IMPOSITION AND COLLECTION OF FINES § 1280.6 Bond to obtain clearance; form. A bond to obtain clearance of a vessel or aircraft under section 231, 237, 239, 243, 251, 253, 254, 255, 256,...

  12. 10 CFR 95.17 - Processing facility clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Processing facility clearance. 95.17 Section 95.17 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FACILITY SECURITY CLEARANCE AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.17 Processing facility clearance....

  13. 10 CFR 95.23 - Termination of facility clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Termination of facility clearance. 95.23 Section 95.23 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FACILITY SECURITY CLEARANCE AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.23 Termination of facility clearance....

  14. 19 CFR 122.157 - Documents required for clearance.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Documents required for clearance. 122.157 Section 122.157 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT... clearance. As a condition precedent to clearance, the aircraft commander shall present to Customs: (a)...

  15. 75 FR 37518 - Agency Information Collection Activities: Emergency Clearance Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-29

    ... ADMINISTRATION Agency Information Collection Activities: Emergency Clearance Request The Social Security Administration (SSA) publishes a list of information collection packages requiring clearance by the Office of... Desk Officer and SSA Reports Clearance Officer to the following addresses or fax numbers. (OMB),...

  16. 8 CFR 280.6 - Bond to obtain clearance; form.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Bond to obtain clearance; form. 280.6 Section 280.6 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS IMPOSITION AND COLLECTION OF FINES § 280.6 Bond to obtain clearance; form. A bond to obtain clearance of a...

  17. 30 CFR 57.9103 - Clearance on adjacent tracks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance on adjacent tracks. 57.9103 Section..., Hauling, and Dumping Traffic Safety § 57.9103 Clearance on adjacent tracks. Railcars shall not be left on side tracks unless clearance is provided for traffic on adjacent tracks....

  18. 14 CFR 1260.63 - Customs clearance and visas.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Customs clearance and visas. 1260.63 Section 1260.63 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GRANTS AND COOPERATIVE AGREEMENTS General Special Conditions § 1260.63 Customs clearance and visas. Customs Clearance and Visas...

  19. 30 CFR 56.9330 - Clearance for surface equipment.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance for surface equipment. 56.9330... NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Loading... Dumping Sites § 56.9330 Clearance for surface equipment. Continuous clearance of at least 30 inches...

  20. 30 CFR 57.9330 - Clearance for surface equipment.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance for surface equipment. 57.9330 Section 57.9330 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND... Dumping Sites § 57.9330 Clearance for surface equipment. Continuous clearance of at least 30 inches...

  1. 31 CFR 205.20 - What is a clearance pattern?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false What is a clearance pattern? 205.20 Section 205.20 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL... Agreement § 205.20 What is a clearance pattern? States use clearance patterns to project when funds are...

  2. 30 CFR 56.9306 - Warning devices for restricted clearances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Warning devices for restricted clearances. 56... Loading and Dumping Sites § 56.9306 Warning devices for restricted clearances. Where restricted clearance creates a hazard to persons on mobile equipment, warning devices shall be installed in advance of...

  3. 30 CFR 56.9306 - Warning devices for restricted clearances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Warning devices for restricted clearances. 56... Loading and Dumping Sites § 56.9306 Warning devices for restricted clearances. Where restricted clearance creates a hazard to persons on mobile equipment, warning devices shall be installed in advance of...

  4. 30 CFR 56.9306 - Warning devices for restricted clearances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Warning devices for restricted clearances. 56... Loading and Dumping Sites § 56.9306 Warning devices for restricted clearances. Where restricted clearance creates a hazard to persons on mobile equipment, warning devices shall be installed in advance of...

  5. 30 CFR 56.9306 - Warning devices for restricted clearances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Warning devices for restricted clearances. 56... Loading and Dumping Sites § 56.9306 Warning devices for restricted clearances. Where restricted clearance creates a hazard to persons on mobile equipment, warning devices shall be installed in advance of...

  6. 48 CFR 245.602-70 - Plant clearance procedures.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Plant clearance procedures... Disposal 245.602-70 Plant clearance procedures. Follow the procedures at PGI 245.602-70 for establishing and processing a plant clearance case....

  7. 48 CFR 245.602-70 - Plant clearance procedures.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Plant clearance procedures... Disposal 245.602-70 Plant clearance procedures. Follow the procedures at PGI 245.602-70 for establishing and processing a plant clearance case....

  8. 48 CFR 245.602-70 - Plant clearance procedures.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Plant clearance procedures... Disposal 245.602-70 Plant clearance procedures. Follow the procedures at PGI 245.602-70 for establishing and processing a plant clearance case....

  9. 48 CFR 945.670-1 - Plant clearance function.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Plant clearance function... MANAGEMENT GOVERNMENT PROPERTY Reporting, Reutilization, and Disposal 945.670-1 Plant clearance function. If the plant clearance function has not been formally delegated to another Federal agency,...

  10. 48 CFR 945.670-1 - Plant clearance function.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Plant clearance function... MANAGEMENT GOVERNMENT PROPERTY Reporting, Reutilization, and Disposal 945.670-1 Plant clearance function. If the plant clearance function has not been formally delegated to another Federal agency,...

  11. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  12. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  13. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 2 2011-10-01 2011-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  14. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  15. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  16. 10 CFR 706.13 - Clearance of counsel.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Clearance of counsel. 706.13 Section 706.13 Energy DEPARTMENT OF ENERGY SECURITY POLICIES AND PRACTICES RELATING TO LABOR-MANAGEMENT RELATIONS Security Policies... responsible for requesting clearance of its counsel well in advance so that clearance requirements will...

  17. Evaluation of an Active Clearance Control System Concept

    NASA Technical Reports Server (NTRS)

    Steinetz, Bruce M.; Lattime, Scott B.; Taylor, Shawn; DeCastro, Jonathan A.; Oswald, Jay; Melcher, Kevin J.

    2005-01-01

    Reducing blade tip clearances through active tip clearance control in the high pressure turbine can lead to significant reductions in emissions and specific fuel consumption as well as dramatic improvements in operating efficiency and increased service life. Current engines employ scheduled cooling of the outer case flanges to reduce high pressure turbine tip clearances during cruise conditions. These systems have relatively slow response and do not use clearance measurement, thereby forcing cold build clearances to set the minimum clearances at extreme operating conditions (e.g., takeoff, reburst) and not allowing cruise clearances to be minimized due to the possibility of throttle transients (e.g., step change in altitude). In an effort to improve upon current thermal methods, a first generation mechanically-actuated active clearance control (ACC) system has been designed and fabricated. The system utilizes independent actuators, a segmented shroud structure, and clearance measurement feedback to provide fast and precise active clearance control throughout engine operation. Ambient temperature performance tests of this first generation ACC system assessed individual seal component leakage rates and both static and dynamic overall system leakage rates. The ability of the nine electric stepper motors to control the position of the seal carriers in both open- and closed-loop control modes for single and multiple cycles was investigated. The ability of the system to follow simulated engine clearance transients in closed-loop mode showed the system was able to track clearances to within a tight tolerance ( 0.001 in. error).

  18. Evaluation of an Active Clearance Control System Concept

    NASA Technical Reports Server (NTRS)

    Steinetz, Bruce M.; Lattime, Scott B.; DeCastro, Jonathan A.; Oswald, Jay; Melcher, Kevin J.

    2005-01-01

    Reducing blade tip clearances through active tip clearance control in the high pressure turbine can lead to significant reductions in emissions and specific fuel consumption as well as dramatic improvements in operating efficiency and increased service life. Current engines employ scheduled cooling of the outer case flanges to reduce high pressure turbine tip clearances during cruise conditions. These systems have relatively slow response and do not use clearance measurement, thereby forcing cold build clearances to set the minimum clearances at extreme operating conditions (e.g., takeoff, reburst) and not allowing cruise clearances to be minimized due to the possibility of throttle transients (e.g., step change in altitude). In an effort to improve upon current thermal methods, a first generation mechanically-actuated active clearance control (ACC) system has been designed and fabricated. The system utilizes independent actuators, a segmented shroud structure, and clearance measurement feedback to provide fast and precise active clearance control throughout engine operation. Ambient temperature performance tests of this first generation ACC system assessed individual seal component leakage rates and both static and dynamic overall system leakage rates. The ability of the nine electric stepper motors to control the position of the seal carriers in both open- and closed-loop control modes for single and multiple cycles was investigated. The ability of the system to follow simulated engine clearance transients in closed-loop mode showed the system was able to track clearances to within a tight tolerance (0.001 in. error).

  19. Success and Challenges of a Community Healthy Lifestyles Intervention in Merseyside (UK) to Target Families at Risk from Coronary Heart Disease

    ERIC Educational Resources Information Center

    Peerbhoy, D.; Majumdar, A. J.; Wightman, N. A.; Brand, V. L.

    2008-01-01

    Objective: To document the lifestyle health impacts (activity, diet and physiological), along with the operational success and challenges, of a programme for families presenting one or more coronary heart disease (CHD) risk factor. Design: Data are based on a wider evaluation of a government-funded community initiative conducted in a deprived area…

  20. The Effect of Contingent Reinforcement on Target Variables in Outpatient Psychotherapy for Depression: A Successful and Unsuccessful Case Using Functional Analytic Psychotherapy

    ERIC Educational Resources Information Center

    Kanter, Jonathan W.; Landes, Sara J.; Busch, Andrew M.; Rusch, Laura C.; Brown, Keri R.; Baruch, David E.; Holman, Gareth I.

    2006-01-01

    The current study investigated a behavior-analytic treatment, functional analytic psychotherapy (FAP), for outpatient depression utilizing two single-subject A/A+B designs. The baseline condition was cognitive behavioral therapy. Results demonstrated treatment success in 1 client after the addition of FAP and treatment failure in the 2nd. This…

  1. Axial compressor blade design for desensitization of aerodynamic performance and stability to tip clearance

    NASA Astrophysics Data System (ADS)

    Erler, Engin

    of the local blade passage. These flow features are isolated and validated based on the reference rotor design through changes in the inlet total pressure condition to alter incoming flow momentum and blade number count to change double leakage rate. In terms of flow mechanism, double leakage is shown to be detrimental to performance and stability, and its proportional increase with tip clearance size explains the sensitivity increase in the presence of double leakage and, conversely, the desensitization effect of reducing or eliminating double leakage. The increase in incoming meridional momentum in the tip region reduces sensitivity to tip clearance through its reduction of double leakage as well as through improved mixing with tip clearance flow, as demonstrated by an analytical model without double leakage flow. The above results imply that any blade design strategy that exploits the two desensitizing flow features would reduce the performance and stability sensitivity to tip clearance size. The increase of the incoming meridional momentum can be achieved through forward chordwise sweep of the blade. The reduction of double leakage without changing blade pitch can be obtained by decreasing the blade stagger angle in the tip region. Examples of blade designs associated with these strategies are shown through CFX simulations to be successful in reducing sensitivity to tip clearance size.

  2. Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition.

    PubMed

    Liu, Chia-Chen; Hu, Jin; Zhao, Na; Wang, Jian; Na, Wang; Cirrito, John R; Kanekiyo, Takahisa; Holtzman, David M; Bu, Guojun

    2017-03-08

    address the role of a critical Aβ receptor, the low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. We found that LRP1 in astrocytes plays a critical role in brain Aβ clearance by modulating several Aβ-degrading enzymes and cellular degradation pathways. Our results establish a critical role of astrocytic LRP1 in brain Aβ clearance and shed light on specific Aβ clearance pathways that may help to establish new targets for AD prevention and therapy.

  3. HPV Clearance and the Neglected Role of Stochasticity

    PubMed Central

    Ryser, Marc D.; Myers, Evan R.; Durrett, Rick

    2015-01-01

    Clearance of anogenital and oropharyngeal HPV infections is attributed primarily to a successful adaptive immune response. To date, little attention has been paid to the potential role of stochastic cell dynamics in the time it takes to clear an HPV infection. In this study, we combine mechanistic mathematical models at the cellular level with epidemiological data at the population level to disentangle the respective roles of immune capacity and cell dynamics in the clearing mechanism. Our results suggest that chance—in form of the stochastic dynamics of basal stem cells—plays a critical role in the elimination of HPV-infected cell clones. In particular, we find that in immunocompetent adolescents with cervical HPV infections, the immune response may contribute less than 20% to virus clearance—the rest is taken care of by the stochastic proliferation dynamics in the basal layer. In HIV-negative individuals, the contribution of the immune response may be negligible. PMID:25769112

  4. Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles

    PubMed Central

    2008-01-01

    Nanoparticle (NP) drug delivery systems (5−250 nm) have the potential to improve current disease therapies because of their ability to overcome multiple biological barriers and releasing a therapeutic load in the optimal dosage range. Rapid clearance of circulating nanoparticles during systemic delivery is a critical issue for these systems and has made it necessary to understand the factors affecting particle biodistribution and blood circulation half-life. In this review, we discuss the factors which can influence nanoparticle blood residence time and organ specific accumulation. These factors include interactions with biological barriers and tunable nanoparticle parameters, such as composition, size, core properties, surface modifications (pegylation and surface charge), and finally, targeting ligand functionalization. All these factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, delaying opsonization, and increasing the extent of tissue specific accumulation. PMID:18672949

  5. The effect of contingent reinforcement on target variables in outpatient psychotherapy for depression: a successful and unsuccessful case using functional analytic psychotherapy.

    PubMed

    Kanter, Jonathan W; Landes, Sara J; Busch, Andrew M; Rusch, Laura C; Brown, Keri R; Baruch, David E; Holman, Gareth I

    2006-01-01

    The current study investigated a behavior-analytic treatment, functional analytic psychotherapy (FAP), for outpatient depression utilizing two single-subject A/A+B designs. The baseline condition was cognitive behavioral therapy. Results demonstrated treatment success in 1 client after the addition of FAP and treatment failure in the 2nd. This study highlights the challenges in measuring treatment progress and outcome idiographically in this population.

  6. Market Mechanism for Line Congestion Clearance

    NASA Astrophysics Data System (ADS)

    Ruiz Monroy, José Joaquín; Kita, Hiroyuki; Tanaka, Eiichi; Hasegawa, Jun

    This paper proposes a mechanism for clearance of line congestion and power flow control in a deregulated market environment. The mechanism applies penalties to the bilateral transactions that cause line congestion by increasing the prices of such transactions. The market regulates itself by redefining the transactions and checking again for violations, applying penalties if necessary and repeating the process until all the demand is satisfied without causing line congestion to the system. A bilateral transaction matrix (BTM) creation algorithm developed by the authors and a DC power flow program are integrated as parts of the market mechanism proposed in this paper. The congestion is cleared by the market participants when they reschedule their transactions. This mechanism is useful to study the effects of bilateral transactions on a power system and helps the Independent System Operator (ISO) to create rules and market mechanisms for line congestion clearance and power flow control.

  7. Clearance Kinetics and Clearance Routes of Molecules From the Suprachoroidal Space After Microneedle Injection

    PubMed Central

    Chiang, Bryce; Wang, Ke; Ethier, C. Ross; Prausnitz, Mark R.

    2017-01-01

    Purpose To determine clearance kinetics and routes of clearance of molecules from the suprachoroidal space (SCS) of live New Zealand White rabbits. Methods Suprachoroidal space collapse rate and pressure changes after microneedle injection into SCS were determined. Fluorescent fundus images were acquired to determine clearance rates of molecules ranging in size from 332 Da to 2 MDa. Microneedle injections of fluorescein were performed, and samples were taken from various sites over time to determine amount of fluorescein exiting the eye. Clearance transport was modeled theoretically and compared with experimental data. Results After injection, pressures in SCS and vitreous humor spiked and returned to baseline within 20 minutes; there was no difference between these two pressures. Suprachoroidal space collapse occurred within 40 minutes. One hour after fluorescein injection, 46% of fluorescein was still present in the eye, 15% had transported across sclera, 6% had been cleared by choroidal vasculature, and 4% had exited via leakage pathways. Characteristic clearance time increased in proportion with molecular radius, but total clearance of 2 MDa FITC-dextran was significantly slower (21 days) than smaller molecules. These data generally agreed with predictions from a theoretical model of molecular transport. Conclusions Guided by experimental data in the context of model predictions, molecular clearance from SCS occurred in three regimes: (1) on a time scale of approximately 10 minutes, fluid and molecules exited SCS by diffusion into sclera and choroid, and by pressure-driven reflux via transscleral leakage sites; (2) in approximately 1 hour, molecules cleared from choroid by blood flow; and (3) in 1 to 10 hours, molecules cleared from sclera by diffusion and convection. PMID:28125841

  8. Effect of ultrafiltration on peritoneal dialysis drug clearances.

    PubMed

    Lau, A H; Chow-Tung, E; Assadi, F K; Fornell, L; John, E

    1985-01-01

    To determine the effect of dialysate osmolarity on peritoneal dialysis drug transfer, peritoneal dialysis clearances of theophylline, phenobarbital, and tobramycin were determined in 10 rabbits using dialysate containing 1.5 and 4.25% glucose. Urea and creatinine clearances were also obtained for comparison. Under similar dialysis conditions, the peritoneal clearances of the three drugs remained unchanged for the two types of dialysate. In contrast, the peritoneal clearances of urea and creatinine were significantly higher with the use of 4.25% glucose dialysate (p less than 0.001). Thus, peritoneal dialysis clearances of theophylline, phenobarbital and tobramycin are not significantly affected by hypertonicity-induced ultrafiltration during acute peritoneal dialysis.

  9. Limiting the protein corona: A successful strategy for in vivo active targeting of anti-HER2 nanobody-functionalized nanostars.

    PubMed

    D'Hollander, Antoine; Jans, Hilde; Velde, Greetje Vande; Verstraete, Charlotte; Massa, Sam; Devoogdt, Nick; Stakenborg, Tim; Muyldermans, Serge; Lagae, Liesbet; Himmelreich, Uwe

    2017-04-01

    Gold nanoparticles hold great promise as anti-cancer theranostic agents against cancer by actively targeting the tumor cells. As this potential has been supported numerously during in vitro experiments, the effective application is hampered by our limited understanding and control of the interactions within complex in vivo biological systems. When these nanoparticles are exposed to a biological environment, their surfaces become covered with proteins and biomolecules, referred to as the protein corona, reducing the active targeting capabilities. We demonstrate a chemical strategy to overcome this issue by reducing the protein corona's thickness by blocking the active groups of the self-assembled monolayer on gold nanostars. An optimal blocking agent, 2-mercapto ethanol, has been selected based on charge and length of the carbon chain. By using a nanobody as a biological ligand of the human epidermal growth factor 2 receptor (HER2), the active targeting is demonstrated in vitro and in vivo in an experimental tumor model by using darkfield microscopy and photoacoustic imaging. In this study, we have established gold nanostars as a conceivable theranostic agent with a specificity for HER2-positive tumors.

  10. Deposition and clearance of inhaled particles.

    PubMed Central

    Stuart, B O

    1976-01-01

    Theoretical models of respiratory tract deposition of inhaled particles are compared to experimental studies of deposition patterns in humans and animals, as determined principally by particle size, density, respiratory rate and flow parameters. Various models of inhaled particle deposition make use of convenient approximations of the respiratory tract to predict tractional deposition according to fundamental physical processes of impaction, sedimentation, and diffusion. These theoretical models for both total deposition and regional (nasopharyngeal, tracheobronchial, and pulmonary) deposition are compared with experimental studies of inhaled dusts in humans or experimental animals that have been performed in many laboratories over several decades. Reasonable correlation has been obtained between theoretical and experimental studies, but the behavior of very fine (less than 0.01 mum) particles requires further refinement.Properties of particle shape, charge, and hygroscopicity as well as the degree of respiratory tract pathology also influence deposition patterns and further experimental work is urgently needed in these areas. The influence upon deposition patterns of dynamic alterations in inspiratory flow profiles caused by a variety of breathing patterns also requires further study, and the use of such techniques with selected inhaled particle size holds promise in possible diagnostic aid in diagnosis of normal versus disease conditions. Mechanisms of conducting airway and alveolar clearance processes involving mucociliary clearance, dissolution, transport to systemic circulation, and translocation via regional lymphatic clearance are discussed. The roles of the pulmonary macrophage in airway and alveolar clearance are described, and the applicability of recent solubility models for translocation or deposited materials to liver, skeleton, or other systemic organs is discussed. PMID:797567

  11. Activating the 42d Clearance Company

    DTIC Science & Technology

    2011-12-01

    System– Enhanced. ■ Establishing supply and maintenance accounts. ■ Procuring the unit guidon . Other documents created to expedite and track the...SUBTITLE Activating the 42d Clearance Company 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) 5d. PROJECT NUMBER 5e. TASK...NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES) Army Engineer School,Engineer Professional Bulletin,464 MANSCEN

  12. Army Delivers Route Clearance Vehicle Capabilities

    DTIC Science & Technology

    2010-08-01

    the Husky Vehicle-Mount- ed Mine-Detection (VMMD) System, the Buffalo® Mine- Protected Clearance Vehicle (MPCV), the Panther Medium Mine-Protected...cord (POR) RCVs—the Husky, the Buf- falo, and the Panther . POR-configured Huskys, Buffalos, and Panthers have already been fielded in-theater—albeit...IED vehicle equipped with a distinctive hydraulic arm that inter- rogates suspected explosive hazards and clears them when necessary. The Panther

  13. Reduced methadone clearance during aromatase inhibition.

    PubMed

    Lu, Wenjie Jessie; Thong, Nancy; Flockhart, David A

    2012-08-01

    Methadone is increasingly used in pain management and is a cornerstone in the treatment of opiate withdrawal. It is subject to highly variable clearance among patients. The complete metabolic disposition of methadone is likely to involve a number of enzymes, including specifically CYP2B6. Previous studies in vitro suggest that metabolism by aromatase may also contribute. Single-dose methadone pharmacokinetics (2 mg, intravenous) were studied in 15 healthy postmenopausal women in the presence and absence of a potent aromatase inhibitor, letrozole. A sequential design was used, involving a control period followed by treatment with letrozole (2.5 mg/d, 11 days), in which each subject served as her own control. On average, letrozole treatment reduced methadone systemic clearance by 22% (P = 0.001), increased methadone AUC by 23% (P = 0.007), and increased elimination half-life by 21% (P = 0.042). The plasma parent-to-metabolite ratio also increased (P = 0.009), and there was a linear relationship (R2 = 0.74) between change in this plasma ratio and change in methadone AUC0-∞. In contrast, there was no such association with change in apparent urinary methadone clearance. Letrozole did not change methadone distribution half-life or its volume of distribution. Overall, these data demonstrate a significant decrease in methadone clearance during coadministration of letrozole, consistent with decreased metabolism brought about by aromatase inhibition. An involvement of aromatase in the disposition of methadone may help explain the difficulty in methadone dosing and suggests a broader role for this catalyst of endogenous steroid metabolism in xenobiotic drug disposition.

  14. The effect of solubility on inhaled uranium compound clearance: a review.

    PubMed

    Eidson, A F

    1994-07-01

    Research on inhaled industrial uranium compounds has shown that solubility influences the target organ, the toxic response, and the mode of uranium excretion. Consideration of physical chemical properties indicates that the dissolution of industrial uranium oxides is expected to be strongly dependent on process history, and that dissolved uranium exists in vivo in the hexavalent state regardless of the oxidation state of the inhaled compound. The overall clearance rate of uranium compounds from the lung reflects both mechanical and dissolution processes. Mechanical clearance rates are highly variable among individual workers studied, but dissolution rates of inhaled compounds are similar among the mammalian species studied. Results from experiments in vivo and accidental worker exposures indicate that the uptake of dissolved uranium from the lung is more rapid than the dissolution rate of most industrial uranium compounds. These results indicate that the absorption rate of inhaled uranium can be approximated by the dissolution rate of most industrial compounds. Dissolution rates of UF6 and UO2(NO3)2 are more rapid than the mechanical clearance rates and dominate the overall lung clearance rate. UF4, UO3, and ammonium diuranate have intermediate dissolution rates that are similar to mechanical clearance rates and exhibit high variability among uranium specimens. U3O8 and UO2 have slow dissolution rates such that pulmonary clearance rates are dominated by mechanical processes. Industrial uranium ores, oxides, and fluorides are often variable mixtures of relatively soluble and insoluble fractions. Dissolution rates measured in vitro can be used with biokinetics models to reduce the uncertainties in dosimetry associated with inhalation exposures to mixtures.

  15. Similarity analysis of compressor tip clearance flow structure

    NASA Technical Reports Server (NTRS)

    Chen, G. T.; Greitzer, E. M.; Tan, C. S.; Marble, F. E.

    1991-01-01

    A new approach is presented for analyzing compressor tip clearance flow. The basic idea is that the clearance velocity field can be (approximately) decomposed into independent throughflow and crossflow, since chordwise pressure gradients are much smaller than normal pressure gradients in the clearance region. As in the slender body approximation in external aerodynamics, this description implies that the three-dimensional steady clearance flow can be viewed as a two-dimensional, unsteady flow. Using this approach, a similarity scaling for the crossflow in the clearance region is developed and a generalized description of the clearance vortex is derived. Calculations based on the similarity scaling agree well with a wide range of experimental data in regard to flow features such as crossflow velocity field, static pressure field, and tip clearance vortex trajectory.

  16. Deposition, retention, and clearance of inhaled particles.

    PubMed Central

    Lippmann, M; Yeates, D B; Albert, R E

    1980-01-01

    The relation between the concentrations and characteristics of air contaminants in the work place and the resultant toxic doses and potential hazards after their inhalation depends greatly on their patterns of deposition and the rates and pathways for their clearance from the deposition sites. The distribution of the deposition sites of inhaled particles is strongly dependent on their aerodynamic diameters. For normal man, inhaled non-hygroscopic particles greater than or equal to 2 micrometers that deposit in the conducting airways by impaction are concentrated on to a small fraction of the surface. Cigarette smoking and bronchitis produce a proximal shift in the deposition pattern. The major factor affecting the deposition of smaller particles is their transfer from tidal to reserve air. For particles soluble in respiratory tract fluid, systemic uptake may be relatively complete for all deposition patterns, and there may be local toxic or irritant effects or both. On the other hand, slowly soluble particles depositing in the conducting airways are carried on the surface to the glottis and are swallowed within one day. Mucociliary transport rates are highly variable, both along the ciliated airways of a given individual and between individuals. The changes in clearance rates produced by drugs, cigarette smoke, and other environmental pollutants can greatly increase or decrease these rates. Particles deposited in non-ciliated airways have large surface-to-volume ratios, and clearance by dissolution can occur for materials generally considered insoluble. They may also be cleared as free particles either by passive transport along surface liquids or, after phagocytosis, by transport within alveolar macrophages. If the particles penetrate the epithelium, either bare or within macrophages, they may be sequestered within cells or enter the lymphatic circulation and be carried to pleural, hilar, and more distant lymph nodes. Non-toxic insoluble particles are cleared from

  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2

    PubMed Central

    Boswell, C Andrew; Mundo, Eduardo E; Firestein, Ron; Zhang, Crystal; Mao, Weiguang; Gill, Herman; Young, Cynthia; Ljumanovic, Nina; Stainton, Shannon; Ulufatu, Sheila; Fourie, Aimee; Kozak, Katherine R; Fuji, Reina; Polakis, Paul; Khawli, Leslie A; Lin, Kedan

    2013-01-01

    Background and Purpose The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental Approach A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography – X-ray computed tomography imaging and immunohistochemistry. Key Results The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and Implications Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues. PMID:22889168

  18. Successful β cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1.

    PubMed

    Chen, Shuyuan; Bastarrachea, Raul A; Roberts, Brad J; Voruganti, V Saroja; Frost, Patrice A; Nava-Gonzalez, Edna J; Arriaga-Cazares, Hector E; Chen, Jiaxi; Huang, Pintong; DeFronzo, Ralph A; Comuzzie, Anthony G; Grayburn, Paul A

    2014-01-01

    Both major forms of diabetes mellitus (DM) involve β-cell destruction and dysfunction. New treatment strategies have focused on replenishing the deficiency of β-cell mass common to both major forms of diabetes by islet transplantation or β-cell regeneration. The pancreas, not the liver, is the ideal organ for islet regeneration, because it is the natural milieu for islets. Since islet mass is known to increase during obesity and pregnancy, the concept of stimulating pancreatic islet regeneration in vivo is both rational and physiologic. This paper proposes a novel approach in which non-viral gene therapy is targeted to pancreatic islets using ultrasound targeted microbubble destruction (UTMD) in a non-human primate model (NHP), the baboon. Treated baboons received a gene cocktail comprised of cyclinD2, CDK, and GLP1, which in rats results in robust and durable islet regeneration with normalization of blood glucose, insulin, and C-peptide levels. We were able to generate important preliminary data indicating that gene therapy by UTMD can achieve in vivo normalization of the intravenous (IV) glucose tolerance test (IVGTT) curves in STZ hyperglycemic-induced conscious tethered baboons. Immunohistochemistry clearly demonstrated evidence of islet regeneration and restoration of β-cell mass.

  19. Evaluation of vascular clearance as a marker for virulence of alphaviruses: disassociation of rapid clearance with low virulence of venezuelan encephalitis virus strains in guinea pigs.

    PubMed Central

    Jahrling, P B; Heisey, G B; Hesse, R A

    1977-01-01

    The concept that relates low virulence of certain alphaviruses to low viremia and efficient vascular clearance of virus was tested in guinea pigs. Previously published studies with hamsters suggested that virulent strains maintain high viremias primarily because they are cleared inefficiently from the blood. In the present study, with guinea pigs, six of six virulent strains of Venezuelan encephalitis virus were cleared inefficiently, whereas three of six nonlethal or benign virus strains were cleared rapidly. However, three other guinea pig-benign Venezuelan encephalitis virus strains cleared slowly, to produce a high viremia was correlated with inefficient growth in primary viral replication sites. Thus, the potential of some alphaviruses to produce destructive lesions may be restricted by efficient clearance of virus from the blood, whereas the growth of other benign alphavirus strains may be restricted after the virus is presented to target cells. PMID:892910

  20. Targeted therapy using nanotechnology: focus on cancer

    PubMed Central

    Sanna, Vanna; Pala, Nicolino; Sechi, Mario

    2014-01-01

    Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication. PMID:24531078

  1. Intrinsic Clearance of Xenobiotic Chemicals by Liver Microsomes: Assessment of Trophic Magnification Potentials.

    PubMed

    Guomao, Zheng; Yi, Wan; Jianying, Hu

    2016-06-21

    The use of trophic magnification factors (TMFs) to characterize the bioaccumulation potentials of chemicals was encouraged; however, the method for the assessment of trophic magnification potentials is still lacking. We optimized the in vitro assays used for the measurement of intrinsic clearance in liver microsomes by incorporating benzo[a]pyrene (B(a)P) as a benchmark compound. The intrinsic clearance of 40 compounds was then measured in microsomes from fish (weevers) and birds (quail); the characteristics of the trophic transfer of these 40 compounds were previously investigated in an aquatic food web in Bohai in northern China. Chemicals that are biotransformed at a rate similar to or higher than that of B[a]P in the microsomes of both weevers and quail (in vitro intrinsic clearance values, CL; CL/CLB[a]P: 0.1 to 2.4) generally exhibited no significant trophic magnification or dilution in the food web (TMF ≈ 1 or < 1), whereas chemicals that are biotransformed at extremely slow rates compared with B[a]P (CL/CLB[a]P: 0 to 0.2) showed significant trophic magnification in the food web (TMF > 1). The in vitro intrinsic clearance values of the target chemicals were found to be consistent with their respective trophic transfer behavior in the aquatic food web. Significant negative correlations were also found between the TMFs and the intrinsic clearance values of all target chemicals obtained in microsomes from both weevers and quail. Multiple linear regression analysis showed that biotransformation rates (CL/CLB[a]P) are a more important factor compared with the lipophilicity of the chemicals (log Kow) in the assessment of the trophic magnification of chemicals in the aquatic food web.

  2. Testing of a Microwave Blade Tip Clearance Sensor at the NASA Glenn Research Center

    NASA Technical Reports Server (NTRS)

    Woike, Mark R.; Roeder, James W.; Hughes, Christopher E.; Bencic, Timothy J.

    2009-01-01

    The development of new active tip clearance control and structural health monitoring schemes in turbine engines and other types of rotating machinery requires sensors that are highly accurate and can operate in a high temperature environment. The use of a microwave sensor to acquire blade tip clearance and tip timing measurements is being explored at the NASA Glenn Research Center. The microwave blade tip clearance sensor works on principles that are very similar to a short range radar system. The sensor sends a continuous microwave signal towards a target and measures the reflected signal. The phase difference of the reflected signal is directly proportional to the distance between the sensor and the target being measured. This type of sensor is beneficial in that it has the ability to operate at extremely high temperatures and is unaffected by contaminants that may be present in turbine engines. The use of microwave sensors for this application is a new concept. Techniques on calibrating the sensors along with installation effects are not well quantified as they are for other sensor technologies. Developing calibration techniques and evaluating installation effects are essential in using these sensors to make tip clearance and tip timing measurements. As a means of better understanding these issues, the microwave sensors were used on a bench top calibration rig, a large axial vane fan, and a turbofan. Background on the microwave tip clearance sensor, an overview of their calibration, and the results from their use on the axial vane fan and the turbofan will be presented in this paper.

  3. Testing of a Microwave Blade Tip Clearance Sensor at the NASA Glenn Research Center

    NASA Technical Reports Server (NTRS)

    Woike, Mark R.; Roeder, James W.; Hughes, Christopher E.; Bencic, Timothy J.

    2009-01-01

    The development of new active tip clearance control and structural health monitoring schemes in turbine engines and other types of rotating machinery requires sensors that are highly accurate and can operate in a high-temperature environment. The use of a microwave sensor to acquire blade tip clearance and tip timing measurements is being explored at the NASA Glenn Research Center. The microwave blade tip clearance sensor works on principles that are very similar to a short-range radar system. The sensor sends a continuous microwave signal towards a target and measures the reflected signal. The phase difference of the reflected signal is directly proportional to the distance between the sensor and the target being measured. This type of sensor is beneficial in that it has the ability to operate at extremely high temperatures and is unaffected by contaminants that may be present in turbine engines. The use of microwave sensors for this application is a new concept. Techniques on calibrating the sensors along with installation effects are not well quantified as they are for other sensor technologies. Developing calibration techniques and evaluating installation effects are essential in using these sensors to make tip clearance and tip timing measurements. As a means of better understanding these issues, the microwave sensors were used on a benchtop calibration rig, a large axial vane fan, and a turbofan. Background on the microwave tip clearance sensor, an overview of their calibration, and the results from their use on the axial vane fan and the turbofan will be presented in this paper.

  4. Human-in-the-Loop Assessment of Alternative Clearances in Interval Management Arrival Operations

    NASA Technical Reports Server (NTRS)

    Baxley, Brian T.; Wilson, Sara R.; Swieringa, Kurt A.; Johnson, William C.; Roper, Roy D.; Hubbs, Clay E.; Goess, Paul A.; Shay, Richard F.

    2016-01-01

    Interval Management Alternative Clearances (IMAC) was a human-in-the-loop simulation experiment conducted to explore the Air Traffic Management (ATM) Technology Demonstration (ATD-1) Concept of Operations (ConOps), which combines advanced arrival scheduling, controller decision support tools, and aircraft avionics to enable multiple time deconflicted, efficient arrival streams into a high-density terminal airspace. Interval Management (IM) is designed to support the ATD-1 concept by having an "Ownship" (IM-capable) aircraft achieve or maintain a specific time or distance behind a "Target" (preceding) aircraft. The IM software uses IM clearance information and the Ownship data (route of flight, current location, and wind) entered by the flight crew, and the Target aircraft's Automatic Dependent Surveillance-Broadcast state data, to calculate the airspeed necessary for the IM-equipped aircraft to achieve or maintain the assigned spacing goal.

  5. Characterisation of foot clearance during gait in people with early Parkinson׳s disease: Deficits associated with a dual task.

    PubMed

    Alcock, Lisa; Galna, Brook; Lord, Sue; Rochester, Lynn

    2016-09-06

    Tripping is a common cause of falls in older adults and people with Parkinson׳s disease (PD). Foot clearance during gait may be impaired when distracted by a dual task and thus inform trip risk. This study aimed to evaluate whether foot clearance is impaired in PD and is adversely affected by a dual task. 81 older adults and 76 PD walked at a comfortable pace for two minutes under single and dual task conditions (digit recall). Temporal spatial gait was measured using an instrumented walkway. Heel and toe trajectories were obtained bilaterally using 3-dimensional motion capture. Foot clearance was reduced in PD (p<.001) and under dual task (p<.027). The take-off (toe) gradient was reduced under dual task irrespective of group and the landing (heel) gradient was reduced in PD irrespective of task (p<.001). An increased proportion of unimodal toe distributions were observed for PD, particularly under dual task. Group differences were retained when controlling for step length (landing gradient and peak toe clearance in late swing) and gait velocity (landing gradient). Distinct differences in foot clearance were observed even in the early clinical stages of PD. Dual tasking may increase trip risk due to insufficient toe clearance (early swing) for both older adults and PD. Inadequate heel clearance (late swing) may increase falls risk in PD. Clearance deficits in PD are partially related to a reduced gait velocity and step length which may be targeted in tailored therapies. Further work is necessary to understand the mechanisms underlying this pathology-associated deficit.

  6. Tip Clearance Control Using Plasma Actuators

    DTIC Science & Technology

    2007-03-01

    Clearance Control Using Plasma Actuators 4 posed by Denton (1993). A number of investigators have used partial shrouds, or " winglet " designs to...main molded blade with a span of 3.42 in., a removable molded blade segment with a span of 0.1875 in., and removable blade tip winglets made of glass...segment and the main blade to vary the distance between the blade end and the front wall of the cascade section. The winglets were machined using a

  7. Statistical Tolerance and Clearance Analysis for Assembly

    NASA Technical Reports Server (NTRS)

    Lee, S.; Yi, C.

    1996-01-01

    Tolerance is inevitable because manufacturing exactly equal parts is known to be impossible. Furthermore, the specification of tolerances is an integral part of product design since tolerances directly affect the assemblability, functionality, manufacturability, and cost effectiveness of a product. In this paper, we present statistical tolerance and clearance analysis for the assembly. Our proposed work is expected to make the following contributions: (i) to help the designers to evaluate products for assemblability, (ii) to provide a new perspective to tolerance problems, and (iii) to provide a tolerance analysis tool which can be incorporated into a CAD or solid modeling system.

  8. Dynamics analysis of space robot manipulator with joint clearance

    NASA Astrophysics Data System (ADS)

    Zhao, Yang; Bai, Zheng Feng

    2011-04-01

    A computational methodology for analysis of space robot manipulator systems, considering the effects of the clearances in the joint, is presented. The contact dynamics model in joint clearance is established using the nonlinear equivalent spring-damp model and the friction effect is considered using the Coulomb friction model. The space robot system dynamic equation of manipulator with clearance is established. Then the dynamics simulation is presented and the dynamics characteristics of robot manipulator with clearance are analyzed. This work provides a practical method to analyze the dynamics characteristics of space robot manipulator with joint clearance and improves the engineering application. The computational methodology can predict the effects of clearance on space robot manipulator preferably, which is the basis of space robot manipulator design, precision analysis and ground test.

  9. Study of blade clearance effects on centrifugal pumps

    NASA Technical Reports Server (NTRS)

    Hoshide, R. K.; Nielson, C. E.

    1972-01-01

    A program of analysis, design, fabrication, and testing has been conducted to develop and experimentally verify analytical models to predict the effects of impeller blade clearance on centrifugal pumps. The effect of tip clearance on pump efficiency, and the relationship between the head coefficient and torque loss with tip clearance was established. Analysis were performed to determine the cost variation in design, manufacture, and test that would occur between unshrouded and shrouded impellers. An impeller, representative of typical rocket engine impellers, was modified by removing its front shroud to permit variation of its blade clearances. It was tested in water with special instrumentation to provide measurements of blade surface pressures during operation. Pump performance data were obtained from tests at various impeller tip clearances. Blade pressure data were obtained at the nominal tip clearance. Comparisons of predicted and measured data are given.

  10. Numerical investigation of hub clearance flow in a Kaplan turbine

    NASA Astrophysics Data System (ADS)

    Wu, H.; Feng, J. J.; Wu, G. K.; Luo, X. Q.

    2012-11-01

    In this paper, the flow field considering the hub clearance flow in a Kaplan turbine has been investigated through using the commercial CFD code ANSYS CFX based on high-quality structured grids generated by ANSYS ICEM CFD. The turbulence is simulated by k-ω based shear stress transport (SST) turbulence model together with automatic near wall treatments. Four kinds of simulations have been conducted for the runner geometry without hub clearance, with only the hub front clearance, with only the rear hub clearance, and with both front and rear clearance. The analysis of the obtained results is focused on the flow structure of the hub clearance flow, the effect on the turbine performance including hydraulic efficiency and cavitation performance, which can improve the understanding on the flow field in a Kaplan turbine.

  11. Peptide-perylene diimide functionalized magnetic nano-platforms for fluorescence turn-on detection and clearance of bacterial lipopolysaccharides.

    PubMed

    Liu, Fang; Mu, Jing; Wu, Xiangyang; Bhattacharjya, Surajit; Yeow, Edwin Kok Lee; Xing, Bengang

    2014-06-14

    A simple and unique strategy has been successfully designed for sensitive detection and rapid clearance of bacterial lipopolysaccharides (LPS) by integration of core-shell Fe3O4@SiO2 magnetic nanoparticles with a perylene-diimide (PDI) conjugated LPS-recognition peptide.

  12. Zygote injection of CRISPR/Cas9 RNA successfully modifies the target gene without delaying blastocyst development or altering the sex ratio in pigs.

    PubMed

    Whitworth, Kristin M; Benne, Joshua A; Spate, Lee D; Murphy, Stephanie L; Samuel, Melissa S; Murphy, Clifton N; Richt, Jürgen A; Walters, Eric; Prather, Randall S; Wells, Kevin D

    2017-02-01

    The CRISPR/Cas9 genome editing tool has increased the efficiency of creating genetically modified pigs for use as biomedical or agricultural models. The objectives were to determine if DNA editing resulted in a delay in development to the blastocyst stage or in a skewing of the sex ratio. Six DNA templates (gBlocks) that were designed to express guide RNAs that target the transmembrane protease, serine S1, member 2 (TMPRSS2) gene were in vitro transcribed. Pairs of CRISPR guide RNAs that flanked the start codon and polyadenylated Cas9 were co-injected into the cytoplasm of zygotes and cultured in vitro to the blastocyst stage. Blastocysts were collected as they formed on days 5, 6 or 7. PCR was performed to determine genotype and sex of each embryo. Separately, embryos were surgically transferred into recipient gilts on day 4 of estrus. The rate of blastocyst development was not significantly different between CRISPR injection embryos or the non-injected controls at day 5, 6 or 7 (p = 0.36, 0.09, 0.63, respectively). Injection of three CRISPR sets of guides resulted in a detectable INDEL in 92-100 % of the embryos analyzed. There was not a difference in the number of edits or sex ratio of male to female embryos when compared between days 5, 6 and 7 to the controls (p > 0.22, >0.85). There were 12 resulting piglets and all 12 had biallelic edits of TMRPSS2. Zygote injection with CRISPR/Cas9 continues to be a highly efficient tool to genetically modify pig embryos.

  13. Measuring foot placement and clearance during stair descent.

    PubMed

    Muhaidat, Jennifer; Kerr, Andrew; Rafferty, Danny; Skelton, Dawn A; Evans, Jonathan J

    2011-03-01

    Falls during stair descent are a serious problem and can lead to accidental death. Inappropriate foot placement on, and clearance over, steps have been identified as causes for falls on stairs. This study investigated a new method for measuring placement and clearance during stair descent in 10 healthy young subjects. The effect of foot length was accounted for during the measurement of foot placement by calculating the percentage length of the foot overhanging the step. Foot clearance was measured as the resultant of the minimum vertical and horizontal distances from the heel of the foot to the edge of the step. Clearance was divided into landing and passing clearance depending on the planned placement of the foot in relation to the step edge being cleared. Each subject performed seven trials of stairs descent. Mean (SD) and CV (SD) were 16% (6), 0.28 (0.15) for placement; 45.88 (10.05), 0.21 (0.07) for landing clearance; 107.25 (5.59), 0.25 (0.08) for passing clearance. There was no statistically significant effect of trial on placement and clearance (p>0.05). There was a significant effect of step number on landing and passing clearance (p=0.01, p<0.001 respectively). Landing and passing clearances were greater for the third step compared to the second step. Passing clearance was also significantly greater than landing clearance (p<0.001). The repeatable methods and findings from this study might be useful in providing a technical background and normal values for the design of future gait studies on stairs.

  14. Deposition and clearance of inhaled particles.

    PubMed Central

    Stuart, B O

    1984-01-01

    Theoretical models of respiratory tract deposition of inhaled particles are compared to experimental studies of deposition patterns in humans and animals, as governed principally by particle size, density, respiratory rate and flow parameters. Various models of inhaled particle deposition make use of approximations of the respiratory tract to predict fractional deposition caused by fundamental physical processes of particle impaction, sedimentation, and diffusion. These models for both total deposition and regional (nasopharyngeal, tracheobronchial, and pulmonary) deposition are compared with early and recent experimental studies. Reasonable correlation has been obtained between theoretical and experimental studies, but the behavior in the respiratory tract of very fine (less than 0.1 micron) particles requires further investigation. Properties of particle shape, charge and hygroscopicity as well as the degree of respiratory tract pathology also influence deposition patterns; definitive experimental work is needed in these areas. The influence upon deposition patterns of dynamic alterations in inspiratory flow profiles caused by a variety of breathing patterns also requires further study, and the use of differing ventilation techniques with selected inhaled particle sizes holds promise in diagnosis of respiratory tract diseases. Mechanisms of conducting airway and alveolar clearance processes involving the pulmonary macrophage, mucociliary clearance, dissolution, transport to systemic circulation, and translocation via regional lymphatic vessels are discussed. PMID:6376108

  15. Fuel conservation through active control of rotor clearances

    NASA Technical Reports Server (NTRS)

    Beitler, R. S.; Saunders, A. A.; Wanger, R. P.

    1980-01-01

    Under the NASA-sponsored Energy Efficient Engine (EEE) Project, technology is being developed which will significantly reduce the fuel consumption of turbofan engines for subsonic transport aircraft. One technology concept being pursued is active control of rotor tip clearances. Attention is given to rotor tip clearance considerations and an overview of preliminary study results as well as the General Electric EEE clearance control approach is presented. Finally, potential fuel savings with active control of rotor clearances for a typical EEE mission are predicted.

  16. ESR measurement of radical clearance in lung of whole mouse

    SciTech Connect

    Takeshita, K.; Utsumi, H.; Hamada, A. )

    1991-06-14

    Clearance of the nitroxide radicals, hydroxy-TEMPO and carboxy-PROxYL, in whole-mouse lung was directly measured by in vivo ESR. After injecting a nitroxide radical, distribution of the nitroxide radical all over the lung was confirmed by ESR imaging. The ESR signal of hydroxy-TEMPO was reduced in the lung and the clearance obeyed first-order kinetics, whereas the signal of carboxy-PROxYL remained constant. Comparison of the clearance rates of live and dead mice indicated the presence of 2 different clearance systems in the lung: loss of its paramagnetism in the lung, and transfer from alveolar to the blood circulation system.

  17. Developing clinically successful biomedical devices by understanding the pathophysiology of the target tissue: insights from over 25 years at the microscope

    NASA Astrophysics Data System (ADS)

    Thomsen, Sharon L.; Coad, James E.

    2007-02-01

    Volumetric conductive-convective heat sources, microwave and radiofrequency energy sources, high intensity focused ultrasound (HIFU), laser irradiation and other non-ionizing irradiation sources can be used to generate hyperthermic tissue injury in a variety of clinical settings with therapeutic temperature gradients ranging from 40 to over 90°C. On the opposite side, cryotherapy can be used to freeze tissues with negative therapeutic temperature gradients. The development of a successful thermal therapy using any one of these devices requires a precise understanding of the desired clinical end point in terms of 1) diagnosis vs. therapy, 2) cure vs. palliative intent, 3) dysfunctional vs. malignant tissue and 4) long-term monitoring issues. The effects of a specific thermal exposure depend on the architecture of the heat source and overall thermal history. During initial treatment before heat generation or cooling becomes dominant, tissue interactions with the delivered treatment may affect the geometry of the treatment effect and body's healing response. These two parameters are also affected by tissue anatomy, blood supply and protein vs. lipid content. The thermal lesion and final clinical outcome represent the sum of direct primary and secondary short and long term delayed injury. The latter occurs primarily from host responses producing ischemia, inflammation and wound healing followed by possible regeneration and/or scar formation. Once the thermal insult has been deployed, the resulting lesions can be broadly divided into two major zones: 1) a complete tissue ablation with lethal tissue injury closer to the device and 2) a peripheral transition zone of partial injury. Hyperthermic complete ablation zones can have two sub-regions: 1) thermal fixation from direct denaturation of cellular and tissue components and 2) coagulative necrosis due to direct injury and delayed secondary host responses. With a variety of special techniques, direct cellular injury can

  18. Vaginal chlamydial clearance following primary or secondary infection in mice occurs independently of TNF-α.

    PubMed

    Kamalakaran, Sangamithra; Chaganty, Bharat K R; Gupta, Rishein; Guentzel, M Neal; Chambers, James P; Murthy, Ashlesh K; Arulanandam, Bernard P

    2013-01-01

    The role of TNF-α in chlamydial clearance is uncertain. Antibody-mediated depletion of TNF-α in mice and guinea pigs has been shown not to significantly affect chlamydial clearance, whereas production of TNF-α in addition to IFN-γ from T cells has been shown to correlate with enhanced clearance. The aim of our study is to evaluate the mechanistic role of TNF-α in clearance of primary and secondary chlamydial infection from the genital tract (GT) using C57BL/6 TNF-α deficient (TNF-α(-/-)) and wild type (WT) mice. Chlamydial shedding from the lower GT was evaluated following primary and secondary intravaginal challenge. Also, antibody and antigen specific cytokine responses were analyzed from the infected GT and spleens, and oviduct pathology determined to analyze the role of TNF-α in upper GT pathological sequelae. MHC II(-/-) mice, known to display muted adaptive immune responses and failure to resolve genital chlamydial infections, were used as a negative control. Following both primary and secondary genital chlamydial infection, TNF-α(-/-) mice exhibited elevated granzyme B production, but similar IFN-γ and antibody responses. Importantly, absence of TNF-α did not significantly alter the resolution of infection. However, TNF-α(-/-) mice displayed significantly reduced upper genital tract (UGT) pathology compared to WT mice. This study demonstrates mechanistically that optimal chlamydial clearance following primary and secondary chlamydial genital infection can occur in the complete absence of TNF-α, and considered with the reduction of upper GT pathology in TNF-α(-/-) mice, suggests that targeted induction of anti-chlamydial TNF-α responses by vaccination may be unnecessary, and moreover could be potentially pathogenic.

  19. Vaginal chlamydial clearance following primary or secondary infection in mice occurs independently of TNF-α

    PubMed Central

    Kamalakaran, Sangamithra; Chaganty, Bharat K. R.; Gupta, Rishein; Guentzel, M. Neal; Chambers, James P.; Murthy, Ashlesh K.; Arulanandam, Bernard P.

    2013-01-01

    The role of TNF-α in chlamydial clearance is uncertain. Antibody-mediated depletion of TNF-α in mice and guinea pigs has been shown not to significantly affect chlamydial clearance, whereas production of TNF-α in addition to IFN-γ from T cells has been shown to correlate with enhanced clearance. The aim of our study is to evaluate the mechanistic role of TNF-α in clearance of primary and secondary chlamydial infection from the genital tract (GT) using C57BL/6 TNF-α deficient (TNF-α−/−) and wild type (WT) mice. Chlamydial shedding from the lower GT was evaluated following primary and secondary intravaginal challenge. Also, antibody and antigen specific cytokine responses were analyzed from the infected GT and spleens, and oviduct pathology determined to analyze the role of TNF-α in upper GT pathological sequelae. MHC II−/− mice, known to display muted adaptive immune responses and failure to resolve genital chlamydial infections, were used as a negative control. Following both primary and secondary genital chlamydial infection, TNF-α−/− mice exhibited elevated granzyme B production, but similar IFN-γ and antibody responses. Importantly, absence of TNF-α did not significantly alter the resolution of infection. However, TNF-α−/− mice displayed significantly reduced upper genital tract (UGT) pathology compared to WT mice. This study demonstrates mechanistically that optimal chlamydial clearance following primary and secondary chlamydial genital infection can occur in the complete absence of TNF-α, and considered with the reduction of upper GT pathology in TNF-α−/− mice, suggests that targeted induction of anti-chlamydial TNF-α responses by vaccination may be unnecessary, and moreover could be potentially pathogenic. PMID:23483844

  20. CSF clearance in Alzheimer Disease measured with dynamic PET.

    PubMed

    de Leon, Mony J; Li, Yi; Okamura, Nobuyuki; Tsui, Wai H; Saint Louis, Les A; Glodzik, Lidia; Osorio, Ricardo S; Fortea, Juan; Butler, Tracy; Pirraglia, Elizabeth; Fossati, Silvia; Kim, Hee-Jin; Carare, Roxana O; Nedergaard, Maiken; Benveniste, Helene; Rusinek, Henry

    2017-03-16

    Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer's disease (AD) comes from primarily from rodent models. However, unlike rodents where predominant extra-cranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Using dynamic Positron Emission Tomography (PET) with (18)F-THK5117 a tracer for tau pathology, the ventricular CSF time activity was used as a biomarker for CSF clearance. We tested three hypotheses: 1. Extra-cranial CSF is detected at the superior turbinates; 2. CSF clearance is reduced in AD; and 3. CSF clearance is inversely associated with amyloid deposition. Methods: 15 subjects, 8 with AD and 7 normal control volunteers were examined with (18)F-THK5117. 10 subjects additionally received (11)C-PiB PET scans and 8 were PiB positive. Ventricular time activity curves (TAC) of (18)F-THK5117 were used to identify highly correlated TAC from extra-cranial voxels. Results: For all subjects, the greatest density of CSF positive extra-cranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinates CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.

  1. Differences in amyloid-β clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling.

    PubMed

    Qosa, Hisham; Abuasal, Bilal S; Romero, Ignacio A; Weksler, Babette; Couraud, Pierre-Oliver; Keller, Jeffrey N; Kaddoumi, Amal

    2014-04-01

    Alzheimer's disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes

  2. The biodistribution of gold nanoparticles designed for renal clearance

    NASA Astrophysics Data System (ADS)

    Alric, Christophe; Miladi, Imen; Kryza, David; Taleb, Jacqueline; Lux, François; Bazzi, Rana; Billotey, Claire; Janier, Marc; Perriat, Pascal; Roux, Stéphane; Tillement, Olivier

    2013-06-01

    Owing to their tunable optical properties and their high absorption cross-section of X- and γ-ray, gold nanostructures appear as promising agents for remotely controlled therapy. Since the efficiency of cancer therapy is not limited to the eradication of the tumour but rests also on the sparing of healthy tissue, a biodistribution study is required in order to determine whether the behaviour of the nanoparticles after intravenous injection is safe (no accumulation in healthy tissue, no uptake by phagocytic cell-rich organs (liver, spleen) and renal clearance). The biodistribution of Au@DTDTPA nanoparticles which are composed of a gold core and a DTDTPA (dithiolated polyaminocarboxylate) shell can be established by X-ray imaging (owing to the X-ray absorption of the gold core) and by magnetic resonance imaging (MRI) since the DTDTPA shell was designed for the immobilization of paramagnetic gadolinium ions. However scintigraphy appears better suited for a biodistribution study owing to a great sensitivity. The successful immobilization of radioelements (99mTc, 111In) in the DTDTPA shell, instead of gadolinium ions, renders possible the follow up of Au@DTDTPA by scintigraphy which showed that Au@DTDTPA nanoparticles exhibit a safe behaviour after intravenous injection to healthy rats.Owing to their tunable optical properties and their high absorption cross-section of X- and γ-ray, gold nanostructures appear as promising agents for remotely controlled therapy. Since the efficiency of cancer therapy is not limited to the eradication of the tumour but rests also on the sparing of healthy tissue, a biodistribution study is required in order to determine whether the behaviour of the nanoparticles after intravenous injection is safe (no accumulation in healthy tissue, no uptake by phagocytic cell-rich organs (liver, spleen) and renal clearance). The biodistribution of Au@DTDTPA nanoparticles which are composed of a gold core and a DTDTPA (dithiolated polyaminocarboxylate

  3. Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

    PubMed Central

    Park, Sang Myun; Kim, Kwang Soo

    2013-01-01

    Many neurodegenerative diseases such as Alzheimer disease and Parkinson disease show similar characteristics. They typically show deposits of protein aggregates, the formation of which is considered important in their pathogenesis. Recently, aggregation-prone proteins have been shown to spread between cells and so may contribute to the pathogenesis of diseases like prion disease. Such a pathogenesis pathway is possibly common to many neurodegenerative diseases. If confirmed, it could allow the development of therapeutic interventions against many such diseases. In Parkinson disease, α-synuclein, a major component of cytosolic protein inclusions named Lewy body, has been shown to be released and taken up by cells, which may facilitate its progressive pathological spreading between cells. Accordingly, inhibition of spreading by targeting extracellular α-synuclein may represent a new therapy against Parkinson disease. Research into the intercellular spreading of extracellular protein aggregations of α-synuclein and its clearance pathway are reviewed here with a focus on the proteolytic clearance pathway as a therapeutic target for the treatment of Parkinson disease. Considering the similar characteristics of aggregation-prone proteins, these clearance systems might allow treatment of other neurodegenerative diseases beyond Parkinson disease. PMID:23154633

  4. Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease.

    PubMed

    Park, Sang Myun; Kim, Kwang Soo

    2013-01-01

    Many neurodegenerative diseases such as Alzheimer disease and Parkinson disease show similar characteristics. They typically show deposits of protein aggregates, the formation of which is considered important in their pathogenesis. Recently, aggregation-prone proteins have been shown to spread between cells and so may contribute to the pathogenesis of diseases like prion disease. Such a pathogenesis pathway is possibly common to many neurodegenerative diseases. If confirmed, it could allow the development of therapeutic interventions against many such diseases. In Parkinson disease, α-synuclein, a major component of cytosolic protein inclusions named Lewy body, has been shown to be released and taken up by cells, which may facilitate its progressive pathological spreading between cells. Accordingly, inhibition of spreading by targeting extracellular α-synuclein may represent a new therapy against Parkinson disease. Research into the intercellular spreading of extracellular protein aggregations of α-synuclein and its clearance pathway are reviewed here with a focus on the proteolytic clearance pathway as a therapeutic target for the treatment of Parkinson disease. Considering the similar characteristics of aggregation-prone proteins, these clearance systems might allow treatment of other neurodegenerative diseases beyond Parkinson disease.

  5. Human papillomavirus type 16 viral load measurement as a predictor of infection clearance

    PubMed Central

    Schlecht, Nicolas F.; Ramanakumar, Agnihotram V.; Villa, Luisa L.; Franco, Eduardo L.

    2013-01-01

    Viral load measurements may predict whether human papillomavirus (HPV) type 16 infections may become persistent and eventually lead to cervical lesions. Today, multiple PCR methods exist to estimate viral load. We tested three protocols to investigate viral load as a predictor of HPV clearance. We measured viral load in 418 HPV16-positive cervical smears from 224 women participating in the Ludwig–McGill Cohort Study by low-stringency PCR (LS-PCR) using consensus L1 primers targeting over 40 known HPV types, and quantitative real-time PCR (qRT-PCR) targeting the HPV16 E6 and L1 genes. HPV16 clearance was determined by MY09/11 and PGMY PCR testing on repeated smears collected over 5 years. Correlation between viral load measurements by qRT-PCR (E6 versus L1) was excellent (Spearman’s rank correlation, ρ = 0.88), but decreased for L1 qRT-PCR versus LS-PCR (ρ = 0.61). Viral load by LS-PCR was higher for HPV16 and related types independently of other concurrent HPV infections. Median duration of infection was longer for smears with high copy number by all three PCR protocols (log rank P<0.05). Viral load is inversely related to HPV16 clearance independently of concurrent HPV infections and PCR protocol. PMID:23677791

  6. Plasmodium Drug Targets Outside the Genetic Control of the Parasite

    PubMed Central

    Sullivan, David J.

    2014-01-01

    Drug development often seeks to find “magic bullets” which target microbiologic proteins while not affecting host proteins. Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are “magic shotguns” which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8-aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials. Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins or unchangeable cellular targets will slow the pace of drug resistance acquisition. PMID:22973888

  7. Validation of Dose Calculation Codes for Clearance

    SciTech Connect

    Menon, S.; Wirendal, B.; Bjerler, J.; Studsvik; Teunckens, L.

    2003-02-27

    Various international and national bodies such as the International Atomic Energy Agency, the European Commission, the US Nuclear Regulatory Commission have put forward proposals or guidance documents to regulate the ''clearance'' from regulatory control of very low level radioactive material, in order to allow its recycling as a material management practice. All these proposals are based on predicted scenarios for subsequent utilization of the released materials. The calculation models used in these scenarios tend to utilize conservative data regarding exposure times and dose uptake as well as other assumptions as a safeguard against uncertainties. None of these models has ever been validated by comparison with the actual real life practice of recycling. An international project was organized in order to validate some of the assumptions made in these calculation models, and, thereby, better assess the radiological consequences of recycling on a practical large scale.

  8. Improved Flight Test Procedures for Flutter Clearance

    NASA Technical Reports Server (NTRS)

    Lind, Rick C.; Brenner, Martin J.; Freudinger, Lawrence C.

    1997-01-01

    Flight flutter testing is an integral part of flight envelope clearance. This paper discusses advancements in several areas that are being investigated to improve efficiency and safety of flight test programs. Results are presented from recent flight testing of the F/A-18 Systems Research Aircraft. A wingtip excitation system was used to generate aeroelastic response data. This system worked well for many flight conditions but still displayed some anomalies. Wavelet processing is used to analyze the flight data. Filtered transfer functions are generated that greatly improve system identification. A flutter margin is formulated that accounts for errors between a model and flight data. Worst-case flutter margins are computed to demonstrate the flutter boundary may lie closer to the flight envelope than previously estimated. This paper concludes with developments for a distributed flight analysis environment and on-line health monitoring.

  9. [Mucociliary clearance function and medicamentous modification].

    PubMed

    Konrad, F

    1996-09-01

    Mucociliary clearance represents a complex self-cleaning mechanism of the lung and is based on the functional unity of ciliated columnar cells and the special viscoelastic properties of the secretion produced in the tracheobronchial system. It has been known for a long time that intubation and mechanical ventilation can impair mucous transport and lead to morphological damage to the tracheobronchial mucosa. Recent studies made it clear, however, that mechanical ventilation during anaesthesia using an appropriate anaesthesiological technique has no deleterious effect on mucus transport in patients with healthy lungs. Ventilated patients in the intensive-care unit frequently have impaired mucus transport, which is associated with the development of retention of secretion and nosocomial pneumonia. In these patients a number of factors combine to form a formidable potential insult to the mucociliary transport mechanism. Numerous drugs can affect mucociliary transport. Beta-mimetics and theophylline, in particular, have a favourable effect on mucociliary transport, whereas the effect of mucolytic agents is controversial.

  10. Tracking short-term biodistribution and long-term clearance of SPIO tracers in magnetic particle imaging.

    PubMed

    Keselman, Paul; Yu, Elaine; Zhou, Xinyi; Goodwill, Patrick; Chandrasekharan, Prashant; Ferguson, R Matthew; Khandhar, Amit; Kemp, Scott; Krishnan, Kannan; Zheng, Bo; Conolly, Steven

    2017-02-08

    Magnetic Particle Imaging (MPI) is an emerging tracer-based medical imaging modality that images non-radioactive, kidney-safe superparamagnetic iron oxide (SPIO) tracers. MPI offers quantitative, high-contrast and high-SNR images, so MPI has exceptional promise for applications such as cell tracking, angiography, brain perfusion, cancer detection, traumatic brain injury and pulmonary imaging. In assessing MPI's utility for applications mentioned above, it is important to be able to assess tracer short-term biodistribution as well as long-term clearance from the body. Here, we describe the biodistribution and clearance for two commonly used tracers in MPI: Ferucarbotran (Meito Sangyo Co., Japan) and LS-oo8 (LodeSpin Labs, Seattle, WA). We successfully demonstrate that 3D MPI is able to quantitatively assess short-term biodistribution, as well as long-term tracking and clearance of these tracers in vivo.

  11. Anthrax edema toxin impairs clearance in mice.

    PubMed

    Sastalla, Inka; Tang, Shixing; Crown, Devorah; Liu, Shihui; Eckhaus, Michael A; Hewlett, Indira K; Leppla, Stephen H; Moayeri, Mahtab

    2012-02-01

    The anthrax edema toxin (ET) of Bacillus anthracis is composed of the receptor-binding component protective antigen (PA) and of the adenylyl cyclase catalytic moiety, edema factor (EF). Uptake of ET into cells raises intracellular concentrations of the secondary messenger cyclic AMP, thereby impairing or activating host cell functions. We report here on a new consequence of ET action in vivo. We show that in mouse models of toxemia and infection, serum PA concentrations were significantly higher in the presence of enzymatically active EF. These higher concentrations were not caused by ET-induced inhibition of PA endocytosis; on the contrary, ET induced increased PA binding and uptake of the PA oligomer in vitro and in vivo through upregulation of the PA receptors TEM8 and CMG2 in both myeloid and nonmyeloid cells. ET effects on protein clearance from circulation appeared to be global and were not limited to PA. ET also impaired the clearance of ovalbumin, green fluorescent protein, and EF itself, as well as the small molecule biotin when these molecules were coinjected with the toxin. Effects on injected protein levels were not a result of general increase in protein concentrations due to fluid loss. Functional markers for liver and kidney were altered in response to ET. Concomitantly, ET caused phosphorylation and activation of the aquaporin-2 water channel present in the principal cells of the collecting ducts of the kidneys that are responsible for fluid homeostasis. Our data suggest that in vivo, ET alters circulatory protein and small molecule pharmacokinetics by an as-yet-undefined mechanism, thereby potentially allowing a prolonged circulation of anthrax virulence factors such as EF during infection.

  12. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  13. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  14. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  15. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 27.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  16. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 27.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  17. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 27.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  18. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  19. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 27.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  20. 76 FR 17978 - Agency Information Collection Activities: Emergency Clearance Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-31

    ... From the Federal Register Online via the Government Publishing Office SOCIAL SECURITY ADMINISTRATION Agency Information Collection Activities: Emergency Clearance Request The Social Security Administration (SSA) publishes a list of information collection packages requiring clearance by the Office of Management and Budget (OMB) in compliance...

  1. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 3 2013-04-01 2013-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  2. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  3. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  4. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  5. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 3 2014-04-01 2014-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  6. Mechanistic evaluation of virus clearance by depth filtration.

    PubMed

    Venkiteshwaran, Adith; Fogle, Jace; Patnaik, Purbasa; Kowle, Ron; Chen, Dayue

    2015-01-01

    Virus clearance by depth filtration has not been well-understood mechanistically due to lack of quantitative data on filter charge characteristics and absence of systematic studies. It is generally believed that both electrostatic interactions and sized based mechanical entrapment contribute to virus clearance by depth filtration. In order to establish whether the effectiveness of virus clearance correlates with the charge characteristics of a given depth filter, a counter-ion displacement technique was employed to determine the ionic capacity for several depth filters. Two depth filters (Millipore B1HC and X0HC) with significant differences in ionic capacities were selected and evaluated for their ability to eliminate viruses. The high ionic capacity X0HC filter showed complete porcine parvovirus (PPV) clearance (eliminating the spiked viruses to below the limit of detection) under low conductivity conditions (≤2.5 mS/cm), achieving a log10 reduction factor (LRF) of > 4.8. On the other hand, the low ionic capacity B1HC filter achieved only ∼2.1-3.0 LRF of PPV clearance under the same conditions. These results indicate that parvovirus clearance by these two depth filters are mainly achieved via electrostatic interactions between the filters and PPV. When much larger xenotropic murine leukemia virus (XMuLV) was used as the model virus, complete retrovirus clearance was obtained under all conditions evaluated for both depth filters, suggesting the involvement of mechanisms other than just electrostatic interactions in XMuLV clearance.

  7. 49 CFR 229.71 - Clearance above top of rail.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Clearance above top of rail. 229.71 Section 229.71....71 Clearance above top of rail. No part or appliance of a locomotive except the wheels, flexible nonmetallic sand pipe extension tips, and trip cock arms may be less than 21/2 inches above the top of rail....

  8. 49 CFR 229.71 - Clearance above top of rail.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Clearance above top of rail. 229.71 Section 229.71....71 Clearance above top of rail. No part or appliance of a locomotive except the wheels, flexible nonmetallic sand pipe extension tips, and trip cock arms may be less than 21/2 inches above the top of rail....

  9. 19 CFR 122.26 - Entry and clearance.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Entry and clearance. 122.26 Section 122.26 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY... information as set forth in § 122.22(c), and grants electronic clearance via electronic mail or telephone....

  10. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  11. 5 CFR 720.307 - Interagency report clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Interagency report clearance. 720.307 Section 720.307 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE... Interagency report clearance. The reports contained in this regulation have been cleared in accordance...

  12. 10 CFR 95.53 - Termination of facility clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Termination of facility clearance. 95.53 Section 95.53 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FACILITY SECURITY CLEARANCE AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION AND RESTRICTED DATA Control of Information § 95.53 Termination of facility...

  13. Benefits of Improved HP Turbine Active Clearance Control

    NASA Technical Reports Server (NTRS)

    Ruiz, Rafael; Albers, Bob; Sak, Wojciech; Seitzer, Ken; Steinetz, Bruce M.

    2007-01-01

    As part of the NASA Propulsion 21 program, GE Aircraft Engines was contracted to develop an improved high pressure turbine(HPT) active clearance control (ACC) system. The system is envisioned to minimize blade tip clearances to improve HPT efficiency throughout the engine operation range simultaneously reducing fuel consumption and emissions.

  14. 48 CFR 245.7310-8 - Antitrust clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Antitrust clearance. 245.7310-8 Section 245.7310-8 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM... Antitrust clearance. When property with an acquisition cost of $3 million or more is to be sold, include...

  15. 30 CFR 77.514 - Switchboards; passageways and clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Switchboards; passageways and clearance. 77.514 Section 77.514 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE... COAL MINES Electrical Equipment-General § 77.514 Switchboards; passageways and clearance....

  16. 14 CFR 93.311 - Minimum terrain clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Minimum terrain clearance. 93.311 Section 93.311 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... of Grand Canyon National Park, AZ § 93.311 Minimum terrain clearance. Except in an emergency,...

  17. 33 CFR 160.115 - Withholding of clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Withholding of clearance. 160.115... § 160.115 Withholding of clearance. Each District Commander or Captain of the Port may request the Secretary of the Treasury, or the authorized representative thereof, to withhold or revoke the...

  18. 7 CFR 1927.55 - Title clearance services.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 12 2012-01-01 2012-01-01 false Title clearance services. 1927.55 Section 1927.55 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE SERVICE, RURAL UTILITIES SERVICE, AND FARM SERVICE AGENCY, DEPARTMENT OF AGRICULTURE PROGRAM REGULATIONS TITLE CLEARANCE AND...

  19. 32 CFR 644.69 - Title Clearance-Easements.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Title Clearance-Easements. 644.69 Section 644.69 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Acquisition Procurement of Title Evidence, Title Clearance, and Closings § 644.69 Title Clearance—Easements. (a)...

  20. 32 CFR 644.69 - Title Clearance-Easements.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Title Clearance-Easements. 644.69 Section 644.69 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Acquisition Procurement of Title Evidence, Title Clearance, and Closings § 644.69 Title Clearance—Easements. (a)...

  1. 32 CFR 644.69 - Title Clearance-Easements.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Title Clearance-Easements. 644.69 Section 644.69 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Acquisition Procurement of Title Evidence, Title Clearance, and Closings § 644.69 Title Clearance—Easements. (a)...

  2. 7 CFR 1927.55 - Title clearance services.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 12 2014-01-01 2013-01-01 true Title clearance services. 1927.55 Section 1927.55 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE SERVICE, RURAL UTILITIES SERVICE, AND FARM SERVICE AGENCY, DEPARTMENT OF AGRICULTURE PROGRAM REGULATIONS TITLE CLEARANCE AND...

  3. 32 CFR 644.521 - Limitations on clearance cost.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Limitations on clearance cost. 644.521 Section 644.521 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  4. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Clearance of military scrap. 644.522 Section 644.522 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  5. 32 CFR 644.521 - Limitations on clearance cost.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Limitations on clearance cost. 644.521 Section 644.521 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  6. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Clearance of military scrap. 644.522 Section 644.522 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  7. 32 CFR 644.527 - Recording Statements of Clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Recording Statements of Clearance. 644.527 Section 644.527 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  8. 32 CFR 644.527 - Recording Statements of Clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Recording Statements of Clearance. 644.527 Section 644.527 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  9. Allometric scaling for predicting human clearance of bisphenol A

    SciTech Connect

    Collet, Séverine H. Picard-Hagen, Nicole Lacroix, Marlène Z. Puel, Sylvie Viguié, Catherine Bousquet-Melou, Alain Toutain, Pierre-Louis Gayrard, Véronique

    2015-05-01

    The investigation of interspecies differences in bisphenol A (BPA) pharmacokinetics (PK) may be useful for translating findings from animal studies to humans, identifying major processes involved in BPA clearance mechanisms, and predicting BPA PK parameters in man. For the first time, a large range of species in terms of body weight, from 0.02 kg (mice) to 495 kg (horses) was used to predict BPA clearance in man by an allometric approach. BPA PK was evaluated after intravenous administration of BPA in horses, sheep, pigs, dogs, rats and mice. A non-compartmental analysis was used to estimate plasma clearance and steady state volume of distribution and predict BPA PK parameters in humans from allometric scaling. In all the species investigated, BPA plasma clearance was high and of the same order of magnitude as their respective hepatic blood flow. By an allometric scaling, the human clearance was estimated to be 1.79 L/min (equivalent to 25.6 mL/kg.min) with a 95% prediction interval of 0.36 to 8.83 L/min. Our results support the hypothesis that there are highly efficient and hepatic mechanisms of BPA clearance in man. - Highlights: • Allometric scaling was used to predict BPA pharmacokinetic parameters in humans. • In all species, BPA plasma clearance approached hepatic blood flow. • Human BPA clearance was estimated to be 1.79 L/min.

  10. 33 CFR 151.1508 - Revocation of clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Revocation of clearance. 151.1508 Section 151.1508 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED... River § 151.1508 Revocation of clearance. A COTP may request the District Director of Customs...

  11. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Clearance of Air Force lands. 644.516 Section 644... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  12. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Clearance of Air Force lands. 644.516 Section 644... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  13. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Clearance of Air Force lands. 644.516 Section... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  14. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Clearance of Air Force lands. 644.516 Section... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  15. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Clearance of military scrap. 644.522 Section 644... Excess Land and Improvements § 644.522 Clearance of military scrap. Military scrap can contain or be... destruction, by using command, of all military scrap and scrap metal from lands suitable for cultivation...

  16. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Clearance of military scrap. 644.522 Section 644... Excess Land and Improvements § 644.522 Clearance of military scrap. Military scrap can contain or be... destruction, by using command, of all military scrap and scrap metal from lands suitable for cultivation...

  17. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Clearance of military scrap. 644.522 Section 644... Excess Land and Improvements § 644.522 Clearance of military scrap. Military scrap can contain or be... destruction, by using command, of all military scrap and scrap metal from lands suitable for cultivation...

  18. 48 CFR 952.204-73 - Facility clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ....204-73 Section 952.204-73 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CLAUSES AND... granted by the Secretary of Energy. In addition, a Facility Clearance and foreign ownership, control and... Department of Energy Facility Clearance generally need not resubmit the following foreign...

  19. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Clearance of Air Force lands. 644.516 Section 644... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  20. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  1. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 1 2012-10-01 2012-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  2. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  3. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  4. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  5. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  6. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  7. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  8. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  9. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 1 2013-10-01 2013-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  10. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  11. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  12. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  13. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  14. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  15. Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo.

    PubMed

    Lu, Ching-Lan; Murakowski, Dariusz K; Bournazos, Stylianos; Schoofs, Till; Sarkar, Debolina; Halper-Stromberg, Ariel; Horwitz, Joshua A; Nogueira, Lilian; Golijanin, Jovana; Gazumyan, Anna; Ravetch, Jeffrey V; Caskey, Marina; Chakraborty, Arup K; Nussenzweig, Michel C

    2016-05-20

    Antiretroviral drugs and antibodies limit HIV-1 infection by interfering with the viral life cycle. In addition, antibodies also have the potential to guide host immune effector cells to kill HIV-1-infected cells. Examination of the kinetics of HIV-1 suppression in infected individuals by passively administered 3BNC117, a broadly neutralizing antibody, suggested that the effects of the antibody are not limited to free viral clearance and blocking new infection but also include acceleration of infected cell clearance. Consistent with these observations, we find that broadly neutralizing antibodies can target CD4(+) T cells infected with patient viruses and can decrease their in vivo half-lives by a mechanism that requires Fcγ receptor engagement in a humanized mouse model. The results indicate that passive immunotherapy can accelerate elimination of HIV-1-infected cells.

  16. Interaction between therapeutic interventions for Alzheimer’s disease and physiological Aβ clearance mechanisms

    PubMed Central

    Morrone, Christopher D.; Liu, Mingzhe; Black, Sandra E.; McLaurin, JoAnne

    2015-01-01

    Most therapeutic agents are designed to target a molecule or pathway without consideration of the mechanisms involved in the physiological turnover or removal of that target. In light of this and in particular for Alzheimer’s disease, a number of therapeutic interventions are presently being developed/investigated which target the amyloid-β peptide (Aβ). However, the literature has not adequately considered which Aβ physiological clearance pathways are necessary and sufficient for the effective action of these therapeutics. In this review, we evaluate the therapeutic strategies targeting Aβ presently in clinical development, discuss the possible interaction of these treatments with pathways that under normal physiological conditions are responsible for the turnover of Aβ and highlight possible caveats. We consider immunization strategies primarily reliant on a peripheral sink mechanism of action, small molecules that are reliant on entry into the CNS and thus degradation pathways within the brain, as well as lifestyle interventions that affect vascular, parenchymal and peripheral degradation pathways. We propose that effective development of Alzheimer’s disease therapeutic strategies targeting Aβ peptide will require consideration of the age- and disease-specific changes to endogenous Aβ clearance mechanisms in order to elicit maximal efficacy. PMID:25999850

  17. Comparison of serum iohexol clearance and plasma creatinine clearance in clinically normal horses.

    PubMed

    Wilson, Katherine E; Wilcke, Jeff R; Crisman, Mark V; Ward, Daniel L; McKenzie, Harold C; Scarratt, W Kent

    2009-12-01

    Objective-To determine whether a limited sampling time method based on serum iohexol clearance (Cl(iohexol)) would yield estimates of glomerular filtration rate (GFR) in clinically normal horses similar to those for plasma creatinine clearance (Cl(creatinine)). Animals-10 clinically normal adult horses. Procedures-A bolus of iohexol (150 mg/kg) was administered IV, and serum samples were obtained 5, 20, 40, 60, 120, 240, and 360 minutes after injection. Urinary clearance of exogenous creatinine was measured during three 20-minute periods. The GFR determined by use of serum Cl(iohexol) and plasma Cl(creatinine) was compared with limits of agreement plots. Results-Values obtained for plasma Cl(creatinine) ranged from 1.68 to 2.69 mL/min/kg (mean, 2.11 mL/min/kg). Mean serum Cl(iohexol) was 2.38 mL/min/kg (range, 1.95 to 3.33 mL/min/kg). Limits of agreement plots indicated good agreement between the methods. Conclusions and Clinical Relevance-Use of serum Cl(iohexol) yielded estimates of GFR in clinically normal adult horses similar to those for plasma Cl(creatinine). This study was the first step in the evaluation of the use of serum Cl(iohexol) for estimating GFR in adult horses.

  18. A model of clearance rate regulation in mussels

    NASA Astrophysics Data System (ADS)

    Fréchette, Marcel

    2012-10-01

    Clearance rate regulation has been modelled as an instantaneous response to food availability, independent of the internal state of the animals. This view is incompatible with latent effects during ontogeny and phenotypic flexibility in clearance rate. Internal-state regulation of clearance rate is required to account for these patterns. Here I develop a model of internal-state based regulation of clearance rate. External factors such as suspended sediments are included in the model. To assess the relative merits of instantaneous regulation and internal-state regulation, I modelled blue mussel clearance rate and growth using a DEB model. In the usual standard feeding module, feeding is governed by a Holling's Type II response to food concentration. In the internal-state feeding module, gill ciliary activity and thus clearance rate are driven by internal reserve level. Factors such as suspended sediments were not included in the simulations. The two feeding modules were compared on the basis of their ability to capture the impact of latent effects, of environmental heterogeneity in food abundance and of physiological flexibility on clearance rate and individual growth. The Holling feeding module was unable to capture the effect of any of these sources of variability. In contrast, the internal-state feeding module did so without any modification or ad hoc calibration. Latent effects, however, appeared transient. With simple annual variability in temperature and food concentration, the relationship between clearance rate and food availability predicted by the internal-state feeding module was quite similar to that observed in Norwegian fjords. I conclude that in contrast with the usual Holling feeding module, internal-state regulation of clearance rate is consistent with well-documented growth and clearance rate patterns.

  19. 76 FR 36167 - Agency Information Collection Activities: Requests for Comments; Clearance of Renewed Approval of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-21

    ... Federal Aviation Administration Agency Information Collection Activities: Requests for Comments; Clearance... the request for OMB's clearance of this information collection. Issued in Washington, DC on June 15, 2011. Carla Scott, FAA Information Collection Clearance Officer, IT Enterprises Business...

  20. Project Success.

    ERIC Educational Resources Information Center

    Meredith, Larry D.

    Project Success consists of after-school, weekend, and summer educational programs geared toward minority and disadvantaged students to increase their numbers seeking postsecondary education from the Meadville, Pennsylvania area. The project is funded primarily through the Edinboro University of Pennsylvania, whose administration is committed to…

  1. A Microwave Blade Tip Clearance Sensor for Propulsion Health Monitoring

    NASA Technical Reports Server (NTRS)

    Woike, Mark R.; Abdul-Aziz, Ali; Bencic, Timothy J.

    2010-01-01

    Microwave sensor technology is being investigated by the NASA Glenn Research Center as a means of making non-contact structural health measurements in the hot sections of gas turbine engines. This type of sensor technology is beneficial in that it is accurate, it has the ability to operate at extremely high temperatures, and is unaffected by contaminants that are present in turbine engines. It is specifically being targeted for use in the High Pressure Turbine (HPT) and High Pressure Compressor (HPC) sections to monitor the structural health of the rotating components. It is intended to use blade tip clearance to monitor blade growth and wear and blade tip timing to monitor blade vibration and deflection. The use of microwave sensors for this application is an emerging concept. Techniques on their use and calibration needed to be developed. As a means of better understanding the issues associated with the microwave sensors, a series of experiments have been conducted to evaluate their performance for aero engine applications. This paper presents the results of these experiments.

  2. Mechanism of hard-nanomaterial clearance by the liver

    NASA Astrophysics Data System (ADS)

    Tsoi, Kim M.; Macparland, Sonya A.; Ma, Xue-Zhong; Spetzler, Vinzent N.; Echeverri, Juan; Ouyang, Ben; Fadel, Saleh M.; Sykes, Edward A.; Goldaracena, Nicolas; Kaths, Johann M.; Conneely, John B.; Alman, Benjamin A.; Selzner, Markus; Ostrowski, Mario A.; Adeyi, Oyedele A.; Zilman, Anton; McGilvray, Ian D.; Chan, Warren C. W.

    2016-11-01

    The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 +/- 6.4%), hepatic B cells (81.5 +/- 9.3%) and liver sinusoidal endothelial cells (64.6 +/- 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 +/- 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.

  3. Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs.

    PubMed

    Giraldez, Antonio J; Mishima, Yuichiro; Rihel, Jason; Grocock, Russell J; Van Dongen, Stijn; Inoue, Kunio; Enright, Anton J; Schier, Alexander F

    2006-04-07

    MicroRNAs (miRNAs) comprise 1 to 3% of all vertebrate genes, but their in vivo functions and mechanisms of action remain largely unknown. Zebrafish miR-430 is expressed at the onset of zygotic transcription and regulates morphogenesis during early development. By using a microarray approach and in vivo target validation, we find that miR-430 directly regulates several hundred target messenger RNA molecules (mRNAs). Most targets are maternally expressed mRNAs that accumulate in the absence of miR-430. We also show that miR-430 accelerates the deadenylation of target mRNAs. These results suggest that miR-430 facilitates the deadenylation and clearance of maternal mRNAs during early embryogenesis.

  4. Crizotinib for the Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: A Success Story to Usher in the Second Decade of Molecular Targeted Therapy in Oncology

    PubMed Central

    Bartlett, Cynthia Huang; Mino-Kenudson, Mari; Cui, Jean; Iafrate, A. John

    2012-01-01

    Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK-rearranged NSCLC. The crizotinib approval was accompanied by the simultaneous approval of an ALK companion diagnostic fluorescent in situ hybridization assay for the detection of ALK-rearranged NSCLC. Crizotinib continued to be developed as an ALK and MET inhibitor in other tumor types driven by alteration in ALK and MET. Crizotinib has recently been shown to be an effective ROS1 inhibitor in ROS1-rearranged NSCLC, with potential future clinical applications in ROS1-rearranged tumors. Here we summarize the heterogeneity within the ALK- and ROS1-rearranged molecular subtypes of NSCLC. We review the past and future clinical development of crizotinib for ALK-rearranged NSCLC and the diagnostic assays to detect ALK-rearranged NSCLC. We highlight how the success of crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a molecular-defined subtype of NSCLC despite its rarity and affected the practice of personalized medicine in oncology, emphasizing close collaboration between clinical oncologists, pathologists, and translational scientists. PMID:22989574

  5. Effects of drugs on mucus clearance.

    PubMed

    Houtmeyers, E; Gosselink, R; Gayan-Ramirez, G; Decramer, M

    1999-08-01

    Mucociliary clearance (MCC), the process in which airway mucus together with substances trapped within are moved out of the lungs, is an important defence mechanism of the human body. Drugs may alter this process, such that it is necessary to know the effect of the drugs on MCC. Indeed, agents stimulating MCC may be used therapeutically in respiratory medicine, especially in patients suspected of having an impairment of their mucociliary transport system. In contrast, caution should be taken with drugs depressing MCC as an undesired side-effect, independently of their therapeutic indication. Since cough clearance (CC) serves as a back-up system when MCC fails, the influence of drugs must be examined not only on MCC but also on CC. Ultimately, the clinical repercussions of alterations in mucus transport induced by drug administration must be studied. Tertiary ammonium compounds (anticholinergics), aspirin, anaesthetic agents and benzodiazepines have been shown to be capable of depressing the mucociliary transport system. Cholinergics, methylxanthines, sodium cromoglycate, hypertonic saline, saline as well as water aerosol have been shown to increase MCC. Adrenergic antagonists, guaifenesin, S-carboxymethylcysteine, sodium 2-mercapto-ethane sulphonate and frusemide have been reported not to alter the mucociliary transport significantly. Amiloride, uridine 5'-triphosphate (UTP), quaternary ammonium compounds (anticholinergics), adrenergic agonists, corticosteroids, recombinant human deoxyribonuclease (rhDNase), N-acetylcysteine, bromhexine and ambroxol have been reported either not to change or to augment MCC. Indirect data suggest that surfactant as well as antibiotics may improve the mucociliary transport system. As for the influence of drugs on CC, amiloride and rhDNase have been demonstrated to increase the effectiveness of cough. A trend towards an improved CC was noted after treatment with adrenergic agonists. The anticholinergic agent ipratropium bromide, which

  6. Foot clearance during stair descent: effects of age and illumination.

    PubMed

    Hamel, Kathryn A; Okita, Noriaki; Higginson, Jill S; Cavanagh, Peter R

    2005-02-01

    It is likely that many stair accidents result from a trip during stair negotiation, yet few studies have examined the exact nature of balance loss during falls on stairs. The purpose of this study was to investigate potential age-related differences in the minimum clearance of the foot during stair descent, and to explore whether the minimum foot clearance was affected by the available ambient lighting. Twelve young adults (24+/-3.3 years) and 10 older adults (73.7+/-1.9 years) participated in the study. The older adults had significantly greater within subject coefficients of variation compared to the young adults, and had a significantly larger number of minimum foot clearances which fell below 5 mm. While the young subjects increased their minimum clearance by 3.6 mm on average in response to a decrease in ambient lighting, the older adults maintained the same clearance over all stairs except one. These results suggest that the variability of minimum foot clearance, and lack of precautionary increases in foot clearance under reduced lighting may contribute to falls on stairs by the elderly.

  7. Integrated Turbine Tip Clearance and Gas Turbine Engine Simulation

    NASA Technical Reports Server (NTRS)

    Chapman, Jeffryes W.; Kratz, Jonathan; Guo, Ten-Huei; Litt, Jonathan

    2016-01-01

    Gas turbine compressor and turbine blade tip clearance (i.e., the radial distance between the blade tip of an axial compressor or turbine and the containment structure) is a major contributing factor to gas path sealing, and can significantly affect engine efficiency and operational temperature. This paper details the creation of a generic but realistic high pressure turbine tip clearance model that may be used to facilitate active tip clearance control system research. This model uses a first principles approach to approximate thermal and mechanical deformations of the turbine system, taking into account the rotor, shroud, and blade tip components. Validation of the tip clearance model shows that the results are realistic and reflect values found in literature. In addition, this model has been integrated with a gas turbine engine simulation, creating a platform to explore engine performance as tip clearance is adjusted. Results from the integrated model explore the effects of tip clearance on engine operation and highlight advantages of tip clearance management.

  8. A novel relay method for determining low-clearance values.

    PubMed

    Di, Li; Trapa, Patrick; Obach, R Scott; Atkinson, Karen; Bi, Yi-An; Wolford, Angela C; Tan, Beijing; McDonald, Thomas S; Lai, Yurong; Tremaine, Larry M

    2012-09-01

    A novel relay method has been developed using cryopreserved human hepatocytes to measure intrinsic clearance of low-clearance compounds. The relay method involved transferring the supernatant from hepatocyte incubations to freshly thawed hepatocytes at the end of the 4-h incubation to prolong the exposure time to active enzymes in hepatocytes. An accumulative incubation time of 20 h or longer in hepatoctyes can be achieved using the method. The relay method was validated using seven commercial drugs (diazepam, disopyramide, theophylline, timolol, tolbutamide, S-warfarin, and zolmitriptan) that were metabolized by various cytochrome P450s with low human in vivo intrinsic clearance at approximately 2 to 15 ml · min⁻¹ · kg⁻¹. The results showed that the relay method produced excellent predictions of human in vivo clearance. The difference between in vitro and in vivo intrinsic clearance was within 2-fold for most compounds, which is similar to the standard prediction accuracy for moderate to high clearance compounds using hepatocytes. The relay method is a straightforward, relatively low cost, and easy-to-use new tool to address the challenges of low clearance in drug discovery and development.

  9. mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases

    PubMed Central

    Palmieri, Michela; Pal, Rituraj; Nelvagal, Hemanth R.; Lotfi, Parisa; Stinnett, Gary R.; Seymour, Michelle L.; Chaudhury, Arindam; Bajaj, Lakshya; Bondar, Vitaliy V.; Bremner, Laura; Saleem, Usama; Tse, Dennis Y.; Sanagasetti, Deepthi; Wu, Samuel M.; Neilson, Joel R.; Pereira, Fred A.; Pautler, Robia G.; Rodney, George G.; Cooper, Jonathan D.; Sardiello, Marco

    2017-01-01

    Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases. PMID:28165011

  10. Ion exchange chromatography of proteins and clearance of aggregates.

    PubMed

    Yigzaw, Y; Hinckley, P; Hewig, A; Vedantham, G

    2009-06-01

    Clearance of product related aggregates in therapeutic proteins is a major focus of purification process development. A typical purification process will have one or two chromatographic steps that remove these product related aggregates to an acceptable level. Both cation exchange and anion exchange chromatography can provide robust clearance of aggregates. The primary factors that are critical for aggregate clearance are: resin chemistry, binding and elution condition, peak collection and column load factor. This review covers how these factors can be optimized to increase the effectiveness of ion exchange chromatography in removing aggregates.

  11. Time-of-Flight Tip-Clearance Measurements

    NASA Technical Reports Server (NTRS)

    Dhadwal, H. S.; Kurkov, A. P.; Janetzke, D. C.

    1999-01-01

    In this paper a time-of-flight probe system incorporating the two integrated fiber optic probes which are tilted equally relative to the probe holder centerline, is applied for the first time to measure the tip clearance of an advanced fan prototype. Tip clearance is largely independent of the signal amplitude and it relies on timing measurement. This work exposes optical effects associated with the fan blade stagger angle that were absent during the original spin-rig experiment on the zero stagger rotor. Individual blade tip clearances were measured with accuracy of +/- 127-mm (+/- 0.005-in). Probe features are discussed and improvements to the design are suggested.

  12. Laser-optical blade tip clearance measurement system

    NASA Technical Reports Server (NTRS)

    Barranger, J. P.; Ford, M. J.

    1979-01-01

    A laser-optical measurement system was developed to measure single blade tip clearances and average blade tip clearances between a rotor and its gas path seal in rotating component rigs and complete engines. The system is applicable to fan, compressor and turbine blade tip clearance measurements. The engine mounted probe is particularly suitable for operation in the extreme turbine environment. The measurement system consists of an optical subsystem, an electronic subsystem and a computing and graphic terminal. Bench tests and environmental tests were conducted to confirm operation at temperatures, pressures, and vibration levels typically encountered in an operating gas turbine engine.

  13. Aerosol Medications for Treatment of Mucus Clearance Disorders.

    PubMed

    Rubin, Bruce K

    2015-06-01

    Airway mucus hypersecretion and secretion retention can result from inflammation, irritation, stimulation, or mucus-producing tumors. Secretion clearance can be furthered hampered by ciliary dysfunction and by weakness or restrictive lung disease, leading to an ineffective cough. There are a number of different mucoactive medications that have been used to reduce hypersecretion, make secretions easier to transport, or increase the efficiency of cough or mucus clearance. In this paper, I review the pathophysiology of secretory hyper-responsiveness and mucus hypersecretion and discuss the different aerosol medications that can be used to augment secretion clearance.

  14. Preliminary Diffusive Clearance of Silicon Nanopore Membranes in a Parallel Plate Configuration for Renal Replacement Therapy

    PubMed Central

    Kim, Steven; Heller, James; Iqbal, Zohora; Kant, Rishi; Kim, Eun Jung; Durack, Jeremy; Saeed, Maythem; Do, Loi; Hetts, Steven; Wilson, Mark; Brakeman, Paul; Fissell, William H.; Roy, Shuvo

    2015-01-01

    Silicon nanopore membranes (SNM) with compact geometry and uniform pore size distribution have demonstrated a remarkable capacity for hemofiltration. These advantages could potentially be used for hemodialysis. Here we present an initial evaluation of the SNM’s mechanical robustness, diffusive clearance, and hemocompatibility in a parallel plate configuration. Mechanical robustness of the SNM was demonstrated by exposing membranes to high flows (200ml/min) and pressures (1,448mmHg). Diffusive clearance was performed in an albumin solution and whole blood with blood and dialysate flow rates of 25ml/min. Hemocompatibility was evaluated using scanning electron microscopy and immunohistochemistry after 4-hours in an extra-corporeal porcine model. The pressure drop across the flow cell was 4.6mmHg at 200ml/min. Mechanical testing showed that SNM could withstand up to 775.7mmHg without fracture. Urea clearance did not show an appreciable decline in blood versus albumin solution. Extra-corporeal studies showed blood was successfully driven via the arterial-venous pressure differential without thrombus formation. Bare silicon showed increased cell adhesion with a 4.1 fold increase and 1.8 fold increase over polyethylene-glycol (PEG)-coated surfaces for tissue plasminogen factor (t-PA) and platelet adhesion (CD-41), respectively. These initial results warrant further design and development of a fully scaled SNM-based parallel plate dialyzer for renal replacement therapy. PMID:26692401

  15. A novel approach to achieving modular retrovirus clearance for a parvovirus filter.

    PubMed

    Stuckey, Juliana; Strauss, Daniel; Venkiteshwaran, Adith; Gao, Jinxin; Luo, Wen; Quertinmont, Michelle; O'Donnell, Sean; Chen, Dayue

    2014-01-01

    Viral filtration is routinely incorporated into the downstream purification processes for the production of biologics produced in mammalian cell cultures (MCC) to remove potential viral contaminants. In recent years, the use of retentive filters designed for retaining parvovirus (~20 nm) has become an industry standard in a conscious effort to further improve product safety. Since retentive filters remove viruses primarily by the size exclusion mechanism, it is expected that filters designed for parvovirus removal can effectively clear larger viruses such as retroviruses (~100 nm). In an attempt to reduce the number of viral clearance studies, we have taken a novel approach to demonstrate the feasibility of claiming modular retrovirus clearance for Asahi Planova 20N filters. Porcine parvovirus (PPV) and xenotropic murine leukemia virus (XMuLV) were co-spiked into six different feedstreams and then subjected to laboratory scale Planova 20N filtration. Our results indicate that Planova 20N filters consistently retain retroviruses and no retrovirus has ever been detected in the filtrates even when significant PPV breakthrough is observed. Based on the data from multiple in-house viral validation studies and the results from the co-spiking experiments, we have successfully claimed a modular retrovirus clearance of greater than 6 log10 reduction factors (LRF) to support clinical trial applications in both USA and Europe.

  16. Clearance mechanisms of Alzheimer's amyloid-beta peptide: implications for therapeutic design and diagnostic tests.

    PubMed

    Bates, K A; Verdile, G; Li, Q-X; Ames, D; Hudson, P; Masters, C L; Martins, R N

    2009-05-01

    Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-beta (Abeta) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Abeta is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Abeta leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Abeta are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Abeta clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Abeta ELISAs are discussed, as are the more promising results of Abeta imaging by positron emission tomography. Current knowledge of Abeta-binding proteins and Abeta-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Abeta remains an attractive therapeutic strategy, and improved understanding of Abeta clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

  17. Novel lanthanide-labeled metal oxide nanoparticles improve the measurement of in vivo clearance and translocation

    PubMed Central

    2013-01-01

    The deposition, clearance and translocation of europium-doped gadolinium oxide nanoparticles in a mouse lung were investigated experimentally. Nanoparticles were synthesized by spray flame pyrolysis. The particle size, crystallinity and surface properties were characterized. Following instillation, the concentrations of particles in organs were determined with inductively coupled plasma mass spectrometry. The protein corona coating the nanoparticles was found to be similar to the coating on more environmentally relevant nanoparticles such as iron oxide. Measurements of the solubility of the nanoparticles in surrogates of biological fluids indicated very little propensity for dissolution, and the elemental ratio of particle constituents did not change, adding further support to the contention that intact nanoparticles were measured. The particles were intratracheally instilled into the mouse lung. After 24 hours, the target organs were harvested, acid digested and the nanoparticle mass in each organ was measured by inductively coupled plasma mass spectrometry (ICP-MS). The nanoparticles were detected in all the studied organs at low ppb levels; 59% of the particles remained in the lung. A significant amount of particles was also detected in the feces, suggesting fast clearance mechanisms. The nanoparticle system used in this work is highly suitable for quantitatively determining deposition, transport and clearance of nanoparticles from the lung, providing a quantified measure of delivered dose. PMID:23305071

  18. Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids

    PubMed Central

    Lauber, K; Keppeler, H; Munoz, L E; Koppe, U; Schröder, K; Yamaguchi, H; Krönke, G; Uderhardt, S; Wesselborg, S; Belka, C; Nagata, S; Herrmann, M

    2013-01-01

    The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8−/− mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs in vitro and in vivo. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE. PMID:23832117

  19. Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids.

    PubMed

    Lauber, K; Keppeler, H; Munoz, L E; Koppe, U; Schröder, K; Yamaguchi, H; Krönke, G; Uderhardt, S; Wesselborg, S; Belka, C; Nagata, S; Herrmann, M

    2013-09-01

    The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8(-/-) mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs in vitro and in vivo. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE.

  20. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

    PubMed

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-21

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases.

  1. Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen

    PubMed Central

    Javid, Ashkan; Zlotnikov, Nataliya; Pětrošová, Helena; Tang, Tian Tian; Zhang, Yang; Bansal, Anil K.; Ebady, Rhodaba; Parikh, Maitry; Ahmed, Mijhgan; Sun, Chunxiang; Newbigging, Susan; Kim, Yae Ram; Santana Sosa, Marianna; Glogauer, Michael

    2016-01-01

    Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted. PMID:27340827

  2. BAG3 facilitates the clearance of endogenous tau in primary neurons.

    PubMed

    Lei, Zhinian; Brizzee, Corey; Johnson, Gail V W

    2015-01-01

    Tau is a microtubule associated protein that is found primarily in neurons, and in pathologic conditions, such as Alzheimer's disease (AD) it accumulates and contributes to the disease process. Because tau plays a fundamental role in the pathogenesis of AD and other tauopathies, and in AD mouse models reducing tau levels improves outcomes, approaches that facilitate tau clearance are being considered as therapeutic strategies. However, fundamental to the development of such interventions is a clearer understanding of the mechanisms that regulate tau clearance. Here, we report a novel mechanism of tau degradation mediated by the co-chaperone BAG3. BAG3 has been shown to be an essential component of a complex that targets substrates to the autophagy pathway for degradation. In rat primary neurons, activation of autophagy by inhibition of proteasome activity or treatment with trehalose resulted in significant decreases in tau and phospho-tau levels. These treatments also induced an upregulation of BAG3. Proteasome inhibition activated JNK, which was responsible for the upregulation of BAG3 and increased tau clearance. Inhibiting JNK or knocking down BAG3 blocked the proteasome inhibition-induced decreases in tau. Further, BAG3 overexpression alone resulted in significant decreases in tau and phospho-tau levels in neurons. These results indicate that BAG3 plays a critical role in regulating the levels of tau in neurons, and interventions that increase BAG3 levels could provide a therapeutic approach in the treatment of AD.

  3. Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier

    PubMed Central

    Keaney, James; Walsh, Dominic M.; O’Malley, Tiernan; Hudson, Natalie; Crosbie, Darragh E.; Loftus, Teresa; Sheehan, Florike; McDaid, Jacqueline; Humphries, Marian M.; Callanan, John J.; Brett, Francesca M.; Farrell, Michael A.; Humphries, Peter; Campbell, Matthew

    2015-01-01

    The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain. PMID:26491725

  4. Use of hardware-in-the-loop (HWIL) testing from early software development through final system test to mitigate risk and to assure mission success for the Hera targets program

    NASA Astrophysics Data System (ADS)

    Marcin, Michael, Jr.

    1996-05-01

    . Comparisons of flight data from three of our test flights and corresponding CIL/HWIL runs show an excellent match of flight performance to pre-flight predictions. The CIL/HWIL testing on the HERA targets program made it possible to have a high degree of confidence in the flight software and hardware before our first mission. We achieved first flight success due in part to the extensive software and hardware testing in the CIL/HWIL environment from software development through system qualification.

  5. Metabolic clearance rate and urinary clearance of purified beta-core

    SciTech Connect

    Wehmann, R.E.; Blithe, D.L.; Flack, M.R.; Nisula, B.C. )

    1989-09-01

    We injected a highly purified preparation of the beta-core molecule, a fragment of hCG beta excreted in pregnancy urine, into five men and three women to determine its kinetic parameters, MCR, and urinary clearance. The beta-core molecule was distributed in an initial volume (1950 +/- 156 (mean +/- SEM) mL/m2 body surface area) approximately equal to the estimated plasma volume. Its disappearance was multiexponential on a semilogarithmic plot, with a rapid phase t1/2 of 3.5 +/- 0.7 min and a slow phase t1/2 of 22.4 +/- 4.2 min. The transit time (the mean time spent by a molecule of beta-core in transit) was 20.6 +/- 2.1 min. The MCR was 192.0 +/- 8.0 mL/min.m2 body surface area. About 5% of the injected dose of beta-core was excreted into the urine in the first 30 min after injection, and low levels of excretion persisted for up to 7 days. The urinary clearance rate of beta-core was 13.7 +/- 1.4 mL/min.m2, accounting for about 8% of the elimination of beta-core from the plasma. The beta-core immunoreactivity in serum and urine was characterized by gel filtration and three independent RIA systems to show that its properties were indistinguishable from those of the injected beta-core. Serum levels of beta-core in pregnant women were less than 0.2 ng/mL, while the amounts excreted in their urine were as much as 5 mg/day. Based on these clearance parameters of beta-core in normal subjects, less than 0.2% of the beta-core excreted in pregnancy urine is derived by urinary clearance of plasma beta-core. Therefore, more than 99% of the beta-core excreted in pregnancy urine is derived from beta-core in a compartment separate from plasma. In particular, these data indicate that there is relatively little placental secretion of beta-core into plasma and that placental secretion does not account for the vast majority of beta-core in pregnancy urine.

  6. Direct measurement of first-pass ileal clearance of a bile acid in humans

    SciTech Connect

    Galatola, G.; Jazrawi, R.P.; Bridges, C.; Joseph, A.E.; Northfield, T.C. )

    1991-04-01

    The purpose of this study was to develop and validate a method of directly measuring ileal bile acid absorption efficiency during a single enterohepatic cycle (first-pass ileal clearance). This has become feasible for the first time because of the availability of the synthetic gamma-labeled bile acid 75Selena-homocholic acid-taurine (75SeHCAT). Together with the corresponding natural bile acid cholic acid-taurine (labeled with 14C), SeHCAT was infused distal to an occluding balloon situated beyond the ampulla of Vater in six healthy subjects. Completion of a single enterohepatic cycle was assessed by obtaining a plateau for 75SeHCAT activity proximal to the occluding balloon, which prevented further cycles. Unabsorbed 75SeHCAT was collected after total gut washout, which was administered distal to the occluding balloon. 75SeHCAT activity in the rectal effluent measured by gamma counter was compared with that of absorbed 75SeHCAT level measured by gamma camera and was used to calculate first-pass ileal clearance. This was very efficient (mean value, 96%) and showed very little variation in the six subjects studied (range, 95%-97%). A parallel time-activity course in hepatic bile for 14C and 75Se during a single enterohepatic cycle, together with a ratio of unity for 14C/75Se in samples obtained at different time intervals, suggests that 75SeHCAT is handled by the ileum like the natural bile acid cholic acid-taurine. Extrapolation of 75SeHCAT first-pass ileal clearance to that of the natural bile acid therefore seems justifiable. In a subsidiary experiment, ileal absorption efficiency per day for 75SeHCAT was also measured by scanning the gallbladder area on 5 successive days after the measurement of first-pass ileal clearance. In contrast with absorption efficiency per cycle, absorption efficiency per day varied widely (49%-86%).

  7. Effect of mouse strain as a background for Alzheimer's disease models on the clearance of amyloid-β.

    PubMed

    Qosa, Hisham; Kaddoumi, Amal

    2016-04-01

    Novel animal models of Alzheimer's disease (AD) are relentlessly being developed and existing ones are being fine-tuned; however, these models face multiple challenges associated with the complexity of the disease where most of these models do not reproduce the full phenotypical disease spectrum. Moreover, different AD models express different phenotypes that could affect their validity to recapitulate disease pathogenesis and/or response to a drug. One of the most important and understudied differences between AD models is differences in the phenotypic characteristics of the background species. Here, we used the brain clearance index (BCI) method to investigate the effect of strain differences on the clearance of amyloid β (Aβ) from the brains of four mouse strains. These mouse strains, namely C57BL/6, FVB/N, BALB/c and SJL/J, are widely used as a background for the development of AD mouse models. Findings showed that while Aβ clearance across the blood-brain barrier (BBB) was comparable between the 4 strains, levels of LRP1, an Aβ clearance protein, was significantly lower in SJL/J mice compared to other mouse strains. Furthermore, these mouse strains showed a significantly different response to rifampicin treatment with regard to Aβ clearance and effect on brain level of its clearance-related proteins. Our results provide for the first time an evidence for strain differences that could affect ability of AD mouse models to recapitulate response to a drug, and opens a new research avenue that requires further investigation to successfully develop mouse models that could simulate clinically important phenotypic characteristics of AD.

  8. Effects of block copolymer properties on nanocarrier protection from in vivo clearance

    PubMed Central

    D’Addio, Suzanne M.; Saad, Walid; Ansell, Steven M.; Squiers, John J.; Adamson, Douglas; Herrera-Alonso, Margarita; Wohl, Adam R.; Hoye, Thomas R.; Macosko, Christopher W.; Mayer, Lawrence D.; Vauthier, Christine; Prud’homme, Robert K.

    2012-01-01

    Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer-directed assembly during rapid precipitation. Nanocarriers are formed using block copolymers with hydrophobic blocks of polystyrene (PS), poly-ε-caprolactone (PCL), poly-D,L-lactide (PLA), or poly-lactide-co-glycolide (PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with molecular weights from 1.5 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs are evaluated in vivo in Foxn1nu mice to determine relative rates of clearance. The amount of nanocarrier in circulation after 4 h varies from 10% to 85% of initial dose, depending on the block copolymer. In vitro complement activation assays are conducted in an effort to correlate the protection of the nanocarrier surface from complement binding and activation and in vivo circulation. Guidelines for optimizing block copolymer structure to maximize circulation of nanocarriers formed by rapid precipitation and directed assembly are proposed, relating to the relative size of the hydrophilic and hydrophobic block, the hydrophobicity of the anchoring block, the absolute size of the PEG block, and polymer crystallinity. The in vitro results distinguish between the poorly circulating PEG5k-PCL9k and the better circulating nanocarriers, but could not rank the better circulating nanocarriers in order of circulation time. Analysis of PEG surface packing on monodisperse 200 nm latex spheres indicates that the sizes of the hydrophobic PCL, PS, and PLA blocks are correlated with the PEG blob size, and possibly the clearance from circulation. Suggestions for next step in vitro measurements are made. PMID:22732478

  9. Intraarticular volume and clearance in human synovial effusions

    SciTech Connect

    Wallis, W.J.; Simkin, P.A.; Nelp, W.B.; Foster, D.M.

    1985-04-01

    Intraarticular volumes were measured by radiolabeled albumin (RISA) distribution in chronic knee effusions from 11 rheumatoid arthritis patients and 9 osteoarthritis patients. Volumes of synovial fluid obtained at joint aspiration were substantially less than those found by RISA dilution. Up to 24 hours was needed for full distribution of RISA throughout the intraarticular compartment. Measured 123I and RISA radioactivity over the knee described monoexponential rate constants, lambda (minute-1). The clearance of 123I and RISA from synovial effusions was derived by the formulation volume (ml) X lambda (minute-1) = clearance (ml/minute). RISA clearance in rheumatoid effusions was significantly greater than that found in osteoarthritis effusions. Intraarticular volume and isotope clearance were easily quantified and provide measures for further evaluating the microvascular physiology of synovial effusions.

  10. High Temperature Evaluation of an Active Clearance Control System Concept

    NASA Technical Reports Server (NTRS)

    Taylor, Shawn C.; Steinetz, Bruce M.; Oswald, Jay J.

    2006-01-01

    A mechanically actuated blade tip clearance control concept was evaluated in a nonrotating test rig to quantify secondary seal leakage at elevated temperatures. These tests were conducted to further investigate the feasibility of actively controlling the clearance between the rotor blade tips and the surrounding shroud seal in the high pressure turbine (HPT) section of a turbine engine. The test environment simulates the state of the back side of the HPT shroud seal with pressure differentials as high as 120 psig and temperatures up to 1000 F. As expected, static secondary seal leakage decreased with increasing temperature. At 1000 F, the test rig's calculated effective clearance (at 120 psig test pressure) was 0.0003 in., well within the industry specified effective clearance goal.

  11. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Clearance, the following information will be furnished to the DE upon completion of the neutralization: (a) Records of the neutralization work performed, including statement of methods employed. (b) List...

  12. 77 FR 44641 - Critical Infrastructure Private Sector Clearance Program Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-30

    ... SECURITY Critical Infrastructure Private Sector Clearance Program Request AGENCY: National Protection and... comments concerning Reinstatement, with change, of a previously approved ICR for the Critical... sector partners who are responsible for critical infrastructure protection but would not otherwise...

  13. Laser-optical blade tip clearance measurement system

    NASA Technical Reports Server (NTRS)

    Barranger, J. P.; Ford, M. J.

    1980-01-01

    The need for blade tip clearance instrumentation has been intensified recently by advances in technology of gas turbine engines. A new laser-optical measurement system has been developed to measure single blade tip clearances and average blade tip clearances between a rotor and its gas path seal in rotating component rigs and complete engines. The system is applicable to fan, compressor and turbine blade tip clearance measurements. The engine mounted probe is particularly suitable for operation in the extreme turbine environment. The measurement system consists of an optical subsystem, an electronic subsystem and a computing and graphic terminal. Bench tests and environmental tests were conducted to confirm operation at temperatures, pressures, and vibration levels typically encountered in an operating gas turbine engine.

  14. Clearance detector and method for motion and distance

    DOEpatents

    Xavier, Patrick G.

    2011-08-09

    A method for correct and efficient detection of clearances between three-dimensional bodies in computer-based simulations, where one or both of the volumes is subject to translation and/or rotations. The method conservatively determines of the size of such clearances and whether there is a collision between the bodies. Given two bodies, each of which is undergoing separate motions, the method utilizes bounding-volume hierarchy representations for the two bodies and, mappings and inverse mappings for the motions of the two bodies. The method uses the representations, mappings and direction vectors to determine the directionally furthest locations of points on the convex hulls of the volumes virtually swept by the bodies and hence the clearance between the bodies, without having to calculate the convex hulls of the bodies. The method includes clearance detection for bodies comprising convex geometrical primitives and more specific techniques for bodies comprising convex polyhedra.

  15. IFNL4 affects clearance of hepatitis C virus

    Cancer.gov

    Scientists have discovered a new human interferon gene, Interferon Lambda 4 (IFNL4), that affects clearance of the hepatitis C virus. They also identified an inherited genetic variant within IFNL4 that predicts how people respond to treatment for hepatit

  16. Antibody-Mediated Clearance of Alphavirus Infection from Neurons

    NASA Astrophysics Data System (ADS)

    Levine, Beth; Hardwick, J. Marie; Trapp, Bruce D.; Crawford, Thomas O.; Bollinger, Robert C.; Griffin, Diane E.

    1991-11-01

    Humoral immunity is important for protection against viral infection and neutralization of extracellular virus, but clearance of virus from infected tissues is thought to be mediated solely by cellular immunity. However, in a SCID mouse model of persistent alphavirus encephalomyelitis, adoptive transfer of hyperimmune serum resulted in clearance of infectious virus and viral RNA from the nervous system, whereas adoptive transfer of sensitized T lymphocytes had no effect on viral replication. Three monoclonal antibodies to two different epitopes on the E2 envelope glycoprotein mediated viral clearance. Treatment of alphavirus-infected primary cultured rat neurons with these monoclonal antibodies to E2 resulted in decreased viral protein synthesis, followed by gradual termination of mature infectious virion production. Thus, antibody can mediate clearance of alphavirus infection from neurons by restricting viral gene expression.

  17. Further Characterization of an Active Clearance Control Concept

    NASA Technical Reports Server (NTRS)

    Taylor, Shawn C.; Steinetz, Bruce M.; Oswald, Jay J.

    2007-01-01

    A new test chamber and precision hydraulic actuation system were incorporated into an active clearance control (ACC) test rig at NASA Glenn Research Center. Using the improved system, a fast-acting, mechanically-actuated, ACC concept was evaluated at engine simulated temperatures and pressure differentials up to 1140 F and 120 psig, on the basis of secondary seal leakage and kinematic controllability. During testing, the ACC concept tracked a simulated flight clearance transient profile at 1140 F, 120 psig, with a maximum error of only 0.0012 in. Comparison of average dynamic leakage of the system with average static leakage did not show significant differences between the two operating conditions. Calculated effective clearance values for the rig were approximately 0.0002 in. at 120 psig, well below the industry specified effective clearance threshold of 0.001 in.

  18. Early Agriculture: Land Clearance and Climate Effects

    NASA Astrophysics Data System (ADS)

    Ruddiman, W. F.

    2013-12-01

    inception. Well-dated high-resolution CO2 (and CH4) records from ice cores show gas decreases that correlate closely with major pandemics and civil strife, but show little if any link to temperature or precipitation trends. One significant (and intriguing) discrepancy with the original hypothesis remains. Most of the CO2 rise occurred between 6000 and 2500 years ago, well before the major increase in global population that has been hindcast from geometric models that assume a constant fractional rate of population increase. Some of this discrepancy has been reconciled by historical evidence showing much higher per-capita clearance millennia ago than later in pre-industrial time, resulting in disproportionately large early clearance and CO2 emissions. In addition, DNA studies and archeological syntheses now indicate that early farming populations initially grew at very fast rates favored by environments rich in basic resources (especially fertile soils), but then slowed in later millennia because of growing resource limitations and the effects of pandemics and civil strife in checking population growth. This emerging view of fast-rising early population trends has the potential to account for the early timing of the CO2 increase.

  19. Enhanced Bomb Effects for Obstacle Clearance (Analysis Task)

    DTIC Science & Technology

    1998-01-01

    Enhanced Bomb Effects for Obstacle Clearance (Analysis Task) Tim Hennessey Diane Nell Naval Surface Warfare Center, Indian Head Division 101 Strauss...need for a system capable of simultaneously breaching obstacles and clearing mines, in-stride, from over the horizon, during an amphibious assault...In response to the obstacle -breaching concern, the Enhanced Bomb Effects for Obstacle Clearance program was started. The purpose of the NSWCDD/CSS

  20. Measuring Motor-Shaft Clearance And Wobble During Operation

    NASA Technical Reports Server (NTRS)

    Chern, Engmin James

    1996-01-01

    Noncontact proximity sensor, preferably eddy-current liftoff probe, provides realtime measurement of distance and small variations of distance between two mechanical components designed to be maintained at precise, fixed distance. In particular, system intended for use in measuring lateral clearance and variations in lateral clearance (wobble) of motor shaft relative to motor housing while shaft turning. Provides early indication of wear in motor bearings. Rate of rotation also measured.

  1. [Methohexital clearance in patients with acute hepatitis (author's transl)].

    PubMed

    Richter, E; Gallenkamp, H; Heusler, H; Zilly, W; Breimer, D D

    1979-10-26

    Pharmacokinetics of methohexital were studied in patients with acute hepatitis and after a treatment period either with "essential phospholipids" or phenobarbital. During the acute phase the distribution of methohexital was significantly altered. No change had been observed in the methohexital clearance. During remission the distribution of methohexital was in a normal range. After treatment with phenobarbital the methohexital clearance increased significantly whereas no change was observed after treatment with "essential phospholipids".

  2. Control of Small Robotic Vehicles In Unexploded Ordnance Clearance

    DTIC Science & Technology

    1997-04-01

    Proceedings of the IEEE ICRA97, Albuquerque, New Mexico, April 20-25, 1997 ISBN 0-7803-3904-5 Control of Small Robotic Vehicles In Unexploded...multiple small robotic vehicles for performing mine field clearance, and the related problem of clearing unexploded ordnance from areas of interest...charge that could be detonated upon command. Results given in this paper includes the performance of clearance operations with behavior based robots

  3. Intradialytic clearance of opioids: methadone versus hydromorphone.

    PubMed

    Perlman, Ryan; Giladi, Hili; Brecht, Krista; Ware, Mark A; Hebert, Terence E; Joseph, Lawrence; Shir, Yoram

    2013-12-01

    Opioids are commonly prescribed to patients with chronic pain associated with end-stage renal disease requiring hemodialysis. The stability of opioid analgesia during dialysis may vary among different opioids. No studies to date have corroborated this clinical observation by directly comparing plasma concentrations of different opioids during dialysis. We compared changes in peridialysis plasma concentrations of 2 pharmacokinetically distinct opioids, methadone and hydromorphone (HM). Fourteen dialysis patients with chronic pain received either methadone or HM for at least 2 weeks before beginning the study. Blood samples were obtained immediately before, during, and after hemodialysis in 2 separate dialysis sessions, 1 week apart, and were analyzed for opioid concentrations. Methadone plasma concentrations were more stable during hemodialysis compared to HM: the mean percent change of methadone plasma levels was 14.9% ± 8.2% (± SD) compared with 55.1% ± 8.1% in the HM treatment group, a difference of 40.2% (95% confidence interval 17.14 to 63.14). The mean plasma clearance of methadone was 19.9 ± 8.5 mL/min (± SD) compared with 105.7 ± 8.3 mL/min for HM, a difference of 85.7 mL/min (95% confidence interval 61.9 to 109.1). There were no differences between the 2 opioid groups in pain scores, side effect profile, and quality of life. Methadone therapy was not associated with an increased rate of adverse events. If confirmed by larger clinical studies, methadone could be considered as one of the opioids of choice in dialysis patients.

  4. Calculation of Tip Clearance Effects in a Transonic Compressor Rotor

    NASA Technical Reports Server (NTRS)

    Chima, R. V.

    1998-01-01

    The flow through the tip clearance region of a transonic compressor rotor (NASA rotor 37) was computed and compared to aerodynamic probe and laser anemometer data. Tip clearance effects were modeled both by gridding the clearance gap and by using a simple periodicity model across the ungridded gap. The simple model was run with both the full gap height, and with half the gap height to simulate a vena-contracta effect. Comparisons between computed and measured performance maps and downstream profiles were used to validate the models and to assess the effects of gap height on the simple clearance model. Recommendations were made concern- ing the use of the simple clearance model Detailed comparisons were made between the gridded clearance gap solution and the laser anemometer data near the tip at two operating points. The computed results agreed fairly well with the data but overpredicted the extent of the casing separation and underpredicted the wake decay rate. The computations were then used to describe the interaction of the tip vortex, the passage shock, and the casing boundary layer.

  5. Calculation of tip clearance effects in a transonic compressor rotor

    NASA Technical Reports Server (NTRS)

    Chima, R. V.

    1996-01-01

    The flow through the tip clearance region of a transonic compressor rotor (NASA rotor 37) was computed and compared to aerodynamic probe and laser anemometer data. Tip clearance effects were modeled both by gridding the clearance gap and by using a simple periodicity model across the ungridded gap. The simple model was run with both the full gap height, and with half the gap height to simulate a vena-contracta effect. Comparisons between computed and measured performance maps and downstream profiles were used to validate the models and to assess the effects of gap height on the simple clearance model. Recommendations were made concerning the use of the simple clearance model. Detailed comparisons were made between the gridded clearance gap solution and the laser anemometer data near the tip at two operating points. The computer results agreed fairly well with the data but overpredicted the extent of the casing separation and underpredicted the wake decay rate. The computations were then used to describe the interaction of the tip vortex, the passage shock, and the casing boundary layer.

  6. Model of mucociliary clearance in cystic fibrosis lungs.

    PubMed

    Kurbatova, P; Bessonov, N; Volpert, V; Tiddens, H A W M; Cornu, C; Nony, P; Caudri, D

    2015-05-07

    Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways.

  7. A high sensitivity inductive sensor for blade tip clearance measurement

    NASA Astrophysics Data System (ADS)

    Du, Li; Zhu, Xiaoliang; Zhe, Jiang

    2014-06-01

    A multiplexed inductive sensor consisting of multiple mini-sized planar spiral coils for detecting multiple tip clearances of rotor blades is presented. The sensor measures the tip clearances by monitoring the inductance changes of planar spiral coils caused by the passage of the rotor blades. A resonance frequency division multiplexing technique and parallel LC resonance measurement were applied to the multiple sensor coils, making it feasible to measure multiple tip clearances using only one set of measurement electronics with high sensitivity and resolution. The results from tests conducted on a bench-top test rig have demonstrated that the sensor is capable of simultaneously measuring multiple tip clearances from 0 to 5 mm with a 10 μm resolution at a high rotary speed up to 80 000 RPM. With its high resolution, high sensitivity and capability of monitoring a large number of tip clearances simultaneously, this sensor can potentially be used for advanced active tip clearance control in turbine machinery.

  8. Succession planning.

    PubMed

    Catanzaro, Thomas E

    2006-03-01

    This article provides the reader with an appreciation of the diverse elements that go into a buy-sell, affiliation, or merger situation for veterinary practices. In the changing market place of American veterinary medicine, old paradigms no longer hold comfort. The generational differences are briefly explored herein as well as the new economic realities. A few examples are offered to illustrate just how much variability exists in the current business of veterinary medicine and the subsequent practice transitions needed to enhance value. Functioning models are explored, as well as affiliation and merger options. Practice valuation is discussed in general terms, referencing the cutting-edge factors. The six-point summary provides almost all practices a solid operational base for daily operations and succession planning.

  9. Autophagy is involved in oral rAAV/Aβ vaccine-induced Aβ clearance in APP/PS1 transgenic mice.

    PubMed

    Wang, He-Cheng; Zhang, Tao; Kuerban, Bolati; Jin, Ying-Lan; Le, Weidong; Hara, Hideo; Fan, Dong-Sheng; Wang, Yan-Jiang; Tabira, Takeshi; Chui, De-Hua

    2015-08-01

    The imbalance between ß-amyloid (Aß) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer's disease (AD). The sporadic form of AD is characterized by an overall impairment in Aß clearance. Immunotherapy targetingclearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aß decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aß antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.

  10. 48 CFR 245.603-70 - Contractor performance of plant clearance duties.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... plant clearance duties. 245.603-70 Section 245.603-70 Federal Acquisition Regulations System DEFENSE..., Redistribution, and Disposal of Contractor Inventory 245.603-70 Contractor performance of plant clearance duties... clearance functions if the volume of plant clearance warrants performance by the contractor. (2) The...

  11. 48 CFR 245.7101-4 - DD Form 1640, Request for Plant Clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Plant Clearance. 245.7101-4 Section 245.7101-4 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT GOVERNMENT PROPERTY Plant Clearance Forms 245.7101-4 DD Form 1640, Request for Plant Clearance. Use to request plant clearance assistance...

  12. 48 CFR 245.7002 - Duties and responsibilities of plant clearance officers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... responsibilities of plant clearance officers. 245.7002 Section 245.7002 Federal Acquisition Regulations System... Appointment of Property Administrators and Plant Clearance Officers 245.7002 Duties and responsibilities of plant clearance officers. The plant clearance officer shall— (a) Instruct the contractor on...

  13. Developing a Successful HIV Vaccine.

    PubMed

    Gallo, Robert C

    2015-07-15

    Human immunodeficiency virus (HIV) genome integration indicates that persistent sterilizing immunity will be needed for a successful vaccine candidate. This suggests a need for broad antibodies targeting the Env protein. Immunogens targeting gp120 have been developed that block infection in monkeys and mimic the modest success of the RV144 clinical trial in that protection is short-lived following a decline in antibody-depending cell-mediated cytotoxicity-like antibodies. Attempts to induce antibody persistence have been complicated by a loss of efficacy, presumably by increasing the number of HIV-target cells. The key seems to be achieving an immune balance.

  14. Eosinophils Contribute to Early Clearance of Pneumocystis murina Infection.

    PubMed

    Eddens, Taylor; Elsegeiny, Waleed; Nelson, Michael P; Horne, William; Campfield, Brian T; Steele, Chad; Kolls, Jay K

    2015-07-01

    Pneumocystis pneumonia remains a common opportunistic infection in the diverse immunosuppressed population. One clear risk factor for susceptibility to Pneumocystis is a declining CD4(+) T cell count in the setting of HIV/AIDS or primary immunodeficiency. Non-HIV-infected individuals taking immunosuppressive drug regimens targeting T cell activation are also susceptible. Given the crucial role of CD4(+) T cells in host defense against Pneumocystis, we used RNA sequencing of whole lung early in infection in wild-type and CD4-depleted animals as an unbiased approach to examine mechanisms of fungal clearance. In wild-type mice, a strong eosinophil signature was observed at day 14 post Pneumocystis challenge, and eosinophils were increased in the bronchoalveolar lavage fluid of wild-type mice. Furthermore, eosinophilopoiesis-deficient Gata1(tm6Sho)/J mice were more susceptible to Pneumocystis infection when compared with BALB/c controls, and bone marrow-derived eosinophils had in vitro Pneumocystis killing activity. To drive eosinophilia in vivo, Rag1(-/-) mice were treated with a plasmid expressing IL-5 (pIL5) or an empty plasmid control via hydrodynamic injection. The pIL5-treated mice had increased serum IL-5 and eosinophilia in the lung, as well as reduced Pneumocystis burden, compared with mice treated with control plasmid. In addition, pIL5 treatment could induce eosinophilia and reduce Pneumocystis burden in CD4-depleted C57BL/6 and BALB/c mice, but not eosinophilopoiesis-deficient Gata1(tm6Sho)/J mice. Taken together, these results demonstrate that an early role of CD4(+) T cells is to recruit eosinophils to the lung and that eosinophils are a novel candidate for future therapeutic development in the treatment of Pneumocystis pneumonia in the immunosuppressed population.

  15. Astrocytes: Targets for Neuroprotection in Stroke

    PubMed Central

    Barreto, George; White, Robin E.; Ouyang, Yibing; Xu, Lijun; Giffard, Rona G.

    2011-01-01

    In the past two decades, over 1000 clinical trials have failed to demonstrate a benefit in treating stroke, with the exception of thrombolytics. Although many targets have been pursued, including antioxidants, calcium channel blockers, glutamate receptor blockers, and neurotrophic factors, often the focus has been on neuronal mechanisms of injury. Broader attention to loss and dysfunction of non-neuronal cell types is now required to increase the chance of success. Of the several glial cell types, this review will focus on astrocytes. Astrocytes are the most abundant cell type in the higher mammalian nervous system, and they play key roles in normal CNS physiology and in central nervous system injury and pathology. In the setting of ischemia astrocytes perform multiple functions, some beneficial and some potentially detrimental, making them excellent candidates as therapeutic targets to improve outcome following stroke and in other central nervous system injuries. The older neurocentric view of the central nervous system has changed radically with the growing understanding of the many essential functions of astrocytes. These include K+ buffering, glutamate clearance, brain antioxidant defense, close metabolic coupling with neurons, and modulation of neuronal excitability. In this review, we will focus on those functions of astrocytes that can both protect and endanger neurons, and discuss how manipulating these functions provides a novel and important strategy to enhance neuronal survival and improve outcome following cerebral ischemia. PMID:21521168

  16. Clearance and binding of native and defucosylated lactoferrin.

    PubMed Central

    Imber, M J; Pizzo, S V

    1983-01-01

    These studies explore the role of carbohydrate recognition systems and the direct involvement of terminal alpha 1-3-linked fucose in the clearance of lactoferrin from the murine circulation and in the specific binding of lactoferrin to receptors on murine peritoneal macrophages. As previously reported, radiolabelled lactoferrin cleared very rapidly (t1/2 less than 1 min) after intravenous injection into mice. However, competing levels of ligands specific for the hepatic galactose receptor (asialo-orosomucoid), the hepatic fucose receptor (fucosyl-bovine serum albumin), and the mononuclear-phagocyte system pathway recognizing mannose, N-acetylglucosamine and fucose (mannosyl-, N-acetylglucosaminyl- and fucosyl-bovine serum albumin) did not block radiolabelled lactoferrin clearance in vivo or binding to mouse peritoneal macrophage monolayers in vitro. Almond emulsin alpha 1-3-fucosidase was used to prepare defucosylated lactoferrin in which 88% of the alpha 1-3-linked fucose was hydrolysed. No difference in clearance or receptor binding was observed between radiolabelled native and defucosylated lactoferrin. Fucoidin, a fucose-rich algal polysaccharide, completely inhibits the clearance in vivo and macrophage binding in vitro of lactoferrin. This effect, however, is probably not the result of competition for binding to the fucose receptor, since gel-filtration studies demonstrated formation of a stable complex between lactoferrin and fucoidin. The present results indicate that the lactoferrin-clearance pathway is distinct from several pathways mediating glycoprotein clearance through recognition of terminal galactose, fucose, N-acetylglucosamine or mannose. Furthermore, alpha 1-3-linked fucose on lactoferrin is not essential for lactoferrin clearance in vivo or specific binding to macrophage receptors in vitro. Images Fig. 3. PMID:6882370

  17. Acute effects of ethanol on renal folate clearance in rats

    SciTech Connect

    Eisenga, B.H.; McMartin, K.E.

    1986-03-05

    Studies of the renal clearance of folic acid in primates demonstrate net reabsorption of folate by a saturable system. The acute administration of ethanol to rats causes a significant increase in urinary folate excretion. The mechanism for this effect is unknown and thus the effect of acute administration of ethanol on the renal absorption and urinary clearance of folate was studied in rats. Folic acid was administered to male Sprague-Dawley rats via continuous intravenous infusion in doses ranging from 3-75 micromoles/kg and renal clearance relative to inulin was determined. The effects of various dose levels of ethanol on these parameters were then determined. At a dose of 15 micromoles/kg, the renal clearance of folate relative to that of inulin was about 0.65 mg/min. At a plasma ethanol level about 100 mg/dl, the renal clearance of folate was not markedly altered. These results suggests that there is net reabsorption of folate in the rat kidney and that moderate doses of ethanol have little effect on renal effect on renal folate reabsorption.

  18. Experimental and Numerical Study on Blanking Process with Negative Clearance

    NASA Astrophysics Data System (ADS)

    Hirota, Kenji; Yanaga, Hiroki; Fukushima, Katsunori

    This study summarizes the characteristics of blanking behavior with a negative clearance. Several experiments were performed for two aluminum sheets over a wide range of clearances including negative values. Blanking with negatively large clearances was found to produce fine cut edges with less roll-over and no fracture zone even for a brittle material. Corresponding simulations were performed using the Ayada's criterion for predicting ductile fracture initiation. Each zone of blanked part edges such as roll-over and fractured zone agreed well with that obtained in the experiments except a few cases accompanied by secondary shear. The reason for prevention of fracture by using negative clearances was explained with the change of the damage value during the process; the damage value was kept low throughout the blanking operation since the mean stress dominating the damage value became compressive around the die edge. Influences of blanking parameters on load-stroke curves were also investigated. The curves for negative clearances showed gradual increase in load toward the end of stroke. The earlier fracture initiated, the earlier the load reached a peak. Simulated curves showed the same tendency and in good agreement with the experimental ones quantitatively.

  19. High Power Cryogenic Targets

    SciTech Connect

    Gregory Smith

    2011-08-01

    The development of high power cryogenic targets for use in parity violating electron scattering has been a crucial ingredient in the success of those experiments. As we chase the precision frontier, the demands and requirements for these targets have grown accordingly. We discuss the state of the art, and describe recent developments and strategies in the design of the next generation of these targets.

  20. Clearance of pathological antibodies using biomimetic nanoparticles

    PubMed Central

    Copp, Jonathan A.; Fang, Ronnie H.; Luk, Brian T.; Hu, Che-Ming J.; Gao, Weiwei; Zhang, Kang; Zhang, Liangfang

    2014-01-01

    Pathological antibodies have been demonstrated to play a key role in type II immune hypersensitivity reactions, resulting in the destruction of healthy tissues and leading to considerable morbidity for the patient. Unfortunately, current treatments present significant iatrogenic risk while still falling short for many patients in achieving clinical remission. In the present work, we explored the capability of target cell membrane-coated nanoparticles to abrogate the effect of pathological antibodies in an effort to minimize disease burden, without the need for drug-based immune suppression. Inspired by antibody-driven pathology, we used intact RBC membranes stabilized by biodegradable polymeric nanoparticle cores to serve as an alternative target for pathological antibodies in an antibody-induced anemia disease model. Through both in vitro and in vivo studies, we demonstrated efficacy of RBC membrane-cloaked nanoparticles to bind and neutralize anti-RBC polyclonal IgG effectively, and thus preserve circulating RBCs. PMID:25197051

  1. Successful Predictions

    NASA Astrophysics Data System (ADS)

    Pierrehumbert, R.

    2012-12-01

    In an observational science, it is not possible to test hypotheses through controlled laboratory experiments. One can test parts of the system in the lab (as is done routinely with infrared spectroscopy of greenhouse gases), but the collective behavior cannot be tested experimentally because a star or planet cannot be brought into the lab; it must, instead, itself be the lab. In the case of anthropogenic global warming, this is all too literally true, and the experiment would be quite exciting if it weren't for the unsettling fact that we and all our descendents for the forseeable future will have to continue making our home in the lab. There are nonetheless many routes though which the validity of a theory of the collective behavior can be determined. A convincing explanation must not be a"just-so" story, but must make additional predictions that can be verified against observations that were not originally used in formulating the theory. The field of Earth and planetary climate has racked up an impressive number of such predictions. I will also admit as "predictions" statements about things that happened in the past, provided that observations or proxies pinning down the past climate state were not available at the time the prediction was made. The basic prediction that burning of fossil fuels would lead to an increase of atmospheric CO2, and that this would in turn alter the Earth's energy balance so as to cause tropospheric warming, is one of the great successes of climate science. It began in the lineage of Fourier, Tyndall and Arrhenius, and was largely complete with the the radiative-convective modeling work of Manabe in the 1960's -- all well before the expected warming had progressed far enough to be observable. Similarly, long before the increase in atmospheric CO2 could be detected, Bolin formulated a carbon cycle model and used it to predict atmospheric CO2 out to the year 2000; the actual values come in at the high end of his predicted range, for

  2. Impaired lipid clearance in patients with previous acute pancreatitis.

    PubMed Central

    Guzmán, S; Nervi, F; Llanos, O; León, P; Valdivieso, V

    1985-01-01

    Fasting serum triglycerides were measured in 52 patients who had sustained an attack of pancreatitis (gall stone related 33, alcoholism six) at least six months earlier. Several patients (23%) had raised fasting serum triglycerides, with a type IV phenotype in all but one patient. The 40 patients with normal fasting serum triglycerides received an oral load of 100 g sunflower oil to compare their clearance of dietary triglycerides with that of a control group of 54 subjects. The clearance of ingested triglycerides was significantly impaired in the patients - irrespective of the presumed aetiological factor, or clinical condition associated with pancreatitis - compared with the clearance in controls. A triglyceride tolerance test is the only way to detect those patients in whom a future attack of pancreatitis may be precipitated by a diet rich in fat, or endogenous over production of triglycerides as after an alcoholic debauch. PMID:4029716

  3. Application of Dsm in Obstacle Clearance Surveying of Aerodrome

    NASA Astrophysics Data System (ADS)

    Qiao, X.; Lv, S. H.; Li, L. L.; Zhou, X. J.; Wang, H. Y.; Li, D.; Liu, J. Y.

    2016-06-01

    Compared to the wide use of digital elevation model (DEM), digital surface model (DSM) receives less attention because that it is composed by not only terrain surface, but also vegetations and man-made objects which are usually regarded as useless information. Nevertheless, these objects are useful for the identification of obstacles around an aerodrome. The primary objective of the study was to determine the applicability of DSM in obstacle clearance surveying of aerodrome. According to the requirements of obstacle clearance surveying at QT airport, aerial and satellite imagery were used to generate DSM, by means of photogrammetry, which was spatially analyzed with the hypothetical 3D obstacle limitation surfaces (OLS) to identify the potential obstacles. Field surveying was then carried out to retrieve the accurate horizontal position and height of the obstacles. The results proved that the application of DSM could make considerable improvement in the efficiency of obstacle clearance surveying of aerodrome.

  4. Fiber-optic laser Doppler turbine tip clearance probe.

    PubMed

    Büttner, Lars; Pfister, Thorsten; Czarske, Jürgen

    2006-05-01

    A laser Doppler based method for in situ single blade tip clearance measurements of turbomachines with high precision is presented for what we believe is the first time. The sensor is based on two superposed fanlike interference fringe systems generated by two laser wavelengths from a fiber-coupled, passive, and therefore compact measurement head employing diffractive optics. Tip clearance measurements at a transonic centrifugal compressor performed during operation at 50,000 rpm (833 Hz, 586 m/s tip speed) are reported. At these speeds the measured uncertainty of the tip position was less than 20 microm, a factor of 2 more accurate than that of capacitive probes. The sensor offers great potential for in situ and online high-precision tip clearance measurements of metallic and nonmetallic turbine blades.

  5. HPT Clearance Control: Intelligent Engine Systems-Phase 1

    NASA Technical Reports Server (NTRS)

    2005-01-01

    The following work has been completed to satisfy the Phase I Deliverables for the "HPT Clearance Control" project under NASA GRC's "Intelligent Engine Systems" program: (1) Need for the development of an advanced HPT ACC system has been very clearly laid out, (2) Several existing and potential clearance control systems have been reviewed, (3) A scorecard has been developed to document the system, performance (fuel burn, range, payload, etc.), thermal, and mechanical characteristics of the existing clearance control systems, (4) Engine size and flight cycle selection for the advanced HPT ACC system has been reviewed with "large engine"/"long range mission" combination showing the most benefit, (5) A scoring criteria has been developed to tie together performance parameters for an objective, data driven comparison of competing systems, and (6) The existing HPT ACC systems have been scored based on this scoring system.

  6. Clearance of inhaled ceramic fibers from rat lungs.

    PubMed Central

    Yamato, H; Tanaka, I; Higashi, T; Kido, M

    1994-01-01

    Deposition, clearance, retention, and durability of inhaled particles in lung are important factors for induction of pulmonary fibrosis or lung cancer. To study the deposition and clearance of aluminium silicate ceramic fibers from the lung, male Wistar rats were exposed to ceramic fibers, with a mass median aerodynamic diameter (MMAD) of 3.7 microns, for 6 hr/day, 5 days/week for 2 weeks. The average exposure concentration was 27.2 mg/m3 (SD 9.0). The rats were killed at 1 day, 1 month, 3 months, and 6 months after the end of exposure, and the fiber numbers and dimensions were measured with a scanning electron microscope. No significant difference in length of residual ceramic fibers in the lungs was found among the groups. The geometric mean diameter and number of ceramic fibers, however, decreased according to the clearance period. These findings suggest that the fibers were dissolved at their surface. PMID:7882924

  7. Effect of Internal Clearance on Load Distribution and Life of Radially Loaded Ball and Roller Bearings

    NASA Technical Reports Server (NTRS)

    Oswald, Fred B.; Zaretsky, Erwin V.; Poplawski, Joseph V.

    2012-01-01

    The effect of internal clearance on radially loaded deepgroove ball and cylindrical roller bearing load distribution and fatigue life was determined for four clearance groups defined in the bearing standards. The analysis was extended to negative clearance (interference) conditions to produce a curve of life factor versus internal clearance. Rolling-element loads can be optimized and bearing life maximized for a small negative operating clearance. Life declines gradually with positive clearance and rapidly with increasing negative clearance. Relationships were found between bearing life and internal clearance as a function of ball or roller diameter, adjusted for load. Results are presented as life factors for radially loaded bearings independent of bearing size or applied load. In addition, a modified Stribeck Equation is presented that relates the maximum rolling-element load to internal bearing clearance.

  8. Rapid Treponema pallidum clearance from blood and ulcer samples following single dose benzathine penicillin treatment of early syphilis.

    PubMed

    Tipple, Craig; Jones, Rachael; McClure, Myra; Taylor, Graham

    2015-02-01

    Currently, the efficacy of syphilis treatment is measured with anti-lipid antibody tests. These can take months to indicate cure and, as a result, syphilis treatment trials require long periods of follow-up. The causative organism, Treponema pallidum (T. pallidum), is detectable in the infectious lesions of early syphilis using DNA amplification. Bacteraemia can likewise be identified, typically in more active disease. We hypothesise that bacterial clearance from blood and ulcers will predict early the standard serology-measured treatment response and have developed a qPCR assay that could monitor this clearance directly in patients with infectious syphilis. Patients with early syphilis were given an intramuscular dose of benzathine penicillin. To investigate the appropriate sampling timeframe samples of blood and ulcer exudate were collected intensively for T. pallidum DNA (tpp047 gene) and RNA (16S rRNA) quantification. Sampling ended when two consecutive PCRs were negative. Four males were recruited. The mean peak level of T. pallidum DNA was 1626 copies/ml whole blood and the mean clearance half-life was 5.7 hours (std. dev. 0.53). The mean peak of 16S rRNA was 8879 copies/ml whole blood with a clearance half-life of 3.9 hours (std. dev. 0.84). From an ulcer, pre-treatment, 67,400 T. pallidum DNA copies and 7.08 x 107 16S rRNA copies were detected per absorbance strip and the clearance half-lives were 3.2 and 4.1 hours, respectively. Overall, T. pallidum nucleic acids were not detected in any sample collected more than 56 hours (range 20-56) after treatment. All patients achieved serologic cure. In patients with active early syphilis, measuring T. pallidum levels in blood and ulcer exudate may be a useful measure of treatment success in therapeutic trials. These laboratory findings need confirmation on a larger scale and in patients receiving different therapies.

  9. Acute exposure to acid fog. Effects on mucociliary clearance

    SciTech Connect

    Laube, B.L.; Bowes, S.M. III; Links, J.M.; Thomas, K.K.; Frank, R. )

    1993-05-01

    Submicrometric sulfuric acid (H2SO4) aerosol can affect mucociliary clearance without eliciting irritative symptoms or changes in pulmonary function. The effect of larger fog droplets containing H2SO4 on mucociliary clearance is unknown. We quantified mucociliary clearance from the trachea (n = 4) and small airways (n = 7) of young healthy male adults after an acute exposure to H2SO4 fog (MMAD = 10.3 microns; pH = 2.0; liquid water content = 481 +/- 65 mg/m3; osmolarity = 30 mOsm). Acid fog (AF) or saline fog (SF) (10.9 microns; 492 +/- 116 mg/m3; 30 mOsm) was administered for 40 min of unencumbered breathing (no mouth-piece) at rest and for 20 min of exercise sufficient to produce oronasal breathing. Fog exposures were followed by a methacholine (MCh) challenge (a measure of airway reactivity) or inhalation of technetium-99M radioaerosol (MMAD = 3.4 microns) on 2 study days each. Changes in symptoms and forced ventilatory function were also assessed. Clearance was quantified from computer-assisted analyses of gamma camera images of the lower respiratory tract in terms of %removal/min of the radiolabel from the trachea 25 min after inhalation and from the outer zone of the right lung after 1.9 to 3 h. Symptoms, forced ventilatory function, and MCh response were unaffected by either fog. Tracheal clearance was more rapid in four of four subjects after AF (0.83 +/- 1.58% removal/min) compared with that after SF (-0.54 +/- 0.85% removal/min). Outer zone clearance was more rapid in six of seven subjects after AF (0.22 +/- 0.15% removal/min) compared with that after SF (0.01 +/- 0.09% removal/min).

  10. Effects of desipramine on norepinephrine clearance in congestive heart failure

    SciTech Connect

    Clemson, B.; Baily, R.G.; Davis, D.; Zelis, R. )

    1990-08-01

    Elevated plasma norepinephrine (NE) in congestive heart failure (CHF) is caused by increased NE spillover and decreased NE clearance. To evaluate the effects of neuronal uptake blockade on NE clearance, we studied NE kinetics during steady-state infusions of (3H)NE, before and after oral desipramine (DMI, 50 mg) in 11 patients with CHF and 8 normal volunteers. Baseline plasma NE was greater in the CHF group (637 +/- 56 vs. 271 +/- 32 pg/ml; P less than 0.001), NE clearance was lower in CHF (1.31 +/- 0.21 vs. 1.94 +/- 0.17 l.min-1.m-2; P = 0.026), and NE spillover was greater in CHF (4.71 +/- 0.78 vs. 3.04 +/- 0.35 nmol.min-1.m-2, P = 0.054). After DMI, plasma NE rose significantly in CHF (778 +/- 67; P = 0.008), and NE clearance decreased further in CHF (0.97 +/- 0.16; P = 0.024), but neither changed in normal subjects. NE spillover did not change in either group. There appears to be an enhanced effect of DMI on NE clearance in CHF patients. Two general mechanisms may be responsible for this finding, an increased concentration of drug, possibly caused by a decreased volume of distribution, and an increased sensitivity of neuronal amine pumps to DMI. Both mechanisms may reflect a more general abnormality of clearance of drugs and hormones related to abnormalities of tissue perfusion in CHF.

  11. Neuronal aggregates: formation, clearance and spreading

    PubMed Central

    Lim, Junghyun; Yue, Zhenyu

    2015-01-01

    Summary Proteostasis is maintained by multiple cellular pathways, including protein synthesis, quality control and degradation. An imbalance of neuronal proteostasis, associated with protein misfolding and aggregation, leads to proteinopathies or neurodegeneration. While genetic variations and protein modifications contribute to aggregate formation, components of the proteostasis network dictate the fate of protein aggregates. Here we provide an overview of proteostasis pathways and their interplay (particularly autophagy) with the metabolism of disease-related proteins. We review recent studies on neuronal activity-mediated regulation of proteostasis and transcellular propagation of protein aggregates in the nervous system. Targeting proteostasis pathways therapeutically remains an attractive but challenging task. PMID:25710535

  12. Effect of oral N-acetylcysteine on mucus clearance.

    PubMed

    Millar, A B; Pavia, D; Agnew, J E; Lopez-Vidriero, M T; Lauque, D; Clarke, S W

    1985-07-01

    Oral N-acetylcysteine has been advocated as a mucolytic agent for use in chronic bronchitis. We have investigated the effects of regular use of this drug at a dose of 200 mg thrice daily for 4 weeks in nine patients with chronic bronchitis on lung function, lung mucociliary clearance and sputum viscosity in a controlled, double-blind, crossover study. No significant differences were found in lung function, mucociliary clearance curves or sputum viscosity following treatment with N-acetylcysteine compared to control or placebo measurements.

  13. Effect of atropine on oral clearance of a radiolabeled sulfur colloid

    SciTech Connect

    LaForce, F.M.; Thompson, B.; Trow, R.

    1984-11-01

    Physical clearance is an important oral defense mechanism against gram-negative rods. The authors describe a simple technique that uses commercially available technetium-99m sulfur colloid to measure oral clearance. Technetium-99m sulfur colloid was sprayed into the mouth, and clearance was measured as the percent decrease in radiolabel counts over 2 hours using a radioisotope camera. Results using this technique compared favorably with clearance data using Tc-99m radiolabeled Escherichia coli. Atropine significantly decreased oral clearance rates of the colloid. Decreased clearance may be an important risk factor in the development of gram-negative rod colonization in hospitalized patients. 15 references, 3 figures.

  14. Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model

    PubMed Central

    Rivera-Burgos, Dinelia; Sarkar, Ujjal; Lever, Amanda R.; Avram, Michael J.; Coppeta, Jonathan R.; Wishnok, John S.; Borenstein, Jeffrey T.

    2016-01-01

    The emergence of microphysiologic epithelial lung models using human cells in a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug development and to improve predictive power regarding in vivo drug clearance. In this study, an in vitro model of the airway comprising human primary lung epithelial cells cultured in a microfluidic platform was used to establish a physiologic state and to observe metabolic changes as a function of glucocorticoid exposure. Evaluation of mucus production rate and barrier function, along with lung-specific markers, demonstrated that the lungs maintained a differentiated phenotype. Initial concentrations of 100 nM hydrocortisone (HC) and 30 nM cortisone (C) were used to evaluate drug clearance and metabolite production. Measurements made using ultra-high-performance liquid chromatography and high-mass-accuracy mass spectrometry indicated that HC metabolism resulted in the production of C and dihydrocortisone (diHC). When the airway model was exposed to C, diHC was identified; however, no conversion to HC was observed. Multicompartmental modeling was used to characterize the lung bioreactor data, and pharmacokinetic parameters, including elimination clearance and elimination half-life, were estimated. Polymerse chain reaction data confirmed overexpression of 11-β hydroxysteroid dehydrogenase 2 (11βHSD2) over 11βHSD1, which is biologically relevant to human lung. Faster metabolism was observed relative to a static model on elevated rates of C and diHC formation. Overall, our results demonstrate that this lung airway model has been successfully developed and could interact with other human tissues in vitro to better predict in vivo drug behavior. PMID:26586376

  15. Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model.

    PubMed

    Rivera-Burgos, Dinelia; Sarkar, Ujjal; Lever, Amanda R; Avram, Michael J; Coppeta, Jonathan R; Wishnok, John S; Borenstein, Jeffrey T; Tannenbaum, Steven R

    2016-02-01

    The emergence of microphysiologic epithelial lung models using human cells in a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug development and to improve predictive power regarding in vivo drug clearance. In this study, an in vitro model of the airway comprising human primary lung epithelial cells cultured in a microfluidic platform was used to establish a physiologic state and to observe metabolic changes as a function of glucocorticoid exposure. Evaluation of mucus production rate and barrier function, along with lung-specific markers, demonstrated that the lungs maintained a differentiated phenotype. Initial concentrations of 100 nM hydrocortisone (HC) and 30 nM cortisone (C) were used to evaluate drug clearance and metabolite production. Measurements made using ultra-high-performance liquid chromatography and high-mass-accuracy mass spectrometry indicated that HC metabolism resulted in the production of C and dihydrocortisone (diHC). When the airway model was exposed to C, diHC was identified; however, no conversion to HC was observed. Multicompartmental modeling was used to characterize the lung bioreactor data, and pharmacokinetic parameters, including elimination clearance and elimination half-life, were estimated. Polymerse chain reaction data confirmed overexpression of 11-β hydroxysteroid dehydrogenase 2 (11βHSD2) over 11βHSD1, which is biologically relevant to human lung. Faster metabolism was observed relative to a static model on elevated rates of C and diHC formation. Overall, our results demonstrate that this lung airway model has been successfully developed and could interact with other human tissues in vitro to better predict in vivo drug behavior.

  16. Clearance Analysis of CTC2 (on ELC4) to S-TRRJ HRS Radiator Rotation Envelope

    NASA Technical Reports Server (NTRS)

    Liddle, Donn

    2014-01-01

    ) as defined by nine preexisting Space Vision System (SVS) targets affixed to the forward/zenith side of the S1 and S3 truss segments. The location of the outboard edge of the S-TRRJ radiator would also be measured when positioned at the angle of closest approach to CTC2 (gamma = 35.0 degrees). This data would allow the Digital Pre-Assembly Group to predict how the ELC4 would sit on the UCCAS and how that would translate into the clearance between CTC2 and the S-TRRJ radiators. Phase II: After the ELC4 was delivered and installed into the UCCAS, the position of the CTC2 mounting plate on the inboard face of ELC4, would be measured in the ISSACS coordinate system relative to the SVS control points used in Phase I. Although CTC2 would not yet be mounted on ELC4, the working envelope of CTC2 could be mathematically added to the measured position of ELC4 to produce a best estimate for CTC2's mounted location. Comparing CTC2's best estimated location to the S-TRRJ radiator (measured in Phase I); relative to the ISSACS coordinate system, would provide a direct measurement of the expected clearance. Due to the impending delivery of ELC4 (scheduled for January 2011), planning for the Phase I clearance analysis began immediately. Using the Dynamic Onboard Ubiquitous Graphics (DOUG) program, ISAG designed a way to acquire images of the SVS control points on truss segments S1 and S3, the aft facing edge of the S-TRRJ Heat Rejection Subsystem (HRS) radiator, and the three UCCAS latch mechanisms mounted on the zenith face of the S3 truss using the Space Station Remote Manipulator System (SSRMS). To minimize the number of SSRMS movements, the Special Purpose Dexterous Manipulator (SPDM) would be attached to the SSRMS. This would make it possible to park the SPDM in one position and acquire multiple images by changing the viewing orientation of the SPDM body cameras using the pan/tilt units on which they are mounted. Using this implementation concept, ISAG identified four SSRMS

  17. Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance

    PubMed Central

    Guo, Dongwei; Zhang, Gang; Wysocki, Tadeusz A.; Wysocki, Beata J.; Gelbard, Harris A.; Liu, Xin-Ming; McMillan, JoEllyn M.

    2014-01-01

    ABSTRACT Limitations of antiretroviral therapy (ART) include poor patient adherence, drug toxicities, viral resistance, and failure to penetrate viral reservoirs. Recent developments in nanoformulated ART (nanoART) could overcome such limitations. To this end, we now report a novel effect of nanoART that facilitates drug depots within intracellular compartments at or adjacent to the sites of the viral replication cycle. Poloxamer 407-coated nanocrystals containing the protease inhibitor atazanavir (ATV) were prepared by high-pressure homogenization. These drug particles readily accumulated in human monocyte-derived macrophages (MDM). NanoATV concentrations were ∼1,000 times higher in cells than those that could be achieved by the native drug. ATV particles in late and recycling endosome compartments were seen following pulldown by immunoaffinity chromatography with Rab-specific antibodies conjugated to magnetic beads. Confocal microscopy provided cross validation by immunofluorescent staining of the compartments. Mathematical modeling validated drug-endosomal interactions. Measures of reverse transcriptase activity and HIV-1 p24 levels in culture media and cells showed that such endosomal drug concentrations enhanced antiviral responses up to 1,000-fold. We conclude that late and recycling endosomes can serve as depots for nanoATV. The colocalization of nanoATV at endosomal sites of viral assembly and its slow release sped antiretroviral activities. Long-acting nanoART can serve as a drug carrier in both cells and subcellular compartments and, as such, can facilitate viral clearance. IMPORTANCE The need for long-acting ART is significant and highlighted by limitations in drug access, toxicity, adherence, and reservoir penetrance. We propose that targeting nanoformulated drugs to infected tissues, cells, and subcellular sites of viral replication may improve clinical outcomes. Endosomes are sites for human immunodeficiency virus assembly, and increasing ART

  18. Acquired CFTR Dysfunction in Chronic Bronchitis and Other Diseases of Mucus Clearance

    PubMed Central

    Raju, S. Vamsee; Solomon, George M.; Dransfield, Mark T; Rowe, Steven M

    2015-01-01

    Summary Chronic obstructive pulmonary disease (COPD) is a major public health problem accounting for more than 100,000 deaths and 750,000 hospitalizations each year in the United States alone. Though bronchodilators, inhaled steroids and other anti-inflammatory drugs can improve symptoms and reduce the risk of exacerbations, no therapies alter the natural history of the disease. This is the result of a number of factors including our poor understanding of the pathobiologic processes that drive specific COPD phenotypes, which has hindered drug development. Chronic bronchitis is perhaps the most clinically troublesome phenotype as most patients with COPD complain of cough and sputum production, and yet there are no effective treatments to target the mucus hypersecretion, accumulation and poor clearance that lead to these symptoms. Though it is well known that the absence of cystic fibrosis (CF) transmembrane receptor (CFTR) is the cause of CF, the prototypical disease of impaired mucociliary clearance, emerging data strongly suggest cigarette smoke and its components can lead to acquired CFTR dysfunction. Findings in vitro, in animal models, as well smokers with and without COPD also exhibit acquired CFTR dysfunction, which is associated with chronic bronchitis. This abnormality is not only present in the airways but is also present in extrapulmonary organs, suggesting CFTR dysfunction may contribute to smoking related lung disease as well as commonly associated comorbidities in which CFTR has a role. The development of potent CFTR modulators for the treatment of CF has made these findings clinically relevant as they may also have a role in treating COPD and other diseases of mucus clearance. PMID:26857776

  19. Mannitol clearance for the determination of glomerular filtration rate-a validation against clearance of (51) Cr-EDTA.

    PubMed

    Kiss, Katalin; Molnár, Miklós; Söndergaard, Sören; Molnár, Gyula; Ricksten, Sven-Erik

    2016-06-03

    We studied the agreement between plasma clearance of mannitol and the reference method, plasma clearance of (51) Cr-EDTA in outpatients with normal to moderately impaired renal function. Forty-one patients with a serum creatinine <200 μmol l(-1) entered the study. (51) Cr-EDTA clearance was measured with the standard bolus injection technique and glomerular filtration rate (GFR) was calculated by the single-sample method described by Jacobsson. Mannitol, 0·25 g kg(-1) body weight (150 mg ml(-1) ), was infused for 4-14 min and blood samples taken at 1-, 2-, 3- and 4-h (n = 24) or 2-, 3-, 3·5- and 4-h after infusion (n = 17). Mannitol in serum was measured by an enzymatic method. Plasma clearance for mannitol and its apparent volume of distribution (Vd) were calculated according to Brøchner-Mortensen. Mean plasma clearance (±SD) for (51) Cr-EDTA was 59·7 ± 18·8 ml min(-1) . The mean plasma clearance for mannitol ranged between 57·0 ± 20·1 and 61·1 ± 16·7 ml min(-1) and Vd was 21·3 ± 6·2% per kg b.w. The between-method bias ranged between -0·23 and 2·73 ml min(-1) , the percentage error between 26·7 and 39·5% and the limits of agreement between -14·3/17·2 and -25·3/19·9 ml min(-1) . The best agreement was seen when three- or four-sample measurements of plasma mannitol were obtained and when sampling started 60 min after injection. Furthermore, accuracy of plasma clearance determinations was 88-96% (P30) and 41-63% (P10) and was highest when three- or four-sample measurements of plasma mannitol were obtained, including the first hour after the bolus dose. We conclude that there is a good agreement between plasma clearances of mannitol and (51) Cr-EDTA for the assessment of GFR.

  20. Desialylation accelerates platelet clearance after refrigeration and initiates GPIbα metalloproteinase-mediated cleavage in mice.

    PubMed

    Jansen, A J Gerard; Josefsson, Emma C; Rumjantseva, Viktoria; Liu, Qiyong Peter; Falet, Hervé; Bergmeier, Wolfgang; Cifuni, Stephen M; Sackstein, Robert; von Andrian, Ulrich H; Wagner, Denisa D; Hartwig, John H; Hoffmeister, Karin M

    2012-02-02

    When refrigerated platelets are rewarmed, they secrete active sialidases, including the lysosomal sialidase Neu1, and express surface Neu3 that remove sialic acid from platelet von Willebrand factor receptor (VWFR), specifically the GPIbα subunit. The recovery and circulation of refrigerated platelets is greatly improved by storage in the presence of inhibitors of sialidases. Desialylated VWFR is also a target for metalloproteinases (MPs), because GPIbα and GPV are cleaved from the surface of refrigerated platelets. Receptor shedding is inhibited by the MP inhibitor GM6001 and does not occur in Adam17(ΔZn/ΔZn) platelets expressing inactive ADAM17. Critically, desialylation in the absence of MP-mediated receptor shedding is sufficient to cause the rapid clearance of platelets from circulation. Desialylation of platelet VWFR therefore triggers platelet clearance and primes GPIbα and GPV for MP-dependent cleavage.

  1. Enhanced clearance of HIV-1-infected cells by anti-HIV-1 broadly neutralizing antibodies in vivo

    PubMed Central

    Lu, Ching-Lan; Murakowski, Dariusz K.; Bournazos, Stylianos; Schoofs, Till; Sarkar, Debolina; Halper-Stromberg, Ariel; Horwitz, Joshua A.; Nogueira, Lilian; Golijanin, Jovana; Gazumyan, Anna; Ravetch, Jeffrey V.; Caskey, Marina; Chakraborty, Arup K.; Nussenzweig, Michel C.

    2016-01-01

    Anti-retroviral drugs and antibodies limit HIV-1 infection by interfering with the viral life-cycle. In addition, antibodies also have the potential to guide host immune effector cells to kill HIV-1 infected cells. Examination of the kinetics of HIV-1 suppression in infected individuals by passively administered 3BNC117, a broadly neutralizing antibody (bNAb), suggested that the effects of the antibody are not limited to free viral clearance and blocking new infection, but also include acceleration of infected cell clearance. Consistent with these observations, we find that bNAbs can target CD4+ T cells infected with patient viruses and decrease their in vivo half-lives by a mechanism that requires FcγR engagement in a humanized mouse model. The results indicate that passive immunotherapy can accelerate elimination of HIV-1 infected cells. PMID:27199430

  2. Mine Clearance Industry: Background, Geography, Funding, Analysis and Future Projections

    DTIC Science & Technology

    2007-12-01

    July 1998. 31 Paul K. Walker, Engineers of Independence, A Documentary History of the Army Engineers in the American Revolution, 1775-1783, (Honolulu...capability. Evaluation is a combination of documentary evidence and practical ability. Theatre specific Techniques/Procedures and Standards...Clearance and Detection, Bolivia, Bosnia- Herzegovina, 218 Jesuit Refugee Service NGO/INGO Humanitarian Coordination, Angola, Australia

  3. 30 CFR 57.9306 - Warning devices for restricted clearances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... creates a hazard to persons on mobile equipment, warning devices shall be installed in advance of the... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Warning devices for restricted clearances. 57... Loading, Hauling, and Dumping Safety Devices, Provisions, and Procedures for Roadways, Railroads,...

  4. 30 CFR 56.9306 - Warning devices for restricted clearances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... creates a hazard to persons on mobile equipment, warning devices shall be installed in advance of the... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Warning devices for restricted clearances. 56... Loading, Hauling, and Dumping Safety Devices, Provisions, and Procedures for Roadways, Railroads,...

  5. Tracheobronchial mucociliary clearance in asthma: impairment during remission.

    PubMed Central

    Pavia, D; Bateman, J R; Sheahan, N F; Agnew, J E; Clarke, S W

    1985-01-01

    Tracheobronchial mucociliary clearance was measured in eight non-smoking patients with asthma in complete remission. The patients were symptom free and required no medication whatsoever for one to six months before assessment. Mucociliary clearance was measured with an objective, radioaerosol technique. For comparison, mucociliary clearance of eight non-smoking, healthy subjects with physical characteristics and pulmonary function similar to those of the asthmatics was also measured on two occasions. In their first assessment the healthy subjects inhaled the tracer radioaerosol under experimental conditions similar to those used for the asthmatics; in the second assessment they inhaled the radioaerosol rapidly to simulate the asthmatic pattern of deposition. Under similar experimental conditions the radioaerosol was deposited more proximally in the asthmatic subjects than in the normal subjects and the difference was statistically significant (p less than 0.01). When, however, the depth of radioaerosol lung penetration was similar in the two groups, there was evidence of a significantly (p less than 0.01) poorer mucociliary clearance six hours after radioaerosol inhalation in the asthmatic than in the healthy group. These findings raise the question whether asthma ever remits completely. PMID:3983883

  6. Modifications of lung clearance mechanisms by acute influenza A infection

    SciTech Connect

    Levandowski, R.A.; Gerrity, T.R.; Garrard, C.S.

    1985-10-01

    Four volunteers with naturally acquired, culture-proved influenza A infection inhaled a radiolabeled aerosol to permit investigation of lung mucociliary clearance mechanisms during and after symptomatic illness. Mucus transport in the trachea was undetectable when monitored with an external multidetector probe within 48 hours of the onset of the illness, but was found at a normal velocity by 1 week in three of the four subjects. In two volunteers who coughed 23 to 48 times during the 4.5-hour observation period, whole lung clearance was as fast within the first 48 hours of illness as during health 3 months later in spite of the absence of measurable tracheal mucus transport. Conversely, in spite of the return 1 week later of mucus transport at velocities expected in the trachea, whole lung clearance for the 4.5-hour period was slowed in two volunteers who coughed less than once an hour. The data offer evidence that cough is important in maintaining lung clearance for at least several days after symptomatic influenza A infection when other mechanisms that depend on ciliary function are severely deficient.

  7. 50 CFR 14.53 - Detention and refusal of clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Detention and refusal of clearance. 14.53 Section 14.53 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR TAKING, POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE...

  8. 50 CFR 14.52 - Clearance of imported wildlife.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Clearance of imported wildlife. 14.52 Section 14.52 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR TAKING, POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE...

  9. Spontaneous Clearance of Viral Infections by Mesoscopic Fluctuations

    PubMed Central

    Chaudhury, Srabanti; Perelson, Alan S.; Sinitstyn, Nikolai A.

    2012-01-01

    Spontaneous disease extinction can occur due to a rare stochastic fluctuation. We explore this process, both numerically and theoretically, in two minimal models of stochastic viral infection dynamics. We propose a method that reduces the complexity in models of viral infections so that the remaining dynamics can be studied by previously developed techniques for analyzing epidemiological models. Using this technique, we obtain an expression for the infection clearance time as a function of kinetic parameters. We apply our theoretical results to study stochastic infection clearance for specific stages of HIV and HCV dynamics. Our results show that the typical time for stochastic clearance of a viral infection increases exponentially with the size of the population, but infection still can be cleared spontaneously within a reasonable time interval in a certain population of cells. We also show that the clearance time is exponentially sensitive to the viral decay rate and viral infectivity but only linearly dependent on the lifetime of an infected cell. This suggests that if standard drug therapy fails to clear an infection then intensifying therapy by adding a drug that reduces the rate of cell infection rather than immune modulators that hasten infected cell death may be more useful in ultimately clearing remaining pockets of infection. PMID:22693646

  10. Celllular Uptake and Clearance of TIO2 Nanoparticles

    EPA Science Inventory

    Differential rates of cellular uptake and clearance of engineered nanomaterials may influence the propensity for tissue accumulation under chronic exposure conditions. A retinal pigment epithelial cell line (ARPE-19) was used to investigate 1) if Ti02 (Degussa, P25) nanoparticles...

  11. Functional interferon system is required for clearance of lassa virus.

    PubMed

    Yun, Nadezhda E; Poussard, Allison L; Seregin, Alexey V; Walker, Aida G; Smith, Jennifer K; Aronson, Judith F; Smith, Jeanon N; Soong, Lynn; Paessler, Slobodan

    2012-03-01

    Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever (LF) in humans, a deadly disease endemic to West Africa that results in 5,000 to 10,000 deaths annually. Here we present results demonstrating that functional type I and type II interferon (IFN) signaling is required for efficient control of LASV dissemination and clearance.

  12. [Airway clearance techniques in chronic obstructive pulmonary syndrome : 2011 update].

    PubMed

    Opdekamp, C

    2011-09-01

    For many years the airway clearance techniques used in chest physical therapy were assimilated with the singular technique of postural drainage, percussions and vibrations. However the side effects and counter indications and the lack of scientific proof regarding this technique have forced reflection and development of other techniques more comfortable and without deleterious effects. If all these techniques show a high efficiency in terms of improved mucociliary clearance, the literature is unanimous on how little effect these techniques have in the short and the long-term with regards to lung function and arterial blood gases. In view of the scientific literature, it is clear that the airway clearance techniques don't have the same recognition concerning their efficiency in all obstructive pulmonary diseases. As the cornerstone in the management of cystic fibrosis, the efficiency of the bronchial hygiene techniques are in general poorly documented in the management of the non-cystic fibrosis bronchiectasis, bronchitis or emphysema. The use of the chest physical therapy seems more to do with the interpretation of the imagery and symptomatology. The airway clearance techniques should be individualised according to symptoms, the amount of expectorated mucus and the objectives signs of secretions retention or subjective signs of difficulty expectorating secretions with progression of the disease.

  13. 7 CFR 1927.55 - Title clearance services.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 12 2013-01-01 2013-01-01 false Title clearance services. 1927.55 Section 1927.55 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE SERVICE, RURAL UTILITIES SERVICE, AND FARM SERVICE AGENCY, DEPARTMENT OF AGRICULTURE...

  14. An Examination of OMB Forms Clearance Aims, Policies and Procedures.

    ERIC Educational Resources Information Center

    Coan, Donald L.; Bertram, Charles L.

    The purposes of this paper are four-fold: (1) to delineate the principal aims and policy objectives of Office of Management and Budget Forms Clearance (OMB FC), as embodied in Federal legislation and executive directives since 1942; (2) to identify the major current thrusts of OMB FC; (3) to suggest possible future policy directions of OMB FC,…

  15. Some Proposals Regarding Copyright Clearance and Digitisation in Higher Education.

    ERIC Educational Resources Information Center

    Bide, Mark; Oppenheim, Charles; Ramsden, Anne

    1997-01-01

    Examines issues of copyright clearance by British universities for digitizing published printed materials. Discusses types of digitization, pricing, contract language, "compliance culture," publishers' rights, terms of licenses, and developing a publishers'"code of practice," and proposes a matrix of uses and users to support…

  16. OMB Forms Clearance: Restrictions on Educational Research Plans.

    ERIC Educational Resources Information Center

    Coan, Donald L.

    Forms Clearance standards and regulations are used by the Office of Management and Budget and by the Education Division of the Department of Health, Education and Welfare in order to upgrade the quality of federal data collection, to minimize cost, minimize reporting burden, maximize utility, and to protect the privacy rights of respondents.…

  17. Royalty Fees Part I: The Copyright Clearance Center and Publishers.

    ERIC Educational Resources Information Center

    Eiblum, Paula; Ardito, Stephanie C.

    1998-01-01

    Discussion of copyrights, royalty fees, and intellectual property focuses on the Copyright Clearance Center and publishers. Topics include results of a survey of library and information science journal publishers; how users verify royalty fees; how publishers determine fees; royalty fee reporting; and terms and conditions imposed on electronic…

  18. Managing Copyright Clearance Services in Higher Education Libraries.

    ERIC Educational Resources Information Center

    Gadd, Elizabeth

    2001-01-01

    Investigated centralized copyright clearance services in higher education institutions based on the findings of a questionnaire survey and five case study interviews in United Kingdom libraries. Examines reasons why services were established, how they were funded and staffed, their overall remit, problems, and good practice guidelines. (Author/LRW)

  19. The Genesis and Justification of Forms Clearance Procedures.

    ERIC Educational Resources Information Center

    Duncan, Joseph W.; Wallman, Katherine K.

    The central reports clearance authority of the Federal Government is a legislatively sanctioned mechanism for applying constraints on the conduct of statistical and other data gathering activities by Federal Departments and agencies and other research parties funded by Federal government contracts. General recommendations for improving the overall…

  20. Seal Investigations of an Active Clearance Control System Concept

    NASA Technical Reports Server (NTRS)

    Steinetz, Bruce M.; Taylor, Shawn; Oswald, Jay; DeCastro, Jonathan A.

    2006-01-01

    In an effort to improve upon current thermal active clearance control methods, a first generation, fast-acting mechanically actuated, active clearance control system has been designed and installed into a non-rotating test rig. In order to harvest the benefit of tighter blade tip clearances, low-leakage seals are required for the actuated carrier segments of the seal shroud to prevent excessive leakage of compressor discharge (P3) cooling air. The test rig was designed and fabricated to facilitate the evaluation of these types of seals, identify seal leakage sources, and test other active clearance control system concepts. The objective of this paper is to present both experimental and analytical investigations into the nature of the face-seal to seal-carrier interface. Finite element analyses were used to examine face seal contact pressures and edge-loading under multiple loading conditions, varied E-seal positions and two new face seal heights. The analyses indicated that moving the E-seal inward radially and reducing face seal height would lead to more uniform contact conditions between the face seal and the carriers. Lab testing confirmed that moving the balance diameter inward radially caused a decrease in overall system leakage.

  1. 46 CFR 61.20-23 - Tailshaft clearance; bearing weardown.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Tailshaft clearance; bearing weardown. 61.20-23 Section...; bearing weardown. (a) Water lubricated bearings, other than rubber, must be rebushed as follows: (1) Where the propelling machinery is located amidship, the after stern tube bearing must be rebushed when it...

  2. 46 CFR 61.20-23 - Tailshaft clearance; bearing weardown.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 2 2011-10-01 2011-10-01 false Tailshaft clearance; bearing weardown. 61.20-23 Section...; bearing weardown. (a) Water lubricated bearings, other than rubber, must be rebushed as follows: (1) Where the propelling machinery is located amidship, the after stern tube bearing must be rebushed when it...

  3. 46 CFR 61.20-23 - Tailshaft clearance; bearing weardown.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Tailshaft clearance; bearing weardown. 61.20-23 Section...; bearing weardown. (a) Water lubricated bearings, other than rubber, must be rebushed as follows: (1) Where the propelling machinery is located amidship, the after stern tube bearing must be rebushed when it...

  4. 46 CFR 61.20-23 - Tailshaft clearance; bearing weardown.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Tailshaft clearance; bearing weardown. 61.20-23 Section...; bearing weardown. (a) Water lubricated bearings, other than rubber, must be rebushed as follows: (1) Where the propelling machinery is located amidship, the after stern tube bearing must be rebushed when it...

  5. 46 CFR 61.20-23 - Tailshaft clearance; bearing weardown.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Tailshaft clearance; bearing weardown. 61.20-23 Section...; bearing weardown. (a) Water lubricated bearings, other than rubber, must be rebushed as follows: (1) Where the propelling machinery is located amidship, the after stern tube bearing must be rebushed when it...

  6. Influence of clearance model on numerical simulation of centrifugal pump

    NASA Astrophysics Data System (ADS)

    Wang, Z.; Gao, B.; Yang, L.; Du, W. Q.

    2016-05-01

    Computing models are always simplified to save the computing resources and time. Particularly, the clearance that between impeller and pump casing is always ignored. But the completer model is, the more precise result of numerical simulation is in theory. This paper study the influence of clearance model on numerical simulation of centrifugal pump. We present such influence via comparing performance, flow characteristic and pressure pulsation of two cases that the one of two cases is the model pump with clearance and the other is not. And the results show that the head decreases and power increases so that efficiency decreases after computing with front and back cavities. Then no-leakage model would improve absolute velocity magnitude in order to reach the rated flow rate. Finally, more disturbance induced by front cavity flow and wear-ring flow would change the pressure pulsation of impeller and volute. The performance of clearance flow is important for the whole pump in performance, flow characteristic, pressure pulsation and other respects.

  7. 78 FR 77027 - Overhead Clearance (Air-Draft) Accidents

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-20

    ... address the problem of overhead clearance (air-draft) accidents. In its petition, which calls for vessel... methods: (1) Federal eRulemaking Portal: http://www.regulations.gov . (2) Fax: 202-493-2251. (3) Mail..., ] contact LCDR William Nabach, Office of Vessel and Facility Operating Standards (CG-OES-2), U.S....

  8. 33 CFR 118.160 - Vertical clearance gauges.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... numerals and foot marks below “low steel” of the bridge whenever the gauge is repainted or the structure is... BRIDGES BRIDGE LIGHTING AND OTHER SIGNALS § 118.160 Vertical clearance gauges. (a) When necessary for... distance between “low steel” of the bridge channel span (in the closed to navigation position...

  9. 48 CFR 801.602-76 - Business clearance review.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Business clearance review. 801.602-76 Section 801.602-76 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS GENERAL DEPARTMENT OF VETERANS AFFAIRS ACQUISITION REGULATION SYSTEM Career Development,...

  10. 31 CFR 205.20 - What is a clearance pattern?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 2 2011-07-01 2011-07-01 false What is a clearance pattern? 205.20 Section 205.20 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY FINANCIAL MANAGEMENT SERVICE RULES AND PROCEDURES FOR EFFICIENT FEDERAL-STATE FUNDS TRANSFERS Rules...

  11. 10 CFR 95.17 - Processing facility clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... related classified information, or process the facility for a facility clearance. Processing will include... concerning the foreign intelligence threat, risk of unauthorized technology transfer, type and sensitivity of... acceptable security review conducted by the NRC; (3) Submitting key management personnel for...

  12. 23 CFR Appendix B to Part 1327 - OMB Clearance

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 23 Highways 1 2011-04-01 2011-04-01 false OMB Clearance B Appendix B to Part 1327 Highways NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PROCEDURES FOR PARTICIPATING IN AND RECEIVING INFORMATION FROM THE NATIONAL DRIVER REGISTER PROBLEM DRIVER POINTER SYSTEM Pt....

  13. 23 CFR Appendix B to Part 1327 - OMB Clearance

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 23 Highways 1 2014-04-01 2014-04-01 false OMB Clearance B Appendix B to Part 1327 Highways NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PROCEDURES FOR PARTICIPATING IN AND RECEIVING INFORMATION FROM THE NATIONAL DRIVER REGISTER PROBLEM DRIVER POINTER SYSTEM Pt....

  14. 23 CFR Appendix B to Part 1327 - OMB Clearance

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false OMB Clearance B Appendix B to Part 1327 Highways NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PROCEDURES FOR PARTICIPATING IN AND RECEIVING INFORMATION FROM THE NATIONAL DRIVER REGISTER PROBLEM DRIVER POINTER SYSTEM Pt....

  15. 23 CFR Appendix B to Part 1327 - OMB Clearance

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 23 Highways 1 2012-04-01 2012-04-01 false OMB Clearance B Appendix B to Part 1327 Highways NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PROCEDURES FOR PARTICIPATING IN AND RECEIVING INFORMATION FROM THE NATIONAL DRIVER REGISTER PROBLEM DRIVER POINTER SYSTEM Pt....

  16. 23 CFR Appendix B to Part 1327 - OMB Clearance

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 23 Highways 1 2013-04-01 2013-04-01 false OMB Clearance B Appendix B to Part 1327 Highways NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PROCEDURES FOR PARTICIPATING IN AND RECEIVING INFORMATION FROM THE NATIONAL DRIVER REGISTER PROBLEM DRIVER POINTER SYSTEM Pt....

  17. 50 CFR 14.55 - Exceptions to clearance requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... wildlife: (a) Shellfish and fishery products imported for purposes of human or animal consumption or taken... 50 Wildlife and Fisheries 1 2013-10-01 2013-10-01 false Exceptions to clearance requirements. 14.55 Section 14.55 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF...

  18. 50 CFR 14.55 - Exceptions to clearance requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... wildlife: (a) Shellfish and fishery products imported for purposes of human or animal consumption or taken... 50 Wildlife and Fisheries 1 2011-10-01 2011-10-01 false Exceptions to clearance requirements. 14.55 Section 14.55 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF...

  19. 50 CFR 14.55 - Exceptions to clearance requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... wildlife: (a) Shellfish and fishery products imported for purposes of human or animal consumption or taken... 50 Wildlife and Fisheries 1 2012-10-01 2012-10-01 false Exceptions to clearance requirements. 14.55 Section 14.55 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF...

  20. Determinant factor for clearance of ceramic fibres from rat lungs.

    PubMed Central

    Yamato, H; Tanaka, I; Higashi, T; Kido, M

    1992-01-01

    Deposition, clearance, retention, and durability of inhaled particles from lungs are known to be important factors for induction of pulmonary fibrosis or lung cancer. To study the deposition and clearance of alumina silicate ceramic fibres from the lung, male Wistar rats were exposed to ceramic fibre particles with a mass median aerodynamic diameter (MMAD) of 4.2 micron, for six hours a day, five days a week for two weeks. The average exposure concentration was 20.7 (standard deviation (SD) 4.5) mg/m3. The rats were killed at one day, three months, and six months after the end of exposure, and the fibre numbers and dimensions were measured with a scanning electron microscope. No significant differences in number and geometric mean length of residual ceramic fibres in the lungs were found between the groups. The geometric mean diameter, however, decreased according to the duration of the clearance period. These findings suggest that solubility of fibre contributes most in the clearance of the inhaled ceramic fibres from the lungs. PMID:1554614

  1. Determinant factor for clearance of ceramic fibres from rat lungs.

    PubMed

    Yamato, H; Tanaka, I; Higashi, T; Kido, M

    1992-03-01

    Deposition, clearance, retention, and durability of inhaled particles from lungs are known to be important factors for induction of pulmonary fibrosis or lung cancer. To study the deposition and clearance of alumina silicate ceramic fibres from the lung, male Wistar rats were exposed to ceramic fibre particles with a mass median aerodynamic diameter (MMAD) of 4.2 micron, for six hours a day, five days a week for two weeks. The average exposure concentration was 20.7 (standard deviation (SD) 4.5) mg/m3. The rats were killed at one day, three months, and six months after the end of exposure, and the fibre numbers and dimensions were measured with a scanning electron microscope. No significant differences in number and geometric mean length of residual ceramic fibres in the lungs were found between the groups. The geometric mean diameter, however, decreased according to the duration of the clearance period. These findings suggest that solubility of fibre contributes most in the clearance of the inhaled ceramic fibres from the lungs.

  2. 48 CFR 2452.237-75 - Clearance of contractor personnel.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... URBAN DEVELOPMENT CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Texts of Provisions and... clause in solicitations and contracts. Clearance of Contractor Personnel (OCT 1999) (a) General. This contract requires contractor employees to work in, and have access to, a HUD facility. All such...

  3. 19 CFR 4.61 - Requirements for clearance.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... vessels. (c) Verification of compliance. Before clearance is granted to a vessel bound to a foreign port... following matters: (1) Accounting for inward cargo (see § 4.62). (2) Outward Cargo Declarations; shippers.... Unless otherwise provided in this section, every vessel bound for a foreign port or ports will be...

  4. 49 CFR Appendix F to Part 512 - OMB Clearance

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 6 2010-10-01 2010-10-01 false OMB Clearance F Appendix F to Part 512 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION CONFIDENTIAL BUSINESS INFORMATION Pt. 512, App. F Appendix F to...

  5. 49 CFR Appendix F to Part 512 - OMB Clearance

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 6 2011-10-01 2011-10-01 false OMB Clearance F Appendix F to Part 512 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION CONFIDENTIAL BUSINESS INFORMATION Pt. 512, App. F Appendix F to...

  6. 50 CFR 14.52 - Clearance of imported wildlife.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 1 2013-10-01 2013-10-01 false Clearance of imported wildlife. 14.52 Section 14.52 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR TAKING, POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE...

  7. 50 CFR 14.52 - Clearance of imported wildlife.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 1 2012-10-01 2012-10-01 false Clearance of imported wildlife. 14.52 Section 14.52 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR TAKING, POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE...

  8. 50 CFR 14.52 - Clearance of imported wildlife.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 1 2011-10-01 2011-10-01 false Clearance of imported wildlife. 14.52 Section 14.52 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR TAKING, POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE...

  9. 50 CFR 14.52 - Clearance of imported wildlife.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 1 2014-10-01 2014-10-01 false Clearance of imported wildlife. 14.52 Section 14.52 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR TAKING, POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE...

  10. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Strength Requirements Control Surface...

  11. Variants in interleukin family of cytokines genes influence clearance of high risk HPV in HIV-1 coinfected African-American adolescents.

    PubMed

    Sudenga, Staci L; Wiener, Howard W; Shendre, Aditi; Wilson, Craig M; Tang, Jianming; Shrestha, Sadeep

    2013-12-01

    Our work aimed to examine the potential influence of variants in interleukin/interleukin receptors genes on high-risk (HR-HPV) HPV clearance. Clearance of genital HR-HPV infection was evaluated for 134 HIV-1 seropositive African-American female adolescents from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort. Genotyping targeted 225 single nucleotide polymorphisms (SNPs) within the exons, 5' untranslated region (UTR) and 3' UTR sequences of 27 immune-related candidate genes encoding interleukin family of cytokines. Cox proportional hazard models were used to determine the association of type-specific HPV clearance adjusting for time-varying CD4+ T-cell count and low-risk (LR-HPV) HPV co-infections. HR-HPV clearance rates were significantly (p < 0.001) associated with five SNPs (rs228942, rs419598, rs315950, rs7737000, and rs9292618) mapped to coding and regulatory regions in three genes (IL2RB, IL1RN, and IL7R). These data suggest that the analyzed genetic variants in interleukin family of cytokines modulate HR-HPV clearance in HIV-1 seropositive African-Americans that warrants replication.

  12. Sub-10-nm Pd nanosheets with renal clearance for efficient near-infrared photothermal cancer therapy.

    PubMed

    Tang, Shaoheng; Chen, Mei; Zheng, Nanfeng

    2014-08-13

    Efficient renal clearance is of fundamentally important property of nanoparticles for their in vivo biomedical applications. In this work, we report the successful synthesis of ultra-small Pd nanosheets (SPNS) with an average diameter of 4.4 nm and their application in photothermal cancer therapy using a near infrared laser. The ultra-small Pd nanosheets have strong optical absorption in the NIR region and high photothermal conversion efficiency (52.0%) at 808 nm. After being surface-functionalized with reduced glutathione (GSH), the SPNS-GSH was administered to mice to investigate the biodistribution, photothermal efficacy and tumor ablation in vivo. The in vivo photothermal therapy studies clearly demonstrate that surface modification with GSH allows the nanosheets to exhibit prolonged blood circulation and thus high accumulation in tumors. Upon 808 nm NIR irradiation, the tumors can be completely ablated. More importantly, with the size below the renal filtration limit (<10 nm), the GSHylated Pd nanosheets can be nicely cleared from body through the renal excretion route and into urine. Together with the high efficacy of NIR photothermal therapy, the unique renal clearance properties make the ultra-small Pd nanosheets promising for practical use in photothermal cancer therapy.

  13. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

    PubMed Central

    Gordts, Philip L.S.M.; Son, Ni-Huiping; Ramms, Bastian; Lew, Irene; Gonzales, Jon C.; Thacker, Bryan E.; Basu, Debapriya; Lee, Richard G.; Mullick, Adam E.; Graham, Mark J.; Goldberg, Ira J.; Crooke, Rosanne M.; Witztum, Joseph L.

    2016-01-01

    Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III–targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO–induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III–rich or ApoC-III–depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis. PMID:27400128

  14. 77 FR 43373 - Emergency Clearance; Public Information Collection Requirements Submitted to the Office of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-24

    ... From the Federal Register Online via the Government Publishing Office NATIONAL SCIENCE FOUNDATION... Budget; Notice AGENCY: National Science Foundation. ACTION: Emergency Clearance: Public Information... addressed to Suzanne Plimpton, Reports Clearance Officer, National Science Foundation, 4201 Wilson Blvd.,...

  15. 78 FR 56222 - Agency Information Collection Activities; Comment Request; Highly Qualified Teachers Clearance

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-12

    ... Agency Information Collection Activities; Comment Request; Highly Qualified Teachers Clearance AGENCY... notice will be considered public records. Title of Collection: Highly Qualified Teachers Clearance OMB... disadvantaged students) are taught by teachers participating in an alternative route to certification...

  16. 78 FR 67344 - Highly Qualified Teachers Clearance; Extension of Public Comment Period; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-12

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF EDUCATION Highly Qualified Teachers Clearance; Extension of Public Comment Period; Correction AGENCY: Department of... comment for an information collection entitled, ``Highly Qualified Teachers Clearance,''...

  17. 19 CFR 122.66 - Clearance or permission to depart denied.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Clearance of Aircraft and Permission To Depart § 122.66 Clearance or permission to depart denied. If advance electronic air cargo information is not received...

  18. 77 FR 6128 - Agency Information Collection Activities: Proposed Collection; Comment Request; Generic Clearance...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-07

    ... Collection; Comment Request; Generic Clearance for the Collection of Qualitative Feedback on Agency Service... Nursing Research (NINR), National Institutes of Health (NIH), has submitted a Generic Information Collection Request (Generic ICR): ``Generic Clearance for the Collection of Qualitative Feedback on...

  19. 78 FR 72153 - Proposed Collection; Comment Request for Generic Clearance for the Collection of Qualitative...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-02

    ... Qualitative Feedback on Agency Service Delivery AGENCY: Internal Revenue Service (IRS), Treasury. ACTION..., the IRS is soliciting comments concerning Generic Clearance for the Collection of Qualitative Feedback... Clearance for the Collection of Qualitative Feedback on Agency Service Delivery. OMB Number:...

  20. 76 FR 74802 - Agency Information Collection Activities: Proposed Collection; Comment Request; Generic Clearance...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-01

    ... Collection; Comment Request; Generic Clearance for the Collection of Qualitative Feedback on Agency Service... ICR): ``Generic Clearance for the Collection of Qualitative Feedback on Agency Service Delivery '' to... policy for Extramural Research Administration, 6705 Rockledge Drive Suite 350, Bethesda, MD...