Entrance and Survival of Brucella pinnipedialis Hooded Seal Strain in Human Macrophages and Epithelial Cells

PubMed Central

Briquemont, Benjamin; Sørensen, Karen K.; Godfroid, Jacques

2013-01-01

Marine mammal Brucella spp. have been isolated from pinnipeds (B. pinnipedialis) and cetaceans (B. ceti) from around the world. Although the zoonotic potential of marine mammal brucellae is largely unknown, reports of human disease exist. There are few studies of the mechanisms of bacterial intracellular invasion and multiplication involving the marine mammal Brucella spp. We examined the infective capacity of two genetically different B. pinnipedialis strains (reference strain; NTCT 12890 and a hooded seal isolate; B17) by measuring the ability of the bacteria to enter and replicate in cultured phagocytes and epithelial cells. Human macrophage-like cells (THP-1), two murine macrophage cell lines (RAW264.7 and J774A.1), and a human malignant epithelial cell line (HeLa S3) were challenged with bacteria in a gentamicin protection assay. Our results show that B. pinnipedialis is internalized, but is then gradually eliminated during the next 72 – 96 hours. Confocal microscopy revealed that intracellular B. pinnipedialis hooded seal strain colocalized with lysosomal compartments at 1.5 and 24 hours after infection. Intracellular presence of B. pinnipedialis hooded seal strain was verified by transmission electron microscopy. By using a cholesterol-scavenging lipid inhibitor, entrance of B. pinnipedialis hooded seal strain in human macrophages was significantly reduced by 65.8 % (± 17.3), suggesting involvement of lipid-rafts in intracellular entry. Murine macrophages invaded by B. pinnipedialis do not release nitric oxide (NO) and intracellular bacterial presence does not induce cell death. In summary, B. pinnipedialis hooded seal strain can enter human and murine macrophages, as well as human epithelial cells. Intracellular entry of B. pinnipedialis hooded seal strain involves, but seems not to be limited to, lipid-rafts in human macrophages. Brucella pinnipedialis does not multiply or survive for prolonged periods intracellulary. PMID:24376851

Entry Pathways of Herpes Simplex Virus Type 1 into Human Keratinocytes Are Dynamin- and Cholesterol-Dependent

PubMed Central

Hsu, Mei-Ju; Rixon, Frazer J.; Knebel-Mörsdorf, Dagmar

2011-01-01

Herpes simplex virus type 1 (HSV-1) can enter cells via endocytic pathways or direct fusion at the plasma membrane depending on the cell line and receptor(s). Most studies into virus entry have used cultured fibroblasts but since keratinocytes represent the primary entry site for HSV-1 infection in its human host, we initiated studies to characterize the entry pathway of HSV-1 into human keratinocytes. Electron microscopy studies visualized free capsids in the cytoplasm and enveloped virus particles in vesicles suggesting viral uptake both by direct fusion at the plasma membrane and by endocytic vesicles. The ratio of the two entry modes differed in primary human keratinocytes and in the keratinocyte cell line HaCaT. Inhibitor studies further support a role for endocytosis during HSV-1 entry. Infection was inhibited by the cholesterol-sequestering drug methyl-β-cyclodextrin, which demonstrates the requirement for host cholesterol during virus entry. Since the dynamin-specific inhibitor dynasore and overexpression of a dominant-negative dynamin mutant blocked infection, we conclude that the entry pathways into keratinocytes are dynamin-mediated. Electron microscopy studies confirmed that virus uptake is completely blocked when the GTPase activity of dynamin is inhibited. Ex vivo infection of murine epidermis that was treated with dynasore further supports the essential role of dynamin during entry into the epithelium. Thus, we conclude that HSV-1 can enter human keratinocytes by alternative entry pathways that require dynamin and host cholesterol. PMID:22022400

The Glycoproteins of All Filovirus Species Use the Same Host Factors for Entry into Bat and Human Cells but Entry Efficiency Is Species Dependent.

PubMed

Hoffmann, Markus; González Hernández, Mariana; Berger, Elisabeth; Marzi, Andrea; Pöhlmann, Stefan

2016-01-01

Ebola and marburgviruses, members of the family Filoviridae, can cause severe hemorrhagic fever in humans. The ongoing Ebola virus (EBOV) disease epidemic in Western Africa claimed more than 11,300 lives and was associated with secondary cases outside Africa, demonstrating that filoviruses pose a global health threat. Bats constitute an important natural reservoir of filoviruses, including viruses of the recently identified Cuevavirus genus within the Filoviridae family. However, the interactions of filoviruses with bat cells are incompletely understood. Here, we investigated whether filoviruses employ different strategies to enter human and bat cells. For this, we examined host cell entry driven by glycoproteins (GP) from all filovirus species into cell lines of human and fruit bat origin. We show that all GPs were able to mediate entry into human and most fruit bat cell lines with roughly comparable efficiency. In contrast, the efficiency of entry into the cell line EidNi/41 derived from a straw-colored fruit bat varied markedly between the GPs of different filovirus species. Furthermore, inhibition studies demonstrated that filoviruses employ the same host cell factors for entry into human, non-human primate and fruit bat cell lines, including cysteine proteases, two pore channels and NPC1 (Niemann-Pick C1 molecule). Finally, processing of GP by furin and the presence of the mucin-like domain in GP were dispensable for entry into both human and bat cell lines. Collectively, these results show that filoviruses rely on the same host cell factors for entry into human and fruit bat cells, although the efficiency of the usage of these factors might differ between filovirus species.

The Glycoproteins of All Filovirus Species Use the Same Host Factors for Entry into Bat and Human Cells but Entry Efficiency Is Species Dependent

PubMed Central

Hoffmann, Markus; González Hernández, Mariana; Berger, Elisabeth; Marzi, Andrea; Pöhlmann, Stefan

2016-01-01

Ebola and marburgviruses, members of the family Filoviridae, can cause severe hemorrhagic fever in humans. The ongoing Ebola virus (EBOV) disease epidemic in Western Africa claimed more than 11,300 lives and was associated with secondary cases outside Africa, demonstrating that filoviruses pose a global health threat. Bats constitute an important natural reservoir of filoviruses, including viruses of the recently identified Cuevavirus genus within the Filoviridae family. However, the interactions of filoviruses with bat cells are incompletely understood. Here, we investigated whether filoviruses employ different strategies to enter human and bat cells. For this, we examined host cell entry driven by glycoproteins (GP) from all filovirus species into cell lines of human and fruit bat origin. We show that all GPs were able to mediate entry into human and most fruit bat cell lines with roughly comparable efficiency. In contrast, the efficiency of entry into the cell line EidNi/41 derived from a straw-colored fruit bat varied markedly between the GPs of different filovirus species. Furthermore, inhibition studies demonstrated that filoviruses employ the same host cell factors for entry into human, non-human primate and fruit bat cell lines, including cysteine proteases, two pore channels and NPC1 (Niemann-Pick C1 molecule). Finally, processing of GP by furin and the presence of the mucin-like domain in GP were dispensable for entry into both human and bat cell lines. Collectively, these results show that filoviruses rely on the same host cell factors for entry into human and fruit bat cells, although the efficiency of the usage of these factors might differ between filovirus species. PMID:26901159

Construction records study : final report.

DOT National Transportation Integrated Search

1975-09-01

The purpose of this study was to determine the extent of change and revision necessary for efficient record keeping and to revise the record keeping process in the field, eliminating irrelevant entries. This study attempted to standardize field recor...

The Hemagglutinin of Bat-Associated Influenza Viruses Is Activated by TMPRSS2 for pH-Dependent Entry into Bat but Not Human Cells

PubMed Central

Hoffmann, Markus; Krüger, Nadine; Zmora, Pawel; Wrensch, Florian; Herrler, Georg; Pöhlmann, Stefan

2016-01-01

New World bats have recently been discovered to harbor influenza A virus (FLUAV)-related viruses, termed bat-associated influenza A-like viruses (batFLUAV). The internal proteins of batFLUAV are functional in mammalian cells. In contrast, no biological functionality could be demonstrated for the surface proteins, hemagglutinin (HA)-like (HAL) and neuraminidase (NA)-like (NAL), and these proteins need to be replaced by their human counterparts to allow spread of batFLUAV in human cells. Here, we employed rhabdoviral vectors to study the role of HAL and NAL in viral entry. Vectors pseudotyped with batFLUAV-HAL and -NAL were able to enter bat cells but not cells from other mammalian species. Host cell entry was mediated by HAL and was dependent on prior proteolytic activation of HAL and endosomal low pH. In contrast, sialic acids were dispensable for HAL-driven entry. Finally, the type II transmembrane serine protease TMPRSS2 was able to activate HAL for cell entry indicating that batFLUAV can utilize human proteases for HAL activation. Collectively, these results identify viral and cellular factors governing host cell entry driven by batFLUAV surface proteins. They suggest that the absence of a functional receptor precludes entry of batFLUAV into human cells while other prerequisites for entry, HAL activation and protonation, are met in target cells of human origin. PMID:27028521

Amygdala activity associated with social choice in mice.

PubMed

Mihara, Takuma; Mensah-Brown, Kobina; Sobota, Rosanna; Lin, Robert; Featherstone, Robert; Siegel, Steven J

2017-08-14

Studies suggest that the amygdala is a key region for regulation of anxiety, fear and social function. Therefore, dysfunction of the amygdala has been proposed as a potential mechanism for negative symptoms in schizophrenia. This may be due to NMDA receptor-mediated hypofunction, which is thought to be related to the pathogenesis of schizophrenia. In this study, electroencephalographic amygdala activity was assessed in mice during the three-chamber social test. This activity was also evaluated following exposure to the NMDA receptor antagonist ketamine. Vehicle-treated mice spent significantly more time in the social than the non-social chamber. This social preference was eliminated by ketamine. However, ketamine-treated mice spent significantly less time in the social chamber and significantly more time in the nonsocial chamber than vehicle-treated mice. There were no significant differences in induced powers between social and non-social chamber entries in vehicle-treated mice, except for theta frequencies, which featured greater induced theta power during non-social chamber entry. Ketamine eliminated differences in induced theta power between social and non-social chamber entries. Moreover, ketamine increased the induced gamma power during social chamber entry compared to that of vehicle-treated mice. All other frequency ranges were not significantly influenced by zone or drug condition. All significant findings were upon entry to chambers not during interaction. Results suggest that impaired function of NMDA receptor-mediated glutamate transmission can induce social impairments and amygdala dysfunction, similar to the pattern in schizophrenia. Future studies will utilize this method to evaluate mechanisms of social dysfunction and development of treatments of social impairments in schizophrenia. Copyright © 2017. Published by Elsevier B.V.

Characterization of the receptor-binding domain of Ebola glycoprotein in viral entry.

PubMed

Wang, Jizhen; Manicassamy, Balaji; Caffrey, Michael; Rong, Lijun

2011-06-01

Ebola virus infection causes severe hemorrhagic fever in human and non-human primates with high mortality. Viral entry/infection is initiated by binding of glycoprotein GP protein on Ebola virion to host cells, followed by fusion of virus-cell membrane also mediated by GP. Using an human immunodeficiency virus (HIV)-based pseudotyping system, the roles of 41 Ebola GP1 residues in the receptor-binding domain in viral entry were studied by alanine scanning substitutions. We identified that four residues appear to be involved in protein folding/structure and four residues are important for viral entry. An improved entry interference assay was developed and used to study the role of these residues that are important for viral entry. It was found that R64 and K95 are involved in receptor binding. In contrast, some residues such as I170 are important for viral entry, but do not play a major role in receptor binding as indicated by entry interference assay and/or protein binding data, suggesting that these residues are involved in post-binding steps of viral entry. Furthermore, our results also suggested that Ebola and Marburg viruses share a common cellular molecule for entry.

HSV-1 infection of human corneal epithelial cells: receptor-mediated entry and trends of re-infection.

PubMed

Shah, Arpeet; Farooq, Asim V; Tiwari, Vaibhav; Kim, Min-Jung; Shukla, Deepak

2010-11-20

The human cornea is a primary target for herpes simplex virus-1 (HSV-1) infection. The goals of the study were to determine the cellular modalities of HSV-1 entry into human corneal epithelial (HCE) cells. Specific features of the study included identifying major entry receptors, assessing pH dependency, and determining trends of re-infection. A recombinant HSV-1 virus expressing beta-galactosidase was used to ascertain HSV-1 entry into HCE cells. Viral replication within cells was confirmed using a time point plaque assay. Lysosomotropic agents were used to test for pH dependency of entry. Flow cytometry and immunocytochemistry were used to determine expression of three cellular receptors--nectin-1, herpesvirus entry mediator (HVEM), and paired immunoglobulin-like 2 receptor alpha (PILR-a). The necessity of these receptors for viral entry was tested using antibody-blocking. Finally, trends of re-infection were investigated using viral entry assay and flow cytometry post-primary infection. Cultured HCE cells showed high susceptibility to HSV-1 entry and replication. Entry was demonstrated to be pH dependent as blocking vesicular acidification decreased entry. Entry receptors expressed on the cell membrane include nectin-1, HVEM, and PILR-α. Receptor-specific antibodies blocked entry receptors, reduced viral entry and indicated nectin-1 as the primary receptor used for entry. Cells re-infected with HSV-1 showed a decrease in entry, which was correlated to decreased levels of nectin-1 as demonstrated by flow cytometry. HSV-1 is capable of developing an infection in HCE cells using a pH dependent entry process that involves primarily nectin-1 but also the HVEM and PILR-α receptors. Re-infected cells show decreased levels of entry, correlated with a decreased level of nectin-1 receptor expression.

Antigenic properties of the human immunodeficiency virus envelope glycoprotein gp120 on virions bound to target cells.

PubMed

Mengistu, Meron; Ray, Krishanu; Lewis, George K; DeVico, Anthony L

2015-03-01

The HIV-1 envelope glycoprotein, gp120, undergoes multiple molecular interactions and structural rearrangements during the course of host cell attachment and viral entry, which are being increasingly defined at the atomic level using isolated proteins. In comparison, antigenic markers of these dynamic changes are essentially unknown for single HIV-1 particles bound to target cells. Such markers should indicate how neutralizing and/or non-neutralizing antibodies might interdict infection by either blocking infection or sensitizing host cells for elimination by Fc-mediated effector function. Here we address this deficit by imaging fluorescently labeled CCR5-tropic HIV-1 pseudoviruses using confocal and superresolution microscopy to track the exposure of neutralizing and non-neutralizing epitopes as they appear on single HIV-1 particles bound to target cells. Epitope exposure was followed under conditions permissive or non-permissive for viral entry to delimit changes associated with virion binding from those associated with post-attachment events. We find that a previously unexpected array of gp120 epitopes is exposed rapidly upon target cell binding. This array comprises both neutralizing and non-neutralizing epitopes, the latter being hidden on free virions yet capable of serving as potent targets for Fc-mediated effector function. Under non-permissive conditions for viral entry, both neutralizing and non-neutralizing epitope exposures were relatively static over time for the majority of bound virions. Under entry-permissive conditions, epitope exposure patterns changed over time on subsets of virions that exhibited concurrent variations in virion contents. These studies reveal that bound virions are distinguished by a broad array of both neutralizing and non-neutralizing gp120 epitopes that potentially sensitize a freshly engaged target cell for destruction by Fc-mediated effector function and/or for direct neutralization at a post-binding step. The elucidation of these epitope exposure patterns during viral entry will help clarify antibody-mediated inhibition of HIV-1 as it is measured in vitro and in vivo.

Field of first magnetic flux entry and pinning strength of superconductors for rf application measured with muon spin rotation

DOE PAGES

Junginger, Tobias; Abidi, S. H.; Maffett, R. D.; ...

2018-03-16

Here, the performance of superconducting radiofrequency (SRF) cavities used for particle accelerators depends on two characteristic material parameters: field of first flux entry H entry and pinning strength. The former sets the limit for the maximum achievable accelerating gradient, while the latter determines how efficiently flux can be expelled related to the maximum achievable quality factor. In this paper, a method based on muon spin rotation (μSR) is developed to probe these parameters on samples. It combines measurements from two different spectrometers, one being specifically built for these studies and samples of different geometries. It is found that annealing atmore » 1400°C virtually eliminates all pinning. Such an annealed substrate is ideally suited to measure H entry of layered superconductors, which might enable accelerating gradients beyond bulk niobium technology.« less

Program for creating an operating system generation cross reference index (SGINDEX)

NASA Technical Reports Server (NTRS)

Barth, C. W.

1972-01-01

Computer program to collect key data from Stage Two input of OS/360 system and to prepare formatted listing of index entries collected is discussed. Program eliminates manual paging through system output by providing comprehensive cross reference.

Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells.

PubMed

The, Inge; Ruijtenberg, Suzan; Bouchet, Benjamin P; Cristobal, Alba; Prinsen, Martine B W; van Mourik, Tim; Koreth, John; Xu, Huihong; Heck, Albert J R; Akhmanova, Anna; Cuppen, Edwin; Boxem, Mike; Muñoz, Javier; van den Heuvel, Sander

2015-01-06

Cyclin-dependent kinases 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry. Most human cancers contain overactive CDK4/6-cyclin D, and CDK4/6-specific inhibitors are promising anti-cancer therapeutics. Here, we investigate the critical functions of CDK4/6-cyclin D kinases, starting from an unbiased screen in the nematode Caenorhabditis elegans. We found that simultaneous mutation of lin-35, a retinoblastoma (Rb)-related gene, and fzr-1, an orthologue to the APC/C co-activator Cdh1, completely eliminates the essential requirement of CDK4/6-cyclin D (CDK-4/CYD-1) in C. elegans. CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 amino terminus, resembling inactivating phosphorylations of the human proteins. In human breast cancer cells, simultaneous knockdown of Rb and FZR1 synergistically bypasses cell division arrest induced by the CDK4/6-specific inhibitor PD-0332991. Our data identify FZR1 as a candidate CDK4/6-cyclin D substrate and point to an APC/C(FZR1) activity as an important determinant in response to CDK4/6-inhibitors.

Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells

PubMed Central

The, Inge; Ruijtenberg, Suzan; Bouchet, Benjamin P.; Cristobal, Alba; Prinsen, Martine B. W.; van Mourik, Tim; Koreth, John; Xu, Huihong; Heck, Albert J. R.; Akhmanova, Anna; Cuppen, Edwin; Boxem, Mike; Muñoz, Javier; van den Heuvel, Sander

2015-01-01

Cyclin-dependent kinases 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry. Most human cancers contain overactive CDK4/6-cyclin D, and CDK4/6-specific inhibitors are promising anti-cancer therapeutics. Here, we investigate the critical functions of CDK4/6-cyclin D kinases, starting from an unbiased screen in the nematode Caenorhabditis elegans. We found that simultaneous mutation of lin-35, a retinoblastoma (Rb)-related gene, and fzr-1, an orthologue to the APC/C co-activator Cdh1, completely eliminates the essential requirement of CDK4/6-cyclin D (CDK-4/CYD-1) in C. elegans. CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 amino terminus, resembling inactivating phosphorylations of the human proteins. In human breast cancer cells, simultaneous knockdown of Rb and FZR1 synergistically bypasses cell division arrest induced by the CDK4/6-specific inhibitor PD-0332991. Our data identify FZR1 as a candidate CDK4/6-cyclin D substrate and point to an APC/CFZR1 activity as an important determinant in response to CDK4/6-inhibitors. PMID:25562820

Efficient computer algebra algorithms for polynomial matrices in control design

NASA Technical Reports Server (NTRS)

Baras, J. S.; Macenany, D. C.; Munach, R.

1989-01-01

The theory of polynomial matrices plays a key role in the design and analysis of multi-input multi-output control and communications systems using frequency domain methods. Examples include coprime factorizations of transfer functions, cannonical realizations from matrix fraction descriptions, and the transfer function design of feedback compensators. Typically, such problems abstract in a natural way to the need to solve systems of Diophantine equations or systems of linear equations over polynomials. These and other problems involving polynomial matrices can in turn be reduced to polynomial matrix triangularization procedures, a result which is not surprising given the importance of matrix triangularization techniques in numerical linear algebra. Matrices with entries from a field and Gaussian elimination play a fundamental role in understanding the triangularization process. In the case of polynomial matrices, matrices with entries from a ring for which Gaussian elimination is not defined and triangularization is accomplished by what is quite properly called Euclidean elimination. Unfortunately, the numerical stability and sensitivity issues which accompany floating point approaches to Euclidean elimination are not very well understood. New algorithms are presented which circumvent entirely such numerical issues through the use of exact, symbolic methods in computer algebra. The use of such error-free algorithms guarantees that the results are accurate to within the precision of the model data--the best that can be hoped for. Care must be taken in the design of such algorithms due to the phenomenon of intermediate expressions swell.

2014 Summer Series - Ethiraj Venkatapathy - Mary Poppins Approach to Human Mars Mission Entry, Descent and Landing

NASA Image and Video Library

2014-06-17

NASA is investing in a number of technologies to extend Entry, Descent and Landing (EDL) capabilities to enable Human Missions to Mars. These technologies will also enable robotic Science missions. Human missions will require landing payloads of 10?s of metric tons, not possible with today's technology. Decelerating from entry speeds around 15,000 miles per hour to landing in a matter of minutes will require very large drag or deceleration. The one way to achieve required deceleration is to deploy a large surface that can be stowed during launch and deployed prior to entry. This talk will highlight a simple concept similar to an umbrella. Though the concept is simple, the size required for human Mars missions and the heating encountered during entry are significant challenges. The mechanically deployable system can also enable robotic science missions to Venus and is also equally applicable for bringing back cube-satellites and other small payloads. The scalable concept called Adaptive Deployable Entry and Placement Technology (ADEPT) is under development and is the focus of this talk.

Protein kinase C activates non-capacitative calcium entry in human platelets

PubMed Central

Rosado, Juan A; Sage, Stewart O

2000-01-01

In many non-excitable cells Ca2+ influx is mainly controlled by the filling state of the intracellular Ca2+ stores. It has been suggested that this store-mediated or capacitative Ca2+ entry is brought about by a physical and reversible coupling of the endoplasmic reticulum with the plasma membrane. Here we provide evidence for an additional, non-capacitative Ca2+ entry mechanism in human platelets. Changes in cytosolic Ca2+ and Sr2+ were measured in human platelets loaded with the fluorescent indicator fura-2. Depletion of the internal Ca2+ stores with thapsigargin plus a low concentration of ionomycin stimulated store-mediated cation entry, as demonstrated upon Ca2+ or Sr2+ addition. Subsequent treatment with thrombin stimulated further divalent cation entry in a concentration-dependent manner. Direct activation of protein kinase C (PKC) by phorbol-12-myristate-13-acetate or 1-oleoyl-2-acetyl-sn-glycerol also stimulated divalent cation entry, without evoking the release of Ca2+ from intracellular stores. Cation entry evoked by thrombin or activators of PKC was abolished by the PKC inhibitor Ro-31-8220. Unlike store-mediated Ca2+ entry, jasplakinolide, which reorganises actin filaments into a tight cortical layer adjacent to the plasma membrane, did not inhibit divalent cation influx evoked by thrombin when applied after Ca2+ store depletion, or by activators of PKC. Thrombin also activated Ca2+ entry in platelets in which the release from intracellular stores and store-mediated Ca2+ entry were blocked by xestospongin C. These results indicate that the non-capacitative divalent cation entry pathway is regulated independently of store-mediated entry and does not require coupling of the endoplasmic reticulum and the plasma membrane. These results support the existence of a mechanism for receptor-evoked Ca2+ entry in human platelets that is independent of Ca2+ store depletion. This Ca2+ entry mechanism may be activated by occupation of G-protein-coupled receptors, which activate PKC, or by direct activation of PKC, thus generating non-capacitative Ca2+ entry alongside that evoked following the release of Ca2+ from the intracellular stores. PMID:11080259

Human Mars Lander Design for NASA's Evolvable Mars Campaign

NASA Technical Reports Server (NTRS)

Polsgrove, Tara; Chapman, Jack; Sutherlin, Steve; Taylor, Brian; Fabisinski, Leo; Collins, Tim; Cianciolo Dwyer, Alicia; Samareh, Jamshid; Robertson, Ed; Studak, Bill;

Evaluation of manhole inserts as structural barriers to mosquito entry into belowground stormwater systems using a simulated treatment device.

PubMed

Harbison, Justin E; Metzger, Marco E; Allen, Vaikko; Hu, Renjie

2009-09-01

Belowground proprietary stormwater treatment devices can produce mosquitoes, including vectors of West Nile virus. Elimination of vertical entry points such as pick holes in manhole covers may reduce the number of mosquitoes entering and reproducing in these structures. Plastic manhole dish inserts were evaluated as structural barriers against mosquito entry through pick holes in a simulated stormwater treatment device. Inserts were 100% effective at preventing mosquito entry through covers when no other openings existed. In devices configured with an open lateral conveyance pipe, the addition of an insert under the cover reduced mosquito oviposition significantly. Subsequent trials to further elucidate mosquito entry through manhole covers found a significant positive correlation between increasing number of pick holes and mosquito oviposition. Results of the study suggest the potential for manhole dish inserts to decrease the number of mosquitoes entering belowground structures. The different available stormwater treatment systems and site-specific installations may, however, provide a much greater variety of possible alternate entry points for mosquitoes than was addressed in the current study. Further work is needed in field installations to quantify the significance of pick holes to mosquito entry and determine under what conditions, if any, manhole dish inserts would be most effective and appropriate.

Presynaptic muscarinic receptors, calcium channels, and protein kinase C modulate the functional disconnection of weak inputs at polyinnervated neonatal neuromuscular synapses.

PubMed

Santafe, M M; Garcia, N; Lanuza, M A; Tomàs, M; Besalduch, N; Tomàs, J

2009-04-01

We studied the relation among calcium inflows, voltage-dependent calcium channels (VDCC), presynaptic muscarinic acetylcholine receptors (mAChRs), and protein kinase C (PKC) activity in the modulation of synapse elimination. We used intracellular recording to determine the synaptic efficacy in dually innervated endplates of the levator auris longus muscle of newborn rats during axonal competition in the postnatal synaptic elimination period. In these dual junctions, the weak nerve terminal was potentiated by partially reducing calcium entry (P/Q-, N-, or L-type VDCC-specific block or 500 muM magnesium ions), M1- or M4-type selective mAChR block, or PKC block. Moreover, reducing calcium entry or blocking PKC or mAChRs results in unmasking functionally silent nerve endings that now recover neurotransmitter release. Our results show interactions between these molecules and indicate that there is a release inhibition mechanism based on an mAChR-PKC-VDCC intracellular cascade. When it is fully active in certain weak motor axons, it can depress ACh release and even disconnect synapses. We suggest that this mechanism plays a central role in the elimination of redundant neonatal synapses, because functional axonal withdrawal can indeed be reversed by mAChRs, VDCCs, or PKC block.

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

Junginger, Tobias; Abidi, S. H.; Maffett, R. D.

Here, the performance of superconducting radiofrequency (SRF) cavities used for particle accelerators depends on two characteristic material parameters: field of first flux entry H entry and pinning strength. The former sets the limit for the maximum achievable accelerating gradient, while the latter determines how efficiently flux can be expelled related to the maximum achievable quality factor. In this paper, a method based on muon spin rotation (μSR) is developed to probe these parameters on samples. It combines measurements from two different spectrometers, one being specifically built for these studies and samples of different geometries. It is found that annealing atmore » 1400°C virtually eliminates all pinning. Such an annealed substrate is ideally suited to measure H entry of layered superconductors, which might enable accelerating gradients beyond bulk niobium technology.« less

Vendors unveil one-step fugitive emissions monitoring, management

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

Walter, M.

1995-04-01

An alliance of manufacturers has developed a ``single-source solution`` for fugitive emissions monitoring. The LeakTracker{trademark} system combines barcode scans, and vapor detection and data collection capabilities to help companies comply with leak detection and repair requirements as mandated by the Environmental Protection Agency`s Method 21 guidelines. LeakTracker doubles productivity and helps eliminate human-error factors associated with fugitive emissions monitoring. Two-person teams, clipboard-and-pencil data entry, and manual data transcription are eliminated. By automating the process and integrating all components, a technician can monitor 500 points daily following Method 21 guidelines, compared to about 250 readings per day using other systems. LeakTrackermore » includes a handheld workstation, sampling probe and laser-scan barcode reader that fit in a vest worn by a field technician. The technician points the workstation toward a barcode tag and pulls the trigger, which initiates a barcode read and automatically records the time, date and location. While the detachable probe ``sniffs`` for emissions, an analyzer interface module converts the gas detection signal from analog to digital format, allowing data to be recorded by the workstation. LeakTracker has an accuracy rate of 1 part per million.« less

Functional characterization of P2Y1 versus P2X receptors in RBA-2 astrocytes: elucidate the roles of ATP release and protein kinase C.

PubMed

Weng, Ju-Yun; Hsu, Tsan-Ting; Sun, Synthia H

2008-05-15

A physiological concentration of extracellular ATP stimulated biphasic Ca(2+) signal, and the Ca(2+) transient was decreased and the Ca(2+) sustain was eliminated immediately after removal of ATP and Ca(2+) in RBA-2 astrocytes. Reintroduction of Ca(2+) induced Ca(2+) sustain. Stimulation of P2Y(1) receptors with 2-methylthioadenosine 5'-diphosphate (2MeSADP) also induced a biphasic Ca(2+) signaling and the Ca(2+) sustains were eliminated using Ca(2+)-free buffer. The 2MeSADP-mediated biphasic Ca(2+) signals were inhibited by phospholipase C (PLC) inhibitor U73122, and completely blocked by P2Y(1) selective antagonist MRS2179 and protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) whereas enhanced by PKC inhibitors GF109203X and Go6979. Inhibition of capacitative Ca(2+) entry (CCE) decreased the Ca(2+)-induced Ca(2+) entry; nevertheless, ATP further enhanced the Ca(2+)-induced Ca(2+) entry in the intracellular Ca(2+) store-emptied and CCE-inhibited cells indicating that ATP stimulated Ca(2+) entry via CCE and ionotropic P2X receptors. Furthermore, the 2MeSADP-induced Ca(2+) sustain was eliminated by apyrase but potentiated by P2X(4) allosteric effector ivermectin (IVM). The agonist ADPbetaS stimulated a lesser P2Y(1)-mediated Ca(2+) signal and caused a two-fold increase in ATP release but that were not affected by IVM whereas inhibited by PMA, PLC inhibitor ET-18-OCH(3) and phospholipase D (PLD) inhibitor D609, and enhanced by removal of intra- or extracellular Ca(2+). Taken together, the P2Y(1)-mediated Ca(2+) sustain was at least in part via P2X receptors activated by the P2Y(1)-induced ATP release, and PKC played a pivotal role in desensitization of P2Y(1) receptors in RBA-2 astrocytes. Copyright 2007 Wiley-Liss, Inc.

Gas powered fluid gun with recoil mitigation

DOEpatents

Grubelich, Mark C; Yonas, Gerold

2013-11-12

A gas powered fluid gun for propelling a stream or slug of a fluid at high velocity toward a target. Recoil mitigation is provided that reduces or eliminates the associated recoil forces, with minimal or no backwash. By launching a quantity of water in the opposite direction, net momentum forces are reduced or eliminated. Examples of recoil mitigation devices include a cone for making a conical fluid sheet, a device forming multiple impinging streams of fluid, a cavitating venturi, one or more spinning vanes, or an annular tangential entry/exit.

Gas powered fluid gun with recoil mitigation

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

Grubelich, Mark C.; Yonas, Gerold

A gas powered fluid gun for propelling a stream or slug of a fluid at high velocity toward a target. Recoil mitigation is provided that reduces or eliminates the associated recoil forces, with minimal or no backwash. By launching a quantity of water in the opposite direction, net momentum forces are reduced or eliminated. Examples of recoil mitigation devices include a cone for making a conical fluid sheet, a device forming multiple impinging streams of fluid, a cavitating venturi, one or more spinning vanes, or an annular tangential entry/exit.

Myxoma and vaccinia viruses exploit different mechanisms to enter and infect human cancer cells

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

Villa, Nancy Y.; Bartee, Eric; Mohamed, Mohamed R.

2010-06-05

Myxoma (MYXV) and vaccinia (VACV) viruses have recently emerged as potential oncolytic agents that can infect and kill different human cancer cells. Although both are structurally similar, it is unknown whether the pathway(s) used by these poxviruses to enter and cause oncolysis in cancer cells are mechanistically similar. Here, we compared the entry of MYXV and VACV-WR into various human cancer cells and observed significant differences: 1 - low-pH treatment accelerates fusion-mediated entry of VACV but not MYXV, 2 - the tyrosine kinase inhibitor genistein inhibits entry of VACV, but not MYXV, 3 - knockdown of PAK1 revealed that itmore » is required for a late stage event downstream of MYXV entry into cancer cells, whereas PAK1 is required for VACV entry into the same target cells. These results suggest that VACV and MYXV exploit different mechanisms to enter into human cancer cells, thus providing some rationale for their divergent cancer cell tropisms.« less

75 FR 70760 - Self-Regulatory Organizations; Municipal Securities Rulemaking Board; Notice of Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-18

...'' and ``Economic indicators'' are added. Delivery Detail under this topic (``Book-entry only;'' ``Bearer... at the Commission's Public Reference Room. II. Self-Regulatory Organization's Statement of the... certain product knowledge and MSRB rules and eliminate redundancy; delete dated references to certain...

On the Wigner law in dilute random matrices

NASA Astrophysics Data System (ADS)

Khorunzhy, A.; Rodgers, G. J.

1998-12-01

We consider ensembles of N × N symmetric matrices whose entries are weakly dependent random variables. We show that random dilution can change the limiting eigenvalue distribution of such matrices. We prove that under general and natural conditions the normalised eigenvalue counting function coincides with the semicircle (Wigner) distribution in the limit N → ∞. This can be explained by the observation that dilution (or more generally, random modulation) eliminates the weak dependence (or correlations) between random matrix entries. It also supports our earlier conjecture that the Wigner distribution is stable to random dilution and modulation.

Correlation of patient entry rates and physician documentation errors in dictated and handwritten emergency treatment records.

PubMed

Dawdy, M R; Munter, D W; Gilmore, R A

1997-03-01

This study was designed to examine the relationship between patient entry rates (a measure of physician work load) and documentation errors/omissions in both handwritten and dictated emergency treatment records. The study was carried out in two phases. Phase I examined handwritten records and Phase II examined dictated and transcribed records. A total of 838 charts for three common chief complaints (chest pain, abdominal pain, asthma/chronic obstructive pulmonary disease) were retrospectively reviewed and scored for the presence or absence of 11 predetermined criteria. Patient entry rates were determined by reviewing the emergency department patient registration logs. The data were analyzed using simple correlation and linear regression analysis. A positive correlation was found between patient entry rates and documentation errors in handwritten charts. No such correlation was found in the dictated charts. We conclude that work load may negatively affect documentation accuracy when charts are handwritten. However, the use of dictation services may minimize or eliminate this effect.

Aerocapture Inflatable Decelerator (AID)

NASA Technical Reports Server (NTRS)

Reza, Sajjad

2007-01-01

Forward Attached Inflatable Decelerators, more commonly known as inflatable aeroshells, provide an effective, cost efficient means of decelerating spacecrafts by using atmospheric drag for aerocapture or planetary entry instead of conventional liquid propulsion deceleration systems. Entry into planetary atmospheres results in significant heating and aerodynamic pressures which stress aeroshell systems to their useful limits. Incorporation of lightweight inflatable decelerator surfaces with increased surface-area footprints provides the opportunity to reduce heat flux and induced temperatures, while increasing the payload mass fraction. Furthermore, inflatable aeroshell decelerators provide the needed deceleration at considerably higher altitudes and Mach numbers when compared with conventional rigid aeroshell entry systems. Inflatable aeroshells also provide for stowage in a compact space, with subsequent deployment of a large-area, lightweight heatshield to survive entry heating. Use of a deployable heatshield decelerator not only enables an increase in the spacecraft payload mass fraction and but may also eliminate the need for a spacecraft backshell and cruise stage. This document is the viewgraph slides for the paper's presentation.

Children's School Readiness: Implications for Eliminating Future Disparities in Health and Education

ERIC Educational Resources Information Center

Pagani, Linda S.; Fitzpatrick, Caroline

2014-01-01

Background: School-entry characteristics predict adult educational attainment, which forecasts dispositions toward disease prevention. Health and education risks can also be transmitted from one generation to the next. As such, school readiness forecasts a set of intertwined biopsychosocial trajectories that can influence the developmental…

An analysis of the adaptability of Loran-C to air navigation

NASA Technical Reports Server (NTRS)

Littlefield, J. A.

1981-01-01

The sources of position errors characteristics of the Loran-C navigation system were identified. Particular emphasis was given to their point on entry as well as their elimination. It is shown that the ratio of realized accuracy to theoretical accuracy of the Loran-C is highly receiver dependent.

Single-Particle Tracking of Human Immunodeficiency Virus Type 1 Productive Entry into Human Primary Macrophages.

PubMed

Li, Qin; Li, Wei; Yin, Wen; Guo, Jia; Zhang, Zhi-Ping; Zeng, Dejun; Zhang, Xiaowei; Wu, Yuntao; Zhang, Xian-En; Cui, Zongqiang

2017-04-25

Macrophages are one of the major targets of human immunodeficiency virus (HIV-1), but the viral entry pathway remains poorly understood in these cells. Noninvasive virus labeling and single-virus tracking are effective tools for studying virus entry. Here, we constructed a quantum dot (QD)-encapsulated infectious HIV-1 particle to track viral entry at a single-particle level in live human primary macrophages. QDs were encapsulated in HIV-1 virions by incorporating viral accessory protein Vpr-conjugated QDs during virus assembly. With the HIV-1 particles encapsulating QDs, we monitored the early phase of viral infection in real time and observed that, during infection, HIV-1 was endocytosed in a clathrin-mediated manner; the particles were translocated into Rab5A-positive endosomes, and the core was released into the cytoplasm by viral envelope-mediated endosomal fusion. Drug inhibition assays verified that endosome fusion contributes to HIV-1 productive infection in primary macrophages. Additionally, we observed that a dynamic actin cytoskeleton is critical for HIV-1 entry and intracellular migration in primary macrophages. HIV-1 dynamics and infection could be blocked by multiple different actin inhibitors. Our study revealed a productive entry pathway in macrophages that requires both endosomal function and actin dynamics, which may assist in the development of inhibitors to block the HIV entry in macrophages.

Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry.

PubMed

Rhein, Bethany A; Brouillette, Rachel B; Schaack, Grace A; Chiorini, John A; Maury, Wendy

2016-07-01

Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion-TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/VSVΔG), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. With more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry

PubMed Central

Rhein, Bethany A.; Brouillette, Rachel B.; Schaack, Grace A.; Chiorini, John A.

2016-01-01

ABSTRACT Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion–TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/VSVΔG), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. IMPORTANCE With more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor. PMID:27122575

Human Mars Entry, Descent and Landing Architectures Study Overview

NASA Technical Reports Server (NTRS)

Polsgrove, Tara T.; Dwyer Cianciolo, Alicia

2016-01-01

Landing humans on Mars will require entry, descent and landing (EDL) capability beyond the current state of the art. Nearly twenty times more delivered payload and an order of magnitude improvement in precision landing capability will be necessary. Several EDL technologies capable of meeting the human class payload delivery requirements are being considered. The EDL technologies considered include low lift-to-drag vehicles like Hypersonic Inflatable Aerodynamic Decelerators (HIAD), Adaptable Deployable Entry and Placement Technology (ADEPT), and mid range lift-to-drag vehicles like rigid aeroshell configurations. To better assess EDL technology options and sensitivities to future human mission design variations, a series of design studies has been conducted. The design studies incorporate EDL technologies with conceptual payload arrangements defined by the Evolvable Mars Campaign to evaluate the integrated system with higher fidelity than have been performed to date. This paper describes the results of the design studies for a lander design using the HIAD, ADEPT and rigid shell entry technologies and includes system and subsystem design details including mass and power estimates. This paper will review the point design for three entry configurations capable of delivering a 20 t human class payload to the surface of Mars.

HIV/AIDS testing at ports of entry in China.

PubMed

Lai, Dejian; Hwang, Lu-Yu; Beasley, R Palmer

2011-05-01

In 2007 the Chinese government issued regulations requiring HIV/AIDS testing for Chinese citizens returning at ports of entry if they had resided outside China for 1 year or longer. Three years after publication and partial implementation of the regulations, the Chinese government decided to eliminate compulsory HIV/AIDS testing of returning Chinese. We examine the history of China's HIV/AIDS testing regulations on entry-exit populations, showing how China has gradually altered its policy. As of December 2010, the policy of compulsory HIV/AIDS testing of returning Chinese has been abandoned; however, the regulations still compel HIV/AIDS testing for other groups inside China. Our review sheds new light on the dynamics of regulatory changes in the last 3 years. The Chinese experience that we observed may provide useful insights for policymakers in other parts of the world.

DEVELOPING AN IPAD® APPLICATION FOR DATA COLLECTION IN A RHEUMATOLOGY RESEARCH CLINIC.

PubMed

Kaka, Hussam; Ayearst, Renise; Tran, Maithy; Touma, Zahi; Bagovich, Maria; Vinik, Ophir; Somaily, Mansour; Haddad, Amir; Gladman, Dafna D; Chandran, Vinod

2015-01-01

Clinical research data are often collected on paper and later inputted onto an electronic database. This method is time consuming and potentially introduces errors. Therefore, to make primary data collection more efficient and less error prone we aimed to develop a touch-screen application for data collection in a psoriatic arthritis research clinic and compared it with the pre-existing paper-based system. We developed a Web application using Java and optimized it for the iPad®. It highlights missing fields for physicians in real time, and only permits submission of data collection form after corrections are made. For its evaluation, seven physicians participated, and before each patient visit they were randomly assigned paper or iPad® data entry. Number of errors, length of visit, and time between clinic visit and completion of data entry were measured. A total of 106 patients seen in the clinic who agreed to participate were randomly assigned to be evaluated by clinic physicians using the iPad® (fifty-three patients) or a paper protocol (fifty-three patients). On average, 3.34 omissions were found per paper form, of which 2.24 would have been detected on the iPad®. The iPad® increased the mean patient encounter time from 37.2 minutes to 46.5 minutes, but eliminated delay between a clinic visit and its data entry. Entering data using the iPad® application makes the patient encounter slightly longer, but reduces "missing fields." It also eliminates the delay between clinic visit and data entry thus improving the efficiency of clinical data capture in a research setting.

A Polymorphism within the Internal Fusion Loop of the Ebola Virus Glycoprotein Modulates Host Cell Entry.

PubMed

Hoffmann, Markus; Crone, Lisa; Dietzel, Erik; Paijo, Jennifer; González-Hernández, Mariana; Nehlmeier, Inga; Kalinke, Ulrich; Becker, Stephan; Pöhlmann, Stefan

2017-05-01

The large scale of the Ebola virus disease (EVD) outbreak in West Africa in 2013-2016 raised the question whether the host cell interactions of the responsible Ebola virus (EBOV) strain differed from those of other ebolaviruses. We previously reported that the glycoprotein (GP) of the virus circulating in West Africa in 2014 (EBOV2014) exhibited reduced ability to mediate entry into two nonhuman primate (NHP)-derived cell lines relative to the GP of EBOV1976. Here, we investigated the molecular determinants underlying the differential entry efficiency. We found that EBOV2014-GP-driven entry into diverse NHP-derived cell lines, as well as human monocyte-derived macrophages and dendritic cells, was reduced compared to EBOV1976-GP, although entry into most human- and all bat-derived cell lines tested was comparable. Moreover, EBOV2014 replication in NHP but not human cells was diminished relative to EBOV1976, suggesting that reduced cell entry translated into reduced viral spread. Mutagenic analysis of EBOV2014-GP and EBOV1976-GP revealed that an amino acid polymorphism in the receptor-binding domain, A82V, modulated entry efficiency in a cell line-independent manner and did not account for the reduced EBOV2014-GP-driven entry into NHP cells. In contrast, polymorphism T544I, located in the internal fusion loop in the GP2 subunit, was found to be responsible for the entry phenotype. These results suggest that position 544 is an important determinant of EBOV infectivity for both NHP and certain human target cells. IMPORTANCE The Ebola virus disease outbreak in West Africa in 2013 entailed more than 10,000 deaths. The scale of the outbreak and its dramatic impact on human health raised the question whether the responsible virus was particularly adept at infecting human cells. Our study shows that an amino acid exchange, A82V, that was acquired during the epidemic and that was not observed in previously circulating viruses, increases viral entry into diverse target cells. In contrast, the epidemic virus showed a reduced ability to enter cells of nonhuman primates compared to the virus circulating in 1976, and a single amino acid exchange in the internal fusion loop of the viral glycoprotein was found to account for this phenotype. Copyright © 2017 American Society for Microbiology.

Earth Return Aerocapture for the TransHab/Ellipsled Vehicle

NASA Technical Reports Server (NTRS)

Muth, W. D.; Hoffmann, C.; Lyne, J. E.

2000-01-01

The current architecture being considered by NASA for a human Mars mission involves the use of an aerocapture procedure at Mars arrival and possibly upon Earth return. This technique would be used to decelerate the vehicles and insert them into their desired target orbits, thereby eliminating the need for propulsive orbital insertions. The crew may make the interplanetary journey in a large, inflatable habitat known as the TransHab. It has been proposed that upon Earth return, this habitat be captured into orbit for use on subsequent missions. In this case, the TransHab would be complimented with an aeroshell, which would protect it from heating during the atmospheric entry and provide the vehicle with aerodynamic lift. The aeroshell has been dubbed the "Ellipsled" because of its characteristic shape. This paper reports the results of a preliminary study of the aerocapture of the TransHab/Ellipsled vehicle upon Earth return. Undershoot and overshoot boundaries have been determined for a range of entry velocities, and the effects of variations in the atmospheric density profile, the vehicle deceleration limit, the maximum vehicle roll rate, the target orbit, and the vehicle ballistic coefficient have been examined. A simple, 180 degree roll maneuver was implemented in the undershoot trajectories to target the desired 407 km circular Earth orbit. A three-roll sequence was developed to target not only a specific orbital energy, but also a particular inclination, thereby decreasing propulsive inclination changes and post-aerocapture delta-V requirements. Results show that the TransHab/Ellipsled vehicle has a nominal corridor width of at least 0.7 degrees for entry speeds up to 14.0 km/s. Most trajectories were simulated using continuum flow aerodynamics, but the impact of high-altitude viscous effects was evaluated and found to be minimal. In addition, entry corridor comparisons have been made between the TransHab/Ellipsled and a modified Apollo capsule which is also being considered as the crew return vehicle; because of its slightly higher lift-to-drag ratio, the TransHab has a modest advantage with regard to corridor width. Stagnation-point heating rates and integrated heat loads were determined for a range of vehicle ballistic coefficients and entry velocities.

A Rigid Mid-Lift-to-Drag Ratio Approach to Human Mars Entry, Descent, and Landing

NASA Technical Reports Server (NTRS)

Cerimele, Christopher J.; Robertson, Edward A.; Sostaric, Ronald R.; Campbell, Charles H.; Robinson, Phil; Matz, Daniel A.; Johnson, Breanna J.; Stachowiak, Susan J.; Garcia, Joseph A.; Bowles, Jeffrey V.;

Unrepaired DNA damage facilitates elimination of uniparental chromosomes in interspecific hybrid cells

PubMed Central

Wang, Zheng; Yin, Hao; Lv, Lei; Feng, Yingying; Chen, Shaopeng; Liang, Junting; Huang, Yun; Jiang, Xiaohua; Jiang, Hanwei; Bukhari, Ihtisham; Wu, Lijun; Cooke, Howard J; Shi, Qinghua

2014-01-01

Elimination of uniparental chromosomes occurs frequently in interspecific hybrid cells. For example, human chromosomes are always eliminated during clone formation when human cells are fused with mouse cells. However, the underlying mechanisms are still elusive. Here, we show that the elimination of human chromosomes in human–mouse hybrid cells is accompanied by continued cell division at the presence of DNA damage on human chromosomes. Deficiency in DNA damage repair on human chromosomes occurs after cell fusion. Furthermore, increasing the level of DNA damage on human chromosomes by irradiation accelerates human chromosome loss in hybrid cells. Our results indicate that the elimination of human chromosomes in human–mouse hybrid cells results from unrepaired DNA damage on human chromosomes. We therefore provide a novel mechanism underlying chromosome instability which may facilitate the understanding of carcinogenesis. PMID:24608870

Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

PubMed

Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

Journal of Human Services Abstracts. Volume 3, Number 3.

ERIC Educational Resources Information Center

Department of Health, Education, and Welfare, Washington, DC. Project Share.

This index, containing 450 abstracts on human services, is published quarterly to make available a broad range of documents to those responsible for the planning, management, and delivery of human services. The entries are arranged alphabetically by title and indexed by subject matter. Each entry includes the title, order number, source, price,…

The Shortage of Skilled and Technical Workers; An Inquiry Into Selected Occupations in Short Supply.

ERIC Educational Resources Information Center

Franke, Walter; Sobel, Irvin

The institutional arrangements through which workers are prepared and employed in selected occupations are examined to determine whether barriers to entry and employment are susceptible to elimination or reduction, and how labor shortages effect employers. It covers six occupations in the St. Louis and Chicago metropolitan areas: licensed…

7 CFR 319.74-2 - Conditions governing the entry of cut flowers.

Code of Federal Regulations, 2014 CFR

2014-01-01

... eliminated. (e) Irradiation. Cut flowers and foliage that are required under this part to be treated or subjected to inspection to control one or more of the plant pests for which irradiation is an approved treatment under part 305 of this chapter may instead be treated with irradiation. Irradiation treatment must...

7 CFR 319.74-2 - Conditions governing the entry of cut flowers.

Code of Federal Regulations, 2013 CFR

2013-01-01

... eliminated. (e) Irradiation. Cut flowers and foliage that are required under this part to be treated or subjected to inspection to control one or more of the plant pests for which irradiation is an approved treatment under part 305 of this chapter may instead be treated with irradiation. Irradiation treatment must...

7 CFR 319.74-2 - Conditions governing the entry of cut flowers.

Code of Federal Regulations, 2012 CFR

2012-01-01

... eliminated. (e) Irradiation. Cut flowers and foliage that are required under this part to be treated or subjected to inspection to control one or more of the plant pests for which irradiation is an approved treatment under part 305 of this chapter may instead be treated with irradiation. Irradiation treatment must...

7 CFR 319.74-2 - Conditions governing the entry of cut flowers.

Code of Federal Regulations, 2011 CFR

2011-01-01

... eliminated. (e) Irradiation. Cut flowers and foliage that are required under this part to be treated or subjected to inspection to control one or more of the plant pests for which irradiation is an approved treatment under part 305 of this chapter may instead be treated with irradiation. Irradiation treatment must...

Human cytoplasmic copper chaperones Atox1 and CCS exchange copper ions in vitro.

PubMed

Petzoldt, Svenja; Kahra, Dana; Kovermann, Michael; Dingeldein, Artur P G; Niemiec, Moritz S; Ådén, Jörgen; Wittung-Stafshede, Pernilla

2015-06-01

After Ctr1-mediated copper ion (Cu) entry into the human cytoplasm, chaperones Atox1 and CCS deliver Cu to P1B-type ATPases and to superoxide dismutase, respectively, via direct protein-protein interactions. Although the two Cu chaperones are presumed to work along independent pathways, we here assessed cross-reactivity between Atox1 and the first domain of CCS (CCS1) using biochemical and biophysical methods in vitro. By NMR we show that CCS1 is monomeric although it elutes differently from Atox1 in size exclusion chromatography (SEC). This property allows separation of Atox1 and CCS1 by SEC and, combined with the 254/280 nm ratio as an indicator of Cu loading, we demonstrate that Cu can be transferred from one protein to the other. Cu exchange also occurs with full-length CCS and, as expected, the interaction involves the metal binding sites since mutation of Cu-binding cysteine in Atox1 eliminates Cu transfer from CCS1. Cross-reactivity between CCS and Atox1 may aid in regulation of Cu distribution in the cytoplasm.

Viral entry mechanisms: the increasing diversity of paramyxovirus entry

PubMed Central

Smith, Everett Clinton; Popa, Andreea; Chang, Andres; Masante, Cyril; Dutch, Rebecca Ellis

2009-01-01

The paramyxovirus family contains established human pathogens such as measles virus and human respiratory syncytial virus, and emerging pathogens including the Hendra and Nipah viruses and the recently identified human metapneumovirus. Two major envelope glycoproteins, the attachment protein and the fusion protein, promote the processes of viral attachment and virus-cell membrane fusion required for entry. While common mechanisms of fusion protein proteolytic activation and the mechanism of membrane fusion promotion have been shown in recent years, considerable diversity exists in the family related to receptor binding and the potential mechanisms of fusion triggering. PMID:19878307

Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune cells

PubMed Central

Sims, Brian; Farrow, Anitra L; Williams, Sparkle D; Bansal, Anju; Krendelchtchikov, Alexandre; Gu, Linlin; Matthews, Qiana L

2017-01-01

Exosomes, 30–200 nm nanostructures secreted from donor cells and internalized by recipient cells, can play an important role in the cellular entry of some viruses. These microvesicles are actively secreted into various body fluids, including blood, urine, saliva, cerebrospinal fluid, and breast milk. We successfully isolated exosomes from human breast milk and plasma. The size and concentration of purified exosomes were measured by nanoparticle tracking, while Western blotting confirmed the presence of the exosomal-associated proteins CD9 and CD63, clathrin, and T cell immunoglobulin and mucin proteins (TIMs). Through viral infection assays, we determined that HIV-1 utilizes an exosome-dependent mechanism for entry into human immune cells. The virus contains high amounts of phosphatidylserine (PtdSer) and may bind PtdSer receptors, such as TIMs. This mechanism is supported by our findings that exosomes from multiple sources increased HIV-1 entry into T cells and macrophages, and viral entry was potently blocked with anti-TIM-4 antibodies. PMID:28740388

DARPin-targeting of Measles Virus: Unique Bispecificity, Effective Oncolysis, and Enhanced Safety

PubMed Central

Friedrich, Katrin; Hanauer, Jan RH; Prüfer, Steffen; Münch, Robert C; Völker, Iris; Filippis, Christodoulos; Jost, Christian; Hanschmann, Kay-Martin; Cattaneo, Roberto; Peng, Kah-Whye; Plückthun, Andreas; Buchholz, Christian J; Cichutek, Klaus; Mühlebach, Michael D

2013-01-01

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Many naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. In addition, specific targeting of cancer cells can be achieved at the virus entry level. We optimized retargeting of cell entry by elongating the measles virus attachment protein with designed ankyrin repeat proteins (DARPins), while simultaneously ablating entry through the natural receptors. DARPin-targeted viruses were strongly attenuated in off-target tissue, thereby enhancing safety, but completely eliminated tumor xenografts. Taking advantage of the unique properties of DARPins of being fused without generating folding problems, we generated a virus simultaneous targeting two different tumor markers. The bispecific virus retained the original oncolytic efficacy, while providing proof of concept for a strategy to counteract issues of resistance development. Thus, DARPin-targeting opens new prospects for the development of personalized, targeted therapeutics. PMID:23380817

CD147 Promotes Entry of Pentamer-Expressing Human Cytomegalovirus into Epithelial and Endothelial Cells

PubMed Central

Pritchard, Sarah R.; Wisner, Todd W.; Liu, Jing; Jardetzky, Ted S.; Johnson, David C.

2018-01-01

ABSTRACT Human cytomegalovirus (HCMV) replicates in many diverse cell types in vivo, and entry into different cells involves distinct entry mechanisms and different envelope glycoproteins. HCMV glycoprotein gB is thought to act as the virus fusogen, apparently after being triggered by different gH/gL proteins that bind distinct cellular receptors or entry mediators. A trimer of gH/gL/gO is required for entry into all cell types, and entry into fibroblasts involves trimer binding to platelet-derived growth factor receptor alpha (PDGFRα). HCMV entry into biologically relevant epithelial and endothelial cells and monocyte-macrophages also requires a pentamer, gH/gL complexed with UL128, UL130, and UL131, and there is evidence that the pentamer binds unidentified receptors. We screened an epithelial cell cDNA library and identified the cell surface protein CD147, which increased entry of pentamer-expressing HCMV into HeLa cells but not entry of HCMV that lacked the pentamer. A panel of CD147-specific monoclonal antibodies inhibited HCMV entry into epithelial and endothelial cells, but not entry into fibroblasts. shRNA silencing of CD147 in endothelial cells inhibited HCMV entry but not entry into fibroblasts. CD147 colocalized with HCMV particles on cell surfaces and in endosomes. CD147 also promoted cell-cell fusion induced by expression of pentamer and gB in epithelial cells. However, soluble CD147 did not block HCMV entry and trimer and pentamer did not bind directly to CD147, supporting the hypothesis that CD147 acts indirectly through other proteins. CD147 represents the first HCMV entry mediator that specifically functions to promote entry of pentamer-expressing HCMV into epithelial and endothelial cells. PMID:29739904

78 FR 13860 - Application(s) for Duty-Free Entry of Scientific Instruments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-01

... human diseases including cancer, cardiovascular disease, immunodeficiency and dementia. Justification... organism levels. The data will be used to improve management of human diseases including cancer, cardiovascular disease, immunodeficiency and dementia. Justification for Duty-Free Entry: There are no...

Mission and Design Sensitivities for Human Mars Landers Using Hypersonic Inflatable Aerodynamic Decelerators

NASA Technical Reports Server (NTRS)

Polsgrove, Tara; Thomas, Herbert D.; Dwyer Cianciolo, Alicia; Collins, Tim; Samareh, Jamshid

2017-01-01

This paper explores the impact of human Mars mission architecture decisions on the design and performance of a lander using the HIAD entry system: (a) Earth departure options, (b) Mars arrival options, (c) Entry Descent and Landing options.

Cdk1 phosphorylates SPAT-1/Bora to trigger PLK-1 activation and drive mitotic entry in C. elegans embryos

PubMed Central

Tavernier, Nicolas; Noatynska, Anna; Panbianco, Costanza; Martino, Lisa; Van Hove, Lucie; Schwager, Françoise; Léger, Thibaut

2015-01-01

The molecular mechanisms governing mitotic entry during animal development are incompletely understood. Here, we show that the mitotic kinase CDK-1 phosphorylates Suppressor of Par-Two 1 (SPAT-1)/Bora to regulate its interaction with PLK-1 and to trigger mitotic entry in early Caenorhabditis elegans embryos. Embryos expressing a SPAT-1 version that is nonphosphorylatable by CDK-1 and that is defective in PLK-1 binding in vitro present delays in mitotic entry, mimicking embryos lacking SPAT-1 or PLK-1 functions. We further show that phospho–SPAT-1 activates PLK-1 by triggering phosphorylation on its activator T loop in vitro by Aurora A. Likewise, we show that phosphorylation of human Bora by Cdk1 promotes phosphorylation of human Plk1 by Aurora A, suggesting that this mechanism is conserved in humans. Our results suggest that CDK-1 activates PLK-1 via SPAT-1 phosphorylation to promote entry into mitosis. We propose the existence of a positive feedback loop that connects Cdk1 and Plk1 activation to ensure a robust control of mitotic entry and cell division timing. PMID:25753036

Involvement of TRPV2 and SOCE in calcium influx disorder in DMD primary human myotubes with a specific contribution of α1-syntrophin and PLC/PKC in SOCE regulation.

PubMed

Harisseh, Rania; Chatelier, Aurélien; Magaud, Christophe; Déliot, Nadine; Constantin, Bruno

2013-05-01

Calcium homeostasis is critical for several vital functions in excitable and nonexcitable cells and has been shown to be impaired in many pathologies including Duchenne muscular dystrophy (DMD). Various studies using murine models showed the implication of calcium entry in the dystrophic phenotype. However, alteration of store-operated calcium entry (SOCE) and transient receptor potential vanilloid 2 (TRPV2)-dependant cation entry has not been investigated yet in human skeletal muscle cells. We pharmacologically characterized basal and store-operated cation entries in primary cultures of myotubes prepared from muscle of normal and DMD patients and found, for the first time, an increased SOCE in DMD myotubes. Moreover, this increase cannot be explained by an over expression of the well-known SOCE actors: TRPC1/4, Orai1, and stromal interaction molecule 1 (STIM1) mRNA and proteins. Thus we investigated the modes of regulation of this cation entry. We firstly demonstrated the important role of the scaffolding protein α1-syntrophin, which regulates SOCE in primary human myotubes through its PDZ domain. We also studied the implication of phospholipase C (PLC) and protein kinase C (PKC) in SOCE and showed that their inhibition restores normal levels of SOCE in DMD human myotubes. In addition, the involvement of TRPV2 in calcium deregulation in DMD human myotubes was explored. We showed an abnormal elevation of TRPV2-dependant cation entry in dystrophic primary human myotubes compared with normal ones. These findings show that calcium homeostasis mishandling in DMD myotubes depends on SOCE under the influence of Ca(2+)/PLC/PKC pathway and α1-syntrophin regulation as well as on TRPV2-dependant cation influx.

EtpE Binding to DNase X Induces Ehrlichial Entry via CD147 and hnRNP-K Recruitment, Followed by Mobilization of N-WASP and Actin.

PubMed

Mohan Kumar, Dipu; Lin, Mingqun; Xiong, Qingming; Webber, Mathew James; Kural, Comert; Rikihisa, Yasuko

2015-11-03

Obligate intracellular bacteria, such as Ehrlichia chaffeensis, perish unless they can enter eukaryotic cells. E. chaffeensis is the etiological agent of human monocytic ehrlichiosis, an emerging infectious disease. To infect cells, Ehrlichia uses the C terminus of the outer membrane invasin entry-triggering protein (EtpE) of Ehrlichia (EtpE-C), which directly binds the mammalian cell surface glycosylphosphatidyl inositol-anchored protein, DNase X. How this binding drives Ehrlichia entry is unknown. Here, using affinity pulldown of host cell lysates with recombinant EtpE-C (rEtpE-C), we identified two new human proteins that interact with EtpE-C: CD147 and heterogeneous nuclear ribonucleoprotein K (hnRNP-K). The interaction of CD147 with rEtpE-C was validated by far-Western blotting and coimmunoprecipitation of native EtpE with endogenous CD147. CD147 was ubiquitous on the cell surface and also present around foci of rEtpE-C-coated-bead entry. Functional neutralization of surface-exposed CD147 with a specific antibody inhibited Ehrlichia internalization and infection but not binding. Downregulation of CD147 by short hairpin RNA (shRNA) impaired E. chaffeensis infection. Functional ablation of cytoplasmic hnRNP-K by a nanoscale intracellular antibody markedly attenuated bacterial entry and infection but not binding. EtpE-C also interacted with neuronal Wiskott-Aldrich syndrome protein (N-WASP), which is activated by hnRNP-K. Wiskostatin, which inhibits N-WASP activation, and cytochalasin D, which inhibits actin polymerization, inhibited Ehrlichia entry. Upon incubation with host cell lysate, EtpE-C but not an EtpE N-terminal fragment stimulated in vitro actin polymerization in an N-WASP- and DNase X-dependent manner. Time-lapse video images revealed N-WASP recruitment at EtpE-C-coated bead entry foci. Thus, EtpE-C binding to DNase X drives Ehrlichia entry by engaging CD147 and hnRNP-K and activating N-WASP-dependent actin polymerization. Ehrlichia chaffeensis, an obligate intracellular bacterium, causes a blood-borne disease called human monocytic ehrlichiosis, one of the most prevalent life-threatening emerging tick-transmitted infectious diseases in the United States. The survival of Ehrlichia bacteria, and hence, their ability to cause disease, depends on their specific mode of entry into eukaryotic host cells. Understanding the mechanism by which E. chaffeensis enters cells will create new opportunities for developing effective therapies to prevent bacterial entry and disease in humans. Our findings reveal a novel cellular signaling pathway triggered by an ehrlichial surface protein called EtpE to induce its infectious entry. The results are also important from the viewpoint of human cell physiology because three EtpE-interacting human proteins, DNase X, CD147, and hnRNP-K, are hitherto unknown partners that drive the uptake of small particles, including bacteria, into human cells. Copyright © 2015 Mohan Kumar et al.

Molecular Determinants of Hepatitis B and D Virus Entry Restriction in Mouse Sodium Taurocholate Cotransporting Polypeptide

PubMed Central

Yan, Huan; Peng, Bo; He, Wenhui; Zhong, Guocai; Qi, Yonghe; Ren, Bijie; Gao, Zhenchao; Jing, Zhiyi; Song, Mei; Xu, Guangwei; Sui, Jianhua

2013-01-01

Human hepatitis B virus (HBV) and its satellite virus, hepatitis D virus (HDV), primarily infect humans, chimpanzees, or tree shrews (Tupaia belangeri). Viral infections in other species are known to be mainly restricted at the entry level since viral replication can be achieved in the cells by transfection of the viral genome. Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for HBV and HDV, and amino acids 157 to 165 of NTCP are critical for viral entry and likely limit viral infection of macaques. However, the molecular determinants for viral entry restriction in mouse NTCP (mNTCP) remain unclear. In this study, mNTCP was found to be unable to support either HBV or HDV infection, although it can bind to pre-S1 of HBV L protein and is functional in transporting substrate taurocholate; comprehensive swapping and point mutations of human NTCP (hNTCP) and mNTCP revealed molecular determinants restricting mNTCP for viral entry of HBV and HDV. Remarkably, when mNTCP residues 84 to 87 were substituted by human counterparts, mNTCP can effectively support viral infections. In addition, a number of cell lines, regardless of their species or tissue origin, supported HDV infection when transfected with hNTCP or mNTCP with residues 84 to 87 replaced by human counterparts, highlighting the central role of NTCP for viral infections mediated by HBV envelope proteins. These studies advance our understanding of NTCP-mediated viral entry of HBV and HDV and have important implications for developing the mouse model for their infections. PMID:23678176

A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations

PubMed Central

Fattebert, Jean-Luc; Emigh, Aiyana

2015-01-01

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures. PMID:25874456

A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

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

Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone andmore » sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.« less

A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

DOE PAGES

Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.; ...

2015-04-13

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone andmore » sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.« less

Policy Changes in Brunei Teacher Education: Implications for the Selection of Trainee Teachers

ERIC Educational Resources Information Center

Mundia, Lawrence

2012-01-01

To improve quality, teacher education programs in Brunei were recently eliminated at the undergraduate level and changed to master of teaching degree courses. Prospective teachers are required to obtain content-rich initial degrees prior to applying for teacher training. This study argues that the high entry qualification to teaching may, in…

A Computer Support System for the Entry and Analysis of Questionnaire Data.

ERIC Educational Resources Information Center

Shale, Douglas G.; Milinusic, Tomislav O.

This paper describes a computer support system that eliminated many of the problems associated with the usual methods of transcribing and analyzing questionnaire data. The system was created to support the course evaluation system at Athabasca University, a distance education university in Canada. The courses evaluated were all home study courses,…

Development and Validation of Students' Stress Rating Scale (SSRS)

ERIC Educational Resources Information Center

Balamurugan, M.; Kumaran, D.

2008-01-01

Each and every person is under the grip of stress. Starting from a two-year infant to an adult, stress takes an entry in different forms but it alters the normal functioning of a person. One cannot eliminate stress but can reduce stress in their life. The stressors are normative demands and critical life events. Normative stressors include…

Entry inhibitors: New advances in HCV treatment

PubMed Central

Qian, Xi-Jing; Zhu, Yong-Zhe; Zhao, Ping; Qi, Zhong-Tian

2016-01-01

Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although current antiviral therapy comprising direct-acting antivirals (DAAs) can achieve a quite satisfying sustained virological response (SVR) rate, it is still limited by viral resistance, long treatment duration, combined adverse reactions, and high costs. Moreover, the currently marketed antivirals fail to prevent graft reinfections in HCV patients who receive liver transplantations, probably due to the cell-to-cell transmission of the virus, which is also one of the main reasons behind treatment failure. HCV entry is a highly orchestrated process involving initial attachment and binding, post-binding interactions with host cell factors, internalization, and fusion between the virion and the host cell membrane. Together, these processes provide multiple novel and promising targets for antiviral therapy. Most entry inhibitors target host cell components with high genetic barriers and eliminate viral infection from the very beginning of the viral life cycle. In future, the addition of entry inhibitors to a combination of treatment regimens might optimize and widen the prevention and treatment of HCV infection. This review summarizes the molecular mechanisms and prospects of the current preclinical and clinical development of antiviral agents targeting HCV entry. PMID:26733381

Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus

PubMed Central

Lipovsky, Alex; Popa, Andreea; Pimienta, Genaro; Wyler, Michael; Bhan, Ashima; Kuruvilla, Leena; Guie, Marie-Aude; Poffenberger, Adrian C.; Nelson, Christian D. S.; Atwood, Walter J.; DiMaio, Daniel

2013-01-01

Despite major advances in our understanding of many aspects of human papillomavirus (HPV) biology, HPV entry is poorly understood. To identify cellular genes required for HPV entry, we conducted a genome-wide screen for siRNAs that inhibited infection of HeLa cells by HPV16 pseudovirus. Many retrograde transport factors were required for efficient infection, including multiple subunits of the retromer, which initiates retrograde transport from the endosome to the trans-Golgi network (TGN). The retromer has not been previously implicated in virus entry. Furthermore, HPV16 capsid proteins arrive in the TGN/Golgi in a retromer-dependent fashion during entry, and incoming HPV proteins form a stable complex with retromer subunits. We propose that HPV16 directly engages the retromer at the early or late endosome and traffics to the TGN/Golgi via the retrograde pathway during cell entry. These results provide important insights into HPV entry, identify numerous potential antiviral targets, and suggest that the role of the retromer in infection by other viruses should be assessed. PMID:23569269

Cardiac re-entry dynamics and self-termination in DT-MRI based model of Human Foetal Heart

NASA Astrophysics Data System (ADS)

Biktasheva, Irina V.; Anderson, Richard A.; Holden, Arun V.; Pervolaraki, Eleftheria; Wen, Fen Cai

2018-02-01

The effect of human foetal heart geometry and anisotropy on anatomy induced drift and self-termination of cardiac re-entry is studied here in MRI based 2D slice and 3D whole heart computer simulations. Isotropic and anisotropic models of 20 weeks of gestational age human foetal heart obtained from 100μm voxel diffusion tensor MRI data sets were used in the computer simulations. The fiber orientation angles of the heart were obtained from the orientation of the DT-MRI primary eigenvectors. In a spatially homogeneous electrophysiological monodomain model with the DT-MRI based heart geometries, cardiac re-entry was initiated at a prescribed location in a 2D slice, and in the 3D whole heart anatomy models. Excitation was described by simplified FitzHugh-Nagumo kinetics. In a slice of the heart, with propagation velocity twice as fast along the fibres than across the fibers, DT-MRI based fiber anisotropy changes the re-entry dynamics from pinned to an anatomical re-entry. In the 3D whole heart models, the fiber anisotropy changes cardiac re-entry dynamics from a persistent re-entry to the re-entry self-termination. The self-termination time depends on the re-entry’s initial position. In all the simulations with the DT-MRI based cardiac geometry, the anisotropy of the myocardial tissue shortens the time to re-entry self-termination several folds. The numerical simulations depend on the validity of the DT-MRI data set used. The ventricular wall showed the characteristic transmural rotation of the helix angle of the developed mammalian heart, while the fiber orientation in the atria was irregular.

Paramyxovirus fusion and entry: multiple paths to a common end.

PubMed

Chang, Andres; Dutch, Rebecca E

2012-04-01

The paramyxovirus family contains many common human pathogenic viruses, including measles, mumps, the parainfluenza viruses, respiratory syncytial virus, human metapneumovirus, and the zoonotic henipaviruses, Hendra and Nipah. While the expression of a type 1 fusion protein and a type 2 attachment protein is common to all paramyxoviruses, there is considerable variation in viral attachment, the activation and triggering of the fusion protein, and the process of viral entry. In this review, we discuss recent advances in the understanding of paramyxovirus F protein-mediated membrane fusion, an essential process in viral infectivity. We also review the role of the other surface glycoproteins in receptor binding and viral entry, and the implications for viral infection. Throughout, we concentrate on the commonalities and differences in fusion triggering and viral entry among the members of the family. Finally, we highlight key unanswered questions and how further studies can identify novel targets for the development of therapeutic treatments against these human pathogens.

Expression of human factors CD81, claudin-1, scavenger receptor, and occludin in mouse hepatocytes does not confer susceptibility to HCV entry.

PubMed

Hikosaka, Keisuke; Noritake, Hidenao; Kimura, Wataru; Sultana, Nishat; Sharkar, Mohammad T K; Tagawa, Yoh-Ichi; Uezato, Tadayoshi; Kobayashi, Yoshimasa; Wakita, Takaji; Miura, Naoyuki

2011-04-01

No suitable mouse model is available for studying chronic liver disease caused by hepatitis C virus (HCV). CD81, claudin-1, scavenger receptor class B type I, and occludin were recently reported to be the important factors in HCV entry into hepatocytes. We made transgenic mice (Alb-CCSO) expressing the four human proteins and examined whether HCV from a patient serum or HCV pseudoparticles (HCVpp) were capable of infecting them. HCV was not detected in the mouse serum after injecting the mice with HCV from a patient serum. We also found no indications of HCVpp entry into primary hepatocytes from Alb-CCSO mice. In addition, HCV-infectible Hep3B cells were fused with HCV-resistant primary mouse hepatocytes and the fused cells showed 35-fold lower infectivity compared to wild-type Hep3B cells, indicating that primary mouse hepatocytes have the inhibitory factor(s) in HCVpp entry. Our results suggest that the expression of the human factors does not confer susceptibility to HCV entry into the liver.

Rabies in a Dog Imported from Egypt with a Falsified Rabies Vaccination Certificate--Virginia, 2015.

PubMed

Sinclair, Julie R; Wallace, Ryan M; Gruszynski, Karen; Freeman, Marilyn Bibbs; Campbell, Colin; Semple, Shereen; Innes, Kristin; Slavinski, Sally; Palumbo, Gabriel; Bair-Brake, Heather; Orciari, Lillian; Condori, Rene E; Langer, Adam; Carroll, Darin S; Murphy, Julia

2015-12-18

Canine rabies virus variant has been eliminated in the United States and multiple other countries. Globally, however, dogs remain the principal source for human rabies infections. The World Health Organization recommends that when dogs cross international borders, national importing authorities should require an international veterinary certificate attesting that the animal did not show signs of rabies at the time of shipment, was permanently identified, vaccinated, or revaccinated, and had been subjected to a serologic test for rabies before shipment. On June 8, 2015, an adult female dog that had recently been picked up from the streets of Cairo, Egypt, and shipped by a U.S. animal rescue organization to the United States was confirmed to have rabies by the Virginia Department of General Services Division of Consolidated Laboratory Services (DCLS). This dog was part of a large shipment of dogs and cats from Egypt that rescue organizations had distributed to multiple states for adoption. During the investigation, public health officials learned that the rabies vaccination certificate used for entry of the rabid dog into the United States had intentionally been falsified to avoid exclusion of the dog from entry under CDC's current dog importation regulations. This report underscores the ongoing risk posed by U.S. importation of domestic animals that have not been adequately vaccinated against rabies.

Determinants in the Ig Variable Domain of Human HAVCR1 (TIM-1) Are Required To Enhance Hepatitis C Virus Entry.

PubMed

Kachko, Alla; Costafreda, Maria Isabel; Zubkova, Iryna; Jacques, Jerome; Takeda, Kazuyo; Wells, Frances; Kaplan, Gerardo; Major, Marian E

2018-03-15

Hepatitis C virus (HCV) is the leading cause of chronic hepatitis in humans. Several host molecules participate in HCV cell entry, but this process remains unclear. The complete unraveling of the HCV entry process is important to further understand viral pathogenesis and develop therapeutics. Human hepatitis A virus (HAV) cellular receptor 1 (HAVCR1), CD365, also known as TIM-1, functions as a phospholipid receptor involved in cell entry of several enveloped viruses. Here, we studied the role of HAVCR1 in HCV infection. HAVCR1 antibody inhibited entry in a dose-dependent manner. HAVCR1 soluble constructs neutralized HCV, which did not require the HAVCR1 mucinlike region and was abrogated by a mutation of N to A at position 94 (N94A) in the Ig variable (IgV) domain phospholipid-binding pocket, indicating a direct interaction of the HAVCR1 IgV domain with HCV virions. However, knockout of HAVCR1 in Huh7 cells reduced but did not prevent HCV growth. Interestingly, the mouse HAVCR1 ortholog, also a phospholipid receptor, did not enhance infection and a soluble form failed to neutralize HCV, although replacement of the mouse IgV domain with the human HAVCR1 IgV domain restored the enhancement of HCV infection. Mutations in the cytoplasmic tail revealed that direct HAVCR1 signaling is not required to enhance HCV infection. Our data show that the phospholipid-binding function and other determinant(s) in the IgV domain of human HAVCR1 enhance HCV infection. Although the exact mechanism is not known, it is possible that HAVCR1 facilitates entry by stabilizing or enhancing attachment, leading to direct interactions with specific receptors, such as CD81. IMPORTANCE Hepatitis C virus (HCV) enters cells through a multifaceted process. We identified the human hepatitis A virus cellular receptor 1 (HAVCR1), CD365, also known as TIM-1, as a facilitator of HCV entry. Antibody blocking and silencing or knockout of HAVCR1 in hepatoma cells reduced HCV entry. Our findings that the interaction of HAVCR1 with HCV early during infection enhances entry but is not required for infection support the hypothesis that HAVCR1 facilitates entry by stabilizing or enhancing virus binding to the cell surface membrane and allowing the correct virus-receptor positioning for interaction with the main HCV receptors. Furthermore, our data show that in addition to the phospholipid-binding function of HAVCR1, the enhancement of HCV infection involves other determinants in the IgV domain of HAVCR1. These findings expand the repertoire of molecules that HCV uses for cell entry, adding to the already complex mechanism of HCV infection and pathogenesis. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Supersonic Retropropulsion Technology Development in NASA's Entry, Descent, and Landing Project

NASA Technical Reports Server (NTRS)

Edquist, Karl T.; Berry, Scott A.; Rhode, Matthew N.; Kelb, Bil; Korzun, Ashley; Dyakonov, Artem A.; Zarchi, Kerry A.; Schauerhamer, Daniel G.; Post, Ethan A.

2012-01-01

NASA's Entry, Descent, and Landing (EDL) space technology roadmap calls for new technologies to achieve human exploration of Mars in the coming decades [1]. One of those technologies, termed Supersonic Retropropulsion (SRP), involves initiation of propulsive deceleration at supersonic Mach numbers. The potential benefits afforded by SRP to improve payload mass and landing precision make the technology attractive for future EDL missions. NASA's EDL project spent two years advancing the technological maturity of SRP for Mars exploration [2-15]. This paper summarizes the technical accomplishments from the project and highlights challenges and recommendations for future SRP technology development programs. These challenges include: developing sufficiently large SRP engines for use on human-scale entry systems; testing and computationally modelling complex and unsteady SRP fluid dynamics; understanding the effects of SRP on entry vehicle stability and controllability; and demonstrating sub-scale SRP entry systems in Earth's atmosphere.

46 CFR 147A.25 - Entry.

Code of Federal Regulations, 2010 CFR

2010-10-01

... During Fumigation § 147A.25 Entry. (a) No person may enter the spaces that immediately adjoin the space that is fumigated during fumigation unless entry is for emergency purposes or the space is tested and declared safe for human occupancy by a marine chemist or other qualified person and is inspected under...

46 CFR 147A.25 - Entry.

Code of Federal Regulations, 2011 CFR

2011-10-01

... During Fumigation § 147A.25 Entry. (a) No person may enter the spaces that immediately adjoin the space that is fumigated during fumigation unless entry is for emergency purposes or the space is tested and declared safe for human occupancy by a marine chemist or other qualified person and is inspected under...

Studies of Ebola Virus Glycoprotein-Mediated Entry and Fusion by Using Pseudotyped Human Immunodeficiency Virus Type 1 Virions: Involvement of Cytoskeletal Proteins and Enhancement by Tumor Necrosis Factor Alpha

PubMed Central

Yonezawa, Akihito; Cavrois, Marielle; Greene, Warner C.

2005-01-01

The Ebola filoviruses are aggressive pathogens that cause severe and often lethal hemorrhagic fever syndromes in humans and nonhuman primates. To date, no effective therapies have been identified. To analyze the entry and fusion properties of Ebola virus, we adapted a human immunodeficiency virus type 1 (HIV-1) virion-based fusion assay by substituting Ebola virus glycoprotein (GP) for the HIV-1 envelope. Fusion was detected by cleavage of the fluorogenic substrate CCF2 by β-lactamase-Vpr incorporated into virions and released as a result of virion fusion. Entry and fusion induced by the Ebola virus GP occurred with much slower kinetics than with vesicular stomatitis virus G protein (VSV-G) and were blocked by depletion of membrane cholesterol and by inhibition of vesicular acidification with bafilomycin A1. These properties confirmed earlier studies and validated the assay for exploring other properties of Ebola virus GP-mediated entry and fusion. Entry and fusion of Ebola virus GP pseudotypes, but not VSV-G or HIV-1 Env pseudotypes, were impaired in the presence of the microtubule-disrupting agent nocodazole but were enhanced in the presence of the microtubule-stabilizing agent paclitaxel (Taxol). Agents that impaired microfilament function, including cytochalasin B, cytochalasin D, latrunculin A, and jasplakinolide, also inhibited Ebola virus GP-mediated entry and fusion. Together, these findings suggest that both microtubules and microfilaments may play a role in the effective trafficking of vesicles containing Ebola virions from the cell surface to the appropriate acidified vesicular compartment where fusion occurs. In terms of Ebola virus GP-mediated entry and fusion to various target cells, primary macrophages proved highly sensitive, while monocytes from the same donors displayed greatly reduced levels of entry and fusion. We further observed that tumor necrosis factor alpha, which is released by Ebola virus-infected monocytes/macrophages, enhanced Ebola virus GP-mediated entry and fusion to human umbilical vein endothelial cells. Thus, Ebola virus infection of one target cell may induce biological changes that facilitate infection of secondary target cells that play a key role in filovirus pathogenesis. Finally, these studies indicate that pseudotyping in the HIV-1 virion-based fusion assay may be a valuable approach to the study of entry and fusion properties mediated through the envelopes of other viral pathogens. PMID:15613320

Progress toward measles elimination in the People's Republic of China, 2000-2009.

PubMed

Ma, Chao; An, Zhijie; Hao, Lixin; Cairns, K Lisa; Zhang, Yan; Ma, Jing; Cao, Lei; Wen, Ning; Xu, Wenbo; Liang, Xiaofeng; Yang, Weizhong; Luo, Huiming

2011-07-01

In 2006, China set a goal of measles elimination by 2012. To describe progress toward this goal, we reviewed relevant policies and strategies and analyzed national data for 2000-2009. In response to implementation of these strategies, including increased routine measles vaccination coverage and province-specific supplementary immunization activities (SIAs), reported measles incidence decreased to a historically low level of 39.5 cases per million in 2009. A synchronized nationwide SIA was scheduled in 2010 to further decrease susceptibility to measles. However, reaching and maintaining measles elimination will require strong political commitment and efforts for strengthening surveillance, increasing 2-dose vaccine coverage to >95%, stricter enforcement of the requirement to check immunization status at school entry, and careful attention to measles susceptibility in those aged ≥15 years. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

Evaluation of heterotrophic plate and chromogenic agar colony counting in water quality laboratories.

PubMed

Hallas, Gary; Monis, Paul

2015-01-01

The enumeration of bacteria using plate-based counts is a core technique used by food and water microbiology testing laboratories. However, manual counting of bacterial colonies is both time and labour intensive, can vary between operators and also requires manual entry of results into laboratory information management systems, which can be a source of data entry error. An alternative is to use automated digital colony counters, but there is a lack of peer-reviewed validation data to allow incorporation into standards. We compared the performance of digital counting technology (ProtoCOL3) against manual counting using criteria defined in internationally recognized standard methods. Digital colony counting provided a robust, standardized system suitable for adoption in a commercial testing environment. The digital technology has several advantages:•Improved measurement of uncertainty by using a standard and consistent counting methodology with less operator error.•Efficiency for labour and time (reduced cost).•Elimination of manual entry of data onto LIMS.•Faster result reporting to customers.

Oncolytic Herpes Simplex Virus Vectors Fully Retargeted to Tumor- Associated Antigens.

PubMed

Uchida, Hiroaki; Hamada, Hirofumi; Nakano, Kenji; Kwon, Heechung; Tahara, Hideaki; Cohen, Justus B; Glorioso, Joseph C

2018-01-01

Oncolytic virotherapy is a novel therapeutic modality for malignant diseases that exploits selective viral replication in cancer cells. Herpes simplex virus (HSV) is a promising agent for oncolytic virotherapy due to its broad cell tropism and the identification of mutations that favor its replication in tumor over normal cells. However, these attenuating mutations also tend to limit the potency of current oncolytic HSV vectors that have entered clinical studies. As an alternative, vector retargeting to novel entry receptors has the potential to achieve tumor specificity at the stage of virus entry, eliminating the need for replication-attenuating mutations. Here, we summarize the molecular mechanism of HSV entry and recent advances in the development of fully retargeted HSV vectors for oncolytic virotherapy. Retargeted HSV vectors offer an attractive platform for the creation of a new generation of oncolytic HSV with improved efficacy and specificity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Carbon phenolic heat shields for Jupiter/Saturn/Uranus entry probes

NASA Technical Reports Server (NTRS)

Mezines, S.

1974-01-01

Carbon phenolic heat shield technology is reviewed. Heat shield results from the outer planetary probe mission studies are summarized along with results of plasma jet testing of carbon phenolic conducted in a ten megawatt facility. Missile flight data is applied to planetary entry conditions. A carbon phenolic heat shield material is utilized and tailored to accommodate each of the probe missions. An integral heat shield approach is selected over in order to eliminate a high temperature interface problem and permit direct bonding of the carbon phenolic to the structural honeycomb sandwich. The sandwich is filled with a very fine powder to minimize degradation of its insulation properties by the high conductive hydrogen/helium gases during the long atmospheric descent phase.

42 CFR 35.13 - Entry for negotiation of release or settlement.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Entry for negotiation of release or settlement. 35.13 Section 35.13 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT General § 35.13 Entry for negotiation of release...

42 CFR 35.13 - Entry for negotiation of release or settlement.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Entry for negotiation of release or settlement. 35.13 Section 35.13 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT General § 35.13 Entry for negotiation of release...

42 CFR 35.13 - Entry for negotiation of release or settlement.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Entry for negotiation of release or settlement. 35.13 Section 35.13 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT General § 35.13 Entry for negotiation of release...

42 CFR 35.13 - Entry for negotiation of release or settlement.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Entry for negotiation of release or settlement. 35.13 Section 35.13 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT General § 35.13 Entry for negotiation of release...

42 CFR 35.13 - Entry for negotiation of release or settlement.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Entry for negotiation of release or settlement. 35.13 Section 35.13 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT General § 35.13 Entry for negotiation of release...

Entry-Level Worker Study: Phase 1 Report. Program Report.

ERIC Educational Resources Information Center

Owens, Thomas; And Others

A study examined innovative workplace practices in companies that employ significant numbers of entry-level workers. Findings were based on a series of personal interviews with human resource directors in 58 companies in the Northwest and the Pacific. Asked about the quality of current entry-level workers, employers reported that a disturbing…

Alpharetroviral self-inactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes.

PubMed

Labenski, Verena; Suerth, Julia D; Barczak, Elke; Heckl, Dirk; Levy, Camille; Bernadin, Ornellie; Charpentier, Emmanuelle; Williams, David A; Fehse, Boris; Verhoeyen, Els; Schambach, Axel

2016-08-01

Primary human T lymphocytes represent an important cell population for adoptive immunotherapies, including chimeric-antigen and T-cell receptor applications, as they have the capability to eliminate non-self, virus-infected and tumor cells. Given the increasing numbers of clinical immunotherapy applications, the development of an optimal vector platform for genetic T lymphocyte engineering, which allows cost-effective high-quality vector productions, remains a critical goal. Alpharetroviral self-inactivating vectors (ARV) have several advantages compared to other vector platforms, including a more random genomic integration pattern and reduced likelihood for inducing aberrant splicing of integrated proviruses. We developed an ARV platform for the transduction of primary human T lymphocytes. We demonstrated functional transgene transfer using the clinically relevant herpes-simplex-virus thymidine kinase variant TK.007. Proof-of-concept of alpharetroviral-mediated T-lymphocyte engineering was shown in vitro and in a humanized transplantation model in vivo. Furthermore, we established a stable, human alpharetroviral packaging cell line in which we deleted the entry receptor (SLC1A5) for RD114/TR-pseudotyped ARVs to prevent superinfection and enhance genomic integrity of the packaging cell line and viral particles. We showed that superinfection can be entirely prevented, while maintaining high recombinant virus titers. Taken together, this resulted in an improved production platform representing an economic strategy for translating the promising features of ARVs for therapeutic T-lymphocyte engineering. Copyright © 2016 Elsevier Ltd. All rights reserved.

Paramyxovirus Fusion and Entry: Multiple Paths to a Common End

PubMed Central

Chang, Andres; Dutch, Rebecca E.

2012-01-01

The paramyxovirus family contains many common human pathogenic viruses, including measles, mumps, the parainfluenza viruses, respiratory syncytial virus, human metapneumovirus, and the zoonotic henipaviruses, Hendra and Nipah. While the expression of a type 1 fusion protein and a type 2 attachment protein is common to all paramyxoviruses, there is considerable variation in viral attachment, the activation and triggering of the fusion protein, and the process of viral entry. In this review, we discuss recent advances in the understanding of paramyxovirus F protein-mediated membrane fusion, an essential process in viral infectivity. We also review the role of the other surface glycoproteins in receptor binding and viral entry, and the implications for viral infection. Throughout, we concentrate on the commonalities and differences in fusion triggering and viral entry among the members of the family. Finally, we highlight key unanswered questions and how further studies can identify novel targets for the development of therapeutic treatments against these human pathogens. PMID:22590688

Identification of a coumarin-based antihistamine-like small molecule as an anti-filoviral entry inhibitor.

PubMed

Cheng, Han; Schafer, Adam; Soloveva, Veronica; Gharaibeh, Dima; Kenny, Tara; Retterer, Cary; Zamani, Rouzbeh; Bavari, Sina; Peet, Norton P; Rong, Lijun

2017-09-01

Filoviruses, consisting of Ebola virus, Marburg virus and Cuevavirus, cause severe hemorrhagic fevers in humans with high mortality rates up to 90%. Currently, there is no approved vaccine or therapy available for the prevention and treatment of filovirus infection in humans. The recent 2013-2015 West African Ebola epidemic underscores the urgency to develop antiviral therapeutics against these infectious diseases. Our previous study showed that GPCR antagonists, particularly histamine receptor antagonists (antihistamines) inhibit Ebola and Marburg virus entry. In this study, we screened a library of 1220 small molecules with predicted antihistamine activity, identified multiple compounds with potent inhibitory activity against entry of both Ebola and Marburg viruses in human cancer cell lines, and confirmed their anti-Ebola activity in human primary cells. These small molecules target a late-stage of Ebola virus entry. Further structure-activity relationship studies around one compound (cp19) reveal the importance of the coumarin fused ring structure, especially the hydrophobic substituents at positions 3 and/or 4, for its antiviral activity, and this identified scaffold represents a favorable starting point for the rapid development of anti-filovirus therapeutic agents. Copyright © 2017 Elsevier B.V. All rights reserved.

External lipid PI3P mediates entry of eukaryotic pathogen effectors into plant and animal host cells.

PubMed

Kale, Shiv D; Gu, Biao; Capelluto, Daniel G S; Dou, Daolong; Feldman, Emily; Rumore, Amanda; Arredondo, Felipe D; Hanlon, Regina; Fudal, Isabelle; Rouxel, Thierry; Lawrence, Christopher B; Shan, Weixing; Tyler, Brett M

2010-07-23

Pathogens of plants and animals produce effector proteins that are transferred into the cytoplasm of host cells to suppress host defenses. One type of plant pathogens, oomycetes, produces effector proteins with N-terminal RXLR and dEER motifs that enable entry into host cells. We show here that effectors of another pathogen type, fungi, contain functional variants of the RXLR motif, and that the oomycete and fungal RXLR motifs enable binding to the phospholipid, phosphatidylinositol-3-phosphate (PI3P). We find that PI3P is abundant on the outer surface of plant cell plasma membranes and, furthermore, on some animal cells. All effectors could also enter human cells, suggesting that PI3P-mediated effector entry may be very widespread in plant, animal and human pathogenesis. Entry into both plant and animal cells involves lipid raft-mediated endocytosis. Blocking PI3P binding inhibited effector entry, suggesting new therapeutic avenues. Copyright 2010 Elsevier Inc. All rights reserved.

Hepatitis C virus utilizes VLDLR as a novel entry pathway.

PubMed

Ujino, Saneyuki; Nishitsuji, Hironori; Hishiki, Takayuki; Sugiyama, Kazuo; Takaku, Hiroshi; Shimotohno, Kunitada

2016-01-05

Various host factors are involved in the cellular entry of hepatitis C virus (HCV). In addition to the factors previously reported, we discovered that the very-low-density lipoprotein receptor (VLDLR) mediates HCV entry independent of CD81. Culturing Huh7.5 cells under hypoxic conditions significantly increased HCV entry as a result of the expression of VLDLR, which was not expressed under normoxic conditions in this cell line. Ectopic VLDLR expression conferred susceptibility to HCV entry of CD81-deficient Huh7.5 cells. Additionally, VLDLR-mediated HCV entry was not affected by the knockdown of cellular factors known to act as HCV receptors or HCV entry factors. Because VLDLR is expressed in primary human hepatocytes, our results suggest that VLDLR functions in vivo as an HCV receptor independent of canonical CD81-mediated HCV entry.

Making non-discrimination and equal opportunity a reality in Kenya's health provider education system: results of a gender analysis.

PubMed

Newman, Constance; Kimeu, Anastasiah; Shamblin, Leigh; Penders, Christopher; McQuide, Pamela A; Bwonya, Judith

2011-01-01

IntraHealth International's USAID-funded Capacity Kenya project conducted a performance needs assessment of the Kenya health provider education system in 2010. Various stakeholders shared their understandings of the role played by gender and identified opportunities to improve gender equality in health provider education. Findings suggest that occupational segregation, sexual harassment and discrimination based on pregnancy and family responsibilities present problems, especially for female students and faculty. To grow and sustain its workforce over the long term, Kenyan human resource leaders and managers must act to eliminate gender-based obstacles by implementing existing non-discrimination and equal opportunity policies and laws to increase the entry, retention and productivity of students and faculty. Families and communities must support girls' schooling and defer early marriage. All this will result in a fuller pool of students, faculty and matriculated health workers and, ultimately, a more robust health workforce to meet Kenya's health challenges.

Broadening the use of antiretroviral therapy: the case for feline leukemia virus

PubMed Central

Greggs, Willie M; Clouser, Christine L; Patterson, Steven E; Mansky, Louis M

2011-01-01

Antiretroviral drugs have saved and extended the lives of millions of individuals infected with HIV. The major classes of anti-HIV drugs include reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry/fusion inhibitors. While antiretroviral drug regimens are not commonly used to treat other types of retroviral infections, there are instances where there is a perceived need for re-evaluation of the benefits of antiretroviral therapy. One case in point is that of feline leukemia virus (FeLV), an infection of companion felines. While vaccines exist to prevent FeLV infection and spread, they have not eliminated FeLV infection. For FeLV-infected felines and their human companions, antiretroviral therapy would be desirable and of practical importance if good options were available. Here, we discuss FeLV biology and current treatment options, and propose that there is a need for antiretroviral treatment options for FeLV infection. The comparative use and analysis of antiretroviral therapy can provide new insights into the mechanism of antiretroviral drug action. PMID:21479142

Comparative evaluation of four mosquitoes sampling methods in rice irrigation schemes of lower Moshi, northern Tanzania.

PubMed

Kweka, Eliningaya J; Mahande, Aneth M

2009-07-06

Adult malaria vector sampling is the most important parameter for setting up an intervention and understanding disease dynamics in malaria endemic areas. The intervention will ideally be species-specific according to sampling output. It was the objective of this study to evaluate four sampling techniques, namely human landing catch, pit shelter, indoor resting collection and odour-baited entry trap. These four sampling methods were evaluated simultaneously for thirty days during October 2008, a season of low mosquitoes density and malaria transmission. These trapping methods were performed in one village for maximizing homogeneity in mosquito density. The cattle and man used in odour-baited entry trap were rotated between the chambers to avoid bias. A total of 3,074 mosquitoes were collected. Among these 1,780 (57.9%) were Anopheles arabiensis and 1,294 (42.1%) were Culex quinquefasciatus. Each trap sampled different number of mosquitoes, Indoor resting collection collected 335 (10.9%), Odour-baited entry trap-cow 1,404 (45.7%), Odour-baited entry trap-human 378 (12.3%), Pit shelter 562 (18.3%) and HLC 395 (12.8%). General linear model univariate analysis method was used, position of the trapping method had no effect on mosquito density catch (DF = 4, F = 35.596, P = 0.78). Days variation had no effect on the collected density too (DF = 29, F = 4.789, P = 0.09). The sampling techniques had significant impact on the caught mosquito densities (DF = 4, F = 34.636, P < 0.0001). The Wilcoxon pair-wise comparison between mosquitoes collected in human landing catch and pit shelter was significant (Z = -3.849, P < 0.0001), human landing catch versus Indoor resting collection was not significant (Z = -0.502, P = 0.615), human landing catch versus odour-baited entry trap-man was significant (Z = -2.687, P = 0.007), human landing catch versus odour-baited entry trap-cow was significant (Z = -3.127, P = 0.002). Odour-baited traps with different baits and pit shelter have shown high productivity in collecting higher densities of mosquitoes than human landing catch. These abilities are the possibilities of replacing the human landing catch practices for sampling malaria vectors in areas with An. arabiensis as malaria vectors. Further evaluations of these sampling methods need to be investigated is other areas with different species.

Novel Insights into Cell Entry of Emerging Human Pathogenic Arenaviruses.

PubMed

Fedeli, Chiara; Moreno, Héctor; Kunz, Stefan

2018-06-22

Viral hemorrhagic fevers caused by emerging RNA viruses of the Arenavirus family are among the most devastating human diseases. Climate change, global trade, and increasing urbanization promote the emergence and re-emergence of these human pathogenic viruses. Emerging pathogenic arenaviruses are of zoonotic origin and reservoir-to-human transmission is crucial for spillover into human populations. Host cell attachment and entry are the first and most fundamental steps of every virus infection and represent major barriers for zoonotic transmission. During host cell invasion, viruses critically depend on cellular factors, including receptors, co-receptors, and regulatory proteins of endocytosis. An in-depth understanding of the complex interaction of a virus with cellular factors implicated in host cell entry is therefore crucial to predict the risk of zoonotic transmission, define the tissue tropism, and assess disease potential. Over the past years, investigation of the molecular and cellular mechanisms underlying host cell invasion of human pathogenic arenaviruses uncovered remarkable viral strategies and provided novel insights into viral adaptation and virus-host co-evolution that will be covered in the present review. Copyright © 2018. Published by Elsevier Ltd.

Computerized clinical documentation system in the pediatric intensive care unit

PubMed Central

2001-01-01

Background To determine whether a computerized clinical documentation system (CDS): 1) decreased time spent charting and increased time spent in patient care; 2) decreased medication errors; 3) improved clinical decision making; 4) improved quality of documentation; and/or 5) improved shift to shift nursing continuity. Methods Before and after implementation of CDS, a time study involving nursing care, medication delivery, and normalization of serum calcium and potassium values was performed. In addition, an evaluation of completeness of documentation and a clinician survey of shift to shift reporting were also completed. This was a modified one group, pretest-posttest design. Results With the CDS there was: improved legibility and completeness of documentation, data with better accessibility and accuracy, no change in time spent in direct patient care or charting by nursing staff. Incidental observations from the study included improved management functions of our nurse manager; improved JCAHO documentation compliance; timely access to clinical data (labs, vitals, etc); a decrease in time and resource use for audits; improved reimbursement because of the ability to reconstruct lost charts; limited human data entry by automatic data logging; eliminated costs of printing forms. CDS cost was reasonable. Conclusions When compared to a paper chart, the CDS provided a more legible, compete, and accessible patient record without affecting time spent in direct patient care. The availability of the CDS improved shift to shift reporting. Other observations showed that the CDS improved management capabilities; helped physicians deliver care; improved reimbursement; limited data entry errors; and reduced costs. PMID:11604105

Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41

PubMed Central

Lu, Lu; Yu, Fei; Cai, Lifeng; Debnath, Asim K.; Jiang, Shibo

2015-01-01

Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus serving as key targets for the development of HIV-1 entry inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV entry inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV entry inhibitor candidates and further predicted the future trend of HIV entry inhibitor development. PMID:26324044

Multiple Cationic Amphiphiles Induce a Niemann-Pick C Phenotype and Inhibit Ebola Virus Entry and Infection

PubMed Central

Shoemaker, Charles J.; Schornberg, Kathryn L.; Delos, Sue E.; Scully, Corinne; Pajouhesh, Hassan; Olinger, Gene G.; Johansen, Lisa M.; White, Judith M.

2013-01-01

Ebola virus (EBOV) is an enveloped RNA virus that causes hemorrhagic fever in humans and non-human primates. Infection requires internalization from the cell surface and trafficking to a late endocytic compartment, where viral fusion occurs, providing a conduit for the viral genome to enter the cytoplasm and initiate replication. In a concurrent study, we identified clomiphene as a potent inhibitor of EBOV entry. Here, we screened eleven inhibitors that target the same biosynthetic pathway as clomiphene. From this screen we identified six compounds, including U18666A, that block EBOV infection (IC50 1.6 to 8.0 µM) at a late stage of entry. Intriguingly, all six are cationic amphiphiles that share additional chemical features. U18666A induces phenotypes, including cholesterol accumulation in endosomes, associated with defects in Niemann–Pick C1 protein (NPC1), a late endosomal and lysosomal protein required for EBOV entry. We tested and found that all six EBOV entry inhibitors from our screen induced cholesterol accumulation. We further showed that higher concentrations of cationic amphiphiles are required to inhibit EBOV entry into cells that overexpress NPC1 than parental cells, supporting the contention that they inhibit EBOV entry in an NPC1-dependent manner. A previously reported inhibitor, compound 3.47, inhibits EBOV entry by blocking binding of the EBOV glycoprotein to NPC1. None of the cationic amphiphiles tested had this effect. Hence, multiple cationic amphiphiles (including several FDA approved agents) inhibit EBOV entry in an NPC1-dependent fashion, but by a mechanism distinct from that of compound 3.47. Our findings suggest that there are minimally two ways of perturbing NPC1-dependent pathways that can block EBOV entry, increasing the attractiveness of NPC1 as an anti-filoviral therapeutic target. PMID:23441171

On optimal improvements of classical iterative schemes for Z-matrices

NASA Astrophysics Data System (ADS)

Noutsos, D.; Tzoumas, M.

2006-04-01

Many researchers have considered preconditioners, applied to linear systems, whose matrix coefficient is a Z- or an M-matrix, that make the associated Jacobi and Gauss-Seidel methods converge asymptotically faster than the unpreconditioned ones. Such preconditioners are chosen so that they eliminate the off-diagonal elements of the same column or the elements of the first upper diagonal [Milaszewicz, LAA 93 (1987) 161-170], Gunawardena et al. [LAA 154-156 (1991) 123-143]. In this work we generalize the previous preconditioners to obtain optimal methods. "Good" Jacobi and Gauss-Seidel algorithms are given and preconditioners, that eliminate more than one entry per row, are also proposed and analyzed. Moreover, the behavior of the above preconditioners to the Krylov subspace methods is studied.

Involvement of Clathrin-Mediated Endocytosis in Human Immunodeficiency Virus Type 1 Entry

PubMed Central

Daecke, Jessica; Fackler, Oliver T.; Dittmar, Matthias T.; Kräusslich, Hans-Georg

2005-01-01

Productive entry of human immunodeficiency virus (HIV) is believed to occur by direct fusion at the plasma membrane. Endocytic uptake of HIV particles has been observed in several studies but is considered to be nonproductive, leading to virus degradation in the lysosome. We show here that endocytosis contributes significantly to productive HIV entry in HeLa cells by using trans dominant-negative mutants of dynamin and Eps15. Inducible expression of a dominant-negative mutant of dynamin in a CD4-positive HeLa cell line reduced HIV infection by 40 to 80%. This effect was independent of the infectious dose and was observed for three different isolates. Analysis of reverse transcription products by real-time PCR and of virus entry by delivery of a virion-associated Vpr-β-lactamase fusion protein revealed a similar reduction, indicating that the block occurred at the entry stage. A strong reduction of HIV entry was also observed upon transient transfection of a different trans dominant-negative variant of dynamin, and this reduction correlated with the relative inhibition of transferrin endocytosis. Expression of a dominant-negative variant of Eps15, which is specific for clathrin-dependent endocytosis, reduced HIV entry in HeLa cells by ca 95%, confirming the role of endocytosis for productive infection. In contrast, no effect was observed for a dominant-negative variant of caveolin. We conclude that dynamin-dependent, clathrin-mediated endocytosis can lead to productive entry of HIV in HeLa cells, suggesting this pathway as an alternative route of virus entry. PMID:15650184

76 FR 18220 - Advisory Council for the Elimination of Tuberculosis; Notice of Charter Renewal

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-01

... Council for the Elimination of Tuberculosis; Notice of Charter Renewal This gives notice under the Federal... of Tuberculosis, Department of Health and Human Services, has been renewed for a 2-year period..., Advisory Council for the Elimination of Tuberculosis, Department of Health and Human Services, 1600 Clifton...

Integrin-Using Rotaviruses Bind α2β1 Integrin α2 I Domain via VP4 DGE Sequence and Recognize αXβ2 and αVβ3 by Using VP7 during Cell Entry

PubMed Central

Graham, Kate L.; Halasz, Peter; Tan, Yan; Hewish, Marilyn J.; Takada, Yoshikazu; Mackow, Erich R.; Robinson, Martyn K.; Coulson, Barbara S.

2003-01-01

Integrins α2β1, αXβ2, and αVβ3 have been implicated in rotavirus cell attachment and entry. The virus spike protein VP4 contains the α2β1 ligand sequence DGE at amino acid positions 308 to 310, and the outer capsid protein VP7 contains the αXβ2 ligand sequence GPR. To determine the viral proteins and sequences involved and to define the roles of α2β1, αXβ2, and αVβ3, we analyzed the ability of rotaviruses and their reassortants to use these integrins for cell binding and infection and the effect of peptides DGEA and GPRP on these events. Many laboratory-adapted human, monkey, and bovine viruses used integrins, whereas all porcine viruses were integrin independent. The integrin-using rotavirus strains each interacted with all three integrins. Integrin usage related to VP4 serotype independently of sialic acid usage. Analysis of rotavirus reassortants and assays of virus binding and infectivity in integrin-transfected cells showed that VP4 bound α2β1, and VP7 interacted with αXβ2 and αVβ3 at a postbinding stage. DGEA inhibited rotavirus binding to α2β1 and infectivity, whereas GPRP binding to αXβ2 inhibited infectivity but not binding. The truncated VP5* subunit of VP4, expressed as a glutathione S-transferase fusion protein, bound the expressed α2 I domain. Alanine mutagenesis of D308 and G309 in VP5* eliminated VP5* binding to the α2 I domain. In a novel process, integrin-using viruses bind the α2 I domain of α2β1 via DGE in VP4 and interact with αXβ2 (via GPR) and αVβ3 by using VP7 to facilitate cell entry and infection. PMID:12941907

Interaction of Human Tumor Viruses with Host Cell Surface Receptors and Cell Entry

PubMed Central

Schäfer, Georgia; Blumenthal, Melissa J.; Katz, Arieh A.

2015-01-01

Currently, seven viruses, namely Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV), high-risk human papillomaviruses (HPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human T cell lymphotropic virus type 1 (HTLV-1), have been described to be consistently associated with different types of human cancer. These oncogenic viruses belong to distinct viral families, display diverse cell tropism and cause different malignancies. A key to their pathogenicity is attachment to the host cell and entry in order to replicate and complete their life cycle. Interaction with the host cell during viral entry is characterized by a sequence of events, involving viral envelope and/or capsid molecules as well as cellular entry factors that are critical in target cell recognition, thereby determining cell tropism. Most oncogenic viruses initially attach to cell surface heparan sulfate proteoglycans, followed by conformational change and transfer of the viral particle to secondary high-affinity cell- and virus-specific receptors. This review summarizes the current knowledge of the host cell surface factors and molecular mechanisms underlying oncogenic virus binding and uptake by their cognate host cell(s) with the aim to provide a concise overview of potential target molecules for prevention and/or treatment of oncogenic virus infection. PMID:26008702

Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model.

PubMed

Dallas, Shannon; Salphati, Laurent; Gomez-Zepeda, David; Wanek, Thomas; Chen, Liangfu; Chu, Xiaoyan; Kunta, Jeevan; Mezler, Mario; Menet, Marie-Claude; Chasseigneaux, Stephanie; Declèves, Xavier; Langer, Oliver; Pierre, Esaie; DiLoreto, Karen; Hoft, Carolin; Laplanche, Loic; Pang, Jodie; Pereira, Tony; Andonian, Clara; Simic, Damir; Rode, Anja; Yabut, Jocelyn; Zhang, Xiaolin; Scheer, Nico

2016-05-01

Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp(-/-)) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murineBcrppromoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Predicting when biliary excretion of parent drug is a major route of elimination in humans.

PubMed

Hosey, Chelsea M; Broccatelli, Fabio; Benet, Leslie Z

2014-09-01

Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry.

PubMed

Gehring, Gerrit; Rohrmann, Katrin; Atenchong, Nkacheh; Mittler, Eva; Becker, Stephan; Dahlmann, Franziska; Pöhlmann, Stefan; Vondran, Florian W R; David, Sascha; Manns, Michael P; Ciesek, Sandra; von Hahn, Thomas

2014-08-01

Filoviruses such as Ebola virus and Marburg virus cause a severe haemorrhagic fever syndrome in humans for which there is no specific treatment. Since filoviruses use a complex route of cell entry that depends on numerous cellular factors, we hypothesized that there may be drugs already approved for human use for other indications that interfere with signal transduction or other cellular processes required for their entry and hence have anti-filoviral properties. We used authentic filoviruses and lentiviral particles pseudotyped with filoviral glycoproteins to identify and characterize such compounds. We discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during anti-arrhythmic therapy. A similar effect was observed with the amiodarone-related agent dronedarone and the L-type calcium channel blocker verapamil. Inhibition by amiodarone was concentration dependent and similarly affected pseudoviruses as well as authentic filoviruses. Inhibition of filovirus entry was observed with most but not all cell types tested and was accentuated by the pre-treatment of cells, indicating a host cell-directed mechanism of action. The New World arenavirus Guanarito was also inhibited by amiodarone while the Old World arenavirus Lassa and members of the Rhabdoviridae (vesicular stomatitis virus) and Bunyaviridae (Hantaan) families were largely resistant. The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Hum-mPLoc: an ensemble classifier for large-scale human protein subcellular location prediction by incorporating samples with multiple sites.

PubMed

Shen, Hong-Bin; Chou, Kuo-Chen

2007-04-20

Proteins may simultaneously exist at, or move between, two or more different subcellular locations. Proteins with multiple locations or dynamic feature of this kind are particularly interesting because they may have some very special biological functions intriguing to investigators in both basic research and drug discovery. For instance, among the 6408 human protein entries that have experimentally observed subcellular location annotations in the Swiss-Prot database (version 50.7, released 19-Sept-2006), 973 ( approximately 15%) have multiple location sites. The number of total human protein entries (except those annotated with "fragment" or those with less than 50 amino acids) in the same database is 14,370, meaning a gap of (14,370-6408)=7962 entries for which no knowledge is available about their subcellular locations. Although one can use the computational approach to predict the desired information for the gap, so far all the existing methods for predicting human protein subcellular localization are limited in the case of single location site only. To overcome such a barrier, a new ensemble classifier, named Hum-mPLoc, was developed that can be used to deal with the case of multiple location sites as well. Hum-mPLoc is freely accessible to the public as a web server at http://202.120.37.186/bioinf/hum-multi. Meanwhile, for the convenience of people working in the relevant areas, Hum-mPLoc has been used to identify all human protein entries in the Swiss-Prot database that do not have subcellular location annotations or are annotated as being uncertain. The large-scale results thus obtained have been deposited in a downloadable file prepared with Microsoft Excel and named "Tab_Hum-mPLoc.xls". This file is available at the same website and will be updated twice a year to include new entries of human proteins and reflect the continuous development of Hum-mPLoc.

Mobile application for field data collection and query: Example from wildlife research (Invited)

NASA Astrophysics Data System (ADS)

Bateman, H.; Lindquist, T.; Whitehouse, R.

2013-12-01

Field data collection is often used in many scientific disciplines and effective approaches rely on accurate data collection and recording. We designed a smartphone and tablet application (app) for field-collected data and tested it during a study on wildlife. The objective of our study was to determine the effectiveness of mobile applications in wildlife field research. Student software developers designed applications for mobile devices on the iOS and Android operating systems. Both platforms had similar user interactions via data entry on a touch screen using pre-programmed fields, checkboxes, drop-down menus, and keypad entry. The mobile application included features to insure collection of all measurements in the field through pop-up messages and could proof entries for valid formats. We used undergraduate student subjects to compare the duration of data recording and data entry, and the frequency of errors between the mobile application and traditional (paper) techniques. We field-tested the mobile application using an existing study on wildlife. From the field, technicians could query a database stored on a mobile device to view histories of previously captured animals. Overall, we found that because the mobile application allowed us to enter data in a digital format in the field we could eliminate timely steps to process handwritten data sheets and double-checking data entries. We estimated that, for a 2-month project, using the mobile application instead of traditional data entry and proofing reduced our total project time by 10%. To our knowledge, this is the first application developed for mobile devices for wildlife users interesting in viewing animal capture histories from the field and could be developed for use in other areas of field research.

[Comparison of acetonitrile, ethanol and chromatographic column to eliminate high-abundance proteins in human serum].

PubMed

Li, Yin; Liao, Ming; He, Xiao; Zhou, Yi; Luo, Rong; Li, Hongtao; Wang, Yun; He, Min

2012-11-01

To compare the effects of acetonitrile precipitation, ethanol precipitation and multiple affinity chromatography column Human 14 removal to eliminate high-abundance proteins in human serum. Elimination of serum high-abundance proteins performed with acetonitrile precipitation, ethanol precipitation and multiple affinity chromatography column Human 14 removal. Bis-Tris Mini Gels electrophoresis and two-dimensional gel electrophoresis to detect the effect. Grey value analysis from 1-DE figure showed that after serum processed by acetonitrile method, multiple affinity chromatography column Human 14 removal method and ethanol method, the grey value of albumin changed into 157.2, 40.8 and 8.2 respectively from the original value of 19. 2-DE analysis results indicated that using multiple affinity chromatography column Human 14 method, the protein points noticeable increased by 137 compared to the original serum. After processed by acetonitrile method and ethanol method, the protein point reduced, but the low abundance protein point emerged. The acetonitrile precipitation could eliminate the vast majority of high abundance proteins in serum and gain more proteins of low molecular weight, ethanol precipitation could eliminate part of high abundance proteins in serum, but low abundance proteins less harvested, and multiple affinity chromatography column Human 14 method could effectively removed the high abundance proteins, and keep a large number of low abundance proteins.

[Challenge and opportunity of entry to WTO brings to scientific and technological periodical].

PubMed

Tian, Yun-Mei

2004-11-01

After our country enters WTO, confronted with the direct influence in big international market opening, editorial department will face fierce competition. Selecting the superior and eliminate the inferior will test every publishing house and every magazine directly. In order to improve the competition level, author has analyzed the current situation of China's periodical development, and then explored the scientific and technological periodical opportunity and challenge faced under the new situation.

Shop Math for the Metal Trades. Combination Welder Apprentice, Machinist Helper, Precision Metal Finisher, Sheet Metal Worker Apprentice. A Report on Metal Trades Industry Certified, Single-Concept, Mathematical Learning Projects to Eliminate Student Math Fears.

ERIC Educational Resources Information Center

Newton, Lawrence R.

This project (1) identifies basic and functional mathematics skills (shop mathematics skills), (2) provides pretests on these functional mathematics skills, and (3) provides student learning projects (project sheets) that prepare metal trades students to read, understand, and apply mathematics and measuring skills that meet entry-level job…

Definition ofthe Design Trajectory and Entry Flight Corridor for the NASA Orion Exploration Mission 1 Entry Trajectory Using an Integrated Approach and Optimization

NASA Technical Reports Server (NTRS)

McNamara, Luke W.; Braun, Robert D.

2014-01-01

One of the key design objectives of NASA's Orion Exploration Mission 1 (EM- 1) is to execute a guided entry trajectory demonstrating GN&C capability. The focus of this paper is defining the flyable entry corridor for EM-1 taking into account multiple subsystem constraints such as complex aerothermal heating constraints, aerothermal heating objectives, landing accuracy constraints, structural load limits, Human-System-Integration-Requirements, Service Module debris disposal limits and other flight test objectives. During the EM-1 Design Analysis Cycle 1 design challenges came up that made defining the flyable entry corridor for the EM-1 mission critical to mission success. This document details the optimization techniques that were explored to use with the 6-DOF ANTARES simulation to assist in defining the design entry interface state and entry corridor with respect to key flight test constraints and objectives.

Quantitative membrane proteomics reveals a role for tetraspanin enriched microdomains during entry of human cytomegalovirus

PubMed Central

John, Nessy; Malouli, Daniel

2017-01-01

Human cytomegalovirus (HCMV) depends on and modulates multiple host cell membrane proteins during each stage of the viral life cycle. To gain a global view of the impact of HCMV-infection on membrane proteins, we analyzed HCMV-induced changes in the abundance of membrane proteins in fibroblasts using stable isotope labeling with amino acids (SILAC), membrane fractionation and protein identification by two-dimensional liquid chromatography and tandem mass spectrometry. This systematic approach revealed that CD81, CD44, CD98, caveolin-1 and catenin delta-1 were down-regulated during infection whereas GRP-78 was up-regulated. Since CD81 downregulation was also observed during infection with UV-inactivated virus we hypothesized that this tetraspanin is part of the viral entry process. Interestingly, additional members of the tetraspanin family, CD9 and CD151, were also downregulated during HCMV-entry. Since tetraspanin-enriched microdomains (TEM) cluster host cell membrane proteins including known CMV receptors such as integrins, we studied whether TEMs are required for viral entry. When TEMs were disrupted with the cholesterol chelator methyl-β-cylcodextrin, viral entry was inhibited and this inhibition correlated with reduced surface levels of CD81, CD9 and CD151, whereas integrin levels remained unchanged. Furthermore, simultaneous siRNA-mediated knockdown of multiple tetraspanins inhibited viral entry whereas individual knockdown had little effect suggesting essential, but redundant roles for individual tetraspanins during entry. Taken together, our data suggest that TEM act as platforms for receptors utilized by HCMV for entry into cells. PMID:29121670

Log-linear human chorionic gonadotropin elimination in cases of retained placenta percreta.

PubMed

Stitely, Michael L; Gerard Jackson, M; Holls, William H

2014-02-01

To describe the human chorionic gonadotropin (hCG) elimination rate in patients with intentionally retained placenta percreta. Medical records for cases of placenta percreta with intentional retention of the placenta were reviewed. The natural log of the hCG levels were plotted versus time and then the elimination rate equations were derived. The hCG elimination rate equations were log-linear in three cases individually (R (2) = 0.96-0.99) and in aggregate R (2) = 0.92). The mean half-life of hCG elimination was 146.3 h (6.1 days). The elimination of hCG in patients with intentionally retained placenta percreta is consistent with a two-compartment elimination model. The hCG elimination in retained placenta percreta is predictable in a log-linear manner that is similar to other reports of retained abnormally adherent placentae treated with or without methotrexate.

Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts.

PubMed

Hansen, Brian J; Zhao, Jichao; Csepe, Thomas A; Moore, Brandon T; Li, Ning; Jayne, Laura A; Kalyanasundaram, Anuradha; Lim, Praise; Bratasz, Anna; Powell, Kimerly A; Simonetti, Orlando P; Higgins, Robert S D; Kilic, Ahmet; Mohler, Peter J; Janssen, Paul M L; Weiss, Raul; Hummel, John D; Fedorov, Vadim V

2015-09-14

The complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial-epicardial (Endo-Epi) mapping coupled with high-resolution 3D structural imaging. Coronary-perfused human right atria from explanted diseased hearts (n = 8, 43-72 years old) were optically mapped simultaneously by three high-resolution CMOS cameras (two aligned Endo-Epi views (330 µm2 resolution) and one panoramic view). 3D gadolinium-enhanced magnetic resonance imaging (GE-MRI, 80 µm3 resolution) revealed the atrial wall structure varied in thickness (1.0 ± 0.7-6.8 ± 2.4 mm), transmural fiber angle differences, and interstitial fibrosis causing transmural activation delay from 23 ± 11 to 43 ± 22 ms at increased pacing rates. Sustained AF (>90 min) was induced by burst pacing during pinacidil (30-100 µM) perfusion. Dual-sided sub-Endo-sub-Epi optical mapping revealed that AF was driven by spatially and temporally stable intramural re-entry with 107 ± 50 ms cycle length and transmural activation delay of 67 ± 31 ms. Intramural re-entrant drivers were captured primarily by sub-Endo mapping, while sub-Epi mapping visualized re-entry or 'breakthrough' patterns. Re-entrant drivers were anchored on 3D micro-anatomic tracks (15.4 ± 2.2 × 6.0 ± 2.3 mm2, 2.9 ± 0.9 mm depth) formed by atrial musculature characterized by increased transmural fiber angle differences and interstitial fibrosis. Targeted radiofrequency ablation of the tracks verified these re-entries as drivers of AF. Integrated 3D structural-functional mapping of diseased human right atria ex vivo revealed that the complex atrial microstructure caused significant differences between Endo vs. Epi activation during pacing and sustained AF driven by intramural re-entry anchored to fibrosis-insulated atrial bundles. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts

PubMed Central

Hansen, Brian J.; Zhao, Jichao; Csepe, Thomas A.; Moore, Brandon T.; Li, Ning; Jayne, Laura A.; Kalyanasundaram, Anuradha; Lim, Praise; Bratasz, Anna; Powell, Kimerly A.; Simonetti, Orlando P.; Higgins, Robert S.D.; Kilic, Ahmet; Mohler, Peter J.; Janssen, Paul M.L.; Weiss, Raul; Hummel, John D.; Fedorov, Vadim V.

2015-01-01

Aims The complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial–epicardial (Endo–Epi) mapping coupled with high-resolution 3D structural imaging. Methods and results Coronary-perfused human right atria from explanted diseased hearts (n = 8, 43–72 years old) were optically mapped simultaneously by three high-resolution CMOS cameras (two aligned Endo–Epi views (330 µm2 resolution) and one panoramic view). 3D gadolinium-enhanced magnetic resonance imaging (GE-MRI, 80 µm3 resolution) revealed the atrial wall structure varied in thickness (1.0 ± 0.7–6.8 ± 2.4 mm), transmural fiber angle differences, and interstitial fibrosis causing transmural activation delay from 23 ± 11 to 43 ± 22 ms at increased pacing rates. Sustained AF (>90 min) was induced by burst pacing during pinacidil (30–100 µM) perfusion. Dual-sided sub-Endo–sub-Epi optical mapping revealed that AF was driven by spatially and temporally stable intramural re-entry with 107 ± 50 ms cycle length and transmural activation delay of 67 ± 31 ms. Intramural re-entrant drivers were captured primarily by sub-Endo mapping, while sub-Epi mapping visualized re-entry or ‘breakthrough’ patterns. Re-entrant drivers were anchored on 3D micro-anatomic tracks (15.4 ± 2.2 × 6.0 ± 2.3 mm2, 2.9 ± 0.9 mm depth) formed by atrial musculature characterized by increased transmural fiber angle differences and interstitial fibrosis. Targeted radiofrequency ablation of the tracks verified these re-entries as drivers of AF. Conclusions Integrated 3D structural–functional mapping of diseased human right atria ex vivo revealed that the complex atrial microstructure caused significant differences between Endo vs. Epi activation during pacing and sustained AF driven by intramural re-entry anchored to fibrosis-insulated atrial bundles. PMID:26059724

Wang OIS glossary package for reformatting documents telecommunicated to the OIS system

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

Markow, S.R.

1983-12-09

Documents that are composed on a computer and then transmitted by telecommunications into a Wang Office Information System (OIS) word processing system need to be reformatted and cleaned up before they can be used properly as word processing documents suitable for further revisions or additions. This report describes a group of glossary entries created for the Wang OIS which simplifies the job of cleaning up telecommunicated documents. This glossary is a semi-automated process designed to eliminate most of the tedious work needed to be performed in removing extra spaces and returns, adjusting formats, moving material, repagination, using tabs or indents,more » and similar problems. The report briefly discusses the problems, describes the glossary approach to solving them, and gives instructions for actually using the glossary entries.« less

Field of first magnetic flux entry and pinning strength of superconductors for rf application measured with muon spin rotation

NASA Astrophysics Data System (ADS)

Junginger, T.; Abidi, S. H.; Maffett, R. D.; Buck, T.; Dehn, M. H.; Gheidi, S.; Kiefl, R.; Kolb, P.; Storey, D.; Thoeng, E.; Wasserman, W.; Laxdal, R. E.

2018-03-01

The performance of superconducting radiofrequency (SRF) cavities used for particle accelerators depends on two characteristic material parameters: field of first flux entry Hentry and pinning strength. The former sets the limit for the maximum achievable accelerating gradient, while the latter determines how efficiently flux can be expelled related to the maximum achievable quality factor. In this paper, a method based on muon spin rotation (μ SR ) is developed to probe these parameters on samples. It combines measurements from two different spectrometers, one being specifically built for these studies and samples of different geometries. It is found that annealing at 1400 °C virtually eliminates all pinning. Such an annealed substrate is ideally suited to measure Hentry of layered superconductors, which might enable accelerating gradients beyond bulk niobium technology.

Tyrosine kinases activate store-mediated Ca2+ entry in human platelets through the reorganization of the actin cytoskeleton.

PubMed Central

Rosado, J A; Graves, D; Sage, S O

2000-01-01

We have recently reported that store-mediated Ca(2+) entry in platelets is likely to be mediated by a reversible trafficking and coupling of the endoplasmic reticulum with the plasma membrane, a model termed 'secretion-like coupling'. In this model the actin cytoskeleton plays a key regulatory role. Since tyrosine kinases have been shown to be important for Ca(2+) entry in platelets and other cells, we have now investigated the possible involvement of tyrosine kinases in the secretion-like-coupling model. Treatment of platelets with thrombin or thapsigargin induced actin polymerization by a calcium-independent pathway. Methyl 2,5-dihydroxycinnamate, a tyrosine kinase inhibitor, prevented thrombin- or thapsigargin-induced actin polymerization. The effects of tyrosine kinases in store-mediated Ca(2+) entry were found to be entirely dependent on the actin cytoskeleton. PP1, an inhibitor of the Src family of proteins, partially inhibited store-mediated Ca(2+) entry. In addition, depletion of intracellular Ca(2+) stores stimulated cytoskeletal association of the cytoplasmic tyrosine kinase pp60(src), a process that was sensitive to treatment with cytochalasin D and PP1, but not to inhibition of Ras proteins using prenylcysteine analogues. Finally, combined inhibition of both Ras proteins and tyrosine kinases resulted in complete inhibition of Ca(2+) entry, suggesting that these two families of proteins have independent effects in the activation of store-mediated Ca(2+) entry in human platelets. PMID:11023829

Development of Thermal Protection Materials for Future Mars Entry, Descent and Landing Systems

NASA Technical Reports Server (NTRS)

Cassell, Alan M.; Beck, Robin A. S.; Arnold, James O.; Hwang, Helen; Wright, Michael J.; Szalai, Christine E.; Blosser, Max; Poteet, Carl C.

2010-01-01

Entry Systems will play a crucial role as NASA develops the technologies required for Human Mars Exploration. The Exploration Technology Development Program Office established the Entry, Descent and Landing (EDL) Technology Development Project to develop Thermal Protection System (TPS) materials for insertion into future Mars Entry Systems. An assessment of current entry system technologies identified significant opportunity to improve the current state of the art in thermal protection materials in order to enable landing of heavy mass (40 mT) payloads. To accomplish this goal, the EDL Project has outlined a framework to define, develop and model the thermal protection system material concepts required to allow for the human exploration of Mars via aerocapture followed by entry. Two primary classes of ablative materials are being developed: rigid and flexible. The rigid ablatives will be applied to the acreage of a 10x30 m rigid mid L/D Aeroshell to endure the dual pulse heating (peak approx.500 W/sq cm). Likewise, flexible ablative materials are being developed for 20-30 m diameter deployable aerodynamic decelerator entry systems that could endure dual pulse heating (peak aprrox.120 W/sq cm). A technology Roadmap is presented that will be used for facilitating the maturation of both the rigid and flexible ablative materials through application of decision metrics (requirements, key performance parameters, TRL definitions, and evaluation criteria) used to assess and advance the various candidate TPS material technologies.

Departure Energies, Trip Times and Entry Speeds for Human Mars Missions

NASA Technical Reports Server (NTRS)

Munk, Michelle M.

1999-01-01

The study examines how the mission design variables departure energy, entry speed, and trip time vary for round-trip conjunction-class Mars missions. These three parameters must be balanced in order to produce a mission that is acceptable in terms of mass, cost, and risk. For the analysis, a simple, massless- planet trajectory program was employed. The premise of this work is that if the trans-Mars and trans-Earth injection stages are designed for the most stringent opportunity in the energy cycle, then there is extra energy capability in the "easier" opportunities which can be used to decrease the planetary entry speed, or shorten the trip time. Both of these effects are desirable for a human exploration program.

Departure Energies, Trip Times and Entry Speeds for Human Mars Missions

NASA Technical Reports Server (NTRS)

Munk, Michelle M.

1999-01-01

The study examines how the mission design variables departure energy, entry speed, and trip time vary for round-trip conjunction-class Mars missions. These three parameters must be balanced in order to produce a mission that is acceptable in terms of mass, cost, and risk. For the analysis, a simple, massless-planet trajectory program was employed. The premise of this work is that if the trans-Mars and trans-Earth injection stages are designed for the most stringent opportunity in the energy cycle, then there is extra energy capability in the "easier" opportunities which can be used to decrease the planetary entry speed, or shorten the trip time. Both of these effects are desirable for a human exploration program.

An understanding of human dynamics in urban subway traffic from the Maximum Entropy Principle

NASA Astrophysics Data System (ADS)

Yong, Nuo; Ni, Shunjiang; Shen, Shifei; Ji, Xuewei

2016-08-01

We studied the distribution of entry time interval in Beijing subway traffic by analyzing the smart card transaction data, and then deduced the probability distribution function of entry time interval based on the Maximum Entropy Principle. Both theoretical derivation and data statistics indicated that the entry time interval obeys power-law distribution with an exponential cutoff. In addition, we pointed out the constraint conditions for the distribution form and discussed how the constraints affect the distribution function. It is speculated that for bursts and heavy tails in human dynamics, when the fitted power exponent is less than 1.0, it cannot be a pure power-law distribution, but with an exponential cutoff, which may be ignored in the previous studies.

Insertion of targeting domains into the envelope glycoprotein of Moloney murine leukemia virus (MoMLV)-based vectors modulates the route of mCAT-1-mediated viral entry.

PubMed

Viejo-Borbolla, A; Pizzato, M; Blair, E D; Schulz, T F

2005-03-01

Several groups have inserted targeting domains into the envelope glycoprotein (Env) of Moloney murine leukemia virus (MoMLV) in an attempt to produce targeted retroviral vectors for human gene therapy. While binding of these modified Envs to the target molecule expressed on the surface of human cells was observed, specific high-titer infection of human cells expressing the target molecule was not achieved. Here we investigate the initial steps in the entry process of targeted MoMLV vectors both in murine and human cells expressing the MoMLV receptor, the mouse cationic amino acid transporter-1 (mCAT-1). We show that insertion of a small ligand targeted to E-selectin and of a single chain antibody (scFv) targeted to folate-binding protein (FBP) into the N-terminus of MoMLV Env results in the reduction of the infectivity and the kinetics of entry of the MoMLV vectors. The use of soluble receptor-binding domain (sRBD), bafilomycin A1 (BafA1) and methyl-beta-cyclodextrin (MbetaC) increase the infectivity of the MoMLV vectors targeted to FBP (MoMLV-FBP) suggesting that the scFv targeted to FBP increases the threshold for fusion and might re-route entry of the targeted MoMLV-FBP vector towards an endocytic, non-productive pathway.

Human Rabies in the WHO Southeast Asia Region: Forward Steps for Elimination

PubMed Central

Gongal, Gyanendra; Wright, Alice E.

2011-01-01

There are eleven Member States in the WHO southeast Asia region (Bangladesh, Bhutan, Democratic People's Republic of Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, Timor-Leste) of which eight are endemic for rabies. More than 1.4 billion people in the Region are at risk of rabies infection, and approximately 45% of worldwide rabies deaths occur in Asia. Dog bites account for 96% of human rabies cases. Progress in preventing human rabies through control of the disease in dogs has been slow due to various factors. Innovative control tools and techniques have been developed and standardized in recent years. The introduction of cost-effective intradermal rabies vaccination regimens in Asian countries has increased the availability and affordability of postexposure prophylaxis. Elimination of rabies is not possible without regional and intersectoral cooperation. Considering the importance of consolidating achievements in rabies control in Member countries, the WHO Regional Office for southeast Asia has developed a regional strategy for elimination of human rabies transmitted by dogs in the Region. They have committed to provide technical leadership, to advocate national health authorities to develop major stakeholder consensus for a comprehensive rabies elimination programme, and to implement national strategies for elimination of human rabies. PMID:21991437

The Use of Nitrone Cycloadditions in the Synthesis of Beta-Amino Aldehydes and Unsaturated Amines.

DTIC Science & Technology

1986-01-01

with alkenes (dipolarophiles) to produce isoxazolidines (2) in a fashion similar to the (4+2] Diels - Alder reaction.’ The cycloaddition results in...structures to study enzyme inhibition, and they serve as useful intermediates in the synthesis of $-lactams. 3 3 Table IV summarizes attempts to oxidize p...84% yield (Table V, entry 3). Due to the mechanistic imperative, acid catalyzed elimination always yielded the allylic amine in which the alkene

Hazardous-Materials Robot

NASA Technical Reports Server (NTRS)

Stone, Henry W.; Edmonds, Gary O.

1995-01-01

Remotely controlled mobile robot used to locate, characterize, identify, and eventually mitigate incidents involving hazardous-materials spills/releases. Possesses number of innovative features, allowing it to perform mission-critical functions such as opening and unlocking doors and sensing for hazardous materials. Provides safe means for locating and identifying spills and eliminates risks of injury associated with use of manned entry teams. Current version of vehicle, called HAZBOT III, also features unique mechanical and electrical design enabling vehicle to operate safely within combustible atmosphere.

Supersonic Aerodynamic Characteristics of Blunt Body Trim Tab Configurations

NASA Technical Reports Server (NTRS)

Korzun, Ashley M.; Murphy, Kelly J.; Edquist, Karl T.

2013-01-01

Trim tabs are aerodynamic control surfaces that can allow an entry vehicle to meet aerodynamic performance requirements while reducing or eliminating the use of ballast mass and providing a capability to modulate the lift-to-drag ratio during entry. Force and moment data were obtained on 38 unique, blunt body trim tab configurations in the NASA Langley Research Center Unitary Plan Wind Tunnel. The data were used to parametrically assess the supersonic aerodynamic performance of trim tabs and to understand the influence of tab area, cant angle, and aspect ratio. Across the range of conditions tested (Mach numbers of 2.5, 3.5, and 4.5; angles of attack from -4deg to +20deg; angles of sideslip from 0deg to +8deg), the effects of varying tab area and tab cant angle were found to be much more significant than effects from varying tab aspect ratio. Aerodynamic characteristics exhibited variation with Mach number and forebody geometry over the range of conditions tested. Overall, the results demonstrate that trim tabs are a viable approach to satisfy aerodynamic performance requirements of blunt body entry vehicles with minimal ballast mass. For a 70deg sphere-cone, a tab with 3% area of the forebody and canted approximately 35deg with no ballast mass was found to give the same trim aerodynamics as a baseline model with ballast mass that was 5% of the total entry mass.

Comparative cyto-histological study of needle tip aspirates and entry sites after intravitreal injection using different needle types

PubMed Central

Lytvynchuk, Lyubomyr; Sergienko, Andrij; Savytska, Iryna; Albert, Réka; Glittenberg, Carl; Binder, Susanne; Petrovski, Goran

2017-01-01

A comparison of the cellular content of needle tip aspirates and entry sites after transconjunctival intravitreal injection (IVI) using different needle types was performed. White outbred rats and human cadaver eyes were used for IVI by hypodermic 27 gauge (G) and 30G needles, and spinal anesthesia Pencan 27G needles. Aspiration of vitreous for quantitative morphological and cell cultivation analysis, as well as cyto-histological analysis of aspirates and entry sites were carried out. The most common cells in the aspirates from all needle types were conjunctival epithelial-, ciliary body non-pigmented epithelial- and sclerocyte-like cells and granular proteins. Crystallized vitreous specimens were present in each aspirate. The entry sites of hypodermic needles showed marked trauma in all wall layers of rat and human eyes accompanied by cellular destruction and hemorrhages. Pencan 27G needle caused less tissue trauma with partial reposition of sclerocytes. Transconjunctival IVIs with hypodermic 27G and 30G, and Pencan 27G needles result in trauma of all layers of the eyeball. The possible consequences of cellular content being cut and injected into the eye, as well as the entry site wound shape deserve future consideration and improvements. PMID:28692684

Cell entry by a novel European filovirus requires host endosomal cysteine proteases and Niemann-Pick C1

PubMed Central

Ng, Melinda; Ndungo, Esther; Jangra, Rohit K.; Cai, Yingyun; Postnikova, Elena; Radoshitzky, Sheli R.; Dye, John M.; de Arellano, Eva Ramírez; Negredo, Ana; Palacios, Gustavo; Kuhn, Jens H.; Chandran, Kartik

2014-01-01

Lloviu virus (LLOV), a phylogenetically divergent filovirus, is the proposed etiologic agent of die-offs of Schreiber’s long-fingered bats (Miniopterus schreibersii) in western Europe. Studies of LLOV remain limited because the infectious agent has not yet been isolated. Here, we generated a recombinant vesicular stomatitis virus expressing the LLOV spike glycoprotein (GP) and used it to show that LLOV GP resembles other filovirus GP proteins in structure and function. LLOV GP must be cleaved by endosomal cysteine proteases during entry, but is much more protease-sensitive than EBOV GP. The EBOV/MARV receptor, Niemann Pick C1 (NPC1), is also required for LLOV entry, and its second luminal domain is recognized with high affinity by a cleaved form of LLOV GP, suggesting that receptor binding would not impose a barrier to LLOV infection of humans and non-human primates. The use of NPC1 as an intracellular entry receptor may be a universal property of filoviruses. PMID:25310500

Human cooperation by lethal group competition.

PubMed

Egas, Martijn; Kats, Ralph; van der Sar, Xander; Reuben, Ernesto; Sabelis, Maurice W

2013-01-01

Why humans are prone to cooperate puzzles biologists, psychologists and economists alike. Between-group conflict has been hypothesized to drive within-group cooperation. However, such conflicts did not have lasting effects in laboratory experiments, because they were about luxury goods, not needed for survival ("looting"). Here, we find within-group cooperation to last when between-group conflict is implemented as "all-out war" (eliminating the weakest groups). Human subjects invested in helping group members to avoid having the lowest collective pay-off, whereas they failed to cooperate in control treatments with random group elimination or with no subdivision in groups. When the game was repeated, experience was found to promote helping. Thus, not within-group interactions alone, not random group elimination, but pay-off-dependent group elimination was found to drive within-group cooperation in our experiment. We suggest that some forms of human cooperation are maintained by multi-level selection: reciprocity within groups and lethal competition among groups acting together.

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

PubMed Central

Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

2014-01-01

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

Histopathological detection of entry and exit holes in human skin wounds caused by firearms.

PubMed

Baptista, Marcus Vinícius; d'Ávila, Solange C G P; d'Ávila, Antônio Miguel M P

2014-07-01

The judiciary needs forensic medicine to determine the difference between an entry hole and an exit hole in human skin caused by firearms for civilian use. This important information would be most useful if a practical and accurate method could be done with low-cost and minimal technological resources. Both macroscopic and microscopic analyses were performed on skin lesions caused by firearm projectiles, to establish histological features of 14 entry holes and 14 exit holes. Microscopically, in the abrasion area macroscopically observed, there were signs of burns (sub-epidermal cracks and keratinocyte necrosis) in the entrance holes in all cases. These signs were not found in three exit holes which showed an abrasion collar, nor in other exit holes. Some other microscopic features not found in every case were limited either to entry holes, such as cotton fibres, grease deposits, or tattooing in the dermis, or to exit holes, such as adipose tissue, bone or muscle tissue in the dermis. Coagulative necrosis of keratinocytes and sub-epidermal cracks are characteristic of entry holes. Despite the small sample size, it can be safely inferred that this is an important microscopic finding, among others less consistently found, to define an entry hole in questionable cases. Copyright © 2014 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

PubMed Central

Li, Qingxue; Fischer, Elizabeth

2016-01-01

ABSTRACT Previously we showed that THY-1 has a critical role in the initial stage of infection of certain cell types with human cytomegalovirus (HCMV) and that THY-1 is important for HCMV-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt during virus entry. THY-1 is known to interact with integrins and is a major cargo protein of clathrin-independent endocytic vesicles. Since macropinocytosis involves integrin signaling, is PI3K/Akt dependent, and is a clathrin-independent endocytic process, we determined whether THY-1 has a role in HCMV entry by macropinocytosis. Using electron microscopy in two cell lines that support HCMV infection in a THY-1-dependent manner, we found that HCMV enters these cells by a macropinocytosis-like process. THY-1 associated with HCMV virions on the cell surface and colocalized with virus inside macropinosomes. 5-(N-Ethyl-N-isopropyl)amiloride (EIPA) and soluble THY-1 blocked HCMV infection in the cell lines by ≥80% and 60%, respectively. HCMV entry into the cells triggered increased influx of extracellular fluid, a marker of macropinocytosis, and this increased fluid uptake was inhibited by EIPA and by soluble THY-1. Blocking actin depolymerization, Na+/H+ exchange, PI3K, and Pak1 kinase, which are critical for macropinocytosis, impaired HCMV infection. Neither internalized HCMV virions nor THY-1 in virus-infected cells colocalized with transferrin as determined by confocal microscopy, indicating that clathrin-mediated endocytosis was not involved in THY-1-associated virus entry. These results suggest that HCMV has adapted to utilize THY-1, a cargo protein of clathrin-independent endocytotic vesicles, to facilitate efficient entry into certain cell types by a macropinocytosis-like process. IMPORTANCE Human cytomegalovirus (HCMV) infects over half of the population and is the most common infectious cause of birth defects. The virus is the most important infection occurring in transplant recipients. The mechanism of how HCMV enters cells is controversial. In this study, we show that THY-1, a cell surface protein that is critical for the early stage of entry of HCMV into certain cell types, contributes to virus entry by macropinocytosis. Our findings suggest that HCMV has adapted to utilize THY-1 to facilitate entry of HCMV into macropinosomes in certain cell types. Further knowledge about the mechanism of HCMV entry into cells may facilitate the development of novel inhibitors of virus infection. PMID:27558416

Where Public Health Meets Human Rights: Integrating Human Rights into the Validation of the Elimination of Mother-to-Child Transmission of HIV and Syphilis.

PubMed

Kismödi, Eszter; Kiragu, Karusa; Sawicki, Olga; Smith, Sally; Brion, Sophie; Sharma, Aditi; Mworeko, Lilian; Iovita, Alexandrina

2017-12-01

In 2014, the World Health Organization (WHO) initiated a process for validation of the elimination of mother-to-child transmission (EMTCT) of HIV and syphilis by countries. For the first time in such a process for the validation of disease elimination, WHO introduced norms and approaches that are grounded in human rights, gender equality, and community engagement. This human rights-based validation process can serve as a key opportunity to enhance accountability for human rights protection by evaluating EMTCT programs against human rights norms and standards, including in relation to gender equality and by ensuring the provision of discrimination-free quality services. The rights-based validation process also involves the assessment of participation of affected communities in EMTCT program development, implementation, and monitoring and evaluation. It brings awareness to the types of human rights abuses and inequalities faced by women living with, at risk of, or affected by HIV and syphilis, and commits governments to eliminate those barriers. This process demonstrates the importance and feasibility of integrating human rights, gender, and community into key public health interventions in a manner that improves health outcomes, legitimizes the participation of affected communities, and advances the human rights of women living with HIV.

Glove-Enabled Computer Operations (GECO): Design and Testing of an Extravehicular Activity Glove Adapted for Human-Computer Interface

NASA Technical Reports Server (NTRS)

Adams, Richard J.; Olowin, Aaron; Krepkovich, Eileen; Hannaford, Blake; Lindsay, Jack I. C.; Homer, Peter; Patrie, James T.; Sands, O. Scott

2013-01-01

The Glove-Enabled Computer Operations (GECO) system enables an extravehicular activity (EVA) glove to be dual-purposed as a human-computer interface device. This paper describes the design and human participant testing of a right-handed GECO glove in a pressurized glove box. As part of an investigation into the usability of the GECO system for EVA data entry, twenty participants were asked to complete activities including (1) a Simon Says Games in which they attempted to duplicate random sequences of targeted finger strikes and (2) a Text Entry activity in which they used the GECO glove to enter target phrases in two different virtual keyboard modes. In a within-subjects design, both activities were performed both with and without vibrotactile feedback. Participants' mean accuracies in correctly generating finger strikes with the pressurized glove were surprisingly high, both with and without the benefit of tactile feedback. Five of the subjects achieved mean accuracies exceeding 99% in both conditions. In Text Entry, tactile feedback provided a statistically significant performance benefit, quantified by characters entered per minute, as well as reduction in error rate. Secondary analyses of responses to a NASA Task Loader Index (TLX) subjective workload assessments reveal a benefit for tactile feedback in GECO glove use for data entry. This first-ever investigation of employment of a pressurized EVA glove for human-computer interface opens up a wide range of future applications, including text "chat" communications, manipulation of procedures/checklists, cataloguing/annotating images, scientific note taking, human-robot interaction, and control of suit and/or other EVA systems.

Glove-Enabled Computer Operations (GECO): Design and Testing of an Extravehicular Activity Glove Adapted for Human-Computer Interface

NASA Technical Reports Server (NTRS)

Adams, Richard J.; Olowin, Aaron; Krepkovich, Eileen; Hannaford, Blake; Lindsay, Jack I. C.; Homer, Peter; Patrie, James T.; Sands, O. Scott

2013-01-01

The Glove-Enabled Computer Operations (GECO) system enables an extravehicular activity (EVA) glove to be dual-purposed as a human-computer interface device. This paper describes the design and human participant testing of a right-handed GECO glove in a pressurized glove box. As part of an investigation into the usability of the GECO system for EVA data entry, twenty participants were asked to complete activities including (1) a Simon Says Games in which they attempted to duplicate random sequences of targeted finger strikes and (2) a Text Entry activity in which they used the GECO glove to enter target phrases in two different virtual keyboard modes. In a within-subjects design, both activities were performed both with and without vibrotactile feedback. Participants mean accuracies in correctly generating finger strikes with the pressurized glove were surprisingly high, both with and without the benefit of tactile feedback. Five of the subjects achieved mean accuracies exceeding 99 in both conditions. In Text Entry, tactile feedback provided a statistically significant performance benefit, quantified by characters entered per minute, as well as reduction in error rate. Secondary analyses of responses to a NASA Task Loader Index (TLX) subjective workload assessments reveal a benefit for tactile feedback in GECO glove use for data entry. This first-ever investigation of employment of a pressurized EVA glove for human-computer interface opens up a wide range of future applications, including text chat communications, manipulation of procedureschecklists, cataloguingannotating images, scientific note taking, human-robot interaction, and control of suit andor other EVA systems.

Tumor detection and elimination by a targeted gallium corrole

PubMed Central

Agadjanian, Hasmik; Ma, Jun; Rentsendorj, Altan; Valluripalli, Vinod; Hwang, Jae Youn; Mahammed, Atif; Farkas, Daniel L.; Gray, Harry B.; Gross, Zeev; Medina-Kauwe, Lali K.

2009-01-01

Sulfonated gallium(III) corroles are intensely fluorescent macrocyclic compounds that spontaneously assemble with carrier proteins to undergo cell entry. We report in vivo imaging and therapeutic efficacy of a tumor-targeted corrole noncovalently assembled with a heregulin-modified protein directed at the human epidermal growth factor receptor (HER). Systemic delivery of this protein-corrole complex results in tumor accumulation, which can be visualized in vivo owing to intensely red corrole fluorescence. Targeted delivery in vivo leads to tumor cell death while normal tissue is spared. These findings contrast with the effects of doxorubicin, which can elicit cardiac damage during therapy and required direct intratumoral injection to yield similar levels of tumor shrinkage compared with the systemically delivered corrole. The targeted complex ablated tumors at >5 times a lower dose than untargeted systemic doxorubicin, and the corrole did not damage heart tissue. Complexes remained intact in serum and the carrier protein elicited no detectable immunogenicity. The sulfonated gallium(III) corrole functions both for tumor detection and intervention with safety and targeting advantages over standard chemotherapeutic agents. PMID:19342490

Operating and hydrodynamic characteristics of a reversed flow jet loop bioreactor (RFJLB) with ejector.

PubMed

Wagh, Sameer M; Koranne, Kishore V; Sonolikar, Ram L

2012-04-01

The hydrodynamic characteristics of RFJLB was studied with superficial liquid velocity (Ul), nozzle diameter (Dn) and nozzle height (Hn) in the range of 0.0293-0.094m/s, 17.4-22.0mm and 50-400mm, respectively. For Dn=17.4mm, Hn=50 and 200mm, with ejector mode and regular operating procedure i.e. simultaneous entry of gas with increasing liquid velocity, had limitation of not establishing the circulation loop. To overcome this limitation a modified operating procedure i.e. entry of gas after established liquid circulation loop is proposed. Also the comparison of gas holdups with ejector and injector mode proves the effectiveness of ejector mode and can eliminate the supply of compressed gas. Thus proper choice of Dn, Hn and also the operating procedure becomes necessary. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Radiobiological effects of total mice irradiation with Bragg's peak protons].

PubMed

Ivanov, A A; Molokanov, A G; Ushakov, I B; Bulynina, T M; Vorozhtsova, S V; Abrosimova, A N; Kryuchkova, D M; Gaevsky, V N

2013-01-01

Outbred CD-1 female mice were irradiated in a proton beam (171 MeV, 5 Gy) on the phasotron at the Joint Institute of Nuclear Research (Dubna, Russia). Radiation was delivered in two points of the depth dose distribution: at the beam entry and on Bragg's peak. Technical requirements for studying the effects of Bragg's peak protons on organism of experimental animals were specified. It was recognized that protons with high linear energy transfer (mean LET = 1.6 keV/microm) cause a more severe damaging effect to the hemopoietic system and cytogenetic apparatus in bone marrow cells as compared with entry protons and 60Co gamma-quanta. It was shown that recovery of the main hemopoietic organs and immunity as well as elimination of chromosomal aberrations take more time following irradiation with Bragg's peak protons but not protons with the energy of 171 MeV.

Web-based data collection: detailed methods of a questionnaire and data gathering tool

PubMed Central

Cooper, Charles J; Cooper, Sharon P; del Junco, Deborah J; Shipp, Eva M; Whitworth, Ryan; Cooper, Sara R

2006-01-01

There have been dramatic advances in the development of web-based data collection instruments. This paper outlines a systematic web-based approach to facilitate this process through locally developed code and to describe the results of using this process after two years of data collection. We provide a detailed example of a web-based method that we developed for a study in Starr County, Texas, assessing high school students' work and health status. This web-based application includes data instrument design, data entry and management, and data tables needed to store the results that attempt to maximize the advantages of this data collection method. The software also efficiently produces a coding manual, web-based statistical summary and crosstab reports, as well as input templates for use by statistical packages. Overall, web-based data entry using a dynamic approach proved to be a very efficient and effective data collection system. This data collection method expedited data processing and analysis and eliminated the need for cumbersome and expensive transfer and tracking of forms, data entry, and verification. The code has been made available for non-profit use only to the public health research community as a free download [1]. PMID:16390556

Ca2+ Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte

PubMed Central

Lee, Jaekwang; Chun, Ye-Eun; Han, Kyung-Seok; Lee, Jungmoo; Woo, Dong Ho

2015-01-01

Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca2+ oscillations. ATP is known to be released from astrocytes by Ca2+-dependent manner. However, the precise source of Ca2+, whether it is Ca2+ entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca2+ was released from intracellular stores by activation of Gαq-coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca2+ was omitted. Our results suggest that Ca2+ entry, but not release from intracellular Ca2+ store, is critical for MS-induced ATP release from astrocyte. PMID:25792866

Human Mars Entry, Descent, and Landing Architecture Study Overview

NASA Technical Reports Server (NTRS)

Cianciolo, Alicia D.; Polsgrove, Tara T.

2016-01-01

The Entry, Descent, and Landing (EDL) Architecture Study is a multi-NASA center activity to analyze candidate EDL systems as they apply to human Mars landing in the context of the Evolvable Mars Campaign. The study, led by the Space Technology Mission Directorate (STMD), is performed in conjunction with the NASA's Science Mission Directorate and the Human Architecture Team, sponsored by NASA's Human Exploration and Operations Mission Directorate. The primary objective is to prioritize future STMD EDL technology investments by (1) generating Phase A-level designs for selected concepts to deliver 20 t human class payloads, (2) developing a parameterized mass model for each concept capable of examining payloads between 5 and 40 t, and (3) evaluating integrated system performance using trajectory simulations. This paper summarizes the initial study results.

Host cell tropism mediated by Australian bat lyssavirus envelope glycoproteins.

PubMed

Weir, Dawn L; Smith, Ina L; Bossart, Katharine N; Wang, Lin-Fa; Broder, Christopher C

2013-09-01

Australian bat lyssavirus (ABLV) is a rhabdovirus of the lyssavirus genus capable of causing fatal rabies-like encephalitis in humans. There are two variants of ABLV, one circulating in pteropid fruit bats and another in insectivorous bats. Three fatal human cases of ABLV infection have been reported with the third case in 2013. Importantly, two equine cases also arose in 2013; the first occurrence of ABLV in a species other than bats or humans. We examined the host cell entry of ABLV, characterizing its tropism and exploring its cross-species transmission potential using maxGFP-encoding recombinant vesicular stomatitis viruses that express ABLV G glycoproteins. Results indicate that the ABLV receptor(s) is conserved but not ubiquitous among mammalian cell lines and that the two ABLV variants can utilize alternate receptors for entry. Proposed rabies virus receptors were not sufficient to permit ABLV entry into resistant cells, suggesting that ABLV utilizes an unknown alternative receptor(s). Published by Elsevier Inc.

78 FR 70951 - Agency Information Collection Activities; Proposed Collection; Comment Request; Importer's Entry...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-27

... written comments on the collection of information to the Division of Dockets Management (HFA- 305), Food... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-1423] Agency Information Collection Activities; Proposed Collection; Comment Request; Importer's Entry Notice...

Telemarketing. Curriculum Guides and Content Outlines for Telemarketing: Entry-Level Position.

ERIC Educational Resources Information Center

Shepard, Del

This curriculum guide and content outline for the telemarketing entry-level position contains seven sections: (1) specialized telemarketing tasks; (2) telemarketing selling skills; (3) marketing tasks; (4) business-related tasks; (5) business-specific tasks; (6) personnel/human resources-related tasks; and (7) communications and minimum skill…

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

System for information discovery

DOEpatents

Pennock, Kelly A [Richland, WA; Miller, Nancy E [Kennewick, WA

2002-11-19

A sequence of word filters are used to eliminate terms in the database which do not discriminate document content, resulting in a filtered word set and a topic word set whose members are highly predictive of content. These two word sets are then formed into a two dimensional matrix with matrix entries calculated as the conditional probability that a document will contain a word in a row given that it contains the word in a column. The matrix representation allows the resultant vectors to be utilized to interpret document contents.

Eliminating Space Debris: Applied Technology and Policy Prescriptions, Fall 2007 - Project 07-02

DTIC Science & Technology

2008-01-01

plan to transfer ownership of the constellation, Iridium satellites were (presume that there was more than one) scheduled to be sent out of orbit to...told the research team that administrators are “not shy” about saying, “We have a problem with your debris plan .” Usually, the licensee will work... planned maneuvers • End-of-life (EOL) support. Includes re-entry support and planned de-orbit operations • Anomaly re configuration • Emergency ser

Technology requirements for a generic aerocapture system. [for atmospheric entry

NASA Technical Reports Server (NTRS)

Cruz, M. I.

1980-01-01

The technology requirements for the design of a generic aerocapture vehicle system are summarized. These spacecraft have the capability of completely eliminating fuel-costly retropropulsion for planetary orbit capture through a single aerodynamically controlled atmospheric braking pass from a hyperbolic trajectory into a near circular orbit. This generic system has application at both the inner and outer planets. Spacecraft design integration, navigation, communications, and aerothermal protection system design problems were assessed in the technology requirements study and are discussed in this paper.

Potent In Vivo NK Cell-Mediated Elimination of HIV-1-Infected Cells Mobilized by a gp120-Bispecific and Hexavalent Broadly Neutralizing Fusion Protein

PubMed Central

Bardhi, Ariola; Wu, Yanling; Chen, Weizao; Li, Wei; Zhu, Zhongyu; Zheng, Jian Hua; Wong, Hing; Jeng, Emily; Jones, Jennifer; Ochsenbauer, Christina; Kappes, John C.; Dimitrov, Dimiter S.; Ying, Tianlei

2017-01-01

ABSTRACT Antibodies bound to human immunodeficiency virus type 1 (HIV-1) envelope protein expressed by infected cells mobilize antibody-dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to a functional HIV-1 cure. The most effective antibodies for controlling and eradicating HIV-1 infection would likely have the dual capacities of potently neutralizing a broad range of HIV-1 isolates and effectively mobilizing HIV-1-specific ADCC to eliminate HIV-1-infected cells. For this purpose, we constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and simian-human immunodeficiency virus (SHIV) infection in humanized mouse and macaque models, respectively, including in vivo neutralization of HIV-1 strains resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. We developed a novel humanized mouse model to evaluate in vivo human NK cell-mediated elimination of HIV-1-infected cells by ADCC and utilized it to demonstrate that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir. IMPORTANCE Mobilization of antibody-dependent cellular cytotoxicity (ADCC) to eliminate reactivated latent HIV-1-infected cells is a strategy which may contribute to depleting the HIV-1 reservoir and achieving a functional HIV-1 cure. To more effectively mobilize ADCC, we designed and constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and SHIV infection in humanized mouse and macaque models, respectively, including in vivo neutralization of an HIV-1 strain resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. Using a novel humanized mouse model, we demonstrated that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir. PMID:28794022

Potent In Vivo NK Cell-Mediated Elimination of HIV-1-Infected Cells Mobilized by a gp120-Bispecific and Hexavalent Broadly Neutralizing Fusion Protein.

PubMed

Bardhi, Ariola; Wu, Yanling; Chen, Weizao; Li, Wei; Zhu, Zhongyu; Zheng, Jian Hua; Wong, Hing; Jeng, Emily; Jones, Jennifer; Ochsenbauer, Christina; Kappes, John C; Dimitrov, Dimiter S; Ying, Tianlei; Goldstein, Harris

2017-10-15

Antibodies bound to human immunodeficiency virus type 1 (HIV-1) envelope protein expressed by infected cells mobilize antibody-dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to a functional HIV-1 cure. The most effective antibodies for controlling and eradicating HIV-1 infection would likely have the dual capacities of potently neutralizing a broad range of HIV-1 isolates and effectively mobilizing HIV-1-specific ADCC to eliminate HIV-1-infected cells. For this purpose, we constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and simian-human immunodeficiency virus (SHIV) infection in humanized mouse and macaque models, respectively, including in vivo neutralization of HIV-1 strains resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. We developed a novel humanized mouse model to evaluate in vivo human NK cell-mediated elimination of HIV-1-infected cells by ADCC and utilized it to demonstrate that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir. IMPORTANCE Mobilization of antibody-dependent cellular cytotoxicity (ADCC) to eliminate reactivated latent HIV-1-infected cells is a strategy which may contribute to depleting the HIV-1 reservoir and achieving a functional HIV-1 cure. To more effectively mobilize ADCC, we designed and constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and SHIV infection in humanized mouse and macaque models, respectively, including in vivo neutralization of an HIV-1 strain resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. Using a novel humanized mouse model, we demonstrated that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir. Copyright © 2017 American Society for Microbiology.

Venus Atmospheric Maneuverable Platform Science Mission

NASA Astrophysics Data System (ADS)

Polidan, Ronald S.; Lee, Gregory; Ross, Floyd; Sokol, Daniel; Bolisay, Linden

2015-11-01

Over the past several years, we have explored a possible new approach to Venus upper atmosphere exploration by applying recent Northrop (non-NASA) development programs and have come up with a new class of exploration vehicle: an atmospheric rover. We will discuss a possible suite of instruments and measurements to study the current climate through detailed characterization of cloud level atmosphere and to understand the processes that control climate on Earth-like planets.Our Venus atmospheric rover concept, the Venus Atmospheric Maneuverable Platform (VAMP), is a hypersonic entry vehicle with an ultra-low ballistic coefficient that transitions to a semi-buoyant air vehicle (AV) after entering the Venus atmosphere. Prior to entry, the AV fully deploys to enable lifting entry and eliminates the need for an aeroshell. The mass savings realized by eliminating the aeroshell allows VAMP to accommodate significantly more instruments compared to previous Venus in situ exploration missions. VAMP targets the global Venus atmosphere between 50-65 km altitudes and would be an ideal, stable platform for atmospheric and surface interaction measurements. We will present a straw man concept of VAMP, including its science instrument accommodation capability and platform’s physical characteristics (mass, power, wingspan, etc). We will discuss the various instrument options.VAMP’s subsonic flight regime starts at ~94 km and after <1 hour, the AV will reach its cruise altitude of ~65 km. During this phase of flight, the VAMP sensor suite will acquire a pre-defined set of upper atmosphere measurements. The nominal VAMP lifetime at cruise altitude is several months to a year, providing numerous circumnavigation cycles of Venus at mid-latitude. The stability of the AV and its extended residence time provide the very long integration times required for isotopic mass analysis. VAMP communicates with the orbiter, which provides data relay and possibly additional science measurements complementing the in situ measurements from the AV. We will specifically focus upon key factors impacting the design and performance of VAMP science.

Cap-independent translation of human SP-A 5′-UTR variants: a double-loop structure and cis-element contribution

PubMed Central

Wang, Guirong; Guo, Xiaoxuan; Silveyra, Patricia; Kimball, Scot R.; Floros, Joanna

2009-01-01

Human surfactant protein A (hSP-A), a molecule of innate immunity and surfactant-related functions, consists of two functional genes, SP-A1 and SP-A2. SP-A expression is regulated by several factors including environmental stressors. SP-A1 and SP-A2 5′-untranslated region (5′-UTR) splice variants have a differential impact on translation efficiency and mRNA stability. To study whether these variants mediate internal ribosome entry site (IRES) activity (i.e., cap-independent translation), we performed transient transfection experiments in H441 cells with constructs containing one SP-A1 (A′D′, AB′D′, or A′CD′) or SP-A2 (ABD) 5′-UTR splice variant between the Renilla and firefly luciferase genes of a bicistronic reporter vector. We found that 1) variants A′D′, ABD, and AB′D′ exhibit significantly higher IRES activities than negative control (no SP-A 5′-UTR) and A′CD′ has no activity; the order of highest IRES activity was ABD > A′D′ > AB′D; 2) IRES activity of ABD significantly increased in response to diesel particulate matter (20 μg/ml) but not in response to ozone (1 ppm for 1 h); 3) deletion mutants of ABD revealed regulatory elements associated with IRES activity; one at the end of exon A attenuated activity, whereas a region containing a short adenosine-rich motif in the second half of exon B and the start of exon D enhanced activity; 4) elimination of a predicted double-loop structure or increase in free energy significantly reduced IRES activity; 5) elimination of one or both double-loop structures in A′D′ did not affect cap-dependent translation activity. Thus several factors, including cis-elements and secondary structure type and stability, are required for hSP-A 5′-UTR variant-mediated cap-independent translation. PMID:19181744

Multifaceted Mechanisms of HIV-1 Entry Inhibition by Human α-Defensin*♦

PubMed Central

Demirkhanyan, Lusine H.; Marin, Mariana; Padilla-Parra, Sergi; Zhan, Changyou; Miyauchi, Kosuke; Jean-Baptiste, Maikha; Novitskiy, Gennadiy; Lu, Wuyuan; Melikyan, Gregory B.

2012-01-01

The human neutrophil peptide 1 (HNP-1) is known to block the human immunodeficiency virus type 1 (HIV-1) infection, but the mechanism of inhibition is poorly understood. We examined the effect of HNP-1 on HIV-1 entry and fusion and found that, surprisingly, this α-defensin inhibited multiple steps of virus entry, including: (i) Env binding to CD4 and coreceptors; (ii) refolding of Env into the final 6-helix bundle structure; and (iii) productive HIV-1 uptake but not internalization of endocytic markers. Despite its lectin-like properties, HNP-1 could bind to Env, CD4, and other host proteins in a glycan- and serum-independent manner, whereas the fusion inhibitory activity was greatly attenuated in the presence of human or bovine serum. This demonstrates that binding of α-defensin to molecules involved in HIV-1 fusion is necessary but not sufficient for blocking the virus entry. We therefore propose that oligomeric forms of defensin, which may be disrupted by serum, contribute to the anti-HIV-1 activity perhaps through cross-linking virus and/or host glycoproteins. This notion is supported by the ability of HNP-1 to reduce the mobile fraction of CD4 and coreceptors in the plasma membrane and to precipitate a core subdomain of Env in solution. The ability of HNP-1 to block HIV-1 uptake without interfering with constitutive endocytosis suggests a novel mechanism for broad activity against this and other viruses that enter cells through endocytic pathways. PMID:22733823

Host Serine/Threonine Kinases mTOR and Protein Kinase C-α Promote InlB-Mediated Entry of Listeria monocytogenes

PubMed Central

Bhalla, Manmeet; Law, Daria; Dowd, Georgina C.

2017-01-01

ABSTRACT The bacterial pathogen Listeria monocytogenes causes foodborne illnesses resulting in gastroenteritis, meningitis, or abortion. Listeria induces its internalization into some human cells through interaction of the bacterial surface protein InlB with the host receptor tyrosine kinase Met. InlB-dependent entry requires localized polymerization of the host actin cytoskeleton. The signal transduction pathways that act downstream of Met to regulate actin filament assembly or other processes during Listeria uptake remain incompletely characterized. Here, we demonstrate important roles for the human serine/threonine kinases mTOR and protein kinase C-α (PKC-α) in InlB-dependent entry. Experiments involving RNA interference (RNAi) indicated that two multiprotein complexes containing mTOR, mTORC1 and mTORC2, are each needed for efficient internalization of Listeria into cells of the human cell line HeLa. InlB stimulated Met-dependent phosphorylation of mTORC1 or mTORC2 substrates, demonstrating activation of both mTOR-containing complexes. RNAi studies indicated that the mTORC1 effectors 4E-BP1 and hypoxia-inducible factor 1α (HIF-1α) and the mTORC2 substrate PKC-α each control Listeria uptake. Genetic or pharmacological inhibition of PKC-α reduced the internalization of Listeria and the accumulation of actin filaments that normally accompanies InlB-mediated entry. Collectively, our results identify mTOR and PKC-α to be host factors exploited by Listeria to promote infection. PKC-α controls Listeria entry, at least in part, by regulating the actin cytoskeleton downstream of the Met receptor. PMID:28461391

Mechanical Barriers Restrict Invasion of Herpes Simplex Virus 1 into Human Oral Mucosa

PubMed Central

Thier, Katharina; Petermann, Philipp; Rahn, Elena; Rothamel, Daniel; Bloch, Wilhelm

2017-01-01

ABSTRACT Oral mucosa is one of the main target tissues of the human pathogen herpes simplex virus 1 (HSV-1). How the virus overcomes the protective epithelial barriers and penetrates the tissue to reach its receptors and initiate infection is still unclear. Here, we established an ex vivo infection assay with human oral mucosa that allows viral entry studies in a natural target tissue. The focus was on the susceptibility of keratinocytes in the epithelium and the characterization of cellular receptors that mediate viral entry. Upon ex vivo infection of gingiva or vestibular mucosa, we observed that intact human mucosa samples were protected from viral invasion. In contrast, the basal layer of the oral epithelium was efficiently invaded once the connective tissue and the basement membrane were removed. Later during infection, HSV-1 spread from basal keratinocytes to upper layers, demonstrating the susceptibility of the stratified squamous epithelium to HSV-1. The analysis of potential receptors revealed nectin-1 on most mucosal keratinocytes, whereas herpesvirus entry mediator (HVEM) was found only on a subpopulation of cells, suggesting that nectin-1 acts as primary receptor for HSV-1 in human oral mucosa. To mimic the supposed entry route of HSV-1 via microlesions in vivo, we mechanically wounded the mucosa prior to infection. While we observed a limited number of infected keratinocytes in some wounded mucosa samples, other samples showed no infected cells. Thus, we conclude that mechanical wounding of mucosa is insufficient for the virus to efficiently overcome epithelial barriers and to make entry-mediating receptors accessible. IMPORTANCE To invade the target tissue of its human host during primary infection, herpes simplex virus (HSV) must overcome the epithelial barriers of mucosa, skin, or cornea. For most viruses, the mechanisms underlying the invasion into the target tissues of their host organism are still open. Here, we established an ex vivo infection model of human oral mucosa to explore how HSV can enter its target tissue. Our results demonstrate that intact mucosa samples and even compromised tissue allow only very limited access of HSV to keratinocytes. Detailed understanding of barrier functions is an essential precondition to unravel how HSV bypasses the barriers and approaches its receptors in tissue and why it is beneficial for the virus to use a cell-cell adhesion molecule, such as nectin-1, as a receptor. PMID:28878080

Mechanical Barriers Restrict Invasion of Herpes Simplex Virus 1 into Human Oral Mucosa.

PubMed

Thier, Katharina; Petermann, Philipp; Rahn, Elena; Rothamel, Daniel; Bloch, Wilhelm; Knebel-Mörsdorf, Dagmar

2017-11-15

Oral mucosa is one of the main target tissues of the human pathogen herpes simplex virus 1 (HSV-1). How the virus overcomes the protective epithelial barriers and penetrates the tissue to reach its receptors and initiate infection is still unclear. Here, we established an ex vivo infection assay with human oral mucosa that allows viral entry studies in a natural target tissue. The focus was on the susceptibility of keratinocytes in the epithelium and the characterization of cellular receptors that mediate viral entry. Upon ex vivo infection of gingiva or vestibular mucosa, we observed that intact human mucosa samples were protected from viral invasion. In contrast, the basal layer of the oral epithelium was efficiently invaded once the connective tissue and the basement membrane were removed. Later during infection, HSV-1 spread from basal keratinocytes to upper layers, demonstrating the susceptibility of the stratified squamous epithelium to HSV-1. The analysis of potential receptors revealed nectin-1 on most mucosal keratinocytes, whereas herpesvirus entry mediator (HVEM) was found only on a subpopulation of cells, suggesting that nectin-1 acts as primary receptor for HSV-1 in human oral mucosa. To mimic the supposed entry route of HSV-1 via microlesions in vivo , we mechanically wounded the mucosa prior to infection. While we observed a limited number of infected keratinocytes in some wounded mucosa samples, other samples showed no infected cells. Thus, we conclude that mechanical wounding of mucosa is insufficient for the virus to efficiently overcome epithelial barriers and to make entry-mediating receptors accessible. IMPORTANCE To invade the target tissue of its human host during primary infection, herpes simplex virus (HSV) must overcome the epithelial barriers of mucosa, skin, or cornea. For most viruses, the mechanisms underlying the invasion into the target tissues of their host organism are still open. Here, we established an ex vivo infection model of human oral mucosa to explore how HSV can enter its target tissue. Our results demonstrate that intact mucosa samples and even compromised tissue allow only very limited access of HSV to keratinocytes. Detailed understanding of barrier functions is an essential precondition to unravel how HSV bypasses the barriers and approaches its receptors in tissue and why it is beneficial for the virus to use a cell-cell adhesion molecule, such as nectin-1, as a receptor. Copyright © 2017 American Society for Microbiology.

[Survival Strategies of Aspergillus in the Human Body].

PubMed

Tashiro, Masato; Izumikawa, Koichi

2017-01-01

 The human body is a hostile environment for Aspergillus species, which originally live outside the human body. There are lots of elimination mechanisms against Aspergillus inhaled into the human body, such as high body temperature, soluble lung components, mucociliary clearance mechanism, or responses of phagocytes. Aspergillus fumigatus, which is the primary causative agent of human infections among the human pathogenic species of Aspergillus, defend itself from the hostile human body environment by various mechanisms, such as thermotolerance, mycotoxin production, and characteristic morphological features. Here we review mechanisms of defense in Aspergillus against elimination from the human body.

Inhibition of Dengue Virus Entry into Target Cells Using Synthetic Antiviral Peptides

PubMed Central

Alhoot, Mohammed Abdelfatah; Rathinam, Alwin Kumar; Wang, Seok Mui; Manikam, Rishya; Sekaran, Shamala Devi

2013-01-01

Despite the importance of DENV as a human pathogen, there is no specific treatment or protective vaccine. Successful entry into the host cells is necessary for establishing the infection. Recently, the virus entry step has become an attractive therapeutic strategy because it represents a barrier to suppress the onset of the infection. Four putative antiviral peptides were designed to target domain III of DENV-2 E protein using BioMoDroid algorithm. Two peptides showed significant inhibition of DENV when simultaneously incubated as shown by plaque formation assay, RT-qPCR, and Western blot analysis. Both DET4 and DET2 showed significant inhibition of virus entry (84.6% and 40.6% respectively) using micromolar concentrations. Furthermore, the TEM images showed that the inhibitory peptides caused structural abnormalities and alteration of the arrangement of the viral E protein, which interferes with virus binding and entry. Inhibition of DENV entry during the initial stages of infection can potentially reduce the viremia in infected humans resulting in prevention of the progression of dengue fever to the severe life-threatening infection, reduce the infected vector numbers, and thus break the transmission cycle. Moreover these peptides though designed against the conserved region in DENV-2 would have the potential to be active against all the serotypes of dengue and might be considered as Hits to begin designing and developing of more potent analogous peptides that could constitute as promising therapeutic agents for attenuating dengue infection. PMID:23630436

Human cooperation by lethal group competition

PubMed Central

Egas, Martijn; Kats, Ralph; van der Sar, Xander; Reuben, Ernesto; Sabelis, Maurice W.

2013-01-01

Why humans are prone to cooperate puzzles biologists, psychologists and economists alike. Between-group conflict has been hypothesized to drive within-group cooperation. However, such conflicts did not have lasting effects in laboratory experiments, because they were about luxury goods, not needed for survival (“looting”). Here, we find within-group cooperation to last when between-group conflict is implemented as “all-out war” (eliminating the weakest groups). Human subjects invested in helping group members to avoid having the lowest collective pay-off, whereas they failed to cooperate in control treatments with random group elimination or with no subdivision in groups. When the game was repeated, experience was found to promote helping. Thus, not within-group interactions alone, not random group elimination, but pay-off-dependent group elimination was found to drive within-group cooperation in our experiment. We suggest that some forms of human cooperation are maintained by multi-level selection: reciprocity within groups and lethal competition among groups acting together. PMID:23459158

Interviews as a Selection Tool for Entry-Level Hospitality Employees.

ERIC Educational Resources Information Center

Martin, Lynda

2002-01-01

Responses from human resource professionals in restaurants (n=85) and hotels (n=118) identified critical entry-level job behaviors that might be used in developing behavior-based interviews. The large variety of responses and lack of agreement suggest that clear identification of these behaviors may be an area of weakness in the hospitality…

A Survey of Supersonic Retropropulsion Technology for Mars Entry, Descent, and Landing

NASA Technical Reports Server (NTRS)

Korzun, Ashley M.; Cruz, Juan R.; Braun, Robert D.

2007-01-01

This paper presents a literature survey on supersonic retropropulsion technology as it applies to Mars entry, descent, and landing (EDL). The relevance of this technology to the feasibility of Mars EDL is shown to increase with ballistic coefficient to the point that it is likely required for human Mars exploration. The use of retropropulsion to decelerate an entry vehicle from hypersonic or supersonic conditions to a subsonic velocity is the primary focus of this review. Discussed are systems-level studies, general flowfield characteristics, static aerodynamics, vehicle and flowfield stability considerations, and aerothermodynamics. The experimental and computational approaches used to develop retropropulsion technology are also reviewed. Finally, the applicability and limitations of the existing literature and current state-of-the-art computational tools to future missions are discussed in the context of human and robotic Mars exploration.

Hood entry coefficients of compound exhaust hoods.

PubMed

Figueroa, Crescente E

2011-12-01

A traditional method for assessing the flow rate in ventilation systems is based on multiple readings of velocity or velocity pressure (VP) (usually 10 or 20 points) taken in ductwork sections located away from fittings (> seven × diameters of straight duct). This study seeks to eliminate the need for a multiple-point evaluation and replace it with a simplified method that requires only a single measurement of hood static pressure (SP(h)) taken at a more accessible location (< three × diameters of straight duct from the hood entry). The SP(h) method is widely used for the assessment of flow rate in simple hoods. However, industrial applications quite often use compound hoods that are regularly of the slot/plenum type. For these hoods, a "compound coefficient of entry" has not been published, which makes the use of the hood static pressure method unfeasible. This study proposes a model for the computation of a "compound coefficient of entry" and validates the use of this model to assess flow rate in two systems of well-defined geometry (multi-slotted/plenum and single-slotted/tapered or "fish-tail" types). When using a conservative value of the slot loss factor (1.78), the proposed model yielded an estimate of the volumetric flow rate within 10% of that provided by a more comprehensive method of assessment. The simplicity of the hood static pressure method makes it very desirable, even in the upper range of experimental error found in this study.

Lifting Entry & Atmospheric Flight (LEAF) System Concept Applications at Solar System Bodies With an Atmosphere

NASA Astrophysics Data System (ADS)

Lee, Greg; Polidan, Ronald; Ross, Floyd; Sokol, Daniel; Warwick, Steve

2015-11-01

Northrop Grumman and L’Garde have continued the development of a hypersonic entry, semi-buoyant, maneuverable platform capable of performing long-duration (months to a year) in situ and remote measurements at any solar system body that possesses an atmosphere.The Lifting Entry & Atmospheric Flight (LEAF) family of vehicles achieves this capability by using a semi-buoyant, ultra-low ballistic coefficient vehicle whose lifting entry allows it to enter the atmosphere without an aeroshell. The mass savings realized by eliminating the heavy aeroshell allows significantly more payload to be accommodated by the platform for additional science collection and return.In this presentation, we discuss the application of the LEAF system at various solar system bodies: Venus, Titan, Mars, and Earth. We present the key differences in platform design as well as operational differences required by the various target environments. The Venus implementation includes propulsive capability to reach higher altitudes during the day and achieves full buoyancy in the mid-cloud layer of Venus’ atmosphere at night.Titan also offers an attractive operating environment, allowing LEAF designs that can target low or medium altitude operations, also with propulsive capabilities to roam within each altitude regime. The Mars version is a glider that descends gradually, allowing targeted delivery of payloads to the surface or high resolution surface imaging. Finally, an Earth version could remain in orbit in a stowed state until activated, allowing rapid response type deployments to any region of the globe.

Linear model analysis of the influencing factors of boar longevity in Southern China.

PubMed

Wang, Chao; Li, Jia-Lian; Wei, Hong-Kui; Zhou, Yuan-Fei; Jiang, Si-Wen; Peng, Jian

2017-04-15

This study aimed to investigate the factors influencing the boar herd life month (BHLM) in Southern China. A total of 1630 records of culling boars from nine artificial insemination centers were collected from January 2013 to May 2016. A logistic regression model and two linear models were used to analyze the effects of breed, housing type, age at herd entry, and seed stock herd on boar removal reason and BHLM, respectively. Boar breed and the age at herd entry had significant effects on the removal reasons (P < 0.001). Results of the two linear models (with or without removal reason including) showed boars raised individually in stalls exhibited shorter BHLM than those raised in pens (P < 0.001). Boars aged 5 and 6 months at herd entry (44.6%) showed shorter BHLM than those aged 8 and 9 months at herd entry (P < 0.05). Approximately 95% boars were culled for different reasons other than old age, and the BHLM of these boars was at least 12.3 months longer than that of boars culled for other reasons (P < 0.001). In conclusion, abnormal elimination in boars is serious and it had a negative effect on boar BHLM. Boar removal reason and BHLM can be affected by breed, housing type, and seed stock herd. Importantly, 8 months is suggested as the most suitable age for boar introduction. Copyright © 2017. Published by Elsevier Inc.

Facilitating treatment entry among out-of-treatment injection drug users.

PubMed Central

Booth, R E; Kwiatkowski, C; Iguchi, M Y; Pinto, F; John, D

1998-01-01

OBJECTIVE: High risk injection practices are common among injecting drug users (IDUs), even following intervention efforts. Moreover, relapse to risk behaviors has been reported among those who initiate risk reduction. Substance abuse treatment offers the potential to reduce or eliminate injecting risk behaviors through drug cessation. We report on the effectiveness of two intervention strategies in facilitating treatment entry among out-of-treatment IDUs: motivational interviewing (MI), and intervention developed to help individuals resolve their ambivalence about behavior change, and free treatment for 90 days. These conditions were compared with an intervention focusing on a hierarchy of safer injecting practice, referred to here as risk reduction (RR), and no free treatment. METHODS: Nearly 200 out-of-treatment IDUs were randomly assigned to one of four experimental conditions: MI/free treatment, MI/no free treatment, RR/free treatment, and RR/no free treatment. Regardless of assignment, we assisted anyone desiring treatment by calling to schedule the appointment, providing transportation, and waiving the intake fee. RESULTS: Overall, 42% of study participants entered treatment. No significant differences were found between MI and RR; however, 52% of those assigned free treatment entered compare with 32% for those who had to pay. Other predictors of treatment entry included prior treatment experiences, perceived chance of contracting acquired immunodeficiency syndrome (AIDS) greater than 50%, "determination" stage of change, greater frequency of heroin injecting, and fewer drug-using friends. CONCLUSIONS: These findings support the importance of removing barriers to treatment entry. PMID:9722817

Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening.

PubMed

Weisshaar, Marco; Cox, Robert; Morehouse, Zachary; Kumar Kyasa, Shiva; Yan, Dan; Oberacker, Phil; Mao, Shuli; Golden, Jennifer E; Lowen, Anice C; Natchus, Michael G; Plemper, Richard K

2016-08-15

Influenza A virus (IAV) infections cause major morbidity and mortality, generating an urgent need for novel antiviral therapeutics. We recently established a dual myxovirus high-throughput screening protocol that combines a fully replication-competent IAV-WSN strain and a respiratory syncytial virus reporter strain for the simultaneous identification of IAV-specific, paramyxovirus-specific, and broad-spectrum inhibitors. In the present study, this protocol was applied to a screening campaign to assess a diverse chemical library with over 142,000 entries. Focusing on IAV-specific hits, we obtained a hit rate of 0.03% after cytotoxicity testing and counterscreening. Three chemically distinct hit classes with nanomolar potency and favorable cytotoxicity profiles were selected. Time-of-addition, minigenome, and viral entry studies demonstrated that these classes block hemagglutinin (HA)-mediated membrane fusion. Antiviral activity extends to an isolate from the 2009 pandemic and, in one case, another group 1 subtype. Target identification through biolayer interferometry confirmed binding of all hit compounds to HA. Resistance profiling revealed two distinct escape mechanisms: primary resistance, associated with reduced compound binding, and secondary resistance, associated with unaltered binding. Secondary resistance was mediated, unusually, through two different pairs of cooperative mutations, each combining a mutation eliminating the membrane-proximal stalk N-glycan with a membrane-distal change in HA1 or HA2. Chemical synthesis of an analog library combined with in silico docking extracted a docking pose for the hit classes. Chemical interrogation spotlights IAV HA as a major druggable target for small-molecule inhibition. Our study identifies novel chemical scaffolds with high developmental potential, outlines diverse routes of IAV escape from entry inhibition, and establishes a path toward structure-aided lead development. This study is one of the first to apply a fully replication-competent third-generation IAV reporter strain to a large-scale high-throughput screen (HTS) drug discovery campaign, allowing multicycle infection and screening in physiologically relevant human respiratory cells. A large number of potential druggable targets was thus chemically interrogated, but mechanistic characterization, positive target identification, and resistance profiling demonstrated that three chemically promising and structurally distinct hit classes selected for further analysis all block HA-mediated membrane fusion. Viral escape from inhibition could be achieved through primary and secondary resistance mechanisms. In silico docking predicted compound binding to a microdomain located at the membrane-distal site of the prefusion HA stalk that was also previously suggested as a target site for chemically unrelated HA inhibitors. This study identifies an unexpected chemodominance of the HA stalk microdomain for small-molecule inhibitors in IAV inhibitor screening campaigns and highlights a novel mechanism of cooperative resistance to IAV entry blockers. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening

PubMed Central

Weisshaar, Marco; Cox, Robert; Morehouse, Zachary; Kumar Kyasa, Shiva; Yan, Dan; Oberacker, Phil; Mao, Shuli; Lowen, Anice C.; Natchus, Michael G.

2016-01-01

ABSTRACT Influenza A virus (IAV) infections cause major morbidity and mortality, generating an urgent need for novel antiviral therapeutics. We recently established a dual myxovirus high-throughput screening protocol that combines a fully replication-competent IAV-WSN strain and a respiratory syncytial virus reporter strain for the simultaneous identification of IAV-specific, paramyxovirus-specific, and broad-spectrum inhibitors. In the present study, this protocol was applied to a screening campaign to assess a diverse chemical library with over 142,000 entries. Focusing on IAV-specific hits, we obtained a hit rate of 0.03% after cytotoxicity testing and counterscreening. Three chemically distinct hit classes with nanomolar potency and favorable cytotoxicity profiles were selected. Time-of-addition, minigenome, and viral entry studies demonstrated that these classes block hemagglutinin (HA)-mediated membrane fusion. Antiviral activity extends to an isolate from the 2009 pandemic and, in one case, another group 1 subtype. Target identification through biolayer interferometry confirmed binding of all hit compounds to HA. Resistance profiling revealed two distinct escape mechanisms: primary resistance, associated with reduced compound binding, and secondary resistance, associated with unaltered binding. Secondary resistance was mediated, unusually, through two different pairs of cooperative mutations, each combining a mutation eliminating the membrane-proximal stalk N-glycan with a membrane-distal change in HA1 or HA2. Chemical synthesis of an analog library combined with in silico docking extracted a docking pose for the hit classes. Chemical interrogation spotlights IAV HA as a major druggable target for small-molecule inhibition. Our study identifies novel chemical scaffolds with high developmental potential, outlines diverse routes of IAV escape from entry inhibition, and establishes a path toward structure-aided lead development. IMPORTANCE This study is one of the first to apply a fully replication-competent third-generation IAV reporter strain to a large-scale high-throughput screen (HTS) drug discovery campaign, allowing multicycle infection and screening in physiologically relevant human respiratory cells. A large number of potential druggable targets was thus chemically interrogated, but mechanistic characterization, positive target identification, and resistance profiling demonstrated that three chemically promising and structurally distinct hit classes selected for further analysis all block HA-mediated membrane fusion. Viral escape from inhibition could be achieved through primary and secondary resistance mechanisms. In silico docking predicted compound binding to a microdomain located at the membrane-distal site of the prefusion HA stalk that was also previously suggested as a target site for chemically unrelated HA inhibitors. This study identifies an unexpected chemodominance of the HA stalk microdomain for small-molecule inhibitors in IAV inhibitor screening campaigns and highlights a novel mechanism of cooperative resistance to IAV entry blockers. PMID:27252534

Human La binds mRNAs through contacts to the poly(A) tail.

PubMed

Vinayak, Jyotsna; Marrella, Stefano A; Hussain, Rawaa H; Rozenfeld, Leonid; Solomon, Karine; Bayfield, Mark A

2018-05-04

In addition to a role in the processing of nascent RNA polymerase III transcripts, La proteins are also associated with promoting cap-independent translation from the internal ribosome entry sites of numerous cellular and viral coding RNAs. La binding to RNA polymerase III transcripts via their common UUU-3'OH motif is well characterized, but the mechanism of La binding to coding RNAs is poorly understood. Using electromobility shift assays and cross-linking immunoprecipitation, we show that in addition to a sequence specific UUU-3'OH binding mode, human La exhibits a sequence specific and length dependent poly(A) binding mode. We demonstrate that this poly(A) binding mode uses the canonical nucleic acid interaction winged helix face of the eponymous La motif, previously shown to be vacant during uridylate binding. We also show that cytoplasmic, but not nuclear La, engages poly(A) RNA in human cells, that La entry into polysomes utilizes the poly(A) binding mode, and that La promotion of translation from the cyclin D1 internal ribosome entry site occurs in competition with cytoplasmic poly(A) binding protein (PABP). Our data are consistent with human La functioning in translation through contacts to the poly(A) tail.

Parents' Support for School-Entry Requirements for Human Papillomavirus Vaccination: A National Study.

PubMed

Calo, William A; Gilkey, Melissa B; Shah, Parth D; Moss, Jennifer L; Brewer, Noel T

2016-09-01

The number of states proposing school-entry requirements for human papillomavirus (HPV) vaccination has increased over the last decade. However, data are currently limited regarding parents' support of such laws. We sought to obtain the first national estimates of parents' support of HPV vaccination school-entry requirements. A national sample of 1,501 parents of 11- to 17-year-old children completed a web-based survey between November 2014 and January 2015. Analyses used multivariable logistic regression to assess correlates of support for school-entry requirements for HPV vaccination. Overall, 21% of parents agreed that laws requiring HPV vaccination for school attendance "are a good idea," and 54% disagreed. If school-entry requirements included opt-out provisions, agreement increased to 57%, and only 21% disagreed. Parents more often agreed with requirements without opt-out provisions if they were Hispanic [OR = 1.53; 95% confidence interval (CI), 1.05-2.22], believed HPV vaccine was as or more important than other adolescent vaccines (OR = 2.76; 95% CI, 1.98-3.83), or believed HPV vaccine was effective for preventing cervical cancer (OR = 2.55; 95% CI, 1.93-3.37). Parents less often agreed if they resided in Midwest states or believed that HPV vaccine was being pushed to make money for drug companies (both P < 0.05). Opt-out provisions almost tripled parents' support for HPV vaccine school-entry requirements. Our findings suggest that race/ethnicity, attitudes about HPV vaccine, and region of residence may influence support for requirements without opt-out provisions. Opt-out provisions greatly increase parent support of school-entry requirements for HPV vaccination but may make them ineffective. Cancer Epidemiol Biomarkers Prev; 25(9); 1317-25. ©2016 AACR. ©2016 American Association for Cancer Research.

Parents’ Support for School-Entry Requirements for Human Papillomavirus Vaccination: A National Study

PubMed Central

Calo, William A.; Gilkey, Melissa B.; Shah, Parth D.; Moss, Jennifer L.; Brewer, Noel T.

2016-01-01

Background The number of states proposing school-entry requirements for human papillomavirus (HPV) vaccination has increased over the last decade. However, data are currently limited regarding parents' support of such laws. We sought to obtain the first national estimates of parents' support of HPV vaccination school-entry requirements. Methods A national sample of 1501 parents of 11- to 17-year-old children completed a web-based survey between November 2014 and January 2015. Analyses used multivariable logistic regression to assess correlates of support for school-entry requirements for HPV vaccination. Results Overall, 21% of parents agreed that laws requiring HPV vaccination for school attendance "are a good idea," and 54% disagreed. If school-entry requirements included opt-out provisions, agreement increased to 57%, and only 21% disagreed. Parents more often agreed with requirements without opt-out provisions if they were Hispanic (OR=1.53, 95% CI: 1.05–2.22), believed HPV vaccine was as or more important than other adolescent vaccines (OR=2.76, 95% CI: 1.98–3.83), or believed HPV vaccine was effective for preventing cervical cancer (OR=2.55, 95% CI: 1.93–3.37). Parents less often agreed if they resided in Midwest states or believed that HPV vaccine was being pushed to make money for drug companies (both p<.05). Conclusion Opt-out provisions almost tripled parents' support for HPV vaccine school-entry requirements. Our findings suggest that race/ethnicity, attitudes about HPV vaccine, and region of residence may influence support for requirements without opt-out provisions. Impact Opt-out provisions greatly increase parent support of school-entry requirements for HPV vaccination but may make them ineffective. PMID:27543621

Multi-modal assessment of on-road demand of voice and manual phone calling and voice navigation entry across two embedded vehicle systems.

PubMed

Mehler, Bruce; Kidd, David; Reimer, Bryan; Reagan, Ian; Dobres, Jonathan; McCartt, Anne

2016-03-01

One purpose of integrating voice interfaces into embedded vehicle systems is to reduce drivers' visual and manual distractions with 'infotainment' technologies. However, there is scant research on actual benefits in production vehicles or how different interface designs affect attentional demands. Driving performance, visual engagement, and indices of workload (heart rate, skin conductance, subjective ratings) were assessed in 80 drivers randomly assigned to drive a 2013 Chevrolet Equinox or Volvo XC60. The Chevrolet MyLink system allowed completing tasks with one voice command, while the Volvo Sensus required multiple commands to navigate the menu structure. When calling a phone contact, both voice systems reduced visual demand relative to the visual-manual interfaces, with reductions for drivers in the Equinox being greater. The Equinox 'one-shot' voice command showed advantages during contact calling but had significantly higher error rates than Sensus during destination address entry. For both secondary tasks, neither voice interface entirely eliminated visual demand. Practitioner Summary: The findings reinforce the observation that most, if not all, automotive auditory-vocal interfaces are multi-modal interfaces in which the full range of potential demands (auditory, vocal, visual, manipulative, cognitive, tactile, etc.) need to be considered in developing optimal implementations and evaluating drivers' interaction with the systems. Social Media: In-vehicle voice-interfaces can reduce visual demand but do not eliminate it and all types of demand need to be taken into account in a comprehensive evaluation.

Descriptive analysis and spatial epidemiology of porcine reproductive and respiratory syndrome (PRRS) for swine sites participating in area regional control and elimination programs from 3 regions of Ontario

PubMed Central

Arruda, Andreia G.; Poljak, Zvonimir; Friendship, Robert; Carpenter, Jane; Hand, Karen

2015-01-01

The objectives of this study were to describe demographics, basic biosecurity practices, ownership structure, and prevalence of porcine reproductive and respiratory syndrome (PRRS) in swine sites located in 3 regions in Ontario, and investigate the presence of spatial clustering and clusters of PRRS positive sites in the 3 regions. A total of 370 swine sites were enrolled in Area Regional Control and Elimination projects in Niagara, Watford, and Perth from 2010 to 2013. Demographics, biosecurity, and site ownership data were collected using a standardized questionnaire and site locations were obtained from an industry organization. Status was assigned on the basis of available diagnostic tests and/or assessment by site veterinarians. Spatial dependence was investigated using the D-function, the spatial scan statistic test and the spatial relative risk method. Results showed that the use of strict all-in all-out (AIAO) pig flow and shower before entry are uncommon biosecurity practices in swine sites, but a larger proportion of sites reported having a Danish entry. The prevalence of PRRS in the 3 regions ranged from 17% to 48% and localized high and low risk clusters were detected. Sites enrolled in the PRRS control projects were characterized by membership in multiple and overlapping ownership structures and networks, which complicates the way the results of monitoring and disease management measures are communicated to the target population. PMID:26424906

Multi-modal assessment of on-road demand of voice and manual phone calling and voice navigation entry across two embedded vehicle systems

PubMed Central

Mehler, Bruce; Kidd, David; Reimer, Bryan; Reagan, Ian; Dobres, Jonathan; McCartt, Anne

2016-01-01

Abstract One purpose of integrating voice interfaces into embedded vehicle systems is to reduce drivers’ visual and manual distractions with ‘infotainment’ technologies. However, there is scant research on actual benefits in production vehicles or how different interface designs affect attentional demands. Driving performance, visual engagement, and indices of workload (heart rate, skin conductance, subjective ratings) were assessed in 80 drivers randomly assigned to drive a 2013 Chevrolet Equinox or Volvo XC60. The Chevrolet MyLink system allowed completing tasks with one voice command, while the Volvo Sensus required multiple commands to navigate the menu structure. When calling a phone contact, both voice systems reduced visual demand relative to the visual–manual interfaces, with reductions for drivers in the Equinox being greater. The Equinox ‘one-shot’ voice command showed advantages during contact calling but had significantly higher error rates than Sensus during destination address entry. For both secondary tasks, neither voice interface entirely eliminated visual demand. Practitioner Summary: The findings reinforce the observation that most, if not all, automotive auditory–vocal interfaces are multi-modal interfaces in which the full range of potential demands (auditory, vocal, visual, manipulative, cognitive, tactile, etc.) need to be considered in developing optimal implementations and evaluating drivers’ interaction with the systems. Social Media: In-vehicle voice-interfaces can reduce visual demand but do not eliminate it and all types of demand need to be taken into account in a comprehensive evaluation. PMID:26269281

Overview of entry risk predictions

NASA Astrophysics Data System (ADS)

Mrozinski, R.; Mendeck, G.; Cutri-Kohart, R.

Risk to people on the ground from uncontrolled entries of spacecraft is a primary concern when analyzing end-of-life disposal options for satellites. Countries must balance this risk with the need to mitigate an exponentially growing space debris population. Currently the United States does this via guidelines that call for a satellite to be disposed of in a controlled manner if an uncontrolled entry would be too risky to people on the ground. This risk is measured by a quantity called "casualty expectation", or E , where casualty expectation is defined as the expectedc number of people suffering death or injury due to a spacecraft entry event. If Ec exceeds 1 in 10,000, U. S. guidelines state that the entry should be controlled rather than uncontrolled. Since this guideline can have serious impacts on the cost, lifetime, and even the mission and functionality of a satellite, it is critical that this quantity be estimated well, and decision makers understand all assumptions and limitations inherent in the resulting value. This paper discusses several issues regarding estimates of casualty expectation, beginning with an overview of relevant United States policies and guidelines. The equation the space industry typically uses to estimate casualty expectation is presented, along with a look at the sensitivity of the results to the typical assumptions, models, and initial condition uncertainties. Differences in these modeling issues with respect to launch failure Ec estimates are included in the discussion. An alternate quantity to assess risks due to spacecraft entries is introduced. "Probability of casualty", or Pc , is defined as the probability of one or more instances of people suffering death or injury due to a spacecraft entry event. The equation to estimate Pc is derived, where the same assumptions, modeling, and initial condition issues for Ec apply. Several examples are then given of both Ec and Pc estimate calculations. Due to the difficult issues in estimating both Ec and Pc, it is argued that "true" absolute quantities can never be computed. However, E and Pc are ideal for relativec analyses against a standard tool that eliminates these issues. Such a tool is recommended for assessing compliance with requirements of regulating institutions.

76 FR 76956 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-09

... location: Delete entry and replace with ``Human Resources Directorate, Labor and Management Employee...: Reasonable Accommodation Program Records. System location: Human Resources Directorate, Labor and Management..., Labor and Management Employee Relations Division, Human Resources Directorate, Washington Headquarters...

Rapid Nipah virus entry into the central nervous system of hamsters via the olfactory route

PubMed Central

Munster, Vincent J.; Prescott, Joseph B.; Bushmaker, Trenton; Long, Dan; Rosenke, Rebecca; Thomas, Tina; Scott, Dana; Fischer, Elizabeth R.; Feldmann, Heinz; de Wit, Emmie

2012-01-01

Encephalitis is a hallmark of Nipah virus (NiV) infection in humans. The exact route of entry of NiV into the central nervous system (CNS) is unknown. Here, we performed a spatio-temporal analysis of NiV entry into the CNS of hamsters. NiV initially predominantly targeted the olfactory epithelium in the nasal turbinates. From there, NiV infected neurons were visible extending through the cribriform plate into the olfactory bulb, providing direct evidence of rapid CNS entry. Subsequently, NiV disseminated to the olfactory tubercle and throughout the ventral cortex. Transmission electron microscopy on brain tissue showed extravasation of plasma cells, neuronal degeneration and nucleocapsid inclusions in affected tissue and axons, providing further evidence for axonal transport of NiV. NiV entry into the CNS coincided with the occurrence of respiratory disease, suggesting that the initial entry of NiV into the CNS occurs simultaneously with, rather than as a result of, systemic virus replication. PMID:23071900

The Secret of Guided Missile Re-Entry,

DTIC Science & Technology

1986-06-25

I RD-PAI169 598 THE SECRET OF GUIDED MISSILE RE-ENTRY(U) FOREIGN / I TECHNOLOGY DIV NRIGHT-PATTERSON RFB OH J CHEN ET AL. I 25 JUN 96 FTD-ID(RS)T...TECHNOLOGY DIVISION THE SECRET OF GUIDED MISSILE RE-ENTRY by Chen Jingzhong, An Sehua J L 0 7 ’:;85’ ’ 0 *Approved for public release; Distribution...unlimite t d. :. 86 7 034.. FTD- ID(RS)T-0459-86 HUMAN TRANSLATION FTD-ID(RS)T-0459-86 25 June 1986 MICROFICHE NR: F - - 0Q 9? THE SECRET OF GUIDED

Addictions and the criminal justice system, what happens on the other side? Post-traumatic stress symptoms and cortisol measures in a police cohort.

PubMed

Austin-Ketch, Tammy L; Violanti, John; Fekedulegn, Desta; Andrew, Michael E; Burchfield, Cecil M; Hartley, Tara A

2012-02-01

The Buffalo Cardio-metabolic Occupational Police Stress study, an occupational cohort study of police officers, was conducted to evaluate physiologic and stress measures in a high-risk occupation where occupational exposure to difficult criminal situations can lead to physiologic and psychological health consequences among those who enforce the law. The chronic exposure to human tragedy may place police officers at special risk for mental health disorders and the potential for misuse of alcohol or drugs. While exact etiologies of post-traumatic stress were not determined by this study, overall post-traumatic stress (PTS) prevalence rates among the police officers was 35%, with 10% of individuals demonstrating severe PTS symptomatology. Waking cortisol measures tended to be higher among officers with more PTS symptomatology, with some gender related differences noted. Given the increase in incarcerations for addictions related offenses over the past 20 years and the chronic exposure to human suffering and tragedy, early recognition of PTS symptoms is essential in making the diagnosis of post-traumatic stress in high-risk occupational cohorts. Providing early entry into treatment and subsequently attempting to eliminate or minimize long-term consequences of post-traumatic stress can have a significant impact on the prevention of long term sequelae of chronic stress, such as the use or misuse of drugs or alcohol.

Entry of Human Papillomavirus Type 16 by Actin-Dependent, Clathrin- and Lipid Raft-Independent Endocytosis

PubMed Central

Schelhaas, Mario; Shah, Bhavin; Holzer, Michael; Blattmann, Peter; Kühling, Lena; Day, Patricia M.; Schiller, John T.; Helenius, Ari

2012-01-01

Infectious endocytosis of incoming human papillomavirus type 16 (HPV-16), the main etiological agent of cervical cancer, is poorly characterized in terms of cellular requirements and pathways. Conflicting reports attribute HPV-16 entry to clathrin-dependent and -independent mechanisms. To comprehensively describe the cell biological features of HPV-16 entry into human epithelial cells, we compared HPV-16 pseudovirion (PsV) infection in the context of cell perturbations (drug inhibition, siRNA silencing, overexpression of dominant mutants) to five other viruses (influenza A virus, Semliki Forest virus, simian virus 40, vesicular stomatitis virus, and vaccinia virus) with defined endocytic requirements. Our analysis included infection data, i.e. GFP expression after plasmid delivery by HPV-16 PsV, and endocytosis assays in combination with electron, immunofluorescence, and video microscopy. The results indicated that HPV-16 entry into HeLa and HaCaT cells was clathrin-, caveolin-, cholesterol- and dynamin-independent. The virus made use of a potentially novel ligand-induced endocytic pathway related to macropinocytosis. This pathway was distinct from classical macropinocytosis in regards to vesicle size, cholesterol-sensitivity, and GTPase requirements, but similar in respect to the need for tyrosine kinase signaling, actin dynamics, Na+/H+ exchangers, PAK-1 and PKC. After internalization the virus was transported to late endosomes and/or endolysosomes, and activated through exposure to low pH. PMID:22536154

Cloud Computing with iPlant Atmosphere.

PubMed

McKay, Sheldon J; Skidmore, Edwin J; LaRose, Christopher J; Mercer, Andre W; Noutsos, Christos

2013-10-15

Cloud Computing refers to distributed computing platforms that use virtualization software to provide easy access to physical computing infrastructure and data storage, typically administered through a Web interface. Cloud-based computing provides access to powerful servers, with specific software and virtual hardware configurations, while eliminating the initial capital cost of expensive computers and reducing the ongoing operating costs of system administration, maintenance contracts, power consumption, and cooling. This eliminates a significant barrier to entry into bioinformatics and high-performance computing for many researchers. This is especially true of free or modestly priced cloud computing services. The iPlant Collaborative offers a free cloud computing service, Atmosphere, which allows users to easily create and use instances on virtual servers preconfigured for their analytical needs. Atmosphere is a self-service, on-demand platform for scientific computing. This unit demonstrates how to set up, access and use cloud computing in Atmosphere. Copyright © 2013 John Wiley & Sons, Inc.

Towards the endgame and beyond: complexities and challenges for the elimination of infectious diseases

PubMed Central

Klepac, Petra; Metcalf, C. Jessica E.; McLean, Angela R.; Hampson, Katie

2013-01-01

Successful control measures have interrupted the local transmission of human infectious diseases such as measles, malaria and polio, and saved and improved billions of lives. Similarly, control efforts have massively reduced the incidence of many infectious diseases of animals, such as rabies and rinderpest, with positive benefits for human health and livelihoods across the globe. However, disease elimination has proven an elusive goal, with only one human and one animal pathogen globally eradicated. As elimination targets expand to regional and even global levels, hurdles may emerge within the endgame when infections are circulating at very low levels, turning the last mile of these public health marathons into the longest mile. In this theme issue, we bring together recurring challenges that emerge as we move towards elimination, highlighting the unanticipated consequences of particular ecologies and pathologies of infection, and approaches to their management. PMID:23798686

The Road to Dog Rabies Control and Elimination—What Keeps Us from Moving Faster?

PubMed Central

Fahrion, Anna S.; Taylor, Louise H.; Torres, Gregorio; Müller, Thomas; Dürr, Salome; Knopf, Lea; de Balogh, Katinka; Nel, Louis H.; Gordoncillo, Mary Joy; Abela-Ridder, Bernadette

2017-01-01

Rabies, a vaccine preventable neglected tropical disease, still claims an estimated 35,000–60,000 human lives annually. The international community, with more than 100 endemic countries, has set a global target of 0 human deaths from dog-transmitted rabies by 2030. While it has been proven in several countries and regions that elimination of rabies as a public health problem is feasible and tools are available, rabies deaths globally have not yet been prevented effectively. While there has been extensive rabies research, specific areas of implementation for control and elimination have not been sufficiently addressed. This article highlights some of the commonest perceived barriers for countries to implementing rabies control and elimination programs and discusses possible solutions for sociopolitical, organizational, technical, and resource-linked requirements, following the pillars of the global framework for the elimination of dog-mediated human rabies adopted at the global rabies meeting in December 2015. PMID:28555183

Do Cryptic Reservoirs Threaten Gambiense-Sleeping Sickness Elimination?

PubMed

Büscher, Philippe; Bart, Jean-Mathieu; Boelaert, Marleen; Bucheton, Bruno; Cecchi, Giuliano; Chitnis, Nakul; Courtin, David; Figueiredo, Luisa M; Franco, José-Ramon; Grébaut, Pascal; Hasker, Epco; Ilboudo, Hamidou; Jamonneau, Vincent; Koffi, Mathurin; Lejon, Veerle; MacLeod, Annette; Masumu, Justin; Matovu, Enock; Mattioli, Raffaele; Noyes, Harry; Picado, Albert; Rock, Kat S; Rotureau, Brice; Simo, Gustave; Thévenon, Sophie; Trindade, Sandra; Truc, Philippe; Van Reet, Nick

2018-03-01

Trypanosoma brucei gambiense causes human African trypanosomiasis (HAT). Between 1990 and 2015, almost 440000 cases were reported. Large-scale screening of populations at risk, drug donations, and efforts by national and international stakeholders have brought the epidemic under control with <2200 cases in 2016. The World Health Organization (WHO) has set the goals of gambiense-HAT elimination as a public health problem for 2020, and of interruption of transmission to humans for 2030. Latent human infections and possible animal reservoirs may challenge these goals. It remains largely unknown whether, and to what extend, they have an impact on gambiense-HAT transmission. We argue that a better understanding of the contribution of human and putative animal reservoirs to gambiense-HAT epidemiology is mandatory to inform elimination strategies. Copyright © 2017 Elsevier Ltd. All rights reserved.

77 FR 39162 - Implementation of the Understandings Reached at the 2011 Australia Group (AG) Plenary Meeting and...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-02

... June 2011 plenary meeting of the Australia Group (AG). This rule amends the Commerce Control List (CCL) entry in the EAR that controls human and zoonotic pathogens and ``toxins'' and the entry that controls...-03] RIN 0694-AF45 Implementation of the Understandings Reached at the 2011 Australia Group (AG...

Adaptable, Deployable Entry and Placement Technology (ADEPT) for Future Mars Missions

NASA Technical Reports Server (NTRS)

Wercinski, P.; Venkatapathy, E.; Gage, P.; Prabhu, D.; Smith, B.; Cassell, A.; Yount, B.; Allen, G.

2013-01-01

The concept of a mechanically deploy- able hypersonic decelerator, developed initially for high mass (40 MT) human Mars missions, is currently funded by OCT for technology maturation. The ADEPT (Adaptive, Deployable Entry and Placement Technology) project has broad, game-changing applicability to in situ science missions to Venus, Mars, and the Outer Planets.

Elimination of Dog-Mediated Human Rabies Deaths by 2030: Needs Assessment and Alternatives for Progress Based on Dog Vaccination.

PubMed

Wallace, Ryan M; Undurraga, Eduardo A; Blanton, Jesse D; Cleaton, Julie; Franka, Richard

2017-01-01

Rabies imposes a substantial burden to about half of the world population. The World Health Organization (WHO), World Organization for Animal Health, and the Food and Agriculture Organization have set the goal of eliminating dog-mediated human rabies deaths by 2030. This could be achieved largely by massive administration of post-exposure prophylaxis-in perpetuity-, through elimination of dog rabies, or combining both. Here, we focused on the resources needed for the elimination of dog rabies virus by 2030. Drawing from multiple datasets, including national dog vaccination campaigns, rabies literature, and expert opinion, we developed a model considering country-specific current dog vaccination capacity to estimate the years and resources required to achieve dog rabies elimination by 2030. Resources were determined based on four factors: (a) country development status, (b) dog vaccination costs, (c) dog rabies vaccine availability, and (d) existing animal health workers. Our calculations were based on the WHO's estimate that vaccinating 70% of the dog population for seven consecutive years would eliminate rabies. If dog rabies vaccine production remains at 2015 levels, we estimate that there will be a cumulative shortage of about 7.5 billion doses to meet expected demand to achieve dog rabies elimination. We estimated a present cost of $6,300 million to eliminate dog rabies in all endemic countries, equivalent to a $3,900 million gap compared to current spending. To eliminate dog rabies, the vaccination workforce may suffice if all public health veterinarians in endemic countries were to dedicate 3 months each year to dog rabies vaccination. We discuss implications of potential technology improvements, including population management, vaccine price reduction, and increases in dog-vaccinating capacities. Our results highlight the resources needed to achieve elimination of dog-mediated human rabies deaths by 2030. As exemplified by multiple successful disease elimination efforts, one size does not fit all. We suggest pragmatic and feasible options toward global dog rabies elimination by 2030, while identifying several benefits and drawbacks of specific approaches. We hope that these results help stimulate and inform a necessary discussion on global and regional strategic planning, resource mobilization, and continuous execution of rabies virus elimination.

Fighting rabies in Eastern Europe, the Middle East and Central Asia--experts call for a regional initiative for rabies elimination.

PubMed

Aikimbayev, A; Briggs, D; Coltan, G; Dodet, B; Farahtaj, F; Imnadze, P; Korejwo, J; Moiseieva, A; Tordo, N; Usluer, G; Vodopija, R; Vranješ, N

2014-05-01

MEEREB is an informal network of rabies experts from the Middle East, Eastern Europe and Central Asia, seeking to eliminate rabies from the region. They met for the second time to review the current rabies situation, both globally and in their respective countries, highlighting current rabies control problems and potential solutions. Success stories in Latin America, in Western Europe, in some Asian countries, as well as in Croatia and Serbia prove that elimination of human rabies is achievable in the MEEREB region. It requires political willingness and cooperation of all stakeholders, including Ministries of Health and of Agriculture; adequate management of animal bites through post-exposure prophylaxis; pre-exposure prophylaxis for populations at high risk of rabies exposure, animal vaccination and humane control of stray dog populations. MEEREB members called for a regional initiative for rabies elimination in Eastern Europe and the Middle East. They are confident that the elimination of human rabies of canine origin can be achieved in the region through adopting a One Health approach, and that campaigns for rabies elimination will have significant benefit for public health, including strengthening the structure for control of other zoonoses. © 2013 Blackwell Verlag GmbH.

Image Data Compression Having Minimum Perceptual Error

NASA Technical Reports Server (NTRS)

Watson, Andrew B. (Inventor)

1997-01-01

A method is presented for performing color or grayscale image compression that eliminates redundant and invisible image components. The image compression uses a Discrete Cosine Transform (DCT) and each DCT coefficient yielded by the transform is quantized by an entry in a quantization matrix which determines the perceived image quality and the bit rate of the image being compressed. The quantization matrix comprises visual masking by luminance and contrast technique all resulting in a minimum perceptual error for any given bit rate, or minimum bit rate for a given perceptual error.

The current impact of entry-level associate and baccalaureate degree education on the diversity of respiratory therapists.

PubMed

Becker, Ellen A; Nguyen, Xuan T

2014-12-01

Transitioning from an associate degree to a baccalaureate degree for respiratory therapists has been suggested as a new entry-level educational standard. One potential risk for this change is that it may limit the diversity of potential applicants for entry-level education. A diverse workforce is important to achieve the goal of reducing healthcare disparities. This study evaluated characteristics of therapists who completed associate and baccalaureate degree entry-level education. A secondary analysis of data collected from the 2009 AARC Respiratory Therapist Human Resource Survey explored relationships between the choice of entry-level associate or baccalaureate education and variables of gender, race, salary, career advancement, and job satisfaction. There were no differences between therapists with entry-level associate and baccalaureate degrees in gender, race, number of additional healthcare credentials, numbers of life support credentials, wages, delivering respiratory care by protocol, and job satisfaction. There were significantly higher percentages of advanced academic degrees, desire to pursue a higher academic degree, registered respiratory therapist credentials, total National Board for Respiratory Care credentials, and leadership roles for therapists with baccalaureate entry-level degrees. Current entry-level associate and baccalaureate degree graduates have similar gender and race proportions. This finding challenges concerns that an entry-level baccalaureate degree would decrease the diversity of the respiratory therapist workforce. Copyright © 2014 by Daedalus Enterprises.

Multiple oxygen entry pathways in globin proteins revealed by intrinsic pathway identification method

NASA Astrophysics Data System (ADS)

Takayanagi, Masayoshi; Kurisaki, Ikuo; Nagaoka, Masataka

2015-12-01

Each subunit of human hemoglobin (HbA) stores an oxygen molecule (O2) in the binding site (BS) cavity near the heme group. The BS is buried in the interior of the subunit so that there is a debate over the O2 entry pathways from solvent to the BS; histidine gate or multiple pathways. To elucidate the O2 entry pathways, we executed ensemble molecular dynamics (MD) simulations of T-state tetramer HbA in high concentration O2 solvent to simulate spontaneous O2 entry from solvent into the BS. By analyzing 128 independent 8 ns MD trajectories by intrinsic pathway identification by clustering (IPIC) method, we found 141 and 425 O2 entry events into the BS of the α and β subunits, respectively. In both subunits, we found that multiple O2 entry pathways through inside cavities play a significant role for O2 entry process of HbA. The rate constants of O2 entry estimated from the MD trajectories correspond to the experimentally observed values. In addition, by analyzing monomer myoglobin, we verified that the high O2 concentration condition can reproduce the ratios of each multiple pathway in the one-tenth lower O2 concentration condition. These indicate the validity of the multiple pathways obtained in our MD simulations.

A high throughput Cre–lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry

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

Esposito, Anthony M.; Cheung, Pamela; Swartz, Talia H.

Enveloped virus entry occurs when viral and cellular membranes fuse releasing particle contents into the target cell. Human immunodeficiency virus (HIV) entry occurs by cell-free virus or virus transferred between infected and uninfected cells through structures called virological synapses. We developed a high-throughput cell-based assay to identify small molecule inhibitors of cell-free or virological synapse-mediated entry. An HIV clone carrying Cre recombinase as a Gag-internal gene fusion releases active Cre into cells upon viral entry activating a recombinatorial gene switch changing dsRed to GFP-expression. A screen of a 1998 known-biological profile small molecule library identified pharmacological HIV entry inhibitors thatmore » block both cell-free and cell-to-cell infection. Many top hits were noted as HIV inhibitors in prior studies, but not previously recognized as entry antagonists. Modest therapeutic indices for simvastatin and nigericin were observed in confirmatory HIV infection assays. This robust assay is adaptable to study HIV and heterologous viral pseudotypes. - Highlights: • Cre recombinase viral fusion assay screens cell-free or cell–cell entry inhibitors. • This Gag-iCre based assay is specific for the entry step of HIV replication. • Screened a library of known pharmacologic compounds for HIV fusion antagonists. • Many top hits were previously noted as HIV inhibitors, but here are classified as entry antagonists. Many top hits were previously noted as HIV inhibitors, but not as entry antagonists. • The assay is compatible with pseudotyping with HIV and heterologous viruses.« less

School-Entry Policies and Skill Accumulation across Directly and Indirectly Affected Individuals

ERIC Educational Resources Information Center

Bedard, Kelly; Dhuey, Elizabeth

2012-01-01

During the past half-century, there has been a trend toward increasing the minimum age a child must reach before entering school in the United States. States have accomplished this by moving the school-entry cutoff date earlier in the school year. The evidence presented in this paper shows that these law changes increased human capital…

Human La binds mRNAs through contacts to the poly(A) tail

PubMed Central

Vinayak, Jyotsna; Marrella, Stefano A; Hussain, Rawaa H; Rozenfeld, Leonid; Solomon, Karine; Bayfield, Mark A

2018-01-01

Abstract In addition to a role in the processing of nascent RNA polymerase III transcripts, La proteins are also associated with promoting cap-independent translation from the internal ribosome entry sites of numerous cellular and viral coding RNAs. La binding to RNA polymerase III transcripts via their common UUU-3’OH motif is well characterized, but the mechanism of La binding to coding RNAs is poorly understood. Using electromobility shift assays and cross-linking immunoprecipitation, we show that in addition to a sequence specific UUU-3’OH binding mode, human La exhibits a sequence specific and length dependent poly(A) binding mode. We demonstrate that this poly(A) binding mode uses the canonical nucleic acid interaction winged helix face of the eponymous La motif, previously shown to be vacant during uridylate binding. We also show that cytoplasmic, but not nuclear La, engages poly(A) RNA in human cells, that La entry into polysomes utilizes the poly(A) binding mode, and that La promotion of translation from the cyclin D1 internal ribosome entry site occurs in competition with cytoplasmic poly(A) binding protein (PABP). Our data are consistent with human La functioning in translation through contacts to the poly(A) tail. PMID:29447394

Historical human exposure to perfluoroalkyl acids in the United States and Australia reconstructed from biomonitoring data using population-based pharmacokinetic modelling.

PubMed

Gomis, Melissa I; Vestergren, Robin; MacLeod, Matthew; Mueller, Jochen F; Cousins, Ian T

2017-11-01

Perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS) are found in the blood of humans and wildlife worldwide. Since the beginning of the 21st century, a downward trend in the human body burden, especially for PFOS and PFOA, has been observed while there is no clear temporal trend in wildlife. The inconsistency between the concentration decline in human serum and in wildlife could be indicative of a historical exposure pathway for humans linked to consumer products that has been reduced or eliminated. In this study, we reconstruct the past human exposure trends in two different regions, USA and Australia, by inferring the historical intake from cross-sectional biomonitoring data of PFOS, PFOA and PFHxS using a population-based pharmacokinetic model. For PFOS in the USA, the reconstructed daily intake peaked at 4.5ng/kg-bw/day between 1988 and 1999 while in Australia it peaked at 4.0ng/kg-bw/day between 1984 and 1996. For PFOA in the USA and Australia, the peak reconstructed daily intake was 1.1ng/kg-bw/day in 1995 and 3.6ng/kg-bw/day in 1992, respectively, and started to decline in 2000 and 1995, respectively. The model could not be satisfactorily fitted to the biomonitoring data for PFHxS within reasonable boundaries for its intrinsic elimination half-life, and thus reconstructing intakes of PFHxS was not possible. Our results indicate that humans experienced similar exposure levels and trends to PFOS and PFOA in the USA and Australia. Our findings support the hypothesis that near-field consumer product exposure pathways were likely dominant prior to the phase-out in industrialized countries. The intrinsic elimination half-life, which represents elimination processes that are common for all humans, and elimination processes unique to women (i.e., menstruation, cord-blood transfer and breastfeeding) were also investigated. The intrinsic elimination half-lives for PFOS and PFOA derived from model fitting for men were 3.8 and 2.4years, respectively, for the USA, and 4.9 and 2years respectively for Australia. Our results show that menstruation is a depuration pathway for PFOA for women, similarly but to a lesser extent compared to previous reports for PFOS. However menstruation, cord-blood transfer and breastfeeding together do not fully explain the apparently more rapid elimination of PFOA and PFOS by women compared to men; the intrinsic elimination half-lives in women were up to 13% lower for PFOS and up to 12% lower for PFOA compared to the corresponding half-lives in men. Copyright © 2017 Elsevier Ltd. All rights reserved.

76 FR 11206 - Proposed Collection; Patent Examiner Employment Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-01

... the Workforce Employment Division, Office of Human Resources, United States Patent and Trademark... rapidly review applications for employment of entry-level patent examiners. The Office of Human Resources... supplied by an applicant seeking a patent examiner position with the USPTO assists the Human Resources...

Entry, Descent and Landing Systems Analysis: Exploration Class Simulation Overview and Results

NASA Technical Reports Server (NTRS)

DwyerCianciolo, Alicia M.; Davis, Jody L.; Shidner, Jeremy D.; Powell, Richard W.

2010-01-01

NASA senior management commissioned the Entry, Descent and Landing Systems Analysis (EDL-SA) Study in 2008 to identify and roadmap the Entry, Descent and Landing (EDL) technology investments that the agency needed to make in order to successfully land large payloads at Mars for both robotic and exploration or human-scale missions. The year one exploration class mission activity considered technologies capable of delivering a 40-mt payload. This paper provides an overview of the exploration class mission study, including technologies considered, models developed and initial simulation results from the EDL-SA year one effort.

Remote Imaging of Exploration Flight Test-1 (EFT-1) Entry Heating Risk Reduction

NASA Technical Reports Server (NTRS)

Schuster, David M.; Horvath, Thomas J.; Schwartz, Richard J.

2016-01-01

A Measure of Performance (MOP) identified with an Exploration Flight Test-1 (EFT-1) Multi- Purpose Crew Vehicle (MPCV) Program Flight Test Objective (FTO) (OFT1.091) specified an observation during reentry though external ground-based or airborne assets with thermal detection capabilities. The objective of this FTO was to be met with onboard Developmental Flight Instrumentation (DFI), but the MOP for external observation was intended to provide complementary quantitative data and serve as a risk reduction in the event of anomalous DFI behavior (or failure). Mr. Gavin Mendeck, the Entry, Descent, and Landing (EDL) Phase Engineer for the MPCV Program (Vehicle Integration Office/Systems & Mission Integration) requested a risk-reduction assessment from the NASA Engineering and Safety Center (NESC) to determine whether quantitative imagery could be obtained from remote aerial assets to support the external observation MOP. If so, then a viable path forward was to be determined, risks identified, and an observation pursued. If not, then the MOP for external observation was to be eliminated.

Animal life support transporters for Shuttle/Spacelab

NASA Technical Reports Server (NTRS)

Berry, W. E.; Hunt, S. R.

1978-01-01

Two transporter devices have been developed by the NASA Ames Research Center, primarily for the purpose of stowing small vertebrates and primates in the mid-deck avionics bay of the Shuttle during launch and re-entry. These animals will be used in Life Science Spacelab experiments. Stowage in the mid-deck area will reduce animal exposure to the high noise levels existing in Spacelab during launch; further, the possible exposure of the animals to high temperatures in Spacelab during re-entry and post-landing will be eliminated. The transporters will provide experimenters more timely access to their animals during experiment-critical, pre-launch, and post-landing periods. Rechargeable batteries in the transporters will provide life support system functions for the animals during periods of transfer and during mission phases in which power is temporarily unavailable. The transporters have been successfully designed, fabricated, and tested. Integrated testing of the transporters was performed in the Space Mission Development III (SMD III) Simulation at the NASA Johnson Space Center.

Can utilizing a computerized provider order entry (CPOE) system prevent hospital medical errors and adverse drug events?

PubMed

Charles, Krista; Cannon, Margaret; Hall, Robert; Coustasse, Alberto

2014-01-01

Computerized provider order entry (CPOE) systems allow physicians to prescribe patient services electronically. In hospitals, CPOE essentially eliminates the need for handwritten paper orders and achieves cost savings through increased efficiency. The purpose of this research study was to examine the benefits of and barriers to CPOE adoption in hospitals to determine the effects on medical errors and adverse drug events (ADEs) and examine cost and savings associated with the implementation of this newly mandated technology. This study followed a methodology using the basic principles of a systematic review and referenced 50 sources. CPOE systems in hospitals were found to be capable of reducing medical errors and ADEs, especially when CPOE systems are bundled with clinical decision support systems designed to alert physicians and other healthcare providers of pending lab or medical errors. However, CPOE systems face major barriers associated with adoption in a hospital system, mainly high implementation costs and physicians' resistance to change.

Evaluation of human papillomavirus elimination from cervix uteri by infrared laser exposure.

PubMed

Dymkovets, V P; Ezhov, V V; Manykin, A A; Belov, S V; Danileiko, Yu K; Osiko, V V; Salyuk, V A

2011-12-01

Elimination of types 16 and 18 human papilloma virus from the surface of cervix uteri for secondary prevention of cervical cancer was evaluated. The method is protected by patent of invention of the Russian Federation. Infrared laser therapy of cervix uteri was carried out in patients with precancer diseases of cervix uteri at Department of Gynecology of Municipal Clinical Hospital No. 52 (Moscow). Papillomavirus infection was eliminated using a Russian diode laser (lambda=1.06 μ, radiation power 10 W) with a collimating headpiece using carbon die at a distance of 10-12 cm from the exposed surface. The treatment resulted in a high percentage of elimination of types 16 and 18 oncogenic virus 4-6 weeks and during delayed periods after exposure.

Understanding the tissue effects of tribo-corrosion: uptake, distribution, and speciation of cobalt and chromium in human bone cells.

PubMed

Shah, Karan M; Quinn, Paul D; Gartland, Alison; Wilkinson, J Mark

2015-01-01

Cobalt and chromium species are released in the local tissues as a result of tribo-corrosion, and affect bone cell survival and function. However we have little understanding of the mechanisms of cellular entry, intracellular distribution, and speciation of the metals that result in impaired bone health. Here we used synchrotron based X-ray fluorescence (XRF), X-ray absorption spectroscopy (XAS), and fluorescent-probing approaches of candidate receptors P2X7R and divalent metal transporter-1 (DMT-1), to better understand the entry, intra-cellular distribution and speciation of cobalt (Co) and chromium (Cr) in human osteoblasts and primary human osteoclasts. We found that both Co and Cr were most highly localized at nuclear and perinuclear sites in osteoblasts, suggesting uptake through cell membrane transporters, and supported by a finding that P2X7 receptor blockade reduced cellular entry of Co. In contrast, metal species were present at discrete sites corresponding to the basolateral membrane in osteoclasts, suggesting cell entry by endocytosis and trafficking through a functional secretory domain. An intracellular reduction of Cr6+ to Cr3+ was the only redox change observed in cells treated with Co2+, Cr3+, and Cr6+. Our data suggest that the cellular uptake and processing of Co and Cr differs between osteoblasts and osteoclasts. © 2014 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society.

Ebola virus entry requires the cholesterol transporter Niemann-Pick C1.

PubMed

Carette, Jan E; Raaben, Matthijs; Wong, Anthony C; Herbert, Andrew S; Obernosterer, Gregor; Mulherkar, Nirupama; Kuehne, Ana I; Kranzusch, Philip J; Griffin, April M; Ruthel, Gordon; Dal Cin, Paola; Dye, John M; Whelan, Sean P; Chandran, Kartik; Brummelkamp, Thijn R

2011-08-24

Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.

NTCP and Beyond: Opening the Door to Unveil Hepatitis B Virus Entry

PubMed Central

Watashi, Koichi; Urban, Stephan; Li, Wenhui; Wakita, Takaji

2014-01-01

Chronic hepatitis B virus (HBV) infection, affecting approximately 240 million people worldwide, is a major public health problem that elevates the risk of developing liver cirrhosis and hepatocellular carcinoma. Given that current anti-HBV drugs are limited to interferon-based regimens and nucleos(t)ide analogs, the development of new anti-HBV agents is urgently needed. The viral entry process is generally an attractive target implicated in antiviral strategies. Using primary cells from humans and Tupaia belangeri, as well as HepaRG cells, important determinants of viral entry have been achieved. Recently, sodium taurocholate cotransporting polypeptide (NTCP) was identified as an HBV entry receptor and enabled the establishment of a susceptible cell line that can efficiently support HBV infection. This finding will allow a deeper understanding of the requirements for efficient HBV infection, including the elucidation of the molecular entry mechanism. In addition, pharmacological studies suggest that NTCP is able to serve as a therapeutic target. This article summarizes our current knowledge on the mechanisms of HBV entry and the role of NTCP in this process. PMID:24557582

NTCP and beyond: opening the door to unveil hepatitis B virus entry.

PubMed

Watashi, Koichi; Urban, Stephan; Li, Wenhui; Wakita, Takaji

2014-02-19

Chronic hepatitis B virus (HBV) infection, affecting approximately 240 million people worldwide, is a major public health problem that elevates the risk of developing liver cirrhosis and hepatocellular carcinoma. Given that current anti-HBV drugs are limited to interferon-based regimens and nucleos(t)ide analogs, the development of new anti-HBV agents is urgently needed. The viral entry process is generally an attractive target implicated in antiviral strategies. Using primary cells from humans and Tupaia belangeri, as well as HepaRG cells, important determinants of viral entry have been achieved. Recently, sodium taurocholate cotransporting polypeptide (NTCP) was identified as an HBV entry receptor and enabled the establishment of a susceptible cell line that can efficiently support HBV infection. This finding will allow a deeper understanding of the requirements for efficient HBV infection, including the elucidation of the molecular entry mechanism. In addition, pharmacological studies suggest that NTCP is able to serve as a therapeutic target. This article summarizes our current knowledge on the mechanisms of HBV entry and the role of NTCP in this process.

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

Bose, Sayantan, E-mail: sayantan_bose@hms.harvard.edu; Jardetzky, Theodore S.; Lamb, Robert A., E-mail: ralamb@northwestern.edu

The Paramyxoviridae include some of the great and ubiquitous disease-causing viruses of humans and animals. In most paramyxoviruses, two viral membrane glycoproteins, fusion protein (F) and receptor binding protein (HN, H or G) mediate a concerted process of recognition of host cell surface molecules followed by fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. The interactions between the F and HN, H or G viral glycoproteins and host molecules are critical in determining host range, virulence and spread of these viruses. Recently, atomic structures, together with biochemical and biophysical studies, have provided major insightsmore » into how these two viral glycoproteins successfully interact with host receptors on cellular membranes and initiate the membrane fusion process to gain entry into cells. These studies highlight the conserved core mechanisms of paramyxovirus entry that provide the fundamental basis for rational anti-viral drug design and vaccine development. - Highlights: • New structural and functional insights into paramyxovirus entry mechanisms. • Current data on paramyxovirus glycoproteins suggest a core conserved entry mechanism. • Diverse mechanisms preventing premature fusion activation exist in these viruses. • Precise spacio-temporal interplay between paramyxovirus glycoproteins initiate entry.« less

A combination HIV reporter virus system for measuring post-entry event efficiency and viral outcome in primary CD4+ T cell subsets.

PubMed

Tilton, Carisa A; Tabler, Caroline O; Lucera, Mark B; Marek, Samantha L; Haqqani, Aiman A; Tilton, John C

2014-01-01

Fusion between the viral membrane of human immunodeficiency virus (HIV) and the host cell marks the end of the HIV entry process and the beginning of a series of post-entry events including uncoating, reverse transcription, integration, and viral gene expression. The efficiency of post-entry events can be modulated by cellular factors including viral restriction factors and can lead to several distinct outcomes: productive, latent, or abortive infection. Understanding host and viral proteins impacting post-entry event efficiency and viral outcome is critical for strategies to reduce HIV infectivity and to optimize transduction of HIV-based gene therapy vectors. Here, we report a combination reporter virus system measuring both membrane fusion and viral promoter-driven gene expression. This system enables precise determination of unstimulated primary CD4+ T cell subsets targeted by HIV, the efficiency of post-entry viral events, and viral outcome and is compatible with high-throughput screening and cell-sorting methods. Copyright © 2013 Elsevier B.V. All rights reserved.

Platelets and cancer: a casual or causal relationship: revisited

PubMed Central

Menter, David G.; Tucker, Stephanie C.; Kopetz, Scott; Sood, Anil K.; Crissman, John D.; Honn, Kenneth V.

2014-01-01

Human platelets arise as subcellular fragments of megakaryocytes in bone marrow. The physiologic demand, presence of disease such as cancer, or drug effects can regulate the production circulating platelets. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. The most critical biological platelet response is serving as “First Responders” during the wounding process. The exposure of extracellular matrix proteins and intracellular components occurs after wounding. Numerous platelet receptors recognize matrix proteins that trigger platelet activation, adhesion, aggregation, and stabilization. Once activated, platelets change shape and degranulate to release growth factors and bioactive lipids into the blood stream. This cyclic process recruits and aggregates platelets along with thrombogenesis. This process facilitates wound closure or can recognize circulating pathologic bodies. Cancer cell entry into the blood stream triggers platelet-mediated recognition and is amplified by cell surface receptors, cellular products, extracellular factors, and immune cells. In some cases, these interactions suppress immune recognition and elimination of cancer cells or promote arrest at the endothelium, or entrapment in the microvasculature, and survival. This supports survival and spread of cancer cells and the establishment of secondary lesions to serve as important targets for prevention and therapy. PMID:24696047

Rabies in South Asia: fighting for elimination.

PubMed

Chowdhury, Fazle-Rabbi; Basher, Ariful; Amin, Mohammad R; Hassan, Nazia; Patwary, Mohammad I

2015-01-01

South Asia is regarded as the hot spot for the tourist and travelers. Unfortunately, three big countries (India, Pakistan and Bangladesh) of this region belong to top five rabies endemic countries of the world. Around 55,000 people die of rabies every year globally and 45% of them belong to South and South East Asia. Countries are now working on the elimination of rabies by the year 2020. Elimination of animal rabies is the pivotal of controlling human rabies. Dog (primary source) registration, population control and mass vaccination are the different ways of eliminating animal rabies. Pre (for risk groups including travelers) and post-exposure vaccine is the core for controlling human rabies. Post-exposure vaccine consists of nerve tissue vaccine and tissue culture vaccine. Due to low antigenicity and post-vaccine neurological complications all countries of South Asia except Pakistan have phased out the production and use of nerve tissue vaccine. To reduce the cost intramuscular regimen is now largely replaced by intradermal regimen and equine rabies immunoglobulin will probably replace human immunoglobulin in future for category III animal bite. 'SAARC' took initiatives for rabies elimination through 'SAARC development fund' which would hopefully play a vital role in regional collaboration to make the region rabies free.

The post-millennium development goals agenda: include 'end to all wars' as a public health goal!

PubMed

Jayasinghe, Saroj

2014-09-01

The process of identifying global post-millennium development goals (post-MDGs) has begun in earnest. Consensus is emerging in certain areas (e.g. eliminating poverty) and conflicts and violence are recognized as key factors that retard human development. However, current discussions focus on tackling intra-state conflicts and individual-based violence and hardly mention eliminating wars as a goal. Wars create public health catastrophes. They kill, maim, displace and affect millions. Inter-state wars fuel intra-state conflicts and violence. The peace agenda should not be the monopoly of the UN Security Council, and the current consensus-building process setting the post-MDG agenda is a rallying point for the global community. The human rights approach will not suffice to eliminate wars, because few are fought to protect human rights. The development agenda should therefore commit to eliminating all wars by 2030. Targets to reduce tensions and discourage wars should be included. We should act now. © The Author(s) 2014.

Tribulations of the Last Mile: Sides from a Regional Program.

PubMed

Del Rio Vilas, Victor J; Freire de Carvalho, Mary J; Vigilato, Marco A N; Rocha, Felipe; Vokaty, Alexandra; Pompei, Julio A; Molina Flores, Baldomero; Fenelon, Natael; Cosivi, Ottorino

2017-01-01

In Latin American and Caribbean (LAC) countries, the number of cases of dog-mediated human rabies is at its lowest since the onset of the Regional Program for Rabies Elimination in 1983, a commitment from LAC countries to eliminate dog-mediated rabies coordinated by the Pan American Health Organization. Despite minor setbacks, the decline in the number of human cases has been constant since 1983. While many LAC countries have significantly reduced rabies to a level where it is no longer significant public health concern, elimination has proven elusive and pockets of the disease remain across the region. In the 33-year period since 1983, the region has set and committed to four dates for elimination (1990, 2000, 2012, and 2015). In this paper, we ponder on the multiple causes behind the elusive goal of rabies elimination, such as blanket regional goals oblivious to the large heterogeneity in national rabies capacities. Looking ahead to the elimination of dog-mediated rabies in the region, now established for 2022, we also review the many challenges and questions that the region faces in the last mile of the epidemic. Given the advanced position of the Americas in the race toward elimination, our considerations could provide valuable knowledge to other regions pursuing elimination goals.

Heterogeneity in the spread and control of infectious disease: consequences for the elimination of canine rabies

NASA Astrophysics Data System (ADS)

Ferguson, Elaine A.; Hampson, Katie; Cleaveland, Sarah; Consunji, Ramona; Deray, Raffy; Friar, John; Haydon, Daniel T.; Jimenez, Joji; Pancipane, Marlon; Townsend, Sunny E.

2015-12-01

Understanding the factors influencing vaccination campaign effectiveness is vital in designing efficient disease elimination programmes. We investigated the importance of spatial heterogeneity in vaccination coverage and human-mediated dog movements for the elimination of endemic canine rabies by mass dog vaccination in Region VI of the Philippines (Western Visayas). Household survey data was used to parameterise a spatially-explicit rabies transmission model with realistic dog movement and vaccination coverage scenarios, assuming a basic reproduction number for rabies drawn from the literature. This showed that heterogeneous vaccination reduces elimination prospects relative to homogeneous vaccination at the same overall level. Had the three vaccination campaigns completed in Region VI in 2010-2012 been homogeneous, they would have eliminated rabies with high probability. However, given the observed heterogeneity, three further campaigns may be required to achieve elimination with probability 0.95. We recommend that heterogeneity be reduced in future campaigns through targeted efforts in low coverage areas, even at the expense of reduced coverage in previously high coverage areas. Reported human-mediated dog movements did not reduce elimination probability, so expending limited resources on restricting dog movements is unnecessary in this endemic setting. Enhanced surveillance will be necessary post-elimination, however, given the reintroduction risk from long-distance dog movements.

Tribulations of the Last Mile: Sides from a Regional Program

PubMed Central

Del Rio Vilas, Victor J.; Freire de Carvalho, Mary J.; Vigilato, Marco A. N.; Rocha, Felipe; Vokaty, Alexandra; Pompei, Julio A.; Molina Flores, Baldomero; Fenelon, Natael; Cosivi, Ottorino

2017-01-01

In Latin American and Caribbean (LAC) countries, the number of cases of dog-mediated human rabies is at its lowest since the onset of the Regional Program for Rabies Elimination in 1983, a commitment from LAC countries to eliminate dog-mediated rabies coordinated by the Pan American Health Organization. Despite minor setbacks, the decline in the number of human cases has been constant since 1983. While many LAC countries have significantly reduced rabies to a level where it is no longer significant public health concern, elimination has proven elusive and pockets of the disease remain across the region. In the 33-year period since 1983, the region has set and committed to four dates for elimination (1990, 2000, 2012, and 2015). In this paper, we ponder on the multiple causes behind the elusive goal of rabies elimination, such as blanket regional goals oblivious to the large heterogeneity in national rabies capacities. Looking ahead to the elimination of dog-mediated rabies in the region, now established for 2022, we also review the many challenges and questions that the region faces in the last mile of the epidemic. Given the advanced position of the Americas in the race toward elimination, our considerations could provide valuable knowledge to other regions pursuing elimination goals. PMID:28197407

Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein

PubMed Central

Millet, Jean Kaoru; Whittaker, Gary R.

2014-01-01

Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly identified betacoronavirus causing high morbidity and mortality in humans. The coronavirus spike (S) protein is the main determinant of viral entry, and although it was previously shown that MERS-CoV S can be activated by various proteases, the details of the mechanisms of proteolytic activation of fusion are still incompletely characterized. Here, we have uncovered distinctive characteristics of MERS-CoV S. We identify, by bioinformatics and peptide cleavage assays, two cleavage sites for furin, a ubiquitously expressed protease, which are located at the S1/S2 interface and at the S2′ position of the S protein. We show that although the S1/S2 site is proteolytically processed by furin during protein biosynthesis, the S2′ site is cleaved upon viral entry. MERS-CoV pseudovirion infection was shown to be enhanced by elevated levels of furin expression, and entry could be decreased by furin siRNA silencing. Enhanced furin activity appeared to partially override the low pH-dependent nature of MERS-CoV entry. Inhibition of furin activity was shown to decrease MERS-CoV S-mediated entry, as well as infection by the virus. Overall, we show that MERS-CoV has evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population. The ability of MERS-CoV to use furin in this manner, along with other proteases, may explain the polytropic nature of the virus. PMID:25288733

Flexible Ablators: Applications and Arcjet Testing

NASA Technical Reports Server (NTRS)

Arnold, James O.; Venkatapathy, Ethiraj; Beck, Robin A S.; Mcguire, Kathy; Prabhu, Dinesh K.; Gorbunov, Sergey

2011-01-01

Flexible ablators were conceived in 2009 to meet the technology pull for large, human Mars Exploration Class, 23 m diameter hypersonic inflatable aerodynamic decelerators. As described elsewhere, they have been recently undergoing initial technical readiness (TRL) advancement by NASA. The performance limits of flexible ablators in terms of maximum heat rates, pressure and shear remain to be defined. Further, it is hoped that this emerging technology will vastly expand the capability of future NASA missions involving atmospheric entry systems. This paper considers four topics of relevance to flexible ablators: (1) Their potential applications to near/far term human and robotic missions (2) Brief consideration of the balance between heat shield diameter, flexible ablator performance limits, entry vehicle controllability and aft-body shear layer impingement of interest to designers of very large entry vehicles, (3) The approach for developing bonding processes of flexible ablators for use on rigid entry bodies and (4) Design of large arcjet test articles that will enable the testing of flexible ablators in flight-like, combined environments (heat flux, pressure, shear and structural tensile loading). Based on a review of thermal protection system performance requirements for future entry vehicles, it is concluded that flexible ablators have broad applications to conventional, rigid entry body systems and are enabling to large deployable (both inflatable and mechanical) heat shields. Because of the game-changing nature of flexible ablators, it appears that NASA's Office of the Chief Technologist (OCT) will fund a focused, 3-year TRL advancement of the new materials capable of performance in heat fluxes in the range of 200-600 W/sq. cm. This support will enable the manufacture and use of the large-scale arcjet test designs that will be a key element of this OCT funded activity.

Atlas instrumentation guided by the medial edge of the posterior arch: An anatomic and radiologic study.

PubMed

Al-Habib, Amro F; Al-Rabie, Abdulkarim; Aleissa, Sami; Albakr, Abdulrahman; Abobotain, Abdulaziz

2017-01-01

This was an interventional human cadaver study and radiological study. Atlas instrumentation is frequently involved in fusion procedures involving the craniocervical junction area. Identification of the entry point at the center of atlas lateral mass (ALM) is challenging because of its rounded posterior surface and the surrounding venous plexus. This report examines using the medial edge of atlas posterior arch (MEC1) as a fixed and reliable anatomic reference to guide the entry point of ALM screws. Fifty, normal, cervical spine computed tomography studies were reviewed. ALM screw trajectories were planned at one point along MEC1 and another point 2 mm lateral to MEC1. Free-hand ALM instrumentation was performed in ten fresh human cadavers using the 2 mm entry point, with a sagittal trajectory parallel to atlas inferior arch (IAC1); three-dimensional imaging was then performed to confirm instrumentation accuracy. The average ALM diameter was 12.35 mm. Inserting a screw using the entry point 2 mm lateral to MEC1 was closer to ALM midpoint than using the entry point along MEC1 ( P < 0.0001). Twenty ALM screws were successfully inserted in the ten cadavers. No encroachments into the spinal canal or foramen transversarium occurred. However, two screws were superiorly directed and violated the occipitocervical joint; they were not parallel to IAC1. MEC1 provides a fixed and reliable landmark for ALM instrumentation. An entry point 2 mm point lateral to MEC1 is close to ALM midpoint. IAC1 also provides a guide for the sagittal trajectory. Attention to anatomic landmarks may help reduce complications associated with atlas instrumentation but should be verified in future clinical studies.

HIV-1 requires Arf6-mediated membrane dynamics to efficiently enter and infect T lymphocytes

PubMed Central

García-Expósito, Laura; Barroso-González, Jonathan; Puigdomènech, Isabel; Machado, José-David; Blanco, Julià; Valenzuela-Fernández, Agustín

2011-01-01

As the initial barrier to viral entry, the plasma membrane along with the membrane trafficking machinery and cytoskeleton are of fundamental importance in the viral cycle. However, little is known about the contribution of plasma membrane dynamics during early human immunodeficiency virus type 1 (HIV-1) infection. Considering that ADP ribosylation factor 6 (Arf6) regulates cellular invasion via several microorganisms by coordinating membrane trafficking, our aim was to study the function of Arf6-mediated membrane dynamics on HIV-1 entry and infection of T lymphocytes. We observed that an alteration of the Arf6–guanosine 5′-diphosphate/guanosine 5′-triphosphate (GTP/GDP) cycle, by GDP-bound or GTP-bound inactive mutants or by specific Arf6 silencing, inhibited HIV-1 envelope–induced membrane fusion, entry, and infection of T lymphocytes and permissive cells, regardless of viral tropism. Furthermore, cell-to-cell HIV-1 transmission of primary human CD4+ T lymphocytes was inhibited by Arf6 knockdown. Total internal reflection fluorescence microscopy showed that Arf6 mutants provoked the accumulation of phosphatidylinositol-(4,5)-biphosphate–associated structures on the plasma membrane of permissive cells, without affecting CD4-viral attachment but impeding CD4-dependent HIV-1 entry. Arf6 silencing or its mutants did not affect fusion, entry, and infection of vesicular stomatitis virus G–pseudotyped viruses or ligand-induced CXCR4 or CCR5 endocytosis, both clathrin-dependent processes. Therefore we propose that efficient early HIV-1 infection of CD4+ T lymphocytes requires Arf6-coordinated plasma membrane dynamics that promote viral fusion and entry. PMID:21346189

Simian hemorrhagic fever virus cell entry is dependent on CD163 and uses a clathrin-mediated endocytosis-like pathway.

PubMed

Caì, Yíngyún; Postnikova, Elena N; Bernbaum, John G; Yú, Shu Qìng; Mazur, Steven; Deiuliis, Nicole M; Radoshitzky, Sheli R; Lackemeyer, Matthew G; McCluskey, Adam; Robinson, Phillip J; Haucke, Volker; Wahl-Jensen, Victoria; Bailey, Adam L; Lauck, Michael; Friedrich, Thomas C; O'Connor, David H; Goldberg, Tony L; Jahrling, Peter B; Kuhn, Jens H

2015-01-01

Simian hemorrhagic fever virus (SHFV) causes a severe and almost uniformly fatal viral hemorrhagic fever in Asian macaques but is thought to be nonpathogenic for humans. To date, the SHFV life cycle is almost completely uncharacterized on the molecular level. Here, we describe the first steps of the SHFV life cycle. Our experiments indicate that SHFV enters target cells by low-pH-dependent endocytosis. Dynamin inhibitors, chlorpromazine, methyl-β-cyclodextrin, chloroquine, and concanamycin A dramatically reduced SHFV entry efficiency, whereas the macropinocytosis inhibitors EIPA, blebbistatin, and wortmannin and the caveolin-mediated endocytosis inhibitors nystatin and filipin III had no effect. Furthermore, overexpression and knockout study and electron microscopy results indicate that SHFV entry occurs by a dynamin-dependent clathrin-mediated endocytosis-like pathway. Experiments utilizing latrunculin B, cytochalasin B, and cytochalasin D indicate that SHFV does not hijack the actin polymerization pathway. Treatment of target cells with proteases (proteinase K, papain, α-chymotrypsin, and trypsin) abrogated entry, indicating that the SHFV cell surface receptor is a protein. Phospholipases A2 and D had no effect on SHFV entry. Finally, treatment of cells with antibodies targeting CD163, a cell surface molecule identified as an entry factor for the SHFV-related porcine reproductive and respiratory syndrome virus, diminished SHFV replication, identifying CD163 as an important SHFV entry component. Simian hemorrhagic fever virus (SHFV) causes highly lethal disease in Asian macaques resembling human illness caused by Ebola or Lassa virus. However, little is known about SHFV's ecology and molecular biology and the mechanism by which it causes disease. The results of this study shed light on how SHFV enters its target cells. Using electron microscopy and inhibitors for various cellular pathways, we demonstrate that SHFV invades cells by low-pH-dependent, actin-independent endocytosis, likely with the help of a cellular surface protein. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

The restructuring and future of {open_quotes}Mendelian Inheritance in Man{close_quotes} (MIM)

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

Pearson, P.L.; Francomano, C.; Antonarakis, S.

1994-09-01

Victor McKusick`s catalog {open_quotes}Mendelian Inheritance in Man{close_quotes} represents the most comprehensive compendum of human genetic disease information available today and has appeared as a series in book form for the last 30 years. The 11th edition will contain almost 7000 entries: approximately 2800 descriptions of human genetic disorders, 700 combined disorder/gene descriptions and 3500 pure gene descriptions. Until recently the content of the catalogs was maintained solely by McKusick with a support staff. However, a distributed editing system has now been established with the following primary components. New entries are initiated in Baltimore by science writers under the guidance ofmore » the senior editors and McKusick, following which the information is made immediately available to the public through online access. The subject editors can then review and edit the new or modified information without impeding the timeliness of entering new information. Entries are being reconstructured so that clinical disorder and gene information is divided into separate entries which will better represent the frequently complex relationship of gene mutations to individual clinical disorders in the data files. Further, each entry is being subdivided into logical topics which will enhance the power of electronic searching, making links between topics and improving readability. The old division of entries into autosomal dominant and recessive, etc., is being abandoned in favor of clinical disorder (phenotypes) and gene catalogs. The information is maintained in an SGML format which facilitates the production of many different types of output varying from the traditional book form to CD ROMs and various online formats including IRx, WAIS, Gopher and World Wide Web. This latter offers the exciting possibility of making hypertext links between entries and other data resources, including photographic, sound and video clips as part of the total MIM information.« less

Technologies for Human Exploration

NASA Technical Reports Server (NTRS)

Drake, Bret G.

2014-01-01

Access to Space, Chemical Propulsion, Advanced Propulsion, In-Situ Resource Utilization, Entry, Descent, Landing and Ascent, Humans and Robots Working Together, Autonomous Operations, In-Flight Maintenance, Exploration Mobility, Power Generation, Life Support, Space Suits, Microgravity Countermeasures, Autonomous Medicine, Environmental Control.

Rabies elimination research: juxtaposing optimism, pragmatism and realism

PubMed Central

Hampson, Katie

2017-01-01

More than 100 years of research has now been conducted into the prevention, control and elimination of rabies with safe and highly efficacious vaccines developed for use in human and animal populations. Domestic dogs are a major reservoir for rabies, and although considerable advances have been made towards the elimination and control of canine rabies in many parts of the world, the disease continues to kill tens of thousands of people every year in Africa and Asia. Policy efforts are now being directed towards a global target of zero human deaths from dog-mediated rabies by 2030 and the global elimination of canine rabies. Here we demonstrate how research provides a cause for optimism as to the feasibility of these goals through strategies based around mass dog vaccination. We summarize some of the pragmatic insights generated from rabies epidemiology and dog ecology research that can improve the design of dog vaccination strategies in low- and middle-income countries and which should encourage implementation without further delay. We also highlight the need for realism in reaching the feasible, although technically more difficult and longer-term goal of global elimination of canine rabies. Finally, we discuss how research on rabies has broader relevance to the control and elimination of a suite of diseases of current concern to human and animal health, providing an exemplar of the value of a ‘One Health’ approach. PMID:29263285

Alirocumab, a Therapeutic Human Antibody to PCSK9, Does Not Affect CD81 Levels or Hepatitis C Virus Entry and Replication into Hepatocytes.

PubMed

Ramanathan, Aarti; Gusarova, Viktoria; Stahl, Neil; Gurnett-Bander, Anne; Kyratsous, Christos A

2016-01-01

Proprotein convertase subtilisin/kexin type 9 (PSCK9) is secreted mainly from the liver and binds to the low-density lipoprotein receptor (LDLR), reducing LDLR availability and thus resulting in an increase in LDL-cholesterol. While the LDLR has been implicated in the cell entry process of the hepatitis C virus (HCV), overexpression of an artificial non-secreted, cell membrane-bound form of PCSK9 has also been shown to reduce surface expression of CD81, a major component of the HCV entry complex, leading to concerns that pharmacological inhibition of PCSK9 may increase susceptibility to HCV infection by increasing either CD81 or LDLR availability. Here, we evaluated effects of PCSK9 and PCSK9 blockade on CD81 levels and HCV entry with a physiologically relevant model using native secreted PCSK9 and a monoclonal antibody to PCSK9, alirocumab. Flow cytometry and Western blotting of human hepatocyte Huh-7 cells showed that, although LDLR levels were reduced when cells were exposed to increasing PCSK9 concentrations, there was no correlation between total or surface CD81 levels and the presence and amount of soluble PCSK9. Moreover, inhibiting PCSK9 with the monoclonal antibody alirocumab did not affect expression levels of CD81. In an in vitro model of HCV entry, addition of soluble PCSK9 or treatment with alirocumab had no effect on the ability of either lentiviral particles bearing the HCV glycoproteins or JFH-1 based cell culture virus to enter hepatocytes. Consistent with these in vitro findings, no differences were observed in hepatic CD81 levels using in vivo mouse models, including Pcsk9-/- mice compared with wild-type controls and hyperlipidemic mice homozygous for human Pcsk9 and heterozygous for Ldlr deletion, treated with either alirocumab or isotype control antibody. These results suggest that inhibition of PCSK9 with alirocumab has no effect on CD81 and does not result in increased susceptibility to HCV entry.

Entry, Descent, and Landing technological barriers and crewed MARS vehicle performance analysis

NASA Astrophysics Data System (ADS)

Subrahmanyam, Prabhakar; Rasky, Daniel

2017-05-01

Mars has been explored historically only by robotic crafts, but a crewed mission encompasses several new engineering challenges - high ballistic coefficient entry, hypersonic decelerators, guided entry for reaching intended destinations within acceptable margins for error in the landing ellipse, and payload mass are all critical factors for evaluation. A comprehensive EDL parametric analysis has been conducted in support of a high mass landing architecture by evaluating three types of vehicles -70° Sphere Cone, Ellipsled and SpaceX hybrid architecture called Red Dragon as potential candidate options for crewed entry vehicles. Aerocapture at the Martian orbit of about 400 km and subsequent Entry-from-orbit scenarios were investigated at velocities of 6.75 km/s and 4 km/s respectively. A study on aerocapture corridor over a range of entry velocities (6-9 km/s) suggests that a hypersonic L/D of 0.3 is sufficient for a Martian aerocapture. Parametric studies conducted by varying aeroshell diameters from 10 m to 15 m for several entry masses up to 150 mt are summarized and results reveal that vehicles with entry masses in the range of about 40-80 mt are capable of delivering cargo with a mass on the order of 5-20 mt. For vehicles with an entry mass of 20 mt to 80 mt, probabilistic Monte Carlo analysis of 5000 cases for each vehicle were run to determine the final landing ellipse and to quantify the statistical uncertainties associated with the trajectory and attitude conditions during atmospheric entry. Strategies and current technological challenges for a human rated Entry, Descent, and Landing to the Martian surface are presented in this study.

Where Public Health Meets Human Rights

PubMed Central

Kiragu, Karusa; Sawicki, Olga; Smith, Sally; Brion, Sophie; Sharma, Aditi; Mworeko, Lilian; Iovita, Alexandrina

2017-01-01

Abstract In 2014, the World Health Organization (WHO) initiated a process for validation of the elimination of mother-to-child transmission (EMTCT) of HIV and syphilis by countries. For the first time in such a process for the validation of disease elimination, WHO introduced norms and approaches that are grounded in human rights, gender equality, and community engagement. This human rights-based validation process can serve as a key opportunity to enhance accountability for human rights protection by evaluating EMTCT programs against human rights norms and standards, including in relation to gender equality and by ensuring the provision of discrimination-free quality services. The rights-based validation process also involves the assessment of participation of affected communities in EMTCT program development, implementation, and monitoring and evaluation. It brings awareness to the types of human rights abuses and inequalities faced by women living with, at risk of, or affected by HIV and syphilis, and commits governments to eliminate those barriers. This process demonstrates the importance and feasibility of integrating human rights, gender, and community into key public health interventions in a manner that improves health outcomes, legitimizes the participation of affected communities, and advances the human rights of women living with HIV. PMID:29302179

Recent Observations on Australian Bat Lyssavirus Tropism and Viral Entry

PubMed Central

Weir, Dawn L.; Annand, Edward J.; Reid, Peter A.; Broder, Christopher C.

2014-01-01

Australian bat lyssavirus (ABLV) is a recently emerged rhabdovirus of the genus lyssavirus considered endemic in Australian bat populations that causes a neurological disease in people indistinguishable from clinical rabies. There are two distinct variants of ABLV, one that circulates in frugivorous bats (genus Pteropus) and the other in insectivorous microbats (genus Saccolaimus). Three fatal human cases of ABLV infection have been reported, the most recent in 2013, and each manifested as acute encephalitis but with variable incubation periods. Importantly, two equine cases also arose recently in 2013, the first occurrence of ABLV in a species other than bats or humans. Similar to other rhabdoviruses, ABLV infects host cells through receptor-mediated endocytosis and subsequent pH-dependent fusion facilitated by its single fusogenic envelope glycoprotein (G). Recent studies have revealed that proposed rabies virus (RABV) receptors are not sufficient to permit ABLV entry into host cells and that the unknown receptor is broadly conserved among mammalian species. However, despite clear tropism differences between ABLV and RABV, the two viruses appear to utilize similar endocytic entry pathways. The recent human and horse infections highlight the importance of continued Australian public health awareness of this emerging pathogen. PMID:24556791

Recent observations on Australian bat lyssavirus tropism and viral entry.

PubMed

Weir, Dawn L; Annand, Edward J; Reid, Peter A; Broder, Christopher C

2014-02-19

Australian bat lyssavirus (ABLV) is a recently emerged rhabdovirus of the genus lyssavirus considered endemic in Australian bat populations that causes a neurological disease in people indistinguishable from clinical rabies. There are two distinct variants of ABLV, one that circulates in frugivorous bats (genus Pteropus) and the other in insectivorous microbats (genus Saccolaimus). Three fatal human cases of ABLV infection have been reported, the most recent in 2013, and each manifested as acute encephalitis but with variable incubation periods. Importantly, two equine cases also arose recently in 2013, the first occurrence of ABLV in a species other than bats or humans. Similar to other rhabdoviruses, ABLV infects host cells through receptor-mediated endocytosis and subsequent pH-dependent fusion facilitated by its single fusogenic envelope glycoprotein (G). Recent studies have revealed that proposed rabies virus (RABV) receptors are not sufficient to permit ABLV entry into host cells and that the unknown receptor is broadly conserved among mammalian species. However, despite clear tropism differences between ABLV and RABV, the two viruses appear to utilize similar endocytic entry pathways. The recent human and horse infections highlight the importance of continued Australian public health awareness of this emerging pathogen.

Resistance of human plasmacytoid dendritic CAL-1 cells to infection with lymphocytic choriomeningitis virus (LCMV) is caused by restricted virus cell entry, which is overcome by contact of CAL-1 cells with LCMV-infected cells.

PubMed

Iwasaki, Masaharu; Sharma, Siddhartha M; Marro, Brett S; de la Torre, Juan C

2017-11-01

Plasmacytoid dendritic cells (pDCs), a main source of type I interferon in response to viral infection, are an early cell target during lymphocytic choriomeningitis virus (LCMV) infection, which has been associated with the LCMV's ability to establish chronic infections. Human blood-derived pDCs have been reported to be refractory to ex vivo LCMV infection. In the present study we show that human pDC CAL-1 cells are refractory to infection with cell-free LCMV, but highly susceptible to infection with recombinant LCMVs carrying the surface glycoprotein of VSV, indicating that LCMV infection of CAL-1 cells is restricted at the cell entry step. Co-culture of uninfected CAL-1 cells with LCMV-infected HEK293 cells enabled LCMV to infect CAL-1 cells. This cell-to-cell spread required direct cell-cell contact and did not involve exosome pathway. Our findings indicate the presence of a novel entry pathway utilized by LCMV to infect pDC. Copyright © 2017. Published by Elsevier Inc.

COMPARISON OF THE USE OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL AND A CLASSICAL PHARMACOKINETIC MODEL FOR DIOXIN EXPOSURE ASSESSMENTS

EPA Science Inventory

In epidemiological studies, exposure assessments to TCDD, known as a possible human carcinogen, assume mono or biphasic elimination rates. Recent data suggests a dose dependent elimination rate for TCDD. A PBPK model, which uses a body burden dependent elimination rate, was dev...

Interleukin 6 inhibits HBV entry through NTCP down regulation.

PubMed

Bouezzedine, Fidaa; Fardel, Olivier; Gripon, Philippe

2015-07-01

Hepatitis B virus (HBV) infection is a major public health problem. Recently, the human liver bile acid transporter Na(+)/taurocholate cotransporting polypeptide (NTCP) has been identified as an HBV specific receptor. NTCP expression is known to be strongly regulated by IL-6. This study was aimed at characterizing the effect of IL-6 on HBV entry. HBV entry was inhibited by up to 90% when cells were pretreated with IL-6 as shown by a strong inhibition of long term HBsAg secretion. This effect was confirmed by showing a severe reduction of intracellular HBV cccDNA. In parallel, we observed a 98% decrease in NTCP mRNA steady state level and an 80% reduction in NTCP-mediated taurocholate uptake. IL-6-mediated inhibition of NTCP-mediated taurocholate uptake and viral entry exhibited similar dose-dependence and kinetics while restoration of NTCP expression suppressed the inhibitory effect of IL-6. NTCP-mediated HBV entry is therefore markedly inhibited by IL-6. Copyright © 2015 Elsevier Inc. All rights reserved.

On-Orbit Maneuver Calibrations for the Stardust Spacecraft

NASA Technical Reports Server (NTRS)

Nandi, Sumita; Kennedy, Brian; Williams, Kenneth E.; Byrnes, Dennis V.

2006-01-01

The Stardust spacecraft, launched February 7, 1999, successfully delivered its sample return capsule to the Utah Test and Training Range on January 15, 2006. The entry maneuver strategy included a trajectory correction at entry minus 10 days (TCM18) targeted to entry with the inclusion of a final biased fixed direction maneuver at entry minus 29 hours (TCM19). To meet the stringent entry targeting requirements necessary for human safety and capsule integrity, a campaign of maneuver calibrations were undertaken in summers of 2003 and 2005 to improve performance for both maneuvers. The results of the calibration program are reported here. The in-flight calibrations included a series of several turns to various final attitudes via deadband walks about each of the three spacecraft axes, as well as 12 in-place burns with magnitudes between 0.5 and 1.0 m/s, the range initially expected for TCM19. The turn and burn calibrations as well as the performance of TCM 17, 18 and 19 are discussed.

[Interspecies differences of noopept pharmacokinetics].

PubMed

Boĭko, S S; Korotkov, S A; Zherdev, V P; Gudasheva, T A; Ostrovskaia, R U; Voronina, T A

2004-01-01

Significant interspecific differences in the pharmacokinetics of noopept are manifested by a decrease in the drug elimination rate on the passage from rats to rabbits and humans. Very intensive metabolism of noopept was observed upon intravenous administration in rats. In these animals, presystemic elimination mechanisms lead to the formation of a specific metabolite representing a product of drug biotransformation hydroxylated at the phenyl ring. In rabbits, unchanged noopept circulates in the blood for a longer time upon both intravenous and peroral introduction, biotransformation proceeds at a much slower rate, and no metabolites analogous to that found in rats are detected. The noopept pharmacokinetics in humans differs from that in animals by still slower elimination and considerable individual variability. No drug metabolites are found in the human blood plasma, probably because of a relatively small dose and low concentration.

Returning nurses to the workforce: developing a fast track back program.

PubMed

Burns, Helen K; Sakraida, Teresa J; Englert, Nadine C; Hoffmann, Rosemary L; Tuite, Patricia; Foley, Susan M

2006-01-01

Fast Track Back: Re-entry into Nursing Practice program. Describes the development, implementation, and evaluation of a state-of-the-art re-entry program facilitating the return of licensed nonpracticing RNs to the workforce through a quality education program that retools them for the workforce in the areas of pharmacology, skill development using the latest technology, practice standards, and nursing issues. The program consists of didactic content taught via classroom, Internet, skills laboratory, and high fidelity human simulated technology and a clinical component. The program is a mechanism that enables re-entry nurses to improve skills and competencies necessary to practice in today's healthcare environment.

Entry, Descent and Landing Systems Analysis Study: Phase 1 Report

NASA Technical Reports Server (NTRS)

DwyerCianciolo, Alicia M.; Davis, Jody L.; Komar, David R.; Munk, Michelle M.; Samareh, Jamshid A.; Powell, Richard W.; Shidner, Jeremy D.; Stanley, Douglas O.; Wilhite, Alan W.; Kinney, David J.;

78 FR 20614 - Application(s) for Duty-Free Entry of Scientific Instruments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-05

... will be used to help understand how the human body functions normally, such as in learning, memory or hearing, and to understand the pathologies of human diseases. In order to understand these functions, this...

Sialic acid-dependent cell entry of human enterovirus D68

DOE PAGES

Liu, Yue; Sheng, Ju; Baggen, Jim; ...

2015-11-13

Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the ‘canyon’ on the virus surface. The sialic acid receptor induces a cascade of conformational changes inmore » the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Furthermore, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry.« less

Sialic acid-dependent cell entry of human enterovirus D68

PubMed Central

Liu, Yue; Sheng, Ju; Baggen, Jim; Meng, Geng; Xiao, Chuan; Thibaut, Hendrik J.; van Kuppeveld, Frank J. M.; Rossmann, Michael G.

2015-01-01

Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the ‘canyon' on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Thus, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry. PMID:26563423

Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes.

PubMed

Guillot, Clément; Martel, Nora; Berby, Françoise; Bordes, Isabelle; Hantz, Olivier; Blanchet, Matthieu; Sureau, Camille; Vaillant, Andrew; Chemin, Isabelle

2017-01-01

Hepatitis B virus (HBV) infection remains a major public health concern worldwide with 240 million individuals chronically infected and at risk of developing cirrhosis and hepatocellular carcinoma. Current treatments rarely cure chronic hepatitis B infection, highlighting the need for new anti-HBV drugs. Nucleic acid polymers (NAPs) are phosphorothioated oligonucleotides that have demonstrated a great potential to inhibit infection with several viruses. In chronically infected human patients, NAPs administration lead to a decline of blood HBsAg and HBV DNA and to HBsAg seroconversion, the expected signs of functional cure. NAPs have also been shown to prevent infection of duck hepatocytes with the Avihepadnavirus duck hepatitis B virus (DHBV) and to exert an antiviral activity against established DHBV infection in vitro and in vivo. In this study, we investigated the specific anti-HBV antiviral activity of NAPs in the HepaRG human hepatoma cell line and primary cultures of human hepatocytes. NAPs with different chemical features (phosphorothioation, 2'O-methyl ribose, 5-methylcytidine) were assessed for antiviral activity when provided at the time of HBV inoculation or post-inoculation. NAPs dose-dependently inhibited HBV entry in a phosphorothioation-dependent, sequence-independent and size-dependent manner. This inhibition of HBV entry by NAPs was impaired by 2'O-methyl ribose modification. NAP treatment after viral inoculation did not elicit any antiviral activity.

The ectodomain of a novel member of the immunoglobulin subfamily related to the poliovirus receptor has the attributes of a bona fide receptor for herpes simplex virus types 1 and 2 in human cells.

PubMed

Cocchi, F; Menotti, L; Mirandola, P; Lopez, M; Campadelli-Fiume, G

1998-12-01

We report on the functional cloning of a hitherto unknown member of the immunoglobulin (Ig) superfamily selected for its ability to confer susceptibility to herpes simplex virus (HSV) infection on a highly resistant cell line (J1.1-2 cells), derived by exposure of BHKtk- cells to a recombinant HSV-1 expressing tumor necrosis factor alpha (TNF-alpha). The sequence of herpesvirus Ig-like receptor (HIgR) predicts a transmembrane protein with an ectodomain consisting of three cysteine-bracketed domains, one V-like and two C-like. HIgR shares its ectodomain with and appears to be an alternative splice variant of the previously described protein PRR-1 (poliovirus receptor-related protein). Both HIgR and PRR-1 conferred on J1.1-2 cells susceptibility to HSV-1, HSV-2, and bovine herpesvirus 1. The viral ligand of HIgR and PRR-1 is glycoprotein D, a constituent of the virion envelope long known to mediate viral entry into cells through interaction with cellular receptor molecules. Recently, PRR-1, renamed HveC (herpesvirus entry mediator C), and the related PRR-2, renamed HveB, were reported to mediate the entry of HSV-1, HSV-2, and bovine herpesvirus 1, and the homologous poliovirus receptor was reported to mediate the entry of pseudorabies virus (R. J. Geraghty, C. Krummenacher, G. H. Cohen, R. J. Eisenberg, and P. G. Spear, Science 280:1618-1620, 1998; M. S. Warner, R. J. Geraghty, W. M. Martinez, R. I. Montgomery, J. C. Whitbeck, R. Xu, R. J. Eisenberg, G. H. Cohen, and P. G. Spear, Virology 246:179-189, 1998). Here we further show that HIgR or PRR-1 proteins detected by using a monoclonal antibody to PRR-1 are widely distributed among human cell lines susceptible to HSV infection and commonly used for HSV studies. The monoclonal antibody neutralized virion infectivity in cells transfected with HIgR or PRR-1 cDNA, as well as in the human cell lines, indicating a direct interaction of virions with the receptor molecule, and preliminarily mapping this function to the ectodomain of HIgR and PRR-1. Northern blot analysis showed that HIgR or PRR-1 mRNAs were expressed in human tissues, with the highest expression being detected in nervous system samples. HIgR adds a novel member to the cluster of Ig superfamily members able to mediate the entry of alphaherpesviruses into cells. The wide distribution of HIgR or PRR-1 proteins among human cell lines susceptible to HSV infection, coupled with the neutralizing activity of the antibody in the same cells, provides direct demonstration of the actual use of this cluster of molecules as HSV-1 and HSV-2 entry receptors in human cell lines. The high level of expression in samples from nervous system makes the use of these proteins in human tissues very likely. This cluster of molecules may therefore be considered to constitute bona fide receptors for HSV-1 and HSV-2.

Human Immunodeficiency Virus Immune Cell Receptors, Coreceptors, and Cofactors: Implications for Prevention and Treatment.

PubMed

Woodham, Andrew W; Skeate, Joseph G; Sanna, Adriana M; Taylor, Julia R; Da Silva, Diane M; Cannon, Paula M; Kast, W Martin

2016-07-01

In the last three decades, extensive research on human immunodeficiency virus (HIV) has highlighted its capability to exploit a variety of strategies to enter and infect immune cells. Although CD4(+) T cells are well known as the major HIV target, with infection occurring through the canonical combination of the cluster of differentiation 4 (CD4) receptor and either the C-C chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4) coreceptors, HIV has also been found to enter other important immune cell types such as macrophages, dendritic cells, Langerhans cells, B cells, and granulocytes. Interestingly, the expression of distinct cellular cofactors partially regulates the rate in which HIV infects each distinct cell type. Furthermore, HIV can benefit from the acquisition of new proteins incorporated into its envelope during budding events. While several publications have investigated details of how HIV manipulates particular cell types or subtypes, an up-to-date comprehensive review on HIV tropism for different immune cells is lacking. Therefore, this review is meant to focus on the different receptors, coreceptors, and cofactors that HIV exploits to enter particular immune cells. Additionally, prophylactic approaches that have targeted particular molecules associated with HIV entry and infection of different immune cells will be discussed. Unveiling the underlying cellular receptors and cofactors that lead to HIV preference for specific immune cell populations is crucial in identifying novel preventative/therapeutic targets for comprehensive strategies to eliminate viral infection.

Human Immunodeficiency Virus Immune Cell Receptors, Coreceptors, and Cofactors: Implications for Prevention and Treatment

PubMed Central

Woodham, Andrew W.; Skeate, Joseph G.; Sanna, Adriana M.; Taylor, Julia R.; Da Silva, Diane M.; Cannon, Paula M.

2016-01-01

Abstract In the last three decades, extensive research on human immunodeficiency virus (HIV) has highlighted its capability to exploit a variety of strategies to enter and infect immune cells. Although CD4+ T cells are well known as the major HIV target, with infection occurring through the canonical combination of the cluster of differentiation 4 (CD4) receptor and either the C-C chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4) coreceptors, HIV has also been found to enter other important immune cell types such as macrophages, dendritic cells, Langerhans cells, B cells, and granulocytes. Interestingly, the expression of distinct cellular cofactors partially regulates the rate in which HIV infects each distinct cell type. Furthermore, HIV can benefit from the acquisition of new proteins incorporated into its envelope during budding events. While several publications have investigated details of how HIV manipulates particular cell types or subtypes, an up-to-date comprehensive review on HIV tropism for different immune cells is lacking. Therefore, this review is meant to focus on the different receptors, coreceptors, and cofactors that HIV exploits to enter particular immune cells. Additionally, prophylactic approaches that have targeted particular molecules associated with HIV entry and infection of different immune cells will be discussed. Unveiling the underlying cellular receptors and cofactors that lead to HIV preference for specific immune cell populations is crucial in identifying novel preventative/therapeutic targets for comprehensive strategies to eliminate viral infection. PMID:27410493

Event detection for car park entries by video-surveillance

NASA Astrophysics Data System (ADS)

Coquin, Didier; Tailland, Johan; Cintract, Michel

2007-10-01

Intelligent surveillance has become an important research issue due to the high cost and low efficiency of human supervisors, and machine intelligence is required to provide a solution for automated event detection. In this paper we describe a real-time system that has been used for detecting car park entries, using an adaptive background learning algorithm and two indicators representing activity and identity to overcome the difficulty of tracking objects.

Trade-associated pathways of alien forest insect entries in Canada

Treesearch

Denys Yemshanov; Frank H. Koch; Mark Ducey; Klaus Koehler

2012-01-01

Long-distance introductions of new invasive species have often been driven by socioeconomic factors, such that traditional ‘‘biological’’ invasion models may not be capable of estimating spread fully and reliably. In this study we present a new methodology to characterize and predict pathways of human-assisted entries of alien forest insects. We have developed a...

Distinct chronology of neuronal cell cycle re-entry and tau pathology in the 3xTg-AD mouse model and Alzheimer's disease patients.

PubMed

Hradek, Alex C; Lee, Hyun-Pil; Siedlak, Sandra L; Torres, Sandy L; Jung, Wooyoung; Han, Ashley H; Lee, Hyoung-gon

2015-01-01

Cell cycle re-entry in Alzheimer's disease (AD) has emerged as an important pathological mechanism in the progression of the disease. This appearance of cell cycle related proteins has been linked to tau pathology in AD, but the causal and temporal relationship between the two is not completely clear. In this study, we found that hyperphosphorylated retinoblastoma protein (ppRb), a key regulator for G1/S transition, is correlated with a late marker for hyperphosphorylation of tau but not with other early markers for tau alteration in the 3xTg-AD mouse model. However, in AD brains, ppRb can colocalize with both early and later markers for tau alterations, and can often be found singly in many degenerating neurons, indicating the distinct development of pathology between the 3xTg-AD mouse model and human AD patients. The conclusions of this study are two-fold. First, our findings clearly demonstrate the pathological link between the aberrant cell cycle re-entry and tau pathology. Second, the chronological pattern of cell cycle re-entry with tau pathology in the 3xTg-AD mouse is different compared to AD patients suggesting the distinct pathogenic mechanism between the animal AD model and human AD patients.

Space and man. [planetary exploration and energy sources

NASA Technical Reports Server (NTRS)

Kolman, E.

1974-01-01

The effects of man's entry into space on changes in economics and technology, politics and law, science, philosophy, and art are considered. A single world economy, extracting from the natural resources of the moon and other cosmic bodies raw materials and energy, will avoid terrestrial limitations and improve society by eliminating the inequalities of economic and social status. However, a spacecraft for interplanetary travel require thermonuclear engines that achieve an escape velocity of 0.1 times the speed of light in order to allow an astronaut stellar expedition corresponding to the active life of a single generation.

Apparatus for measuring charged particle beam

NASA Technical Reports Server (NTRS)

Gregory, D. A.; Stocks, C. D. (Inventor)

1984-01-01

An apparatus to measure the incident charged particle beam flux while effectively eliminating losses to reflection and/or secondary emission of the charged particle beam being measured is described. It comprises a sense cup through which the charged particle beam enters. A sense cone forms the rear wall of the interior chamber with the cone apex adjacent the entry opening. An outer case surrounds the sense cup and is electrically insulated therefrom. Charged particles entering the interior chamber are trapped and are absorbed by the sense cup and cone and travel through a current measuring device to ground.

In silico assessment of phosphorylation and O-β-GlcNAcylation sites in human NPC1 protein critical for Ebola virus entry.

PubMed

Basharat, Zarrin; Yasmin, Azra

2015-08-01

Ebola is a highly pathogenic enveloped virus responsible for deadly outbreaks of severe hemorrhagic fever. It enters human cells by binding a multifunctional cholesterol transporter Niemann-Pick C1 (NPC1) protein. Post translational modification (PTM) information for NPC1 is crucial to understand Ebola virus (EBOV) entry and action due to changes in phosphorylation or glycosylation at the binding site. It is difficult and costly to experimentally assess this type of interaction, so in silico strategy was employed. Identification of phosphorylation sites, including conserved residues that could be possible targets for 21 predicted kinases was followed by interplay study between phosphorylation and O-β-GlcNAc modification of NPC1. Results revealed that only 4 out of 48 predicted phosphosites exhibited O-β-GlcNAc activity. Predicted outcomes were integrated with residue conservation and 3D structural information. Three Yin Yang sites were located in the α-helix regions and were conserved in studied vertebrate and mammalian species. Only one modification site S425 was found in β-turn region located near the N-terminus of NPC1 and was found to differ in pig, mouse, cobra and humans. The predictions suggest that Yin Yang sites may not be important for virus attachment to NPC1, whereas phosphosite 473 may be important for binding and hence entry of Ebola virus. This information could be useful in addressing further experimental studies and therapeutic strategies targeting PTM events in EBOV entry. Copyright © 2015 Elsevier B.V. All rights reserved.

78 FR 69393 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-19

.... FOR FURTHER INFORMATION CONTACT: National Geospatial-Intelligence Agency (NGA), ATTN: Human...: Delete entry and replace with ``Human Development Directorate, National Geospatial-Intelligence Agency...; System of Records AGENCY: National Geospatial-Intelligence Agency, DoD. ACTION: Notice to alter a System...

Perilymph pharmacokinetics of markers and dexamethasone applied and sampled at the lateral semi-circular canal.

PubMed

Salt, Alec N; Hartsock, Jared J; Gill, Ruth M; Piu, Fabrice; Plontke, Stefan K

2012-12-01

Perilymph pharmacokinetics was investigated by a novel approach, in which solutions containing drug or marker were injected from a pipette sealed into the perilymphatic space of the lateral semi-circular canal (LSCC). The cochlear aqueduct provides the outlet for fluid flow so this procedure allows almost the entire perilymph to be exchanged. After wait times of up to 4 h the injection pipette was removed and multiple, sequential samples of perilymph were collected from the LSCC. Fluid efflux at this site results from cerebrospinal fluid (CSF) entry into the basal turn of scala tympani (ST) so the samples allow drug levels from different locations in the ear to be defined. This method allows the rate of elimination of substances from the inner ear to be determined more reliably than with other delivery methods in which drug may only be applied to part of the ear. Results were compared for the markers trimethylphenylammonium (TMPA) and fluorescein and for the drug dexamethasone (Dex). For each substance, the concentration in fluid samples showed a progressive decrease as the delay time between injection and sampling was increased. This is consistent with the elimination of substance from the ear with time. The decline with time was slowest for fluorescein, was fastest for Dex, with TMPA at an intermediate rate. Simulations of the experiments showed that elimination occurred more rapidly from scala tympani (ST) than from scala vestibuli (SV). Calculated elimination half-times from ST averaged 54.1, 24.5 and 22.5 min for fluorescein, TMPA and Dex respectively and from SV 1730, 229 and 111 min respectively. The elimination of Dex from ST occurred considerably faster than previously appreciated. These pharmacokinetic parameters provide an important foundation for understanding of drug treatments of the inner ear.

Content Guidelines for an Undergraduate Human Resources Curriculum: Recommendations from Human Resources Professionals

ERIC Educational Resources Information Center

Sincoff, Michael Z.; Owen, Crystal L.

2004-01-01

In this study, the authors surveyed 445 human resources (HR) professionals to determine their views regarding the HR curriculum content that will lead to graduates' success in entry-level (first-job) HR positions. Ninety-eight questionnaires (22%) were returned. Respondents identified five topics--equal employment opportunity/affirmative action…

Human Elimination of Organochlorine Pesticides: Blood, Urine, and Sweat Study

PubMed Central

Lane, Kevin; Birkholz, Detlef

2016-01-01

Background. Many individuals have been exposed to organochlorinated pesticides (OCPs) through food, water, air, dermal exposure, and/or vertical transmission. Due to enterohepatic reabsorption and affinity to adipose tissue, OCPs are not efficiently eliminated from the human body and may accrue in tissues. Many epidemiological studies demonstrate significant exposure-disease relationships suggesting OCPs can alter metabolic function and potentially lead to illness. There is limited study of interventions to facilitate OCP elimination from the human body. This study explored the efficacy of induced perspiration as a means to eliminate OCPs. Methods. Blood, urine, and sweat (BUS) were collected from 20 individuals. Analysis of 23 OCPs was performed using dual-column gas chromatography with electron-capture detectors. Results. Various OCPs and metabolites, including DDT, DDE, methoxychlor, endrin, and endosulfan sulfate, were excreted into perspiration. Generally, sweat samples showed more frequent OCP detection than serum or urine analysis. Many OCPs were not readily detected in blood testing while still being excreted and identified in sweat. No direct correlation was found among OCP concentrations in the blood, urine, or sweat compartments. Conclusions. Sweat analysis may be useful in detecting some accrued OCPs not found in regular serum testing. Induced perspiration may be a viable clinical tool for eliminating some OCPs. PMID:27800487

Towards Canine Rabies Elimination in Cebu, Philippines: Assessment of Health Economic Data.

PubMed

Miranda, L M; Miranda, M E; Hatch, B; Deray, R; Shwiff, S; Roces, M C; Rupprecht, C E

2017-02-01

Rabies is endemic in the Philippines. In 2010, with support from the Bill and Melinda Gates Foundation, a canine rabies elimination project was initiated in the Philippine Archipelago of Visayan. We conducted an analysis of dog vaccination and human PEP costs for dog bite patients in a highly urbanized area and a low-income rural municipality in Cebu Province, Philippines, from 2010 to 2012. Our findings indicated that eliminating rabies in dogs through mass vaccination is more cost-effective than treating rabies exposures in humans. The average costs (in USD) per human life saved through PEP were $1620.28 in Cebu City and $1498 in Carmen. Costs per dog vaccinated ranged from $1.18 to $5.79 in Cebu City and $2.15 to $3.38 in Carmen. Mass dog vaccination campaigns conducted in each village were more cost-effective than fixed-site campaigns. The costs of dog vaccination can be reduced further through bulk vaccine purchase by the national government or large donor agency, for example the BMGF. As communities achieve canine rabies elimination, more judicious use of PEP will result in significant public savings. The study affirms the willingness of local governments to invest and reassure donors of their cooperation and resource contribution to sustain disease elimination efforts. © 2015 Blackwell Verlag GmbH.

Human Elimination of Organochlorine Pesticides: Blood, Urine, and Sweat Study.

PubMed

Genuis, Stephen J; Lane, Kevin; Birkholz, Detlef

2016-01-01

Background . Many individuals have been exposed to organochlorinated pesticides (OCPs) through food, water, air, dermal exposure, and/or vertical transmission. Due to enterohepatic reabsorption and affinity to adipose tissue, OCPs are not efficiently eliminated from the human body and may accrue in tissues. Many epidemiological studies demonstrate significant exposure-disease relationships suggesting OCPs can alter metabolic function and potentially lead to illness. There is limited study of interventions to facilitate OCP elimination from the human body. This study explored the efficacy of induced perspiration as a means to eliminate OCPs. Methods . Blood, urine, and sweat (BUS) were collected from 20 individuals. Analysis of 23 OCPs was performed using dual-column gas chromatography with electron-capture detectors. Results . Various OCPs and metabolites, including DDT, DDE, methoxychlor, endrin, and endosulfan sulfate, were excreted into perspiration. Generally, sweat samples showed more frequent OCP detection than serum or urine analysis. Many OCPs were not readily detected in blood testing while still being excreted and identified in sweat. No direct correlation was found among OCP concentrations in the blood, urine, or sweat compartments. Conclusions . Sweat analysis may be useful in detecting some accrued OCPs not found in regular serum testing. Induced perspiration may be a viable clinical tool for eliminating some OCPs.

Enhancement of Ebola Virus Infection via Ficolin-1 Interaction with the Mucin Domain of GP Glycoprotein.

PubMed

Favier, Anne-Laure; Gout, Evelyne; Reynard, Olivier; Ferraris, Olivier; Kleman, Jean-Philippe; Volchkov, Viktor; Peyrefitte, Christophe; Thielens, Nicole M

2016-06-01

Ebola virus infection requires the surface viral glycoprotein to initiate entry into the target cells. The trimeric glycoprotein is a highly glycosylated viral protein which has been shown to interact with host C-type lectin receptors and the soluble complement recognition protein mannose-binding lectin, thereby enhancing viral infection. Similarly to mannose-binding lectin, ficolins are soluble effectors of the innate immune system that recognize particular glycans at the pathogen surface. In this study, we demonstrate that ficolin-1 interacts with the Zaire Ebola virus (EBOV) glycoprotein, and we characterized this interaction by surface plasmon resonance spectroscopy. Ficolin-1 was shown to bind to the viral glycoprotein with a high affinity. This interaction was mediated by the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of the viral glycoprotein. Using a ficolin-1 control mutant devoid of sialic acid-binding capacity, we identified sialylated moieties of the mucin domain to be potential ligands on the glycoprotein. In cell culture, using both pseudotyped viruses and EBOV, ficolin-1 was shown to enhance EBOV infection independently of the serum complement. We also observed that ficolin-1 enhanced EBOV infection on human monocyte-derived macrophages, described to be major viral target cells,. Competition experiments suggested that although ficolin-1 and mannose-binding lectin recognized different carbohydrate moieties on the EBOV glycoprotein, the observed enhancement of the infection likely depended on a common cellular receptor/partner. In conclusion, ficolin-1 could provide an alternative receptor-mediated mechanism for enhancing EBOV infection, thereby contributing to viral subversion of the host innate immune system. A specific interaction involving ficolin-1 (M-ficolin), a soluble effector of the innate immune response, and the glycoprotein (GP) of EBOV was identified. Ficolin-1 enhanced virus infection instead of tipping the balance toward its elimination. An interaction between the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of Ebola virus GP occurred. In this model, the enhancement of infection was shown to be independent of the serum complement. The facilitation of EBOV entry into target host cells by the interaction with ficolin-1 and other host lectins shunts virus elimination, which likely facilitates the survival of the virus in infected host cells and contributes to the virus strategy to subvert the innate immune response. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

An early colonisation pathway into northwest Australia 70-60,000 years ago

NASA Astrophysics Data System (ADS)

Norman, Kasih; Inglis, Josha; Clarkson, Chris; Faith, J. Tyler; Shulmeister, James; Harris, Daniel

2018-01-01

Colonisation of Sahul 70-60 thousand years ago (kya) represents the first great maritime migration undertaken by anatomically modern humans in one of the final phases of the Out of Africa dispersal. Visual connectivity network analyses, agent-based simulations and ocean current modelling reveal that modern humans could follow numerous northern and southern migration pathways into Sahul. Our results support a southern route out of Africa through South Asia with entry into ISEA through the Banda Arc, culminating in an early colonisation of Sahul on the northwest shelf. Our results show multiple colonisation events through other entry points were also probable, and raise interesting possibilities for complex regional migration and population histories.

Zoonoses-With Friends Like This, Who Needs Enemies?

PubMed Central

Baum, Stephen G.

2008-01-01

Zoonoses are infections that are spread from animals to humans. Most often, humans are “dead-end” hosts, meaning that there is no subsequent human-to-human transmission. If one considers most of the emerging infections that were recognized at the end of the last century and the beginning of this century, they would fall into the category of zoonoses. One of the most important common traits exhibited by infections that have been or can be eliminated from the face of the earth (e.g. smallpox, measles, polio) is the absence of any host other than humans. Therefore, zoonses represent infections that can never be eliminated and must be considered as permanent and recurrent factors to be dealt with in protecting human health. PMID:18596867

Zoonoses-with friends like this, who needs enemies?

PubMed

Baum, Stephen G

2008-01-01

Zoonoses are infections that are spread from animals to humans. Most often, humans are "dead-end" hosts, meaning that there is no subsequent human-to-human transmission. If one considers most of the emerging infections that were recognized at the end of the last century and the beginning of this century, they would fall into the category of zoonoses. One of the most important common traits exhibited by infections that have been or can be eliminated from the face of the earth (e.g. smallpox, measles, polio) is the absence of any host other than humans. Therefore, zoonses represent infections that can never be eliminated and must be considered as permanent and recurrent factors to be dealt with in protecting human health.

Consoer et al PFOS dataset

EPA Pesticide Factsheets

This ScienceHub entry was developed for the published paper: Consoer et al., 2016, Toxicokinetics of perfluorooctane sulfonate in rainow trout (Oncorhynchus mykiss), Environ. Toxicol. Chem. 35:717-727. Individual rainbow trout were exposed to PFOS by bolus injection (elimination studies) or by adding PFOS to incoming water (branchial uptake studies). The trout were fitted with indwelling catheters and urinary cannulae to permit periodic collection of blood and urine. Additional sampling was conducted to evaluate PFOS uptake from and elimination to respired water. Data obtained from each fish was evaluated using a clearance-volume pharmacokinetic model. Modeled kinetic parameters were then averaged to develop summary statistics which were used as a basis for interpreting modeled results and making comparisons to a previous study of rainbow trout exposed to perfluorooctanoate (PFOA; Consoer et al., 2014, Aquat. Toxicol. 156:65-73). The results of this study, combined with that of the previous PFOA study, suggest that PFOA is a substrate for renal transporters in fish while glomerular filtration alone may be sufficient to explain the observed renal elimination of PFOS. These findings demonstrate that models developed to predict the bioaccumulation of perfluoroalkyl acids by fish must account for differences in renal clearance of individual compounds.This dataset is associated with the following publication:Consoer, D., A. Hoffman , P. Fitzsimmons , P. Kosia

Efficacy of imidocarb dipropionate in eliminating Theileria equi from experimentally infected horses.

PubMed

Grause, Juanita F; Ueti, Massaro W; Nelson, Jeffrey T; Knowles, Donald P; Kappmeyer, Lowell S; Bunn, Thomas O

2013-06-01

Theileria equi, one of the causative agents of equine piroplasmosis, is endemic in many regions of the world but is considered a 'foreign' animal disease in the USA. In an effort to prevent the importation of T. equi, stringent serological screening of horses is practiced prior to entry to the USA. Current regulatory options available where horses are found to be infected include permanent quarantine with or without chemotherapy, repatriation, or euthanasia. Chemotherapeutics that eliminate infection and subsequently transmission risk are critical in the management of infected horses. In this study, the efficacy of the drug imidocarb dipropionate against experimental T. equi infection was assessed. Of nine horses experimentally inoculated with T. equi isolated from an animal previously imported from Peru, six were treated with imidocarb dipropionate after the resolution of the acute phase of the disease. Elimination of the parasite was demonstrated in 5/6 by nested PCR, blood transfusions to naïve horses, and reversion to seronegative status. The findings support the use of this drug as a potential treatment option in controlling outbreaks of T. equi, and also suggest that 'combination testing' using both serological and PCR detection methods are necessary to demonstrate clearance of infection. Published by Elsevier Ltd.

Herpes simplex virus type 2 glycoprotein H interacts with integrin αvβ3 to facilitate viral entry and calcium signaling in human genital tract epithelial cells.

PubMed

Cheshenko, Natalia; Trepanier, Janie B; González, Pablo A; Eugenin, Eliseo A; Jacobs, William R; Herold, Betsy C

2014-09-01

Herpes simplex virus (HSV) entry requires multiple interactions at the cell surface and activation of a complex calcium signaling cascade. Previous studies demonstrated that integrins participate in this process, but their precise role has not been determined. These studies were designed to test the hypothesis that integrin αvβ3 signaling promotes the release of intracellular calcium (Ca2+) stores and contributes to viral entry and cell-to-cell spread. Transfection of cells with small interfering RNA (siRNA) targeting integrin αvβ3, but not other integrin subunits, or treatment with cilengitide, an Arg-Gly-Asp (RGD) mimetic, impaired HSV-induced Ca2+ release, viral entry, plaque formation, and cell-to-cell spread of HSV-1 and HSV-2 in human cervical and primary genital tract epithelial cells. Coimmunoprecipitation studies and proximity ligation assays indicated that integrin αvβ3 interacts with glycoprotein H (gH). An HSV-2 gH-null virus was engineered to further assess the role of gH in the virus-induced signaling cascade. The gH-2-null virus bound to cells and activated Akt to induce a small Ca2+ response at the plasma membrane, but it failed to trigger the release of cytoplasmic Ca2+ stores and was impaired for entry and cell-to-cell spread. Silencing of integrin αvβ3 and deletion of gH prevented phosphorylation of focal adhesion kinase (FAK) and the transport of viral capsids to the nuclear pore. Together, these findings demonstrate that integrin signaling is activated downstream of virus-induced Akt signaling and facilitates viral entry through interactions with gH by activating the release of intracellular Ca2+ and FAK phosphorylation. These findings suggest a new target for HSV treatment and suppression. Herpes simplex viruses are the leading cause of genital disease worldwide, the most common infection associated with neonatal encephalitis, and a major cofactor for HIV acquisition and transmission. There is no effective vaccine. These epidemiological findings underscore the urgency to develop novel HSV treatment or prevention strategies. This study addresses this gap by further defining the signaling pathways the virus usurps to enter human genital tract epithelial cells. Specifically, the study defines the role played by integrins and by the viral envelope glycoprotein H in entry and cell-to-cell spread. This knowledge will facilitate the identification of new targets for the development of treatment and prevention. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry

PubMed Central

Boos, Simone; Resch, Moritz; Brizic, Ilija; Mach, Michael; Scrivano, Laura

2017-01-01

Herpesvirus gH/gL envelope glycoprotein complexes are key players in virus entry as ligands for host cell receptors and by promoting fusion of viral envelopes with cellular membranes. Human cytomegalovirus (HCMV) has two alternative gH/gL complexes, gH/gL/gO and gH/gL/UL128,130,131A which both shape the HCMV tropism. By studying binding of HCMV particles to fibroblasts, we could for the first time show that virion gH/gL/gO binds to platelet-derived growth factor-α (PDGFR-α) on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex. PDGFR-α-dependent entry is not dependent on activation of PDGFR-α. We could also show that the gH/gL/gO—PDGFR-α interaction starts the predominant entry pathway for infection of fibroblasts with free virus. Cell-associated virus spread is either driven by gH/gL/gO interacting with PDGFR-α or by the gH/gL/UL128,130,131A complex. PDGFR-α-positive cells may thus be preferred first target cells for infections with free virus which might have implications for the design of future HCMV vaccines or anti-HCMV drugs. PMID:28403202

Evaluating long-term effectiveness of sleeping sickness control measures in Guinea.

PubMed

Pandey, Abhishek; Atkins, Katherine E; Bucheton, Bruno; Camara, Mamadou; Aksoy, Serap; Galvani, Alison P; Ndeffo-Mbah, Martial L

2015-10-22

Human African Trypanosomiasis threatens human health across Africa. The subspecies T.b. gambiense is responsible for the vast majority of reported HAT cases. Over the past decade, expanded control efforts accomplished a substantial reduction in HAT transmission, spurring the WHO to include Gambian HAT on its roadmap for 2020 elimination. To inform the implementation of this elimination goal, we evaluated the likelihood that current control interventions will achieve the 2020 target in Boffa prefecture in Guinea, which has one of the highest prevalences for HAT in the country, and where vector control measures have been implemented in combination with the traditional screen and treat strategy. We developed a three-species mathematical model of HAT and used a Bayesian melding approach to calibrate the model to epidemiological and entomological data from Boffa. From the calibrated model, we generated the probabilistic predictions regarding the likelihood that the current HAT control programs could achieve elimination by 2020 in Boffa. Our model projections indicate that if annual vector control is implemented in combination with annual or biennial active case detection and treatment, the probability of eliminating HAT as public health problem in Boffa by 2020 is over 90%. Annual implementation of vector control alone has a significant impact but a decreased chance of reaching the objective (77%). However, if the ongoing control efforts are interrupted, HAT will continue to remain a public health problem. In the presence of a non-human animal transmission reservoir, intervention strategies must be maintained at high coverage, even after 2020 elimination, to prevent HAT reemerging as a public health problem. Complementing active screening and treatment with vector control has the potential to achieve the elimination target before 2020 in the Boffa focus. However, surveillance must continue after elimination to prevent reemergence.

77 FR 69443 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-19

... ``Human Capital Office'' and replace with ``Human Resources.'' Notification procedure: Delete entry and... requests should contain the individual's full name and Social Security Number (SSN).'' Record access.... Written requests should contain the individual's full name and Social Security Number (SSN).'' Contesting...

Aviation human-in-the-loop simulation studies : experimental planning, design, and data management.

DOT National Transportation Integrated Search

2014-01-01

Researchers from the NASAAmes Flight Cognition Laband the FAAs Aerospace Human Factors Research Lab at the Civil Aerospace Medical Instituteexamined task and workload management by single pilots in very light jets, also called entry-level jets.Thi...

Multiscale Modeling of Virus Entry via Receptor-Mediated Endocytosis

NASA Astrophysics Data System (ADS)

Liu, Jin

2012-11-01

Virus infections are ubiquitous and remain major threats to human health worldwide. Viruses are intracellular parasites and must enter host cells to initiate infection. Receptor-mediated endocytosis is the most common entry pathway taken by viruses, the whole process is highly complex and dictated by various events, such as virus motions, membrane deformations, receptor diffusion and ligand-receptor reactions, occurring at multiple length and time scales. We develop a multiscale model for virus entry through receptor-mediated endocytosis. The binding of virus to cell surface is based on a mesoscale three dimensional stochastic adhesion model, the internalization (endocytosis) of virus and cellular membrane deformation is based on the discretization of Helfrich Hamiltonian in a curvilinear space using Monte Carlo method. The multiscale model is based on the combination of these two models. We will implement this model to study the herpes simplex virus entry into B78 cells and compare the model predictions with experimental measurements.

Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry

PubMed Central

Bose, Sayantan; Jardetzky, Theodore S.; Lamb, Robert A.

2015-01-01

The Paramyxoviridae include some of the great and ubiquitous disease-causing viruses of humans and animals. In most paramyxoviruses, two viral membrane glycoproteins, fusion protein (F) and receptor binding protein (HN, H or G) mediate a concerted process of recognition of host cell surface molecules followed by fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. The interactions between the F and HN, H or G viral glycoproteins and host molecules are critical in determining host range, virulence and spread of these viruses. Recently, atomic structures, together with biochemical and biophysical studies, have provided major insights into how these two viral glycoproteins successfully interact with host receptors on cellular membranes and initiate the membrane fusion process to gain entry into cells. These studies highlight the conserved core mechanisms of paramyxovirus entry that provide the fundamental basis for rational anti-viral drug design and vaccine development. PMID:25771804

Human Reliability and the Cost of Doing Business

NASA Technical Reports Server (NTRS)

DeMott, Diana

2014-01-01

Most businesses recognize that people will make mistakes and assume errors are just part of the cost of doing business, but does it need to be? Companies with high risk, or major consequences, should consider the effect of human error. In a variety of industries, Human Errors have caused costly failures and workplace injuries. These have included: airline mishaps, medical malpractice, administration of medication and major oil spills have all been blamed on human error. A technique to mitigate or even eliminate some of these costly human errors is the use of Human Reliability Analysis (HRA). Various methodologies are available to perform Human Reliability Assessments that range from identifying the most likely areas for concern to detailed assessments with human error failure probabilities calculated. Which methodology to use would be based on a variety of factors that would include: 1) how people react and act in different industries, and differing expectations based on industries standards, 2) factors that influence how the human errors could occur such as tasks, tools, environment, workplace, support, training and procedure, 3) type and availability of data and 4) how the industry views risk & reliability influences ( types of emergencies, contingencies and routine tasks versus cost based concerns). The Human Reliability Assessments should be the first step to reduce, mitigate or eliminate the costly mistakes or catastrophic failures. Using Human Reliability techniques to identify and classify human error risks allows a company more opportunities to mitigate or eliminate these risks and prevent costly failures.

A role for SNAP-25 but not VAMPs in store-mediated Ca2+ entry in human platelets

PubMed Central

Redondo, Pedro C; Harper, Alan G S; Salido, Ginés M; Pariente, Jose A; Sage, Stewart O; Rosado, Juan A

2004-01-01

Store-mediated Ca2+ entry (SMCE) is a major mechanism for Ca2+ influx in non-excitable cells. Recently, a conformational coupling mechanism allowing coupling between transient receptor potential channels (TRPCs) and IP3 receptors has been proposed to activate SMCE. Here we have investigated the role of two soluble N-ethylmaleimide-sensitive-factor attachment protein receptors (SNAREs), which are involved in membrane trafficking and docking, in SMCE in human platelets. We found that the synaptosome-associated protein (SNAP-25) and the vesicle-associated membrane proteins (VAMP) coimmunoprecipitate with hTRPC1 in platelets. Treatment with botulinum toxin (BoNT) E or with tetanus toxin (TeTx), induced cleavage and inactivation of SNAP-25 and VAMPs, respectively. BoNTs significantly reduced thapsigargin- (TG) and agonist-evoked SMCE. Treatment with BoNTs once SMCE had been activated decreased Ca2+ entry, indicating that SNAP-25 is required for the activation and maintenance of SMCE. In contrast, treatment with TeTx had no effect on either the activation or the maintenance of SMCE in platelets. Finally, treatment with BoNT E impaired the coupling between naturally expressed hTRPC1 and IP3 receptor type II in platelets. From these findings we suggest SNAP-25 has a role in SMCE in human platelets. PMID:15121806

Design Projects in Human Anatomy & Physiology

ERIC Educational Resources Information Center

Polizzotto, Kristin; Ortiz, Mary T.

2008-01-01

Very often, some type of writing assignment is required in college entry-level Human Anatomy and Physiology courses. This assignment can be anything from an essay to a research paper on the literature, focusing on a faculty-approved topic of interest to the student. As educators who teach Human Anatomy and Physiology at an urban community college,…

Early events in herpes simplex virus lifecycle with implications for an infection of lifetime.

PubMed

Salameh, Sarah; Sheth, Urmi; Shukla, Deepak

2012-01-01

Affecting a large percentage of human population herpes simplex virus (HSV) types -1 and -2 mainly cause oral, ocular, and genital diseases. Infection begins with viral entry into a host cell, which may be preceded by viral "surfing" along filopodia. Viral glycoproteins then bind to one or more of several cell surface receptors, such as herpesvirus entry mediator (HVEM), nectin-1, 3-O sulfated heparan sulfate (3-OS HS), paired immunoglobulin-like receptor α, and non-muscle myosin-IIA. At least five viral envelope glycoproteins participate in entry and these include gB, gC, gD and gH-gL. Post-entry, these glycoproteins may also facilitate cell-to-cell spread of the virus, which helps in the evasion of physical barriers as well as several components of the innate and adaptive immune responses. The spread may be facilitated by membrane fusion, movement across tight junctions, transfer across neuronal synapses, or the recruitment of actin-containing structures. This review summarizes some of the recent advances in our understanding of HSV entry and cell-to-cell spread.

Ebola virus host cell entry.

PubMed

Sakurai, Yasuteru

2015-01-01

Ebola virus is an enveloped virus with filamentous structure and causes a severe hemorrhagic fever in human and nonhuman primates. Host cell entry is the first essential step in the viral life cycle, which has been extensively studied as one of the therapeutic targets. A virus factor of cell entry is a surface glycoprotein (GP), which is an only essential viral protein in the step, as well as the unique particle structure. The virus also interacts with a lot of host factors to successfully enter host cells. Ebola virus at first binds to cell surface proteins and internalizes into cells, followed by trafficking through endosomal vesicles to intracellular acidic compartments. There, host proteases process GPs, which can interact with an intracellular receptor. Then, under an appropriate circumstance, viral and endosomal membranes are fused, which is enhanced by major structural changes of GPs, to complete host cell entry. Recently the basic research of Ebola virus infection mechanism has markedly progressed, largely contributed by identification of host factors and detailed structural analyses of GPs. This article highlights the mechanism of Ebola virus host cell entry, including recent findings.

78 FR 39712 - University of Illinois, et al.; Notice of Decision on Applications for Duty-Free Entry of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-02

.... Reasons: The instrument will be used to help understand how the human body functions normally, such as in learning, memory or hearing, and to understand the pathologies of human diseases. In order to understand...

CPAS Parachute Testing, Model Development, & Verification

NASA Technical Reports Server (NTRS)

Romero, Leah M.

2013-01-01

Capsule Parachute Assembly System (CPAS) is the human rated parachute system for the Orion vehicle used during re-entry. Similar to Apollo parachute design. Human rating requires additional system redundancy. A Government Furnished Equipment (GFE) project responsible for: Design; Development testing; Performance modeling; Fabrication; Qualification; Delivery

Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

PubMed

Kamimura, Hidetaka; Ito, Satoshi

2016-01-01

1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

An evaluation of voluntary 2-dose varicella vaccination coverage in New York City public schools.

PubMed

Doll, Margaret K; Rosen, Jennifer B; Bialek, Stephanie R; Szeto, Hiram; Zimmerman, Christopher M

2015-05-01

We assessed coverage for 2-dose varicella vaccination, which is not required for school entry, among New York City public school students and examined characteristics associated with receipt of 2 doses. We measured receipt of either at least 1 or 2 doses of varicella vaccine among students aged 4 years and older in a sample of 336 public schools (n = 223 864 students) during the 2010 to 2011 school year. Data came from merged student vaccination records from 2 administrative data systems. We conducted multivariable regression to assess associations of age, gender, race/ethnicity, and school location with 2-dose prevalence. Coverage with at least 1 varicella dose was 96.2% (95% confidence interval [CI] = 96.2%, 96.3%); coverage with at least 2 doses was 64.8% (95% CI = 64.6%, 64.9%). Increasing student age, non-Hispanic White race/ethnicity, and attendance at school in Staten Island were associated with lower 2-dose coverage. A 2-dose varicella vaccine requirement for school entry would likely improve 2-dose coverage, eliminate coverage disparities, and prevent disease.

Elimination of Mycoplasma Contamination from Infected Human Hepatocyte C3A Cells by Intraperitoneal Injection in BALB/c Mice.

PubMed

Weng, Jun; Li, Yang; Cai, Lei; Li, Ting; Peng, Gongze; Fu, Chaoyi; Han, Xu; Li, Haiyan; Jiang, Zesheng; Zhang, Zhi; Du, Jiang; Peng, Qing; Gao, Yi

2017-01-01

Background/Aims: The use of antibiotics to eliminate Mycoplasma contamination has some serious limitations. Mycoplasma contamination can be eliminated by intraperitoneal injection of BALB/c mice with contaminated cells combined with screening monoclonal cells. However, in vivo passage in mice after injection with contaminated cells requires a long duration (20-54 days). Furthermore, it is important to monitor for cross-contamination of mouse and human cells, xenotropic murine leukemia virus-related virus (XMRV) infection, and altered cell function after the in vivo treatment. The present study aimed to validate a reliable and simplified method to eliminate mycoplasma contamination from human hepatocytes. BALB/c mice were injected with paraffin oil prior to injection with cells, in order to shorten duration of intraperitoneal passage. Cross-contamination of mouse and human cells, XMRV infection and cell function-related genes and proteins were also evaluated. Methods: PCR and DNA sequencing were used to confirm Mycoplasma hyorhinis ( M. hyorhinis ) contamination in human hepatocyte C3A cells. Five BALB/c mice were intraperitoneally injected with 0.5 ml paraffin oil 1 week before injection of the cells. The mice were then intraperitoneally injected with C3A hepatocytes (5.0 × 10 6 /ml) contaminated with M. hyorhinis (6.2 ± 2.2 × 10 8 CFU/ml). Ascites were collected for monoclonal cell screening on the 14th day after injection of contaminated cells. Elimination of mycoplasma from cells was determined by PCR and Transmission Electron Microscopy (TEM). Human-mouse cell and XMRV contamination were also detected by PCR. Quantitative reverse transcription PCR and western blotting were used to compare the expression of genes and proteins among treated cells, non-treated infected cells, and uninfected cells. Results: Fourteen days after injection with cells, 4 of the 5 mice had ascites. Hepatocyte colonies extracted from the ascites of four mice were all mycoplasma-free. There was no cell cross-contamination or XMRV infection in treated cell cultures. Elimination of Mycoplasma resulted in partial or complete recovery in the expression of ALB, TF, and CYP3A4 genes as well as proteins. Proliferation of the treated cells was not significantly affected by this management. Conclusion: The method of elimination of Mycoplasma contamination in this study was validated and reproducible. Success was achieved in four of five cases examined. Compared to the previous studies, the duration of intraperitoneal passage in this study was significantly shorter.

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

PubMed Central

Cerqueira, Carla; Samperio Ventayol, Pilar; Vogeley, Christian

2015-01-01

ABSTRACT The entry of human papillomaviruses into host cells is a complex process. It involves conformational changes at the cell surface, receptor switching, internalization by a novel endocytic mechanism, uncoating in endosomes, trafficking of a subviral complex to the Golgi complex, and nuclear entry during mitosis. Here, we addressed how the stabilizing contacts in the capsid of human papillomavirus 16 (HPV16) may be reversed to allow uncoating of the viral genome. Using biochemical and cell-biological analyses, we determined that the major capsid protein L1 underwent proteolytic cleavage during entry. In addition to a dispensable cathepsin-mediated proteolysis that occurred likely after removal of capsomers from the subviral complex in endosomes, at least two further proteolytic cleavages of L1 were observed, one of which was independent of the low-pH environment of endosomes. This cleavage occurred extracellularly. Further analysis showed that the responsible protease was the secreted trypsin-like serine protease kallikrein-8 (KLK8) involved in epidermal homeostasis and wound healing. Required for infection, the cleavage was facilitated by prior interaction of viral particles with heparan sulfate proteoglycans. KLK8-mediated cleavage was crucial for further conformational changes exposing an important epitope of the minor capsid protein L2. Occurring independently of cyclophilins and of furin that mediate L2 exposure, KLK8-mediated cleavage of L1 likely facilitated access to L2, located in the capsid lumen, and potentially uncoating. Since HPV6 and HPV18 also required KLK8 for entry, we propose that the KLK8-dependent entry step is conserved. IMPORTANCE Our analysis of the proteolytic processing of incoming HPV16, an etiological agent of cervical cancer, demonstrated that the capsid is cleaved extracellularly by a serine protease active during wound healing and that this cleavage was crucial for infection. The cleavage of L1 is one of at least four structural alterations that prime the virus extracellularly for receptor switching, internalization, and possibly uncoating. This step was also important for HPV6 and HPV18, which may suggest that it is conserved among the papillomaviruses. This study advances the understanding of how HPV16 initially infects cells, strengthens the notion that wounding facilitates infection of epidermal tissue, and may help the development of antiviral measures. PMID:25926655

Engineering of a Potent Recombinant Lectin-Toxin Fusion Protein to Eliminate Human Pluripotent Stem Cells.

PubMed

Tateno, Hiroaki; Saito, Sayoko

2017-07-10

The use of human pluripotent stem cells (hPSCs) such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) in regenerative medicine is hindered by their tumorigenic potential. Previously, we developed a recombinant lectin-toxin fusion protein of the hPSC-specific lectin rBC2LCN, which has a 23 kDa catalytic domain (domain III) of Pseudomonas aeruginosa exotoxin A (rBC2LCN-PE23). This fusion protein could selectively eliminate hPSCs following its addition to the cell culture medium. Here we conjugated rBC2LCN lectin with a 38 kDa domain of exotoxin A containing domains Ib and II in addition to domain III (PE38). The developed rBC2LCN-PE38 fusion protein could eliminate 50% of 201B7 hPSCs at a concentration of 0.003 μg/mL (24 h incubation), representing an approximately 556-fold higher activity than rBC2LCN-PE23. Little or no effect on human fibroblasts, human mesenchymal stem cells, and hiPSC-derived hepatocytes was observed at concentrations lower than 1 μg/mL. Finally, we demonstrate that rBC2LCN-PE38 selectively eliminates hiPSCs from a mixed culture of hiPSCs and hiPSC-derived hepatocytes. Since rBC2LCN-PE38 can be prepared from soluble fractions of E. coli culture at a yield of 9 mg/L, rBC2LCN-PE38 represents a practical reagent to remove human pluripotent stem cells residing in cultured cells destined for transplantation.

Interaction of Mycobacterium leprae with human airway epithelial cells: adherence, entry, survival, and identification of potential adhesins by surface proteome analysis.

PubMed

Silva, Carlos A M; Danelishvili, Lia; McNamara, Michael; Berredo-Pinho, Márcia; Bildfell, Robert; Biet, Franck; Rodrigues, Luciana S; Oliveira, Albanita V; Bermudez, Luiz E; Pessolani, Maria C V

2013-07-01

This study examined the in vitro interaction between Mycobacterium leprae, the causative agent of leprosy, and human alveolar and nasal epithelial cells, demonstrating that M. leprae can enter both cell types and that both are capable of sustaining bacterial survival. Moreover, delivery of M. leprae to the nasal septum of mice resulted in macrophage and epithelial cell infection in the lung tissue, sustaining the idea that the airways constitute an important M. leprae entry route into the human body. Since critical aspects in understanding the mechanisms of infection are the identification and characterization of the adhesins involved in pathogen-host cell interaction, the nude mouse-derived M. leprae cell surface-exposed proteome was studied to uncover potentially relevant adhesin candidates. A total of 279 cell surface-exposed proteins were identified based on selective biotinylation, streptavidin-affinity purification, and shotgun mass spectrometry; 11 of those proteins have been previously described as potential adhesins. In vitro assays with the recombinant forms of the histone-like protein (Hlp) and the heparin-binding hemagglutinin (HBHA), considered to be major mycobacterial adhesins, confirmed their capacity to promote bacterial attachment to epithelial cells. Taking our data together, they suggest that the airway epithelium may act as a reservoir and/or portal of entry for M. leprae in humans. Moreover, our report sheds light on the potentially critical adhesins involved in M. leprae-epithelial cell interaction that may be useful in designing more effective tools for leprosy control.

Hepatitis C virus depends on E-cadherin as an entry factor and regulates its expression in epithelial-to-mesenchymal transition.

PubMed

Li, Qisheng; Sodroski, Catherine; Lowey, Brianna; Schweitzer, Cameron J; Cha, Helen; Zhang, Fang; Liang, T Jake

2016-07-05

Hepatitis C virus (HCV) enters the host cell through interactions with a cascade of cellular factors. Although significant progress has been made in understanding HCV entry, the precise mechanisms by which HCV exploits the receptor complex and host machinery to enter the cell remain unclear. This intricate process of viral entry likely depends on additional yet-to-be-defined cellular molecules. Recently, by applying integrative functional genomics approaches, we identified and interrogated distinct sets of host dependencies in the complete HCV life cycle. Viral entry assays using HCV pseudoparticles (HCVpps) of various genotypes uncovered multiple previously unappreciated host factors, including E-cadherin, that mediate HCV entry. E-cadherin silencing significantly inhibited HCV infection in Huh7.5.1 cells, HepG2/miR122/CD81 cells, and primary human hepatocytes at a postbinding entry step. Knockdown of E-cadherin, however, had no effect on HCV RNA replication or internal ribosomal entry site (IRES)-mediated translation. In addition, an E-cadherin monoclonal antibody effectively blocked HCV entry and infection in hepatocytes. Mechanistic studies demonstrated that E-cadherin is closely associated with claudin-1 (CLDN1) and occludin (OCLN) on the cell membrane. Depletion of E-cadherin drastically diminished the cell-surface distribution of these two tight junction proteins in various hepatic cell lines, indicating that E-cadherin plays an important regulatory role in CLDN1/OCLN localization on the cell surface. Furthermore, loss of E-cadherin expression in hepatocytes is associated with HCV-induced epithelial-to-mesenchymal transition (EMT), providing an important link between HCV infection and liver cancer. Our data indicate that a dynamic interplay among E-cadherin, tight junctions, and EMT exists and mediates an important function in HCV entry.

Renewed Global Partnerships and Redesigned Roadmaps for Rabies Prevention and Control

PubMed Central

Lembo, Tiziana; Attlan, Michaël; Bourhy, Hervé; Cleaveland, Sarah; Costa, Peter; de Balogh, Katinka; Dodet, Betty; Fooks, Anthony R.; Hiby, Elly; Leanes, Fernando; Meslin, François-Xavier; Miranda, Mary Elizabeth; Müller, Thomas; Nel, Louis H.; Rupprecht, Charles E.; Tordo, Noël; Tumpey, Abbigail; Wandeler, Alexander; Briggs, Deborah J.

2011-01-01

Canine rabies, responsible for most human rabies deaths, is a serious global public health concern. This zoonosis is entirely preventable, but by focusing solely upon rabies prevention in humans, this “incurable wound” persists at high costs. Although preventing human deaths through canine rabies elimination is feasible, dog rabies control is often neglected, because dogs are not considered typical economic commodities by the animal health sector. Here, we demonstrate that the responsibility of managing rabies falls upon multiple sectors, that a truly integrated approach is the key to rabies elimination, and that considerable progress has been made to this effect. Achievements include the construction of global rabies networks and organizational partnerships; development of road maps, operational toolkits, and a blueprint for rabies prevention and control; and opportunities for scaling up and replication of successful programs. Progress must continue towards overcoming the remaining challenges preventing the ultimate goal of rabies elimination. PMID:21776359

Locating the scala media in the fixed human temporal bone for therapeutic access: a preliminary study.

PubMed

Pau, H; Fagan, P; Oleskevich, S

2006-11-01

To investigate the location of the scala media in relation to the round window niche in human temporal bones. Ten human temporal bones were investigated by radical mastoidectomy and promontory drill-out. Temporal bone laboratory. The distance from the scala media to the anterior edge of the round window niche, measured by Fisch's stapedectomy measuring cylinders. The scala media was identified at the transection point of a vertical line 1.6 to 2.2 mm (mean=1.8 mm; standard deviation=0.2) anterior to the anterior edge of the round window niche and a horizontal line 0.2 mm inferior to the lower border of the oval window. This report demonstrates the point of entry into the scala media via the promontory in fixed temporal bone models, which may provide a site of entry for stem cells and gene therapy insertion.

Antibody neutralization of retargeted measles viruses

PubMed Central

Lech, Patrycja J.; Pappoe, Roland; Nakamura, Takafumi; Tobin, Gregory J.; Nara, Peter L.; Russell, Stephen J.

2014-01-01

The measles virus (MV) vaccine lineage is a promising oncolytic but prior exposure to the measles vaccine or wild-type MV strains limits treatment utility due to the presence of anti-measles antibodies. MV entry can be redirected by displaying a polypeptide ligand on the Hemagglutinin (H) C-terminus. We hypothesized that retargeted MV would escape neutralization by monoclonal antibodies (mAbs) recognizing the H receptor-binding surface and be less susceptible to neutralization by human antisera. Using chimeric H proteins, with and without mutations that ablate MV receptor binding, we show that retargeted MVs escape mAbs that target the H receptor-binding surface by virtue of mutations that ablate infection via SLAM and CD46. However, C-terminally displayed domains do not mediate virus entry in the presence of human antibodies that bind to the underlying H domain. In conclusion, utility of retargeted oncolytic measles viruses does not extend to evasion of human serum neutralization. PMID:24725950

Small molecule inhibitors of the annexin A2 heterotetramer prevent human papillomavirus type 16 infection.

PubMed

Woodham, Andrew W; Taylor, Julia R; Jimenez, Andrew I; Skeate, Joseph G; Schmidt, Thomas; Brand, Heike E; Da Silva, Diane M; Kast, W Martin

2015-01-01

High-risk human papillomavirus (HPV) infection leads to the development of several human cancers that cause significant morbidity and mortality worldwide. HPV type 16 (HPV16) is the most common of the cancer-causing genotypes and gains entry to the basal cells of the epithelium through a non-canonical endocytic pathway that involves the annexin A2/S100A10 heterotetramer (A2t). A2t is composed of two annexin A2 monomers bound to an S100A10 dimer and this interaction is a potential target to block HPV16 infection. Here, recently identified small molecule inhibitors of A2t (A2ti) were investigated for their ability to prevent HPV16 infection in vitro. A2ti were added to HeLa cells in increasing concentrations prior to the addition of HPV16. Cytotoxicity was evaluated via trypan blue exclusion. HPV16 pseudovirion infection and fluorescently labelled HPV16 capsid internalization was measured with flow cytometry. A2ti blocked HPV16 infection by 100% without substantial cellular toxicity or reduction in cell growth. Furthermore, A2ti blocked HPV16 entry into epithelial cells by 65%, indicating that the observed inhibition of HPV16 infection is in part due to a block in entry and that non-infectious entry may occur in the absence of A2t binding. These results demonstrate that targeting A2t may be an effective strategy to prevent HPV16 infection. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Scaleable manufacture of HIV-1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component

PubMed Central

O'Keefe, Barry R.; Vojdani, Fakhrieh; Buffa, Viviana; Shattock, Robin J.; Montefiori, David C.; Bakke, James; Mirsalis, Jon; d'Andrea, Anna-Lisa; Hume, Steven D.; Bratcher, Barry; Saucedo, Carrie J.; McMahon, James B.; Pogue, Gregory P.; Palmer, Kenneth E.

2009-01-01

To prevent sexually transmitted HIV, the most desirable active ingredients of microbicides are antiretrovirals (ARVs) that directly target viral entry and avert infection at mucosal surfaces. However, most promising ARV entry inhibitors are biologicals, which are costly to manufacture and deliver to resource-poor areas where effective microbicides are urgently needed. Here, we report a manufacturing breakthrough for griffithsin (GRFT), one of the most potent HIV entry inhibitors. This red algal protein was produced in multigram quantities after extraction from Nicotiana benthamiana plants transduced with a tobacco mosaic virus vector expressing GRFT. Plant-produced GRFT (GRFT-P) was shown as active against HIV at picomolar concentrations, directly virucidal via binding to HIV envelope glycoproteins, and capable of blocking cell-to-cell HIV transmission. GRFT-P has broad-spectrum activity against HIV clades A, B, and C, with utility as a microbicide component for HIV prevention in established epidemics in sub-Saharan Africa, South Asia, China, and the industrialized West. Cognizant of the imperative that microbicides not induce epithelial damage or inflammatory responses, we also show that GRFT-P is nonirritating and noninflammatory in human cervical explants and in vivo in the rabbit vaginal irritation model. Moreover, GRFT-P is potently active in preventing infection of cervical explants by HIV-1 and has no mitogenic activity on cultured human lymphocytes. PMID:19332801

Porcine, murine and human sialoadhesin (Sn/Siglec-1/CD169): portals for porcine reproductive and respiratory syndrome virus entry into target cells.

PubMed

Van Breedam, Wander; Verbeeck, Mieke; Christiaens, Isaura; Van Gorp, Hanne; Nauwynck, Hans J

2013-09-01

Porcine sialoadhesin (pSn; a sialic acid-binding lectin) and porcine CD163 (pCD163) are molecules that facilitate infectious entry of porcine reproductive and respiratory syndrome virus (PRRSV) into alveolar macrophages. In this study, it was shown that murine Sn (mSn) and human Sn (hSn), like pSn, can promote PRRSV infection of pCD163-expressing cells. Intact sialic acid-binding domains are crucial, since non-sialic acid-binding mutants of pSn, mSn and hSn did not promote infection. Endodomain-deletion mutants of pSn, mSn and hSn promoted PRRSV infection less efficiently, but also showed markedly reduced expression levels, making further research into the potential role of the Sn endodomain in PRRSV receptor activity necessary. These data further complement our knowledge on Sn as an important PRRSV receptor, and suggest - in combination with other published data - that species differences in the main PRRSV entry mediators Sn and CD163 do not account for the strict host species specificity displayed by the virus.

A to Z List of Cancer Drugs

MedlinePlus

... T) Purinethol (Mercaptopurine) Purixan (Mercaptopurine) Q [No Entries] R Radium 223 Dichloride Raloxifene Hydrochloride Ramucirumab Rasburicase R-CHOP R-CVP Recombinant Human Papillomavirus (HPV) Bivalent ...

Influence of Sulforaphane Metabolites on Activities of Human Drug-Metabolizing Cytochrome P450 and Determination of Sulforaphane in Human Liver Cells.

PubMed

Vanduchova, Alena; Tomankova, Veronika; Anzenbacher, Pavel; Anzenbacherova, Eva

2016-12-01

The influence of metabolites of sulforaphane, natural compounds present in broccoli (Brassica oleracea var. botrytis italica) and in other cruciferous vegetables, on drug-metabolizing cytochrome P450 (CYP) enzymes in human liver microsomes and possible entry of sulforaphane into human hepatic cells were investigated. Metabolites studied are compounds derived from sulforaphane by the mercapturic acid pathway (conjugation with glutathione and by following reactions), namely sulforaphane glutathione and sulforaphane cysteine conjugates and sulforaphane-N-acetylcysteine. Their possible effect on four drug-metabolizing CYP enzymes, CYP3A4 (midazolam 1'-hydroxylation), CYP2D6 (bufuralol 1'-hydroxylation), CYP1A2 (7-ethoxyresorufin O-deethylation), and CYP2B6 (7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation), was tested. Inhibition of four prototypical CYP activities by sulforaphane metabolites was studied in pooled human liver microsomes. Sulforaphane metabolites did not considerably affect biological function of drug-metabolizing CYPs in human liver microsomes except for CYP2D6, which was found to be inhibited down to 73-78% of the original activity. Analysis of the entry of sulforaphane into human hepatocytes was done by cell disruption by sonication, methylene chloride extraction, and modified high-performance liquid chromatography method. The results have shown penetration of sulforaphane into the human hepatic cells.

Single-wall carbon nanohorns (SWNHs) inhibited proliferation of human glioma cells and promoted its apoptosis

NASA Astrophysics Data System (ADS)

Li, Yunjun; Zhang, Jinqian; Zhao, Ming; Shi, Zujin; Chen, Xin; He, Xihui; Han, Nanyin; Xu, Ruxiang

2013-08-01

Although single-wall carbon nanohorns (SWNHs) have been demonstrated to accumulate to cytotoxic levels within organs of various animal models and cell types, they have been exploited for cancer therapies. The role of SWNHs in human glioma cell lines was unclear. To address this question, the research about direct role of SWNHs on the growth, proliferation, and apoptosis of human glioma cell lines (U87, U251, and U373) had been performed. Our results indicate that particle size of SWNHs in water is between 342 and 712 nm, the films of SEM show that SWNHs on PS surface are individual particles. SWNHs significantly delayed mitotic entry of human glioma cell lines cells, and inhibited its proliferation in a time- and dose-dependent manner. SWNHs induced a significant increase in G1 phase and inhibition of S phase followed the gradually increasing concentrations. SWNHs in human glioma cell lines cells significantly induced apoptosis followed by their gradually increasing concentrations. The TEM images showed that individual spherical SWNHs particles smaller than 100 nm in diameters were localized inside lysosomes of human glioma cell lines. SWNHs inhibited mitotic entry, growth, and proliferation of human glioma cell lines, and promoted its apoptosis. SWNHs may be a novel opportunity or method for the research on treatment of human glioma.

Progress towards eliminating canine rabies: policies and perspectives from Latin America and the Caribbean.

PubMed

Vigilato, Marco Antonio Natal; Clavijo, Alfonso; Knobl, Terezinha; Silva, Hugo Marcelo Tamayo; Cosivi, Ottorino; Schneider, Maria Cristina; Leanes, Luis Fernando; Belotto, Albino José; Espinal, Marcos Antonio

2013-08-05

Human rabies transmitted by dogs is considered a neglected disease that can be eliminated in Latin America and the Caribbean (LAC) by 2015. The aim of this paper is to discuss canine rabies policies and projections for LAC regarding current strategies for achieving this target and to critically review the political, economic and geographical factors related to the successful elimination of this deadly disease in the context of the difficulties and challenges of the region. The strong political and technical commitment to control rabies in LAC in the 1980s, started with the regional programme coordinated by the Pan American Health Organization. National and subnational programmes involve a range of strategies including mass canine vaccination with more than 51 million doses of canine vaccine produced annually, pre- and post-exposure prophylaxis, improvements in disease diagnosis and intensive surveillance. Rabies incidence in LAC has dramatically declined over the last few decades, with laboratory confirmed dog rabies cases decreasing from approximately 25 000 in 1980 to less than 300 in 2010. Dog-transmitted human rabies cases also decreased from 350 to less than 10 during the same period. Several countries have been declared free of human cases of dog-transmitted rabies, and from the 35 countries in the Americas, there is now only notification of human rabies transmitted by dogs in seven countries (Bolivia, Peru, Honduras, Haiti, Dominican Republic, Guatemala and some states in north and northeast Brazil). Here, we emphasize the importance of the political commitment in the final progression towards disease elimination. The availability of strategies for rabies control, the experience of most countries in the region and the historical ties of solidarity between countries with the support of the scientific community are evidence to affirm that the elimination of dog-transmitted rabies can be achieved in the short term. The final efforts to confront the remaining obstacles, like achieving and sustaining high vaccination coverage in communities that are most impoverished or in remote locations, are faced by countries that struggle to allocate sufficient financial and human resources for rabies control. Continent-wide cooperation is therefore required in the final efforts to secure the free status of remaining countries in the Americas, which is key to the regional elimination of human rabies transmitted by dogs.

Progress towards eliminating canine rabies: policies and perspectives from Latin America and the Caribbean

PubMed Central

Vigilato, Marco Antonio Natal; Clavijo, Alfonso; Knobl, Terezinha; Silva, Hugo Marcelo Tamayo; Cosivi, Ottorino; Schneider, Maria Cristina; Leanes, Luis Fernando; Belotto, Albino José; Espinal, Marcos Antonio

2013-01-01

Human rabies transmitted by dogs is considered a neglected disease that can be eliminated in Latin America and the Caribbean (LAC) by 2015. The aim of this paper is to discuss canine rabies policies and projections for LAC regarding current strategies for achieving this target and to critically review the political, economic and geographical factors related to the successful elimination of this deadly disease in the context of the difficulties and challenges of the region. The strong political and technical commitment to control rabies in LAC in the 1980s, started with the regional programme coordinated by the Pan American Health Organization. National and subnational programmes involve a range of strategies including mass canine vaccination with more than 51 million doses of canine vaccine produced annually, pre- and post-exposure prophylaxis, improvements in disease diagnosis and intensive surveillance. Rabies incidence in LAC has dramatically declined over the last few decades, with laboratory confirmed dog rabies cases decreasing from approximately 25 000 in 1980 to less than 300 in 2010. Dog-transmitted human rabies cases also decreased from 350 to less than 10 during the same period. Several countries have been declared free of human cases of dog-transmitted rabies, and from the 35 countries in the Americas, there is now only notification of human rabies transmitted by dogs in seven countries (Bolivia, Peru, Honduras, Haiti, Dominican Republic, Guatemala and some states in north and northeast Brazil). Here, we emphasize the importance of the political commitment in the final progression towards disease elimination. The availability of strategies for rabies control, the experience of most countries in the region and the historical ties of solidarity between countries with the support of the scientific community are evidence to affirm that the elimination of dog-transmitted rabies can be achieved in the short term. The final efforts to confront the remaining obstacles, like achieving and sustaining high vaccination coverage in communities that are most impoverished or in remote locations, are faced by countries that struggle to allocate sufficient financial and human resources for rabies control. Continent-wide cooperation is therefore required in the final efforts to secure the free status of remaining countries in the Americas, which is key to the regional elimination of human rabies transmitted by dogs. PMID:23798691

Automation of Command and Data Entry in a Glovebox Work Volume: An Evaluation of Data Entry Devices

NASA Technical Reports Server (NTRS)

Steele, Marianne K.; Nakamura, Gail; Havens, Cindy; LeMay, Moira

1996-01-01

The present study was designed to examine the human-computer interface for data entry while performing experimental procedures within a glovebox work volume in order to make a recommendation to the Space Station Biological Research Project for a data entry system to be used within the Life Sciences Glovebox. Test subjects entered data using either a manual keypad, similar to a standard computer numerical keypad located within the glovebox work volume, or a voice input system using a speech recognition program with a microphone headset. Numerical input and commands were programmed in an identical manner between the two systems. With both electronic systems, a small trackball was available within the work volume for cursor control. Data, such as sample vial identification numbers, sample tissue weights, and health check parameters of the specimen, were entered directly into procedures that were electronically displayed on a video monitor within the glovebox. A pen and paper system with a 'flip-chart' format for procedure display, similar to that currently in use on the Space Shuttle, was used as a baseline data entry condition. Procedures were performed by a single operator; eight test subjects were used in the study. The electronic systems were tested under both a 'nominal' or 'anomalous' condition. The anomalous condition was introduced into the experimental procedure to increase the probability of finding limitations or problems with human interactions with the electronic systems. Each subject performed five test runs during a test day: two procedures each with voice and keypad, one with and one without anomalies, and one pen and paper procedure. The data collected were both quantitative (times, errors) and qualitative (subjective ratings of the subjects).

A wireless mobile health-related quality of life assessment.

PubMed

Wu, Cai; Volk, Robert J; Steinbauer, Jeffrey R; Kuo, Grace M; Smith, J Scott

2003-01-01

Self-administered waiting room questionnaires are popular tools for gathering health information from patients, but they require optical scanning or manual data entry to obtain survey results. The application described here eliminates those extra steps by inputting the results into a remote database directly through wireless connection, and the assessment can be finished easily anywhere in the clinic through a mobile platform. A measure of health-related quality of life, the SF-8 Health Survey, was used in developing this application for using in the clinical setting. It has only eight questions measuring each of the eight domains of health in the longer SF-36 Health Survey.

Image data compression having minimum perceptual error

NASA Technical Reports Server (NTRS)

Watson, Andrew B. (Inventor)

1995-01-01

A method for performing image compression that eliminates redundant and invisible image components is described. The image compression uses a Discrete Cosine Transform (DCT) and each DCT coefficient yielded by the transform is quantized by an entry in a quantization matrix which determines the perceived image quality and the bit rate of the image being compressed. The present invention adapts or customizes the quantization matrix to the image being compressed. The quantization matrix comprises visual masking by luminance and contrast techniques and by an error pooling technique all resulting in a minimum perceptual error for any given bit rate, or minimum bit rate for a given perceptual error.

Image-adapted visually weighted quantization matrices for digital image compression

NASA Technical Reports Server (NTRS)

Watson, Andrew B. (Inventor)

1994-01-01

A method for performing image compression that eliminates redundant and invisible image components is presented. The image compression uses a Discrete Cosine Transform (DCT) and each DCT coefficient yielded by the transform is quantized by an entry in a quantization matrix which determines the perceived image quality and the bit rate of the image being compressed. The present invention adapts or customizes the quantization matrix to the image being compressed. The quantization matrix comprises visual masking by luminance and contrast techniques and by an error pooling technique all resulting in a minimum perceptual error for any given bit rate, or minimum bit rate for a given perceptual error.

Development and Testing of a New Family of Supersonic Decelerators

NASA Technical Reports Server (NTRS)

Clark, Ian G.; Adler, Mark; Rivellini, Tommaso P.

2013-01-01

The state of the art in Entry, Descent, and Landing systems for Mars applications is largely based on technologies developed in the late 1960's and early 1970's for the Viking Lander program. Although the 2011 Mars Science Laboratory has made advances in EDL technology, these are predominantly in the areas of entry (new thermal protection systems and guided hypersonic flight) and landing (the sky crane architecture). Increases in entry mass, landed mass, and landed altitude beyond MSL capabilities will require advances predominantly in the field of supersonic decelerators. With this in mind, a multi-year program has been initiated to advance three new types of supersonic decelerators that would enable future large-robotic and human-precursor class missions to Mars.

Medicinal chemistry of small molecule CCR5 antagonists for blocking HIV-1 entry: a review of structural evolution.

PubMed

Tian, Ye; Zhang, Dujuan; Zhan, Peng; Liu, Xinyong

2014-01-01

CCR5, a member of G protein-coupled receptors superfamily, plays an important role in the HIV-1 entry process. Antagonism of this receptor finally leads to the inhibition of R5 strains of HIV entry into the human cells. The identification of CCR5 antagonists as antiviral agents will provide more option for HAART. Now, more than a decade after the first small molecule CCR5 inhibitor was discovered, great achievements have been made. In this article, we will give a brief introduction of several series of small molecule CCR5 antagonists, focused on their appealing structure evolution, essential SAR information and thereof the enlightenment of strategies on CCR5 inhibitors design.

Tropomyosin modulates erythrocyte membrane stability

PubMed Central

An, Xiuli; Salomao, Marcela; Guo, Xinhua; Gratzer, Walter; Mohandas, Narla

2007-01-01

The ternary complex of spectrin, actin, and 4.1R (human erythrocyte protein 4.1) defines the nodes of the erythrocyte membrane skeletal network and is inseparable from membrane stability under mechanical stress. These junctions also contain tropomyosin (TM) and the other actin-binding proteins, adducin, protein 4.9, tropomodulin, and a small proportion of capZ, the functions of which are poorly defined. Here, we have examined the consequences of selective elimination of TM from the membrane. We have shown that the mechanical stability of the membranes of resealed ghosts devoid of TM is grossly, but reversibly, impaired. That the decreased membrane stability of TM-depleted membranes is the result of destabilization of the ternary complex of the network junctions is demonstrated by the strongly facilitated entry into the junctions in situ of a β-spectrin peptide, containing the actin- and 4.1R-binding sites, after extraction of the TM. The stabilizing effect of TM is highly specific, in that it is only the endogenous isotype, and not the slightly longer muscle TM that can bind to the depleted membranes and restore their mechanical stability. These findings have enabled us identify a function for TM in elevating the mechanical stability of erythrocyte membranes by stabilizing the spectrin-actin-4.1R junctional complex. PMID:17008534

Problems Related to the Use of Human Subjects in Clinical Evaluation/Responsibility for Follow-up Care.

ERIC Educational Resources Information Center

Buchanan, Richard N.

1991-01-01

This presentation on licensing and credentialing in dentistry denounces the use of human subjects for entry level clinical examinations in dentistry as contrary to the values of the profession that the patient's welfare is paramount. Recommended, instead, are various forms of simulation. (DB)

Environmentally friendly tool to control mosquito populations without risk of insecticide resistance: the Lehmann’s funnel entry trap

PubMed Central

2013-01-01

Background Current malaria control strategies have cut down the malaria burden in many endemic areas, however the emergence and rapid spread of insecticide and drug resistance undermine the success of these efforts. There is growing concern that malaria eradication will not be achieved without the introduction of novel control tools. One approach that has been developed in the last few years is based on house screening to reduce indoor mosquito vector densities and consequently decrease malaria transmission. Here screening and trapping were combined in one tool to control mosquito populations. The trap does not require an insecticide or even an attractant, yet it effectively collects incoming resistant and susceptible mosquitoes and kills them. Results Performance of the funnel entry trap was tested in low and high malaria vector density areas. An overall reduction of 70 to 80% of mosquito density was seen in both. Species and molecular forms of Anopheles gambiae identification indicated no variation in the number of Anopheles arabiensis and the molecular forms of An. gambiae between houses and traps. Mosquitoes collected in the traps and in houses were highly resistant to pyrethroids (0.9 kdr-based mechanism). Conclusion There is a global consensus that new intervention tools are needed to cross the last miles in malaria elimination/eradication. The funnel entry trap showed excellent promise in suppressing mosquito densities even in area of high insecticide resistance. It requires no chemicals and is self-operated. PMID:23758904

An important date in rabies history.

PubMed

Dodet, Betty

2007-12-17

Rabies is estimated to cause 31,000 human deaths in Asia annually. Several recent events, including World Rabies Day have brought this neglected disease to the attention of the scientific community, governmental authorities, the media and the public. It is hoped that this will result in an increased collaboration between veterinary and human health authorities, and an involvement at all levels necessary for the control and elimination of rabies in dogs, the main reservoir and vector of rabies in Asia. Dog rabies elimination is considered as the most cost-effective solution to prevent rabies deaths in humans. Asian countries such as India and the Philippines have recently adopted the objective of eliminating rabies by 2020. To support World Rabies Day, the Asian Rabies Expert Bureau (AREB) had its 4th annual meeting from 5 to 7 September 2007, with the objective of debating strategies for lowering the human rabies toll. Human rabies deaths can already be prevented by improving the compliance to WHO post-exposure prophylaxis recommendations. In addition, in regions with a high incidence of canine rabies and where rabies control in dogs is not yet achieved or not effective, systematic pre-exposure vaccination of children who are the main victims of rabies, may prevent their premature deaths.

Orion Flight Test-1 Thermal Protection System Instrumentation

NASA Technical Reports Server (NTRS)

Kowal, T. John

2011-01-01

The Orion Crew Exploration Vehicle (CEV) was originally under development to provide crew transport to the International Space Station after the retirement of the Space Shuttle, and to provide a means for the eventual return of astronauts to the Moon. With the current changes in the future direction of the United States human exploration programs, the focus of the Orion project has shifted to the project s first orbital flight test, designated Orion Flight Test 1 (OFT-1). The OFT-1 is currently planned for launch in July 2013 and will demonstrate the Orion vehicle s capability for performing missions in low Earth orbit (LEO), as well as extensibility beyond LEO for select, critical areas. Among the key flight test objectives are those related to validation of the re-entry aerodynamic and aerothermal environments, and the performance of the thermal protection system (TPS) when exposed to these environments. A specific flight test trajectory has been selected to provide a high energy entry beyond that which would be experienced during a typical low Earth orbit return, given the constraints imposed by the possible launch vehicles. This trajectory resulted from a trade study that considered the relative benefit of conflicting objectives from multiple subsystems, and sought to provide the maximum integrated benefit to the re-entry state-of-the-art. In particular, the trajectory was designed to provide: a significant, measureable radiative heat flux to the windward surface; data on boundary transition from laminar to turbulent flow; and data on catalytic heating overshoot on non-ablating TPS. In order to obtain the necessary flight test data during OFT-1, the vehicle will need to have an adequate quantity of instrumentation. A collection of instrumentation is being developed for integration in the OFT-1 TPS. In part, this instrumentation builds upon the work performed for the Mars Science Laboratory Entry, Descent and Landing Instrument (MEDLI) suite to instrument the OFT-1 ablative heat shield. The MEDLI integrated sensor plugs and pressure sensors will be adapted for compatibility with the Orion TPS design. The sensor plugs will provide in-depth temperature data to support aerothermal and TPS model correlation, and the pressure sensors will provide a flush air data system for validation of the entry and descent aerodynamic environments. In addition, a radiometer design will be matured to measure the radiative component of the reentry heating at two locations on the heat shield. For the back shell, surface thermocouple and pressure port designs will be developed and applied which build upon the heritage of the Space Shuttle Program for instrumentation of reusable surface insulation (RSI) tiles. The quantity and location of the sensors has been determined to balance the needs of the reentry disciplines with the demands of the hardware development, manufacturing and integration. Measurements which provided low relative value and presented significant engineering development effort were, unfortunately, eliminated. The final TPS instrumentation has been optimized to target priority test objectives. The data obtained will serve to provide a better understanding of reentry environments for the Orion capsule design, reduce margins, and potentially reduce TPS mass or provide TPS extensibility for alternative missions.

Human Papillomavirus 16 Infection Induces VAP-Dependent Endosomal Tubulation.

PubMed

Siddiqa, Abida; Massimi, Paola; Pim, David; Broniarczyk, Justyna; Banks, Lawrence

2018-03-15

Human papillomavirus (HPV) infection involves complex interactions with the endocytic transport machinery, which ultimately facilitates the entry of the incoming viral genomes into the trans -Golgi network (TGN) and their subsequent nuclear entry during mitosis. The endosomal pathway is a highly dynamic intracellular transport system, which consists of vesicular compartments and tubular extensions, although it is currently unclear whether incoming viruses specifically alter the endocytic machinery. In this study, using MICAL-L1 as a marker for tubulating endosomes, we show that incoming HPV-16 virions induce a profound alteration in global levels of endocytic tubulation. In addition, we also show a critical requirement for the endoplasmic reticulum (ER)-anchored protein VAP in this process. VAP plays an essential role in actin nucleation and endosome-to-Golgi transport. Indeed, the loss of VAP results in a dramatic decrease in the level of endosomal tubulation induced by incoming HPV-16 virions. This is also accompanied by a marked reduction in virus infectivity. In VAP knockdown cells, we see that the defect in virus trafficking occurs after capsid disassembly but prior to localization at the trans -Golgi network, with the incoming virion-transduced DNA accumulating in Vps29/TGN46-positive hybrid vesicles. Taken together, these studies demonstrate that infection with HPV-16 virions induces marked alterations of endocytic transport pathways, some of which are VAP dependent and required for the endosome-to-Golgi transport of the incoming viral L2/DNA complex. IMPORTANCE Human papillomavirus infectious entry involves multiple interactions with the endocytic transport machinery. In this study, we show that incoming HPV-16 virions induce a dramatic increase in endocytic tubulation. This tubulation requires ER-associated VAP, which plays a critical role in ensuring the delivery of cargoes from the endocytic compartments to the trans -Golgi network. Indeed, the loss of VAP blocks HPV infectious entry at a step after capsid uncoating but prior to localization at the trans -Golgi network. These results define a critical role for ER-associated VAP in endocytic tubulation and in HPV-16 infectious entry. Copyright © 2018 American Society for Microbiology.

Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists

PubMed Central

Cheng, Han; Lear-Rooney, Calli M.; Johansen, Lisa; Varhegyi, Elizabeth; Chen, Zheng W.; Olinger, Gene G.

2015-01-01

ABSTRACT Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chemical library of small molecules and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addition experiment and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy. IMPORTANCE Infection of Ebola virus and Marburg virus can cause severe illness in humans with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The 2013-2015 epidemic in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we have identified numerous inhibitors that are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. Our results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy. PMID:26202243

Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists.

PubMed

Cheng, Han; Lear-Rooney, Calli M; Johansen, Lisa; Varhegyi, Elizabeth; Chen, Zheng W; Olinger, Gene G; Rong, Lijun

2015-10-01

Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chemical library of small molecules and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addition experiment and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy. Infection of Ebola virus and Marburg virus can cause severe illness in humans with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The 2013-2015 epidemic in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we have identified numerous inhibitors that are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. Our results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Transmission dynamics and elimination potential of zoonotic tuberculosis in morocco

PubMed Central

Justus Bless, Philipp; Crump, Lisa; Lohmann, Petra; Laager, Mirjam; Chitnis, Nakul; Zinsstag, Jakob

2017-01-01

Bovine tuberculosis (BTB) is an endemic zoonosis in Morocco caused by Mycobacterium bovis, which infects many domestic animals and is transmitted to humans through consumption of raw milk or from contact with infected animals. The prevalence of BTB in Moroccan cattle is estimated at 18%, and 33% at the individual and the herd level respectively, but the human M. bovis burden needs further clarification. The current control strategy based on test and slaughter should be improved through local context adaptation taking into account a suitable compensation in order to reduce BTB prevalence in Morocco and decrease the disease burden in humans and animals. We established a simple compartmental deterministic mathematical model for BTB transmission in cattle and humans to provide a general understanding of BTB, in particular regarding transmission to humans. Differential equations were used to model the different pathways between the compartments for cattle and humans. Scenarios of test and slaughter were simulated to determine the effects of varying the proportion of tested animals (p) on the time to elimination of BTB (individual animal prevalence of less than one in a thousand) in cattle and humans. The time to freedom from disease ranged from 75 years for p = 20% to 12 years for p = 100%. For p > 60% the time to elimination was less than 20 years. The cumulated cost was largely stable: for p values higher than 40%, cost ranged from 1.47 to 1.60 billion euros with a time frame of 12 to 32 years to reach freedom from disease. The model simulations also suggest that using a 2mm cut off instead of a 4mm cut off in the Single Intradermal Comparative Cervical Tuberculin skin test (SICCT) would result in cheaper and quicker elimination programs. This analysis informs Moroccan bovine tuberculosis control policy regarding time frame, range of cost and levels of intervention. However, further research is needed to clarify the national human-bovine tuberculosis ratio in Morocco. PMID:28152056

Transmission dynamics and elimination potential of zoonotic tuberculosis in morocco.

PubMed

Abakar, Mahamat Fayiz; Yahyaoui Azami, Hind; Justus Bless, Philipp; Crump, Lisa; Lohmann, Petra; Laager, Mirjam; Chitnis, Nakul; Zinsstag, Jakob

2017-02-01

Bovine tuberculosis (BTB) is an endemic zoonosis in Morocco caused by Mycobacterium bovis, which infects many domestic animals and is transmitted to humans through consumption of raw milk or from contact with infected animals. The prevalence of BTB in Moroccan cattle is estimated at 18%, and 33% at the individual and the herd level respectively, but the human M. bovis burden needs further clarification. The current control strategy based on test and slaughter should be improved through local context adaptation taking into account a suitable compensation in order to reduce BTB prevalence in Morocco and decrease the disease burden in humans and animals. We established a simple compartmental deterministic mathematical model for BTB transmission in cattle and humans to provide a general understanding of BTB, in particular regarding transmission to humans. Differential equations were used to model the different pathways between the compartments for cattle and humans. Scenarios of test and slaughter were simulated to determine the effects of varying the proportion of tested animals (p) on the time to elimination of BTB (individual animal prevalence of less than one in a thousand) in cattle and humans. The time to freedom from disease ranged from 75 years for p = 20% to 12 years for p = 100%. For p > 60% the time to elimination was less than 20 years. The cumulated cost was largely stable: for p values higher than 40%, cost ranged from 1.47 to 1.60 billion euros with a time frame of 12 to 32 years to reach freedom from disease. The model simulations also suggest that using a 2mm cut off instead of a 4mm cut off in the Single Intradermal Comparative Cervical Tuberculin skin test (SICCT) would result in cheaper and quicker elimination programs. This analysis informs Moroccan bovine tuberculosis control policy regarding time frame, range of cost and levels of intervention. However, further research is needed to clarify the national human-bovine tuberculosis ratio in Morocco.

The Role of Phlebovirus Glycoproteins in Viral Entry, Assembly and Release

PubMed Central

Spiegel, Martin; Plegge, Teresa; Pöhlmann, Stefan

2016-01-01

Bunyaviruses are enveloped viruses with a tripartite RNA genome that can pose a serious threat to animal and human health. Members of the Phlebovirus genus of the family Bunyaviridae are transmitted by mosquitos and ticks to humans and include highly pathogenic agents like Rift Valley fever virus (RVFV) and severe fever with thrombocytopenia syndrome virus (SFTSV) as well as viruses that do not cause disease in humans, like Uukuniemi virus (UUKV). Phleboviruses and other bunyaviruses use their envelope proteins, Gn and Gc, for entry into target cells and for assembly of progeny particles in infected cells. Thus, binding of Gn and Gc to cell surface factors promotes viral attachment and uptake into cells and exposure to endosomal low pH induces Gc-driven fusion of the viral and the vesicle membranes. Moreover, Gn and Gc facilitate virion incorporation of the viral genome via their intracellular domains and Gn and Gc interactions allow the formation of a highly ordered glycoprotein lattice on the virion surface. Studies conducted in the last decade provided important insights into the configuration of phlebovirus Gn and Gc proteins in the viral membrane, the cellular factors used by phleboviruses for entry and the mechanisms employed by phlebovirus Gc proteins for membrane fusion. Here, we will review our knowledge on the glycoprotein biogenesis and the role of Gn and Gc proteins in the phlebovirus replication cycle. PMID:27455305

F-box proteins Pof3 and Pof1 regulate Wee1 degradation and mitotic entry in fission yeast.

PubMed

Qiu, Cui; Yi, Yuan-Yuan; Lucena, Rafael; Wu, Meng-Juan; Sun, Jia-Hao; Wang, Xi; Jin, Quan-Wen; Wang, Yamei

2018-02-02

The key cyclin-dependent kinase Cdk1 (Cdc2) promotes irreversible mitotic entry, mainly by activating the phosphatase Cdc25 while suppressing the tyrosine kinase Wee1. Wee1 needs to be downregulated at the onset of mitosis to ensure rapid activation of Cdk1. In human somatic cells, one mechanism of suppressing Wee1 activity is mediated by ubiquitylation-dependent proteolysis through the Skp1/Cul1/F-box protein (SCF) ubiquitin E3 ligase complex. This mechanism is believed to be conserved from yeasts to humans. So far, the best-characterized human F-box proteins involved in recognition of Wee1 are β-TrCP (BTRCP) and Tome-1 (CDCA3). Although fission yeast Wee1 was the first identified member of its conserved kinase family, the F-box proteins involved in recognition and ubiquitylation of Wee1 have not been identified in this organism. In this study, our screen using Wee1- Renilla luciferase as the reporter revealed that two F-box proteins, Pof1 and Pof3, are required for downregulating Wee1 and are possibly responsible for recruiting Wee1 to SCF. Our genetic analyses supported a functional relevance between Pof1 and Pof3 and the rate of mitotic entry, and Pof3 might play a major role in this process. © 2018. Published by The Company of Biologists Ltd.

Dfam: a database of repetitive DNA based on profile hidden Markov models.

PubMed

Wheeler, Travis J; Clements, Jody; Eddy, Sean R; Hubley, Robert; Jones, Thomas A; Jurka, Jerzy; Smit, Arian F A; Finn, Robert D

2013-01-01

We present a database of repetitive DNA elements, called Dfam (http://dfam.janelia.org). Many genomes contain a large fraction of repetitive DNA, much of which is made up of remnants of transposable elements (TEs). Accurate annotation of TEs enables research into their biology and can shed light on the evolutionary processes that shape genomes. Identification and masking of TEs can also greatly simplify many downstream genome annotation and sequence analysis tasks. The commonly used TE annotation tools RepeatMasker and Censor depend on sequence homology search tools such as cross_match and BLAST variants, as well as Repbase, a collection of known TE families each represented by a single consensus sequence. Dfam contains entries corresponding to all Repbase TE entries for which instances have been found in the human genome. Each Dfam entry is represented by a profile hidden Markov model, built from alignments generated using RepeatMasker and Repbase. When used in conjunction with the hidden Markov model search tool nhmmer, Dfam produces a 2.9% increase in coverage over consensus sequence search methods on a large human benchmark, while maintaining low false discovery rates, and coverage of the full human genome is 54.5%. The website provides a collection of tools and data views to support improved TE curation and annotation efforts. Dfam is also available for download in flat file format or in the form of MySQL table dumps.

Characterization of the Solution Structure of Human Serum Albumin Loaded with a Metal Porphyrin and Fatty Acids

PubMed Central

Junk, Matthias J.N.; Spiess, Hans W.; Hinderberger, Dariush

2011-01-01

The structure of human serum albumin loaded with a metal porphyrin and fatty acids in solution is characterized by orientation-selective double electron-electron resonance (DEER) spectroscopy. Human serum albumin, spin-labeled fatty acids, and Cu(II) protoporphyrin IX—a hemin analog—form a fully self-assembled system that allows obtaining distances and mutual orientations between the paramagnetic guest molecules. We report a simplified analysis for the orientation-selective DEER data which can be applied when the orientation selection of one spin in the spin pair dominates the orientation selection of the other spin. The dipolar spectra reveal a dominant distance of 3.85 nm and a dominant orientation of the spin-spin vectors between Cu(II) protoporphyrin IX and 16-doxyl stearic acid, the electron paramagnetic resonance reporter group of the latter being located near the entry points to the fatty acid binding sites. This observation is in contrast to crystallographic data that suggest an asymmetric distribution of the entry points in the protein and hence the occurrence of various distances. In conjunction with the findings of a recent DEER study, the obtained data are indicative of a symmetric distribution of the binding site entries on the protein's surface. The overall anisotropic shape of the protein is reflected by one spin-spin vector orientation dominating the DEER data. PMID:21539799

Human movement data for malaria control and elimination strategic planning.

PubMed

Pindolia, Deepa K; Garcia, Andres J; Wesolowski, Amy; Smith, David L; Buckee, Caroline O; Noor, Abdisalan M; Snow, Robert W; Tatem, Andrew J

2012-06-18

Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets. Accounting for human population movement (HPM) in planning for control, elimination and post-elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM. Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion. HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement. While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within-country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk. A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning. This review aims to (i) discuss relevant types of HPM across spatial and temporal scales, (ii) document where datasets exist to quantify HPM, (iii) highlight where data gaps remain and (iv) briefly put forward methods for integrating these datasets in a Geographic Information System (GIS) framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements.

Human movement data for malaria control and elimination strategic planning

PubMed Central

2012-01-01

Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets. Accounting for human population movement (HPM) in planning for control, elimination and post-elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM. Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion. HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement. While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within-country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk. A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning. This review aims to (i) discuss relevant types of HPM across spatial and temporal scales, (ii) document where datasets exist to quantify HPM, (iii) highlight where data gaps remain and (iv) briefly put forward methods for integrating these datasets in a Geographic Information System (GIS) framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements. PMID:22703541

Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter BCRP/ABCG2

PubMed Central

Hosomi, Atsushi; Nakanishi, Takeo; Fujita, Takuya; Tamai, Ikumi

2012-01-01

Urinary excretion accounts for two-thirds of total elimination of uric acid and the remainder is excreted in feces. However, the mechanism of extra-renal elimination is poorly understood. In the present study, we aimed to clarify the mechanism and the extent of elimination of uric acid through liver and intestine using oxonate-treated rats and Caco-2 cells as a model of human intestinal epithelium. In oxonate-treated rats, significant amounts of externally administered and endogenous uric acid were recovered in the intestinal lumen, while biliary excretion was minimal. Accordingly, direct intestinal secretion was thought to be a substantial contributor to extra-renal elimination of uric acid. Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and genetic polymorphism causing a decrease of BCRP activity is known to be associated with hyperuricemia and gout, the contribution of rBcrp to intestinal secretion was examined. rBcrp was confirmed to transport uric acid in a membrane vesicle study, and intestinal regional differences of expression of rBcrp mRNA were well correlated with uric acid secretory activity into the intestinal lumen. Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor, elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of elacridar. These results demonstrate that BCRP contributes at least in part to the intestinal excretion of uric acid as extra-renal elimination pathway in humans and rats. PMID:22348008

Analysis of the entry mechanism of Crimean-Congo hemorrhagic fever virus, using a vesicular stomatitis virus pseudotyping system.

PubMed

Suda, Yuto; Fukushi, Shuetsu; Tani, Hideki; Murakami, Shin; Saijo, Masayuki; Horimoto, Taisuke; Shimojima, Masayuki

2016-06-01

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease causing severe hemorrhagic symptoms with a nearly 30 % case-fatality rate in humans. The experimental use of CCHF virus (CCHFV), which causes CCHF, requires high-biosafety-level (BSL) containment. In contrast, pseudotyping of various viral glycoproteins (GPs) onto vesicular stomatitis virus (VSV) can be used in facilities with lower BSL containment, and this has facilitated studies on the viral entry mechanism and the measurement of neutralizing activity, especially for highly pathogenic viruses. In the present study, we generated high titers of pseudotyped VSV bearing the CCHFV envelope GP and analyzed the mechanisms involved in CCHFV infection. A partial deletion of the CCHFV GP cytoplasmic domain increased the titer of the pseudotyped VSV, the entry mechanism of which was dependent on the CCHFV envelope GP. Using the pseudotype virus, DC-SIGN (a calcium-dependent [C-type] lectin cell-surface molecule) was revealed to enhance viral infection and act as an entry factor for CCHFV.

Natural resistance-associated macrophage protein is a cellular receptor for sindbis virus in both insect and mammalian hosts.

PubMed

Rose, Patrick P; Hanna, Sheri L; Spiridigliozzi, Anna; Wannissorn, Nattha; Beiting, Daniel P; Ross, Susan R; Hardy, Richard W; Bambina, Shelly A; Heise, Mark T; Cherry, Sara

2011-08-18

Alphaviruses, including several emerging human pathogens, are a large family of mosquito-borne viruses with Sindbis virus being a prototypical member of the genus. The host factor requirements and receptors for entry of this class of viruses remain obscure. Using a Drosophila system, we identified the divalent metal ion transporter natural resistance-associated macrophage protein (NRAMP) as a host cell surface molecule required for Sindbis virus binding and entry into Drosophila cells. Consequently, flies mutant for dNRAMP were protected from virus infection. NRAMP2, the ubiquitously expressed vertebrate homolog, mediated binding and infection of Sindbis virus into mammalian cells, and murine cells deficient for NRAMP2 were nonpermissive to infection. Alphavirus glycoprotein chimeras demonstrated that the requirement for NRAMP2 is at the level of Sindbis virus entry. Given the conserved structure of alphavirus glycoproteins, and the widespread use of transporters for viral entry, other alphaviruses may use conserved multipass membrane proteins for infection. Copyright © 2011 Elsevier Inc. All rights reserved.

Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry.

PubMed

Bose, Sayantan; Jardetzky, Theodore S; Lamb, Robert A

2015-05-01

The Paramyxoviridae include some of the great and ubiquitous disease-causing viruses of humans and animals. In most paramyxoviruses, two viral membrane glycoproteins, fusion protein (F) and receptor binding protein (HN, H or G) mediate a concerted process of recognition of host cell surface molecules followed by fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. The interactions between the F and HN, H or G viral glycoproteins and host molecules are critical in determining host range, virulence and spread of these viruses. Recently, atomic structures, together with biochemical and biophysical studies, have provided major insights into how these two viral glycoproteins successfully interact with host receptors on cellular membranes and initiate the membrane fusion process to gain entry into cells. These studies highlight the conserved core mechanisms of paramyxovirus entry that provide the fundamental basis for rational anti-viral drug design and vaccine development. Copyright © 2015 Elsevier Inc. All rights reserved.

Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model

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

Emond, Claude, E-mail: claude.emond@umontreal.ca; Departments of Environmental and Occupational Health, Medicine Faculty, University of Montreal, Montreal, Quebec; Sanders, J. Michael, E-mail: sander10@mail.nih.gov

2013-12-01

Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine themore » mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. - Highlights: • We report the first study on PBPK model on flame retardant in mice for BDE-47. • We examine mechanism of urinary elimination of BDE-47 in mice using a PBPK model. • We investigated roles of m-MUP and P-gp as transporters in urinary elimination.« less

c-Myc-Dependent Cell Competition in Human Cancer Cells.

PubMed

Patel, Manish S; Shah, Heta S; Shrivastava, Neeta

2017-07-01

Cell Competition is an interaction between cells for existence in heterogeneous cell populations of multicellular organisms. This phenomenon is involved in initiation and progression of cancer where heterogeneous cell populations compete directly or indirectly for the survival of the fittest based on differential gene expression. In Drosophila, cells having lower dMyc expression are eliminated by cell competition through apoptosis when present in the milieu of cells having higher dMyc expression. Thus, we designed a study to develop c-Myc (human homolog) dependent in vitro cell competition model of human cancer cells. Cells with higher c-Myc were transfected with c-myc shRNA to prepare cells with lower c-Myc and then co-cultured with the same type of cells having a higher c-Myc in equal ratio. Cells with lower c-Myc showed a significant decrease in numbers when compared with higher c-Myc cells, suggesting "loser" and "winner" status of cells, respectively. During microscopy, engulfment of loser cells by winner cells was observed with higher expression of JNK in loser cells. Furthermore, elimination of loser cells was prevented significantly, when co-cultured cells were treated with the JNK (apoptosis) inhibitor. Above results indicate elimination of loser cells in the presence of winner cells by c-Myc-dependent mechanisms of cell competition in human cancer cells. This could be an important mechanism in human tumors where normal cells are eliminated by c-Myc-overexpressed tumor cells. J. Cell. Biochem. 118: 1782-1791, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mycoplasma detection and elimination are necessary for the application of stem cell from human dental apical papilla to tissue engineering and regenerative medicine.

PubMed

Kim, Byung-Chul; Kim, So Yeon; Kwon, Yong-Dae; Choe, Sung Chul; Han, Dong-Wook; Hwang, Yu-Shik

2015-01-01

Recently, postnatal stem cells from dental papilla with neural crest origin have been considered as one of potent stem cell sources in regenerative medicine regarding their multi-differentiation capacity and relatively easy access. However, almost human oral tissues have been reported to be infected by mycoplasma which gives rise to oral cavity in teeth, and mycoplasma contamination of ex-vivo cultured stem cells from such dental tissues and its effect on stem cell culture has received little attention. In this study, mycoplama contamination was evaluated with stem cells from apical papilla which were isolated from human third molar and premolars from various aged patients undergoing orthodontic therapy. The ex-vivo expanded stem cells from apical papilla were found to express stem cell markers such as Stro-1, CD44, nestin and CD133, but mycoplama contamination was detected in almost all cell cultures of the tested 20 samples, which was confirmed by mycoplasma-specific gene expression and fluorescence staining. Such contaminated mycoplasma could be successfully eliminated using elimination kit, and proliferation test showed decreased proliferation activity in mycoplasma-contaminated cells. After elimination of contaminated mycoplasma, stem cells from apical papilla showed osteogenic and neural lineage differentiation under certain culture conditions. Our study proposes that the evaluation of mycoplasma contamination and elimination process might be required in the use of stem cells from apical papilla for their potent applications to tissue engineering and regenerative medicine.

Sphingosine kinase inhibition alleviates endothelial permeability induced by thrombin and activated neutrophils.

PubMed

Itagaki, Kiyoshi; Zhang, Qin; Hauser, Carl J

2010-04-01

Inflammation and microvascular thrombosis are interrelated causes of acute lung injury in the systemic inflammatory response syndrome. Neutrophils (polymorphonuclear neutrophil [PMN]) and endothelial cells (EC) activated by systemic inflammatory response syndrome interact to increase pulmonary vascular permeability, but the interactions between PMN and EC are difficult to study. Recently, we reported that sphingosine 1-phosphate is a second messenger eliciting store-operated calcium entry (SOCE) in response to inflammatory agonists in both PMN and EC. Store-operated calcium entry is therefore a target mechanism for the therapeutic modulation of inflammatory PMN-EC interactions. Here, we isolated, modeled, and studied the effects of pharmacologic SOCE inhibition using real-time systems to monitor EC permeability after exposure to activated PMN. We created systems to continuously assess permeability of human pulmonary artery endothelial cells and human microvascular endothelial cells from lung. Endothelial cells show increased permeability after challenge by activated PMN. Such permeability increases can be attenuated by exposure of the cocultures to sphingosine kinase (SK) inhibitors (SKI-2, N,N-dimethylsphingosine [DMS]) or Ca2+ entry inhibitors (Gd3+, MRS-1845). Human microvascular endothelial cells from lung pretreated with SKI-2 or DMS showed decreased permeability when later exposed to activated PMN. Likewise, when PMNs were activated with thapsigargin (TG) in the presence of SKI-2, DMS, Gd, or MRS-1845, their ability to cause EC permeability subsequently was reduced. SKI-2 also inhibited the activation of human pulmonary artery ECs by thrombin. These studies will provide a firm mechanistic foundation for understanding how systemic SOCE inhibition may be used to prevent acute lung injury in vivo.

Interaction of Mycobacterium leprae with Human Airway Epithelial Cells: Adherence, Entry, Survival, and Identification of Potential Adhesins by Surface Proteome Analysis

PubMed Central

Silva, Carlos A. M.; Danelishvili, Lia; McNamara, Michael; Berredo-Pinho, Márcia; Bildfell, Robert; Biet, Franck; Rodrigues, Luciana S.; Oliveira, Albanita V.

2013-01-01

This study examined the in vitro interaction between Mycobacterium leprae, the causative agent of leprosy, and human alveolar and nasal epithelial cells, demonstrating that M. leprae can enter both cell types and that both are capable of sustaining bacterial survival. Moreover, delivery of M. leprae to the nasal septum of mice resulted in macrophage and epithelial cell infection in the lung tissue, sustaining the idea that the airways constitute an important M. leprae entry route into the human body. Since critical aspects in understanding the mechanisms of infection are the identification and characterization of the adhesins involved in pathogen-host cell interaction, the nude mouse-derived M. leprae cell surface-exposed proteome was studied to uncover potentially relevant adhesin candidates. A total of 279 cell surface-exposed proteins were identified based on selective biotinylation, streptavidin-affinity purification, and shotgun mass spectrometry; 11 of those proteins have been previously described as potential adhesins. In vitro assays with the recombinant forms of the histone-like protein (Hlp) and the heparin-binding hemagglutinin (HBHA), considered to be major mycobacterial adhesins, confirmed their capacity to promote bacterial attachment to epithelial cells. Taking our data together, they suggest that the airway epithelium may act as a reservoir and/or portal of entry for M. leprae in humans. Moreover, our report sheds light on the potentially critical adhesins involved in M. leprae-epithelial cell interaction that may be useful in designing more effective tools for leprosy control. PMID:23670556

Technology support of the handover: promoting observability, flexibility and efficiency.

PubMed

Patterson, Emily S

2012-12-01

Efforts to standardise data elements and increase the comprehensiveness of information included in patient handovers have produced a growing interest in augmenting the verbal exchange of information with written communications conducted through health information technology (HIT). The aim of this perspective is to offer recommendations to optimise technology support of handovers, based on a review of the relevant scientific literature. Review of the literature on human factors and the study of communication produced three recommendations. The first entails making available "shared knowledge" relevant to the handover and subsequent clinical management with intended and unintended recipients. The second is to create a flexible narrative structure (unstructured text fields) for human-human communications facilitated by technology. The third recommendation is to avoid reliance on real-time data entry during busy periods. Implementing these recommendations is anticipated to increase the observability (the ability to readily determine current status), flexibility, and efficiency of HIT-supported patient handovers. Anticipated benefits of technology-supported handovers include reducing reliance on human memory, increasing the efficiency and structure of the verbal exchange, avoiding readbacks of numeric data, and aiding clinical management following the handover. In cases when verbal handovers are delayed, do not occur, or involve members of the health care team without first-hand access to critical information, making 'common ground' observable for all recipients, creating a flexible narrative structure for communication and avoiding reliance on real-time data entry during the busiest times has implications for HIT design and day to day data entry and management operations. Benefits include increased observability, flexibility, and efficiency of HIT-supported patient handovers.

A single ubiquitin is sufficient for cargo protein entry into MVBs in the absence of ESCRT ubiquitination

PubMed Central

Stringer, Daniel K.

2011-01-01

ESCRTs (endosomal sorting complexes required for transport) bind and sequester ubiquitinated membrane proteins and usher them into multivesicular bodies (MVBs). As Ubiquitin (Ub)-binding proteins, ESCRTs themselves become ubiquitinated. However, it is unclear whether this regulates a critical aspect of their function or is a nonspecific consequence of their association with the Ub system. We investigated whether ubiquitination of the ESCRTs was required for their ability to sort cargo into the MVB lumen. Although we found that Rsp5 was the main Ub ligase responsible for ubiquitination of ESCRT-0, elimination of Rsp5 or elimination of the ubiquitinatable lysines within ESCRT-0 did not affect MVB sorting. Moreover, by fusing the catalytic domain of deubiquitinating peptidases onto ESCRTs, we could block ESCRT ubiquitination and the sorting of proteins that undergo Rsp5-dependent ubiquitination. Yet, proteins fused to a single Ub moiety were efficiently delivered to the MVB lumen, which strongly indicates that a single Ub is sufficient in sorting MVBs in the absence of ESCRT ubiquitination. PMID:21242292

Two pore channels control Ebolavirus host cell entry and are drug targets for disease treatment

PubMed Central

Sakurai, Yasuteru; Kolokoltsov, Andrey A.; Chen, Cheng-Chang; Tidwell, Michael W.; Bauta, William E.; Klugbauer, Norbert; Grimm, Christian; Wahl-Schott, Christian; Biel, Martin; Davey, Robert A.

2015-01-01

Ebolavirus causes sporadic outbreaks of lethal hemorrhagic fever in humans with no currently approved therapy. Cells take up Ebolavirus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebolavirus entry into host cells requires the endosomal calcium channels called two pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs or small molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule we tested, inhibited infection of human macrophages, the primary target of Ebolavirus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebolavirus infection and may be effective targets for antiviral therapy. PMID:25722412

Alphavirus entry into host cells.

PubMed

Vancini, Ricardo; Hernandez, Raquel; Brown, Dennis

2015-01-01

Viruses have evolved to exploit the vast complexity of cellular processes for their success within the host cell. The entry mechanisms of enveloped viruses (viruses with a surrounding outer lipid bilayer membrane) are usually classified as being either endocytotic or fusogenic. Different mechanisms have been proposed for Alphavirus entry and genome delivery. Indirect observations led to a general belief that enveloped viruses can infect cells either by protein-assisted fusion with the plasma membrane in a pH-independent manner or by endocytosis and fusion with the endocytic vacuole in a low-pH environment. The mechanism of Alphavirus penetration has been recently revisited using direct observation of the processes by electron microscopy under conditions of different temperatures and time progression. Under conditions nonpermissive for endocytosis or any vesicular transport, events occur which allow the entry of the virus genome into the cells. When drug inhibitors of cellular functions are used to prevent entry, only ionophores are found to significantly inhibit RNA delivery. Arboviruses are agents of significant human and animal disease; therefore, strategies to control infections are needed and include development of compounds which will block critical steps in the early infection events. It appears that current evidence points to an entry mechanism, in which alphaviruses infect cells by direct penetration of cell plasma membranes through a pore structure formed by virus and, possibly, host proteins. © 2015 Elsevier Inc. All rights reserved.

Novel Small Molecule Entry Inhibitors of Ebola Virus

PubMed Central

Basu, Arnab; Mills, Debra M.; Mitchell, Daniel; Ndungo, Esther; Williams, John D.; Herbert, Andrew S.; Dye, John M.; Moir, Donald T.; Chandran, Kartik; Patterson, Jean L.; Rong, Lijun; Bowlin, Terry L.

2015-01-01

Background. The current Ebola virus (EBOV) outbreak has highlighted the troubling absence of available antivirals or vaccines to treat infected patients and stop the spread of EBOV. The EBOV glycoprotein (GP) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-EBOV drugs. We report the identification of 2 novel EBOV inhibitors targeting viral entry. Methods. To identify small molecule inhibitors of EBOV entry, we carried out a cell-based high-throughput screening using human immunodeficiency virus–based pseudotyped viruses expressing EBOV-GP. Two compounds were identified, and mechanism-of-action studies were performed using immunoflourescence, AlphaLISA, and enzymatic assays for cathepsin B inhibition. Results. We report the identification of 2 novel entry inhibitors. These inhibitors (1) inhibit EBOV infection (50% inhibitory concentration, approximately 0.28 and approximately 10 µmol/L) at a late stage of entry, (2) induce Niemann-Pick C phenotype, and (3) inhibit GP–Niemann-Pick C1 (NPC1) protein interaction. Conclusions. We have identified 2 novel EBOV inhibitors, MBX2254 and MBX2270, that can serve as starting points for the development of an anti-EBOV therapeutic agent. Our findings also highlight the importance of NPC1-GP interaction in EBOV entry and the attractiveness of NPC1 as an antifiloviral therapeutic target. PMID:26206510

Study and Development of a Sub-Orbital Re-Entry Demonstrator

NASA Astrophysics Data System (ADS)

Savino, R.

The Italian and European Space Agencies are supporting a research programme, developed in Campania region by a cluster of industries, research institutes and universities, on a low-cost re-entry capsule, able to return payloads from the ISS to Earth and/or to perform short-duration scientific missions in Low Earth Orbit (LEO). The ballistic capsule is characterized by a deployable, disposable "umbrella-like" heat shield that allows relatively small dimensions at launch and a sufficient exposed surface area in re-entry conditions, reducing the ballistic coefficient and leading to acceptable heat fluxes, mechanical loads and final descent velocity. ESA is supporting a preliminary study to develop a flight demonstrator of the capsule to be embarked as a secondary payload onboard a sub-orbital sounding rocket. The deployable thermal protection system concept may be applied to future science and robotic exploration mission requiring planetary entry and, possibly also to missions in the framework of Human Space flight, requiring planetary entry or re-entry. The technology offers also an interesting potential for aerobraking, aerocapture and for de-orbiting. This paper summarizes the results of these activities, which are being more and more refined as the work proceeds, including the definition and analysis of the mission scenario, the aerodynamic, aerothermodynamic, mechanical and structural analyses and the technical definition of avionics, instrumentation and main subsystems.

Evaluation and identification of hepatitis B virus entry inhibitors using HepG2 cells overexpressing a membrane transporter NTCP.

PubMed

Iwamoto, Masashi; Watashi, Koichi; Tsukuda, Senko; Aly, Hussein Hassan; Fukasawa, Masayoshi; Fujimoto, Akira; Suzuki, Ryosuke; Aizaki, Hideki; Ito, Takayoshi; Koiwai, Osamu; Kusuhara, Hiroyuki; Wakita, Takaji

2014-01-17

Hepatitis B virus (HBV) entry has been analyzed using infection-susceptible cells, including primary human hepatocytes, primary tupaia hepatocytes, and HepaRG cells. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) membrane transporter was reported as an HBV entry receptor. In this study, we established a strain of HepG2 cells engineered to overexpress the human NTCP gene (HepG2-hNTCP-C4 cells). HepG2-hNTCP-C4 cells were shown to be susceptible to infection by blood-borne and cell culture-derived HBV. HBV infection was facilitated by pretreating cells with 3% dimethyl sulfoxide permitting nearly 50% of the cells to be infected with HBV. Knockdown analysis suggested that HBV infection of HepG2-hNTCP-C4 cells was mediated by NTCP. HBV infection was blocked by an anti-HBV surface protein neutralizing antibody, by compounds known to inhibit NTCP transporter activity, and by cyclosporin A and its derivatives. The infection assay suggested that cyclosporin B was a more potent inhibitor of HBV entry than was cyclosporin A. Further chemical screening identified oxysterols, oxidized derivatives of cholesterol, as inhibitors of HBV infection. Thus, the HepG2-hNTCP-C4 cell line established in this study is a useful tool for the identification of inhibitors of HBV infection as well as for the analysis of the molecular mechanisms of HBV infection. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

A push-pull system to reduce house entry of malaria mosquitoes

PubMed Central

2014-01-01

Background Mosquitoes are the dominant vectors of pathogens that cause infectious diseases such as malaria, dengue, yellow fever and filariasis. Current vector control strategies often rely on the use of pyrethroids against which mosquitoes are increasingly developing resistance. Here, a push-pull system is presented, that operates by the simultaneous use of repellent and attractive volatile odorants. Method/Results Experiments were carried out in a semi-field set-up: a traditional house which was constructed inside a screenhouse. The release of different repellent compounds, para-menthane-3,8-diol (PMD), catnip oil e.o. and delta-undecalactone, from the four corners of the house resulted in significant reductions of 45% to 81.5% in house entry of host-seeking malaria mosquitoes. The highest reductions in house entry (up to 95.5%), were achieved by simultaneously repelling mosquitoes from the house (push) and removing them from the experimental set-up using attractant-baited traps (pull). Conclusions The outcome of this study suggests that a push-pull system based on attractive and repellent volatiles may successfully be employed to target mosquito vectors of human disease. Reductions in house entry of malaria vectors, of the magnitude that was achieved in these experiments, would likely affect malaria transmission. The repellents used are non-toxic and can be used safely in a human environment. Delta-undecalactone is a novel repellent that showed higher effectiveness than the established repellent PMD. These results encourage further development of the system for practical implementation in the field. PMID:24674451

Role of phosphatidylserine receptors in enveloped virus infection.

PubMed

Morizono, Kouki; Chen, Irvin S Y

2014-04-01

We recently demonstrated that a soluble protein, Gas6, can facilitate viral entry by bridging viral envelope phosphatidylserine to Axl, a receptor tyrosine kinase expressed on target cells. The interaction between phosphatidylserine, Gas6, and Axl was originally shown to be a molecular mechanism through which phagocytes recognize phosphatidylserine exposed on dead cells. Since our initial report, several groups have confirmed that Axl/Gas6, as well as other phosphatidylserine receptors, facilitate entry of dengue, West Nile, and Ebola viruses. Virus binding by viral envelope phosphatidylserine is now a viral entry mechanism generalized to many families of viruses. In addition to Axl/Gas6, various molecules are known to recognize phosphatidylserine; however, the effects of these molecules on virus binding and entry have not been comprehensively evaluated and compared. In this study, we examined most of the known human phosphatidylserine-recognizing molecules, including MFG-E8, TIM-1, -3, and -4, CD300a, BAI1, and stabilin-1 and -2, for their abilities to facilitate virus binding and infection. Using pseudotyped lentiviral vectors, we found that a soluble phosphatidylserine-binding protein, MFG-E8, enhances transduction. Cell surface receptors TIM-1 and -4 also enhance virus binding/transduction. The extent of enhancement by these molecules varies, depending on the type of pseudotyping envelope proteins. Mutated MFG-E8, which binds viral envelope phosphatidylserine without bridging virus to cells, but, surprisingly, not annexin V, which has been used to block phagocytosis of dead cells by concealing phosphatidylserine, efficiently blocks these phosphatidylserine-dependent viral entry mechanisms. These results provide insight into understanding the role of viral envelope phosphatidylserine in viral infection. Envelope phosphatidylserine has previously been shown to be important for replication of various envelope viruses, but details of this mechanism(s) were unclear. We were the first to report that a bifunctional serum protein, Gas6, bridges envelope phosphatidylserine to a cell surface receptor, Axl. Recent studies demonstrated that many envelope viruses, including vaccinia, dengue, West Nile, and Ebola viruses, utilize Axl/Gas6 to facilitate their entry, suggesting that the phosphatidylserine-mediated viral entry mechanism can be shared by various enveloped viruses. In addition to Axl/Gas6, various molecules are known to recognize phosphatidylserine; however, the effects of these molecules on virus binding and entry have not been comprehensively evaluated and compared. In this study, we examined most human phosphatidylserine-recognizing molecules for their abilities to facilitate viral infection. The results provide insights into the role(s) of envelope phosphatidylserine in viral infection, which can be applicable to the development of novel antiviral reagents that block phosphatidylserine-mediated viral entry.

Animated Agents Teaching Helping Skills in an Online Environment: A Pilot Study

ERIC Educational Resources Information Center

Duggan, Molly H.; Adcock, Amy B.

2007-01-01

Human service educators constantly struggle with how to best teach students the communication skills required of entry-level human service professionals. While teaching such skills is easier in a traditional face-to-face environment, teaching communication skills via distance learning presents its own challenges. Developing interactive web-based…

Improving Faculty Perceptions of and Intent to Use Simulation: An Intervention Project

ERIC Educational Resources Information Center

Tucker, Charles

2013-01-01

Human patient simulation is an innovative teaching strategy that can facilitate practice development and preparation for entry into today's healthcare environment for nursing students. Unfortunately, the use of human patient simulation has been limited due to the perceptions of nursing faculty members. This project sought to explore those…

Career Management for Human Resource Professionals.

ERIC Educational Resources Information Center

Wiley, Carolyn

1992-01-01

Claims growing importance of human resource (HR) management suggests there are extensive career opportunities in HR. Notes there is no single entry position in HR management, and only one in seven HR professionals believes luck was a factor in his or her success. Concludes HR professionals must be able to deliver usual services and effectively…

A Uniform System For The Annotation Of Human microRNA Genes And The Evolution Of The Human microRNAome

PubMed Central

Fromm, Bastian; Billipp, Tyler; Peck, Liam E.; Johansen, Morten; Tarver, James E.; King, Benjamin L.; Newcomb, James M.; Sempere, Lorenzo F.; Flatmark, Kjersti; Hovig, Eivind; Peterson, Kevin J.

2016-01-01

Although microRNAs (miRNAs) are among the most intensively studied molecules of the past 20 years, determining what is and what is not a miRNA has not been straightforward. Here, we present a uniform system for the annotation and nomenclature of miRNA genes. We show that fewer than a third of the 1,881 human miRBase entries, and only approximately 16% of the 7,095 metazoan miRBase entries, are robustly supported as miRNA genes. Furthermore, we show that the human repertoire of miRNAs has been shaped by periods of intense miRNA innovation, and that mature gene products show a very different tempo and mode of sequence evolution than star products. We establish a new open access database -- MirGeneDB (http://mirgenedb.org) -- to catalog this set of robustly supported miRNAs, which complements the efforts of miRBase, but differs from it by annotating the mature versus star products, and by imposing an evolutionary hierarchy upon this curated and consistently named repertoire. PMID:26473382

Mission and Design Sensitivities for Human Mars Landers Using Hypersonic Inflatable Aerodynamic Decelerators

NASA Technical Reports Server (NTRS)

Polsgrove, Tara P.; Thomas, Herbert D.; Dwyer Ciancio, Alicia; Collins, Tim; Samareh, Jamshid

2017-01-01

Landing humans on Mars is one of NASA's long term goals. NASA's Evolvable Mars Campaign (EMC) is focused on evaluating architectural trade options to define the capabilities and elements needed to sustain human presence on the surface of Mars. The EMC study teams have considered a variety of in-space propulsion options and surface mission options. Understanding how these choices affect the performance of the lander will allow a balanced optimization of this complex system of systems problem. This paper presents the effects of mission and vehicle design options on lander mass and performance. Beginning with Earth launch, options include fairing size assumptions, co-manifesting elements with the lander, and Earth-Moon vicinity operations. Capturing into Mars orbit using either aerocapture or propulsive capture is assessed. For entry, descent, and landing both storable as well as oxygen and methane propellant combinations are considered, engine thrust level is assessed, and sensitivity to landed payload mass is presented. This paper focuses on lander designs using the Hypersonic Inflatable Aerodynamic Decelerators, one of several entry system technologies currently considered for human missions.

Mars Sample Return Using Commercial Capabilities: Propulsive Entry, Descent, and Landing of a Capsule Form Vehicle

NASA Technical Reports Server (NTRS)

Gonzales, Andrew A.; Lemke, Lawrence G.; Huynh, Loc C.

2014-01-01

This paper describes a critical portion of the work that has been done at NASA, Ames Research Center regarding the use of the commercially developed Dragon capsule as a delivery vehicle for the elements of a high priority Mars Sample Return mission. The objective of the investigation was to determine entry and landed mass capabilities that cover anticipated mission conditions. The "Red Dragon", Mars configuration, uses supersonic retro-propulsion, with no required parachute system, to perform Entry, Descent, and Landing (EDL) maneuvers. The propulsive system proposed for use is the same system that will perform an abort, if necessary, for a human rated version of the Dragon capsule. Standard trajectory analysis tools are applied to publically available information about Dragon and other legacy capsule forms in order to perform the investigation. Trajectory simulation parameters include entry velocity, flight path angle, lift to drag Ratio (L/D), landing site elevation, atmosphere density, and total entry mass, in addition engineering assumptions for the performance of the propulsion system are stated. Mass estimates for major elements of the overall proposed architecture are coupled to this EDL analysis to close the overall architecture. Three synodic launch opportunities, beginning with the 2022 opportunity, define the arrival conditions. Results state the relations between the analysis parameters as well as sensitivities to those parameters. The EDL performance envelope includes landing altitudes between 0 and -4 km referenced to the Mars Orbiter Laser Altimeter datum as well as minimum and maximum atmosphere density. Total entry masses between 7 and 10 mt are considered with architecture closure occurring between 9.0 and 10 mt. Propellant mass fractions for each major phase of the EDL - Entry, Terminal Descent, and Hazard Avoidance - have been derived. An assessment of the effect of the entry conditions on the Thermal Protection System (TPS) currently in use for Dragon missions shows no significant stressors. A useful payload mass of 2.0 mt is provided and includes mass and grow allowance for a Mars Ascent Vehicle (MAV), Earth Return Vehicle (ERV), and mission unique equipment. The useful payload supports an architecture that receives a sample from another surface asset and sends it directly back to Earth for recovery in a high Earth orbit. The work shows that emerging commercial capabilities as well as previously studied EDL methodologies can be used to efficiently support an important planetary science objective. The work also has applications for human exploration missions that will also use propulsive EDL techniques

Simian Immunodeficiency Virus SIVagm Efficiently Utilizes Non-CCR5 Entry Pathways in African Green Monkey Lymphocytes: Potential Role for GPR15 and CXCR6 as Viral Coreceptors.

PubMed

Riddick, Nadeene E; Wu, Fan; Matsuda, Kenta; Whitted, Sonya; Ourmanov, Ilnour; Goldstein, Simoy; Goeken, Robert M; Plishka, Ronald J; Buckler-White, Alicia; Brenchley, Jason M; Hirsch, Vanessa M

2015-12-09

African green monkeys (AGM) are natural hosts of simian immunodeficiency virus (SIV), and infection in these animals is generally nonpathogenic, whereas infection of nonnatural hosts, such as rhesus macaques (RM), is commonly pathogenic. CCR5 has been described as the primary entry coreceptor for SIV in vivo, while human-derived CXCR6 and GPR15 also appear to be used in vitro. However, sooty mangabeys that are genetically deficient in CCR5 due to an out-of-frame deletion are infectible with SIVsmm, indicating that SIVsmm can use alternative coreceptors in vivo. In this study, we examined the CCR5 dependence of SIV strains derived from vervet AGM (SIVagmVer) and the ability of AGM-derived GPR15 and CXCR6 to serve as potential entry coreceptors. We found that SIVagmVer replicated efficiently in AGM and RM peripheral blood mononuclear cells (PBMC) in the presence of the CCR5 antagonist maraviroc, despite the fact that maraviroc was capable of blocking the CCR5-tropic strains SIVmac239, SIVsmE543-3, and simian-human immunodeficiency virus SHIV-AD8 in RM PBMC. We also found that AGM CXCR6 and AGM GPR15, to a lesser extent, supported entry of pseudotype viruses bearing SIVagm envelopes, including SIVagm transmitted/founder envelopes. Lastly, we found that CCR5, GPR15, and CXCR6 mRNAs were detected in AGM and RM memory CD4(+) T cells. These results suggest that GPR15 and CXCR6 are expressed on AGM CD4(+) T cells and are potential alternative coreceptors for SIVagm use in vivo. These data suggest that the use of non-CCR5 entry pathways may be a common feature of SIV replication in natural host species, with the potential to contribute to nonpathogenicity in these animals. African green monkeys (AGM) are natural hosts of SIV, and infection in these animals generally does not cause AIDS, whereas SIV-infected rhesus macaques (RM) typically develop AIDS. Although it has been reported that SIV generally uses CD4 and CCR5 to enter target cells in vivo, other molecules, such as GPR15 and CXCR6, also function as SIV coreceptors in vitro. In this study, we investigated whether SIV from vervet AGM can use non-CCR5 entry pathways, as has been observed in sooty mangabeys. We found that SIVagmVer efficiently replicated in AGM and RM peripheral blood mononuclear cells in the presence of the CCR5 antagonist maraviroc, suggesting that non-CCR5 entry pathways can support SIVagm entry. We found that AGM-derived GPR15 and CXCR6 support SIVagmVer entry in vitro and may serve as entry coreceptors for SIVagm in vivo, since their mRNAs were detected in AGM memory CD4(+) T cells, the preferred target cells of SIV. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Simian Immunodeficiency Virus SIVagm Efficiently Utilizes Non-CCR5 Entry Pathways in African Green Monkey Lymphocytes: Potential Role for GPR15 and CXCR6 as Viral Coreceptors

PubMed Central

Riddick, Nadeene E.; Wu, Fan; Matsuda, Kenta; Whitted, Sonya; Ourmanov, Ilnour; Goldstein, Simoy; Goeken, Robert M.; Plishka, Ronald J.; Buckler-White, Alicia; Brenchley, Jason M.

2015-01-01

ABSTRACT African green monkeys (AGM) are natural hosts of simian immunodeficiency virus (SIV), and infection in these animals is generally nonpathogenic, whereas infection of nonnatural hosts, such as rhesus macaques (RM), is commonly pathogenic. CCR5 has been described as the primary entry coreceptor for SIV in vivo, while human-derived CXCR6 and GPR15 also appear to be used in vitro. However, sooty mangabeys that are genetically deficient in CCR5 due to an out-of-frame deletion are infectible with SIVsmm, indicating that SIVsmm can use alternative coreceptors in vivo. In this study, we examined the CCR5 dependence of SIV strains derived from vervet AGM (SIVagmVer) and the ability of AGM-derived GPR15 and CXCR6 to serve as potential entry coreceptors. We found that SIVagmVer replicated efficiently in AGM and RM peripheral blood mononuclear cells (PBMC) in the presence of the CCR5 antagonist maraviroc, despite the fact that maraviroc was capable of blocking the CCR5-tropic strains SIVmac239, SIVsmE543-3, and simian-human immunodeficiency virus SHIV-AD8 in RM PBMC. We also found that AGM CXCR6 and AGM GPR15, to a lesser extent, supported entry of pseudotype viruses bearing SIVagm envelopes, including SIVagm transmitted/founder envelopes. Lastly, we found that CCR5, GPR15, and CXCR6 mRNAs were detected in AGM and RM memory CD4+ T cells. These results suggest that GPR15 and CXCR6 are expressed on AGM CD4+ T cells and are potential alternative coreceptors for SIVagm use in vivo. These data suggest that the use of non-CCR5 entry pathways may be a common feature of SIV replication in natural host species, with the potential to contribute to nonpathogenicity in these animals. IMPORTANCE African green monkeys (AGM) are natural hosts of SIV, and infection in these animals generally does not cause AIDS, whereas SIV-infected rhesus macaques (RM) typically develop AIDS. Although it has been reported that SIV generally uses CD4 and CCR5 to enter target cells in vivo, other molecules, such as GPR15 and CXCR6, also function as SIV coreceptors in vitro. In this study, we investigated whether SIV from vervet AGM can use non-CCR5 entry pathways, as has been observed in sooty mangabeys. We found that SIVagmVer efficiently replicated in AGM and RM peripheral blood mononuclear cells in the presence of the CCR5 antagonist maraviroc, suggesting that non-CCR5 entry pathways can support SIVagm entry. We found that AGM-derived GPR15 and CXCR6 support SIVagmVer entry in vitro and may serve as entry coreceptors for SIVagm in vivo, since their mRNAs were detected in AGM memory CD4+ T cells, the preferred target cells of SIV. PMID:26656714

Mid-Lift-to-Drag Ratio Rigid Vehicle Control System Design and Simulation for Human Mars Entry

NASA Technical Reports Server (NTRS)

Johnson, Breanna J.; Cerimele, Christopher J.; Stachowiak, Susan J.; Sostaric, Ronald R.; Matz, Daniel A.; Lu, Ping

2018-01-01

The Mid-Lift-to-Drag Ratio Rigid Vehicle (MRV) is a proposed candidate in the NASA Evolvable Mars Campaign's (EMC) Pathfinder Entry, Descent, and Landing (EDL) architecture study. The purpose of the study is to design a mission and vehicle capable of transporting a 20mt payload to the surface of Mars. The MRV is unique in its rigid, asymmetrical lifting-body shape which enables a higher lift-to-drag ratio (L/D) than the typical robotic Mars entry capsule vehicles that carry much less mass. This paper presents the formulation and six-degree-of-freedom (6DOF) performance of the MRV's control system, which uses both aerosurfaces and a propulsive reaction control system (RCS) to affect longitudinal and lateral directional behavior.

Genetic Thinking in the Study of Social Relationships: Five Points of Entry.

PubMed

Reiss, David

2010-09-01

For nearly a generation, researchers studying human behavioral development have combined genetically informed research designs with careful measures of social relationships such as parenting, sibling relationships, peer relationships, marital processes, social class stratifications, and patterns of social engagement in the elderly. In what way have these genetically informed studies altered the construction and testing of social theories of human development? We consider five points of entry where genetic thinking is taking hold. First, genetic findings suggest an alternative scenario for explaining social data. Associations between measures of the social environment and human development may be due to genes that influence both. Second, genetic studies add to other prompts to study the early developmental origins of current social phenomena in midlife and beyond. Third, genetic analyses promise to shed light on understudied social systems, such as sibling relationships, that have an impact on human development independent of genotype. Fourth, genetic analyses anchor in neurobiology individual differences in resilience and sensitivity to both adverse and favorable social environments. Finally, genetic analyses increase the utility of laboratory simulations of human social processes and of animal models. © The Author(s) 2010.

Role of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors for Herpes Simplex Virus 1 on Primary Murine Dermal Fibroblasts.

PubMed

Petermann, Philipp; Rahn, Elena; Thier, Katharina; Hsu, Mei-Ju; Rixon, Frazer J; Kopp, Sarah J; Knebel-Mörsdorf, Dagmar

2015-09-01

The cellular proteins nectin-1 and herpesvirus entry mediator (HVEM) can both mediate the entry of herpes simplex virus 1 (HSV-1). We have recently shown how these receptors contribute to infection of skin by investigating HSV-1 entry into murine epidermis. Ex vivo infection studies reveal nectin-1 as the primary receptor in epidermis, whereas HVEM has a more limited role. Although the epidermis represents the outermost layer of skin, the contribution of nectin-1 and HVEM in the underlying dermis is still open. Here, we analyzed the role of each receptor during HSV-1 entry in murine dermal fibroblasts that were deficient in expression of either nectin-1 or HVEM or both receptors. Because infection was not prevented by the absence of either nectin-1 or HVEM, we conclude that they can act as alternative receptors. Although HVEM was found to be highly expressed on fibroblasts, entry was delayed in nectin-1-deficient cells, suggesting that nectin-1 acts as the more efficient receptor. In the absence of both receptors, entry was strongly delayed leading to a much reduced viral spread and virus production. These results suggest an unidentified cellular component that acts as alternate but inefficient receptor for HSV-1 on dermal fibroblasts. Characterization of the cellular entry mechanism suggests that HSV-1 can enter dermal fibroblasts both by direct fusion with the plasma membrane and via endocytic vesicles and that this is not dependent on the presence or absence of nectin-1. Entry was also shown to require dynamin and cholesterol, suggesting comparable entry pathways in keratinocytes and dermal fibroblasts. Herpes simplex virus (HSV) is a human pathogen which infects its host via mucosal surfaces or abraded skin. To understand how HSV-1 overcomes the protective barrier of mucosa or skin and reaches its receptors in tissue, it is essential to know which receptors contribute to the entry into individual skin cells. Previously, we have explored the contribution of nectin-1 and herpesvirus entry mediator (HVEM) as receptors for HSV-1 entry into murine epidermis, where keratinocytes form the major cell type. Since the underlying dermis consists primarily of fibroblasts, we have now extended our study of HSV-1 entry to dermal fibroblasts isolated from nectin-1- or HVEM-deficient mice or from mice deficient in both receptors. Our results demonstrate a role for both nectin-1 and HVEM as receptors and suggest a further receptor which appears much less efficient. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Revised genetic requirements for the decatenation G2 checkpoint: the role of ATM

PubMed Central

Bower, Jacquelyn J.; Zhou, Yingchun; Zhou, Tong; Simpson, Dennis A.; Arlander, Sonnet J.; Paules, Richard S.; Cordeiro-Stone, Marila; Kaufmann, William K.

2010-01-01

The decatenation G2 checkpoint is proposed to delay cellular progression from G2 into mitosis when intertwined daughter chromatids are insufficiently decatenated. Previous studies indicated that the ATM- and Rad3-related (ATR) checkpoint kinase, but not the ataxia telangiectasia-mutated (ATM) kinase, was required for decatenation G2 checkpoint function. Here, we show that the method used to quantify decatenation G2 checkpoint function can influence the identification of genetic requirements for the checkpoint. Normal human diploid fibroblast (NHDF) lines responded to the topoisomerase II (topo II) catalytic inhibitor ICRF-193 with a stringent G2 arrest and a reduction in the mitotic index. While siRNA-mediated depletion of ATR and CHEK1 increased the mitotic index in ICRF-193 treated NHDF lines, depletion of these proteins did not affect the mitotic entry rate, indicating that the decatenation G2 checkpoint was functional. These results suggest that ATR and CHEK1 are not required for the decatenation G2 checkpoint, but may influence mitotic exit after inhibition of topo II. A re-evaluation of ataxia telangiectasia (AT) cell lines using the mitotic entry assay indicated that ATM was required for the decatenation G2 checkpoint. Three NHDF cell lines responded to ICRF-193 with a mean 98% inhibition of the mitotic entry rate. Examination of the mitotic entry rates in AT fibroblasts upon treatment with ICRF-193 revealed a significantly attenuated decatenation G2 checkpoint response, with a mean 59% inhibition of the mitotic entry rate. In addition, a normal lymphoblastoid line exhibited a 95% inhibition of the mitotic entry rate after incubation with ICRF-193, whereas two AT lymphoblastoid lines displayed only 36% and 20% inhibition of the mitotic entry rate. Stable depletion of ATM in normal human fibroblasts with short hairpin RNA also attenuated decatenation G2 checkpoint function by an average of 40%. Western immunoblot analysis demonstrated that treatment with ICRF-193 induced ATM autophosphorylation and ATM-dependent phosphorylation of Ser15-p53 and Thr68 in CHEK2, but no appreciable phosphorylation of Ser139 on H2AX. The results suggest that inhibition of topo II induces ATM to phosphorylate selected targets that contribute to a G2 arrest independently of DNA damage. PMID:20372057

Health disparities: a primer for public health social workers.

PubMed

Keefe, Robert H

2010-05-01

In 2001, the U.S. Department of Health and Human Services published Healthy People 2010, which identified objectives to guide health promotion and to eliminate health disparities. Since 2001, much research has been published documenting racial and ethnic disparities in healthcare. Although progress has been made in eliminating the disparities, ongoing work by public health social workers, researchers, and policy analysts is needed. This paper focuses on racial and ethnic health disparities, why they exist, where they can be found, and some of the key health/medical conditions identified by the U.S. Department of Health and Human Services to receive attention. Finally, there is a discussion of what policy, professional and community education, and research can to do to eliminate racial and ethnic disparities in healthcare.

Epigallocatechin-3-gallate (EGCG) up-regulates miR-15b expression thus attenuating store operated calcium entry (SOCE) into murine CD4+ T cells and human leukaemic T cell lymphoblasts.

PubMed

Zhang, Shaqiu; Al-Maghout, Tamer; Bissinger, Rosi; Zeng, Ni; Pelzl, Lisann; Salker, Madhuri S; Cheng, Anchun; Singh, Yogesh; Lang, Florian

2017-10-27

CD4 + T cells are key elements in immune responses and inflammation. Activation of T cell receptors in CD4 + T cells triggers cytosolic Ca 2+ release with subsequent store operated Ca 2+ entry (SOCE), which is accomplished by the pore forming Ca 2+ release activated Ca 2+ (CRAC) channel Orai1 and its regulator stromal cell-interaction molecule 2 (STIM2). Green tea polyphenol epigallocatechin-3-gallate (EGCG) acts as a potent anti-inflammatory and anti-oxidant agent for various types of cells including immune cells. However, how post-transcriptional gene regulators such as miRNAs are involved in the regulation of Ca 2+ influx into murine CD4 + T cells and human Jurkat T cells through EGCG is not defined. EGCG treatment of murine CD4 + T cells significantly down-regulated the expression of STIM2 and Orai1 both at mRNA and protein levels. Furthermore, EGCG significantly decreased SOCE in both murine and human T cells. EGCG treatment increased miRNA-15b (miR-15b) abundance in both murine and human T cells. Bioinformatics analysis reveals that miR-15b, which has a STIM2 binding site, is involved in the down-regulation of SOCE. Overexpression of miR-15b significantly decreased the mRNA and protein expression of STIM2 and Orai1 in murine T cells. Treatment of Jurkat T cells with 10 μM EGCG further decreased mTOR and PTEN protein levels. EGCG decreased mitochondrial membrane potential (MMP) in both human and murine T cells. In conclusion, the observations suggest that EGCG inhibits the Ca 2+ entry into murine and human T cells, an effect accomplished at least in part by up-regulation of miR-15b.

Development of a data entry auditing protocol and quality assurance for a tissue bank database.

PubMed

Khushi, Matloob; Carpenter, Jane E; Balleine, Rosemary L; Clarke, Christine L

2012-03-01

Human transcription error is an acknowledged risk when extracting information from paper records for entry into a database. For a tissue bank, it is critical that accurate data are provided to researchers with approved access to tissue bank material. The challenges of tissue bank data collection include manual extraction of data from complex medical reports that are accessed from a number of sources and that differ in style and layout. As a quality assurance measure, the Breast Cancer Tissue Bank (http:\\\\www.abctb.org.au) has implemented an auditing protocol and in order to efficiently execute the process, has developed an open source database plug-in tool (eAuditor) to assist in auditing of data held in our tissue bank database. Using eAuditor, we have identified that human entry errors range from 0.01% when entering donor's clinical follow-up details, to 0.53% when entering pathological details, highlighting the importance of an audit protocol tool such as eAuditor in a tissue bank database. eAuditor was developed and tested on the Caisis open source clinical-research database; however, it can be integrated in other databases where similar functionality is required.

Backshell Radiative Heating on Human-Scale Mars Entry Vehicles

NASA Technical Reports Server (NTRS)

West,Thomas K., IV; Theisinger, John E.; Brune, Andrew J.; Johnston, Christopher O.

2017-01-01

This work quantifies the backshell radiative heating experienced by payloads on human- scale vehicles entering the Martian atmosphere. Three underlying configurations were studied: a generic sphere, a sphere-cone forebody with a cylindrical payload, and an ellipsled. Computational fluid dynamics simulations of the flow field and radiation were performed using the LAURA and HARA codes, respectively. Results of this work indicated the primary contributor to radiative heating is emission from the CO2 IR band system. Furthermore, the backshell radiation component of heating can persist lower than 2 km/s during entry and descent. For the sphere-cone configuration a peak heat flux of about 3.5 W/cm(exp. 2) was observed at the payload juncture during entry. At similar conditions, the ellipsled geometry experienced about 1.25 W/cm(exp. 2) on the backshell, but as much as 8 W/cm(exp. 2) on the base at very high angle of attack. Overall, this study sheds light on the potential magnitudes of backshell radiative heating that various configurations may experience. These results may serve as a starting point for thermal protection system design or configuration changes necessary to accommodate thermal radiation levels.

Rationale and support for a One Health program for canine vaccination as the most cost-effective means of controlling zoonotic rabies in endemic settings.

PubMed

Lavan, Robert P; King, Alasdair I MacG; Sutton, David J; Tunceli, Kaan

2017-03-23

Although dog vaccination has been demonstrated to reduce and eliminate rabies in humans, during meetings there are often calls for further pilot studies. The assembled data proves that a widespread approach is now required. While zoonotic rabies has a minimal presence in developed nations, it is endemic throughout most of Asia and Africa, where it is considered to be a neglected tropical disease. In these areas, rabies causes an estimated annual mortality of at least 55,000 human deaths. Worldwide rabid dogs are the source of the vast majority of human rabies exposures. The World Health Organization (WHO), the Food and Agriculture Organization (FAO) of the United Nations and the World Organization for Animal Health (OIE) advocate a collaborative One Health approach involving human public health and veterinary agencies, with mass canine vaccination programs in endemic areas being the mainstay of strategies to eliminate dog-mediated human rabies. While post-exposure prophylaxis (PEP) is effective in preventing deaths in people exposed to rabies, it is comparatively expensive and has little impact on the canine reservoir that is the primary source of zoonotic rabies. Indiscriminate culling of the dog population is expensive and there is little evidence that it is effective in controlling rabies in non-island locations. Mass canine vaccination programs using a One Health framework that achieves a minimum 70% vaccination coverage during annual campaigns have proven to be cost-effective in controlling zoonotic rabies in endemic, resource-poor regions. Case studies, such as in Tanzania and Bhutan, illustrate how an approach based on mass canine rabies vaccination has effectively reduced both canine and human rabies to minimal levels. The multiple benefits of mass canine rabies vaccination in these cases included eliminating rabies in the domestic dog reservoirs, eliminating human rabies cases, and decreasing the rabies economic burden by reducing expenditures on PEP. Copyright © 2017. Published by Elsevier Ltd.

Structures and Mechanisms Design Concepts for Adaptive Deployable Entry Placement Technology

NASA Technical Reports Server (NTRS)

Yount, Bryan C.; Arnold, James O.; Gage, Peter J.; Mockelman, Jeffrey; Venkatapathy, Ethiraj

2012-01-01

System studies have shown that large deployable aerodynamic decelerators such as the Adaptive Deployable Entry and Placement Technology (ADEPT) concept can revolutionize future robotic and human exploration missions involving atmospheric entry, descent and landing by significantly reducing the maximum heating rate, total heat load, and deceleration loads experienced by the spacecraft during entry [1-3]. ADEPT and the Hypersonic Inflatable Aerodynamic Decelerator (HIAD) [4] share the approach of stowing the entry system in the shroud of the launch vehicle and deploying it to a much larger diameter prior to entry. The ADEPT concept provides a low ballistic coefficient for planetary entry by employing an umbrella-like deployable structure consisting of ribs, struts and a fabric cover that form an aerodynamic decelerator capable of undergoing hypersonic flight. The ADEPT "skin" is a 3-D woven carbon cloth that serves as a thermal protection system (TPS) and as a structural surface that transfers aerodynamic forces to the underlying ribs [5]. This paper focuses on design activities associated with integrating ADEPT components (cloth, ribs, struts and mechanisms) into a system that can function across all configurations and environments of a typical mission concept: stowed during launch, in-space deployment, entry, descent, parachute deployment and separation from the landing payload. The baseline structures and mechanisms were selected via trade studies conducted during the summer and fall of 2012. They are now being incorporated into the design of a ground test article (GTA) that will be fabricated in 2013. It will be used to evaluate retention of the stowed configuration in a launch environment, mechanism operation for release, deployment and locking, and static strength of the deployed decelerator. Of particular interest are the carbon cloth interfaces, underlying hot structure, (Advanced Carbon- Carbon ribs) and other structural components (nose cap, struts, and main body) designed to withstand the pressure and extremely high heating experienced during planetary entry.

Physician support of HPV vaccination school-entry requirements.

PubMed

Califano, Sophia; Calo, William A; Weinberger, Morris; Gilkey, Melissa B; Brewer, Noel T

2016-06-02

School-entry requirements in the US have led to high coverage for several vaccines, but few states and jurisdictions have adopted these policies for human papillomavirus (HPV) vaccination. Because physicians play a key role in advocating for vaccination policies, we assessed physician support of requiring HPV vaccine for school entry and correlates of this support. Participants were a national sample of 775 physicians who provide primary care, including vaccines, to adolescents. Physicians completed an online survey in 2014 that assessed their support for school-entry requirements for HPV vaccination of 11 and 12 y olds. We used multivariable logistic regression to assess correlates of support for these requirements. The majority of physicians (74%) supported some form of school-entry requirements, with or without opt-out provisions. When opt-out provisions were not specified, 47% agreed that laws requiring HPV vaccination for school attendance were a "good idea." Physicians more often agreed with requirements, without opt-out provisions, if they: had more years in practice (OR=1.49; 95% CI: 1.09-2.04), gave higher quality HPV vaccine recommendations (OR=2.06; 95% CI: 1.45-2.93), believed that having requirements for Tdap, but not HPV, vaccination undermined its importance (OR=3.33; 95% CI: 2.26-4.9), and believed HPV vaccination was as or more important than other adolescent vaccinations (OR=2.30; 95% CI: 1.65-3.18). In conclusion, we found that many physicians supported school-entry requirements for HPV vaccination. More research is needed to investigate the extent to which opt-out provisions might weaken or strengthen physician support of HPV vaccination school-entry requirements.

A comparative review of the pharmacokinetics of boric acid in rodents and humans.

PubMed

Murray, F J

1998-01-01

The pharmacokinetics of boric acid (BA) have been studied in animals and humans. Orally administered BA is readily and completely absorbed in rats, rabbits, and humans, as well as other animal species. In animals and humans, absorbed BA appears to be rapidly distributed throughout the body water via passive diffusion. Following administration of BA, the ratio of blood: soft tissue concentrations of boron (B) is approx 1.0 in rats and humans; in contrast, concentrations of B in bone exceed those in blood by a factor of approx 4 in both rats and humans. In rats, adipose tissue concentrations of B are only 20% of the levels found in blood and soft tissues; however, human data on adipose tissue levels are not available. BA does not appear to be metabolized in either animals or humans owing to the excessive energy required to break the B-O bond. BA has an affinity for cis-hydroxy groups, and it has been hypothesized to elicit its biological activity through this mechanism. The elimination kinetics of BA also appear to be similar for rodents and humans. BA is eliminated unchanged in the urine. The kinetics of elimination were evaluated in human volunteers given BA orally or intravenously; the half-life for elimination was essentially the same (approx 21 h) by either route of exposure. In rats, blood and tissue levels of B reached steady-state after 3-4 d of oral administration of BA; assuming first-order kinetics, a half-life of 14-19 h may be calculated. The lack of metabolism of BA eliminates metabolic clearance as a potential source of interspecies variation. Accordingly, in the absence of differences in metabolic clearance, renal clearance is expected to be the major determinant of interspecies variation in pharmacokinetics. Because glomerular filtration rates are slightly higher in rats than in humans, the slight difference in half-lives may be readily explained. The most sensitive toxicity end point for BA appears to be developmental toxicity in rats, with a No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) of 55 and 76 mg BA/kg/d, respectively. Mean blood B levels in pregnant rats on gestation day 20 in the pivotal developmental toxicity study were reported to be 1.27 and 1.53 mcg B/g at the NOAEL and LOAEL, respectively. Blood B concentrations in humans are well below these levels. Average blood B levels in the most heavily exposed worker population at a borate mine was 0.24 mcg B/mL, and the estimated daily occupational exposure was equivalent to 160 mg BA/d. Blood B levels in the general population generally range from 0.03 to 0.09 mcg B/mL. These blood B values indicate an ample margin of safety for humans. In summary, the pharmacokinetics of BA in humans and rodents are remarkably similar, and interspecies differences in pharmacokinetics appear to be minimal.

Tick-borne encephalitis virus infects human brain microvascular endothelial cells without compromising blood-brain barrier integrity.

PubMed

Palus, Martin; Vancova, Marie; Sirmarova, Jana; Elsterova, Jana; Perner, Jan; Ruzek, Daniel

2017-07-01

Alteration of the blood-brain barrier (BBB) is a hallmark of tick-borne encephalitis (TBE), a life-threating human viral neuroinfection. However, the mechanism of BBB breakdown during TBE, as well as TBE virus (TBEV) entry into the brain is unclear. Here, primary human microvascular endothelial cells (HBMECs) were infected with TBEV to study interactions with the BBB. Although the number of infected cells was relatively low in culture (<5%), the infection was persistent with high TBEV yields (>10 6 pfu/ml). Infection did not induce any significant changes in the expression of key tight junction proteins or upregulate the expression of cell adhesion molecules, and did not alter the highly organized intercellular junctions between HBMECs. In an in vitro BBB model, the virus crossed the BBB via a transcellular pathway without compromising the integrity of the cell monolayer. The results indicate that HBMECs may support TBEV entry into the brain without altering BBB integrity. Copyright © 2017 Elsevier Inc. All rights reserved.

Antibody neutralization of retargeted measles viruses.

PubMed

Lech, Patrycja J; Pappoe, Roland; Nakamura, Takafumi; Tobin, Gregory J; Nara, Peter L; Russell, Stephen J

2014-04-01

The measles virus (MV) vaccine lineage is a promising oncolytic but prior exposure to the measles vaccine or wild-type MV strains limits treatment utility due to the presence of anti-measles antibodies. MV entry can be redirected by displaying a polypeptide ligand on the Hemagglutinin (H) C-terminus. We hypothesized that retargeted MV would escape neutralization by monoclonal antibodies (mAbs) recognizing the H receptor-binding surface and be less susceptible to neutralization by human antisera. Using chimeric H proteins, with and without mutations that ablate MV receptor binding, we show that retargeted MVs escape mAbs that target the H receptor-binding surface by virtue of mutations that ablate infection via SLAM and CD46. However, C-terminally displayed domains do not mediate virus entry in the presence of human antibodies that bind to the underlying H domain. In conclusion, utility of retargeted oncolytic measles viruses does not extend to evasion of human serum neutralization. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Assessing Gale Crater as an Exploration Zone for the First Human Mission to Mars

NASA Technical Reports Server (NTRS)

Calef, A. F. J., III; Archer, D.; Clark, B.; Day, M.; Goetz, W.; Lasue, J.; Martin-Torres, J.; Zorzano-Mier, M.; Navarro-Gonzalez, R.

2016-01-01

Mars is the "horizon goal" for human space flight [1]. Towards that endeavor, one must consider several factors in regards to choosing a landing site suitable for a human-rated mission including: entry, descent, and landing (EDL) characteristics, scientific diversity, and possible insitu resources [2]. Selecting any one place is a careful balance of reducing risks and increasing scientific return for the mission.

Entry and Elimination of Marine Mammal Brucella spp. by Hooded Seal (Cystophora cristata) Alveolar Macrophages In Vitro

PubMed Central

Larsen, Anett K.; Nymo, Ingebjørg H.; Boysen, Preben; Tryland, Morten; Godfroid, Jacques

2013-01-01

A high prevalence of Brucella pinnipedialis serology and bacteriology positive animals has been found in the Northeast Atlantic stock of hooded seal ( Cystophora cristata ); however no associated gross pathological changes have been identified. Marine mammal brucellae have previously displayed different infection patterns in human and murine macrophages. To investigate if marine mammal Brucella spp. are able to invade and multiply in cells originating from a presumed host species, we infected alveolar macrophages from hooded seal with a B . pinnipedialis hooded seal isolate. Hooded seal alveolar macrophages were also challenged with B . pinnipedialis reference strain (NCTC 12890) from harbor seal ( Phoca vitulina ), B . ceti reference strain (NCTC 12891) from harbor porpoise ( Phocoena phocoena ) and a B . ceti Atlantic white-sided dolphin ( Lagenorhynchus acutus ) isolate (M83/07/1), to evaluate possible species-specific differences. Brucella suis 1330 was included as a positive control. Alveolar macrophages were obtained by post mortem bronchoalveolar lavage of euthanized hooded seals. Phenotyping of cells in the lavage fluid was executed by flow cytometry using the surface markers CD14 and CD18. Cultured lavage cells were identified as alveolar macrophages based on morphology, expression of surface markers and phagocytic ability. Alveolar macrophages were challenged with Brucella spp. in a gentamicin protection assay. Following infection, cell lysates from different time points were plated and evaluated quantitatively for colony forming units. Intracellular presence of B . pinnipedialis hooded seal isolate was verified by immunocytochemistry. Our results show that the marine mammal brucellae were able to enter hooded seal alveolar macrophages; however, they did not multiply intracellularly and were eliminated within 48 hours, to the contrary of B. suis that showed the classical pattern of a pathogenic strain. In conclusion, none of the four marine mammal strains tested were able to establish a persistent infection in primary alveolar macrophages from hooded seal. PMID:23936159

Cost implications of implementation of pathogen-inactivated platelets

PubMed Central

McCullough, Jeffrey; Goldfinger, Dennis; Gorlin, Jed; Riley, William J; Sandhu, Harpreet; Stowell, Christopher; Ward, Dawn; Clay, Mary; Pulkrabek, Shelley; Chrebtow, Vera; Stassinopoulos, Adonis

2015-01-01

BACKGROUND Pathogen inactivation (PI) is a new approach to blood safety that may introduce additional costs. This study identifies costs that could be eliminated, thereby mitigating the financial impact. STUDY DESIGN AND METHODS Cost information was obtained from five institutions on tests and procedures (e.g., irradiation) currently performed, that could be eliminated. The impact of increased platelet (PLT) availability due to fewer testing losses, earlier entry into inventory, and fewer outdates with a 7-day shelf life were also estimated. Additional estimates include costs associated with managing 1) special requests and 2) test results, 3) quality control and proficiency testing, 4) equipment acquisition and maintenance, 5) replacement of units lost to positive tests, 6) seasonal or geographic testing, and 7) health department interactions. RESULTS All costs are mean values per apheresis PLT unit in USD ($/unit). The estimated test costs that could be eliminated are $71.76/unit and a decrease in transfusion reactions corresponds to $2.70/unit. Avoiding new tests (e.g., Babesia and dengue) amounts to $41.80/unit. Elimination of irradiation saves $8.50/unit, while decreased outdating with 7-day storage can be amortized to $16.89/unit. Total potential costs saved with PI is $141.65/unit. Costs are influenced by a variety of factors specific to institutions such as testing practices and the location in which such costs are incurred and careful analysis should be performed. Additional benefits, not quantified, include retention of some currently deferred donors and scheduling flexibility due to 7-day storage. CONCLUSIONS While PI implementation will result in additional costs, there are also potential offsetting cost reductions, especially after 7-day storage licensing. PMID:25989465

Decreasing the Preincision Time for Pulmonary Lobectomy: The Process of Lean and Value Stream Mapping.

PubMed

Cerfolio, Robert James; Steenwyk, Brad L; Watson, Caroline; Sparrow, James; Belopolsky, Victoria; Townsley, Matthew; Lyerly, Ralph; Downing, Michelle; Bryant, Ayesha; Gurley, William Quinton; Henling, Colleen; Crawford, Jack; Gayeski, Thomas E

2016-03-01

Our objective was to evaluate our results after the implementation of lean (the elimination of wasteful parts of a process). After meetings with our anesthesiologists, we standardized our "in the operating room-to-skin incision protocols" before pulmonary lobectomy. Patients were divided into consecutive cohorts of 300 lobectomy patients. Several protocols were slowly adopted and outcomes were evaluated. One surgeon performed 2,206 pulmonary lobectomies, of which 84% were for cancer. Protocols for lateral decubitus positioning changed over time. We eliminated axillary rolls, arm boards, and beanbags. Monitoring devices were slowly eliminated. Central catheters decreased from 75% to 0% of patients, epidurals from 84% to 3%, arterial catheters from 93% to 4%, and finally, Foley catheters were reduced from 99% to 11% (p ≤ 0.001 for all). A protocol for the insertion of double-lumen endotracheal tubes was established and times decreased (mean, 14 minutes to 1 minute; p = 0.001). After all changes were made, the time between operating room entry and incision decreased from a mean of 64 minutes to 37 minutes (p < 0.001). Outcomes improved, mortality decreased from 3.2% to 0.26% (p = 0.015), and major morbidity decreased from 15.2% to 5.3% (p = 0.042). Lean and value stream mapping can be safely applied to the clinical algorithms of high-risk patient care. We demonstrate that elimination of non-value-added steps can safely decrease preincision time without increasing patient risk in patients who undergo pulmonary lobectomy. Selected centers may be able to adopt some of these lean-driven protocols. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Cost implications of implementation of pathogen-inactivated platelets.

PubMed

McCullough, Jeffrey; Goldfinger, Dennis; Gorlin, Jed; Riley, William J; Sandhu, Harpreet; Stowell, Christopher; Ward, Dawn; Clay, Mary; Pulkrabek, Shelley; Chrebtow, Vera; Stassinopoulos, Adonis

2015-10-01

Pathogen inactivation (PI) is a new approach to blood safety that may introduce additional costs. This study identifies costs that could be eliminated, thereby mitigating the financial impact. Cost information was obtained from five institutions on tests and procedures (e.g., irradiation) currently performed, that could be eliminated. The impact of increased platelet (PLT) availability due to fewer testing losses, earlier entry into inventory, and fewer outdates with a 7-day shelf life were also estimated. Additional estimates include costs associated with managing (1) special requests and (2) test results, (3) quality control and proficiency testing, (4) equipment acquisition and maintenance, (5) replacement of units lost to positive tests, (6) seasonal or geographic testing, and (7) health department interactions. All costs are mean values per apheresis PLT unit in USD ($/unit). The estimated test costs that could be eliminated are $71.76/unit and a decrease in transfusion reactions corresponds to $2.70/unit. Avoiding new tests (e.g., Babesia and dengue) amounts to $41.80/unit. Elimination of irradiation saves $8.50/unit, while decreased outdating with 7-day storage can be amortized to $16.89/unit. Total potential costs saved with PI is $141.65/unit. Costs are influenced by a variety of factors specific to institutions such as testing practices and the location in which such costs are incurred and careful analysis should be performed. Additional benefits, not quantified, include retention of some currently deferred donors and scheduling flexibility due to 7-day storage. While PI implementation will result in additional costs, there are also potential offsetting cost reductions, especially after 7-day storage licensing. © 2015 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

77 FR 30871 - Implementing the Prison Rape Elimination Act

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-23

... Prison Rape Elimination Act Memorandum for the Heads of Executive Departments and Agencies Sexual violence, against any victim, is an assault on human dignity and an affront to American values. The Prison... agencies that operate confinement facilities adopt high standards to prevent, detect, and respond to sexual...

TRPC1 is involved in Ca²⁺ influx and cytotoxicity following Pb²⁺ exposure in human embryonic kidney cells.

PubMed

Zhang, Hongmei; Li, Wenjun; Xue, Yong; Zou, Fei

2014-08-17

Lead (Pb(2+)) is a divalent heavy metal ion which causes severe damage to almost all life forms and is therefore considered a notorious toxicant. Exposure to Pb(2+) is associated with poor cognitive development in children at relatively low levels that previously were thought to be safe. The mechanism through which Pb(2+) enters cells, however, is unclear. Previous studies have showed that Ca(2+) release-activated Ca(2+) protein 1 (Orai1), a component of store-operated Ca(2+) channels (SOCs), contributes to Pb(2+) cellular entry. Canonical transient receptor potential (TRPC1) channel 1 is a transient receptor potential (TRP) channel which is sometimes referred to as a SOC. The present study was designed to investigate the role of TRPC1 in Pb(2+) entry and toxicity in human embryonic kidney cells (HEK293). Additionally, changes in intracellular Ca(2+) concentration were determined through Fluo-4 and Mag-fluo-4 fluorescent Ca(2+) imaging. Following Pb(2+) exposure, there was a dose-dependent decrease in cell viability. Overexpression of TRPC1 increased Pb(2+)-induced cell death, while knockdown of this channel attenuated cell death. There was increased entry of Pb(2+), as measured by inductively coupled plasma mass spectrometry (ICP-MS), following overexpression of TRPC1. Conversely, knockdown of TRPC1 led to a decrease in Pb(2+) influx. Down-regulation of STIM1 by RNA interference attenuated the Pb(2+) influx, and transfection with a mutant STIM1, which could not gate TRPC1, had a similar effect. Co-transfection of mutant STIM1 and mutant TRPC1, which restore the electrostatic interaction between STIM1 and TRPC1, resumed Pb(2+) entry in HEK293 cells. Down-regulation of TRPC1 by RNA interference decreased Ca(2+) influx whilst its overexpression increased Ca(2+) entry in HEK293 cells. These results suggest that TRPC1 is involved in the cytotoxicity and entry of Pb(2+) through molecular interactions with STIM1 and subsequent Ca(2+) influx in HEK293 cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Molecular Signaling Involved in Entry and Exit of Malaria Parasites from Host Erythrocytes.

PubMed

Singh, Shailja; Chitnis, Chetan E

2017-10-03

During the blood stage, Plasmodium spp. merozoites invade host red blood cells (RBCs), multiply, exit, and reinvade uninfected RBCs in a continuing cycle that is responsible for all the clinical symptoms associated with malaria. Entry into (invasion) and exit from (egress) RBCs are highly regulated processes that are mediated by an array of parasite proteins with specific functional roles. Many of these parasite proteins are stored in specialized apical secretory vesicles, and their timely release is critical for successful invasion and egress. For example, the discharge of parasite protein ligands to the apical surface of merozoites is required for interaction with host receptors to mediate invasion, and the timely discharge of proteases and pore-forming proteins helps in permeabilization and dismantling of limiting membranes during egress. This review focuses on our understanding of the signaling mechanisms that regulate apical organelle secretion during host cell invasion and egress by malaria parasites. The review also explores how understanding key signaling mechanisms in the parasite can open opportunities to develop novel strategies to target Plasmodium parasites and eliminate malaria. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

An Evaluation of Voluntary 2-Dose Varicella Vaccination Coverage in New York City Public Schools

PubMed Central

Rosen, Jennifer B.; Bialek, Stephanie R.; Szeto, Hiram; Zimmerman, Christopher M.

2015-01-01

Objectives. We assessed coverage for 2-dose varicella vaccination, which is not required for school entry, among New York City public school students and examined characteristics associated with receipt of 2 doses. Methods. We measured receipt of either at least 1 or 2 doses of varicella vaccine among students aged 4 years and older in a sample of 336 public schools (n = 223 864 students) during the 2010 to 2011 school year. Data came from merged student vaccination records from 2 administrative data systems. We conducted multivariable regression to assess associations of age, gender, race/ethnicity, and school location with 2-dose prevalence. Results. Coverage with at least 1 varicella dose was 96.2% (95% confidence interval [CI] = 96.2%, 96.3%); coverage with at least 2 doses was 64.8% (95% CI = 64.6%, 64.9%). Increasing student age, non-Hispanic White race/ethnicity, and attendance at school in Staten Island were associated with lower 2-dose coverage. Conclusions. A 2-dose varicella vaccine requirement for school entry would likely improve 2-dose coverage, eliminate coverage disparities, and prevent disease. PMID:25521904

Memory load as a cognitive antidote to performance decrements in data entry.

PubMed

Chapman, Mary J; Healy, Alice F; Kole, James A

2016-10-01

In two experiments, subjects trained in data entry, typing one 4-digit number at a time. At training, subjects either typed the numbers immediately after they appeared (immediate) or typed the previous number from memory while viewing the next number (delayed). In Experiment 2 stimulus presentation time was limited and either nothing or a space (gap) was inserted between the second and third digits. In both experiments after training, all subjects completed a test with no gap and typed numbers immediately. Training with a memory load improved speed across training blocks (Experiment 1) and eliminated the decline in accuracy across training blocks (Experiment 2), thus serving as a cognitive antidote to performance decrements. An analysis of each keystroke revealed different underlying processes and strategies for the two training conditions, including when encoding took place. Chunking (in which the first and last two digits are treated separately) was more evident in the immediate than in the delayed condition and was exaggerated with a gap, even at test when there was no gap. These results suggest that such two-digit chunking is due to stimulus encoding and motor planning processes as well as memory, and those processes transferred from training to testing.

Detecting and Preventing Sybil Attacks in Wireless Sensor Networks Using Message Authentication and Passing Method.

PubMed

Dhamodharan, Udaya Suriya Raj Kumar; Vayanaperumal, Rajamani

2015-01-01

Wireless sensor networks are highly indispensable for securing network protection. Highly critical attacks of various kinds have been documented in wireless sensor network till now by many researchers. The Sybil attack is a massive destructive attack against the sensor network where numerous genuine identities with forged identities are used for getting an illegal entry into a network. Discerning the Sybil attack, sinkhole, and wormhole attack while multicasting is a tremendous job in wireless sensor network. Basically a Sybil attack means a node which pretends its identity to other nodes. Communication to an illegal node results in data loss and becomes dangerous in the network. The existing method Random Password Comparison has only a scheme which just verifies the node identities by analyzing the neighbors. A survey was done on a Sybil attack with the objective of resolving this problem. The survey has proposed a combined CAM-PVM (compare and match-position verification method) with MAP (message authentication and passing) for detecting, eliminating, and eventually preventing the entry of Sybil nodes in the network. We propose a scheme of assuring security for wireless sensor network, to deal with attacks of these kinds in unicasting and multicasting.

Detecting and Preventing Sybil Attacks in Wireless Sensor Networks Using Message Authentication and Passing Method

PubMed Central

Dhamodharan, Udaya Suriya Raj Kumar; Vayanaperumal, Rajamani

2015-01-01

Wireless sensor networks are highly indispensable for securing network protection. Highly critical attacks of various kinds have been documented in wireless sensor network till now by many researchers. The Sybil attack is a massive destructive attack against the sensor network where numerous genuine identities with forged identities are used for getting an illegal entry into a network. Discerning the Sybil attack, sinkhole, and wormhole attack while multicasting is a tremendous job in wireless sensor network. Basically a Sybil attack means a node which pretends its identity to other nodes. Communication to an illegal node results in data loss and becomes dangerous in the network. The existing method Random Password Comparison has only a scheme which just verifies the node identities by analyzing the neighbors. A survey was done on a Sybil attack with the objective of resolving this problem. The survey has proposed a combined CAM-PVM (compare and match-position verification method) with MAP (message authentication and passing) for detecting, eliminating, and eventually preventing the entry of Sybil nodes in the network. We propose a scheme of assuring security for wireless sensor network, to deal with attacks of these kinds in unicasting and multicasting. PMID:26236773

El Camino Hospital: using health information technology to promote patient safety.

PubMed

Bukunt, Susan; Hunter, Christine; Perkins, Sharon; Russell, Diana; Domanico, Lee

2005-10-01

El Camino Hospital is a leader in the use of health information technology to promote patient safety, including bar coding, computerized order entry, electronic medical records, and wireless communications. Each year, El Camino Hospital's board of directors sets performance expectations for the chief executive officer, which are tied to achievement of local, regional, and national safety and quality standards, including the six Institute of Medicine quality dimensions. He then determines a set of explicit quality goals and measurable actions, which serve as guidelines for the overall hospital. The goals and progress reports are widely shared with employees, medical staff, patients and families, and the public. For safety, for example, the medication error reduction team tracks and reviews medication error rates. The hospital has virtually eliminated transcription errors through its 100% use of computerized physician order entry. Clinical pathways and standard order sets have reduced practice variation, providing a safer environment. Many projects focused on timeliness, such as emergency department wait time, lab turnaround time, and pneumonia time to initial antibiotic. Results have been mixed, with projects most successful when a link was established with patient outcomes, such as in reducing time to percutaneous transluminal coronary angioplasty for patients with acute myocardial infarction.

Rapid one-step recombinational cloning

PubMed Central

Fu, Changlin; Wehr, Daniel R.; Edwards, Janice; Hauge, Brian

2008-01-01

As an increasing number of genes and open reading frames of unknown function are discovered, expression of the encoded proteins is critical toward establishing function. Accordingly, there is an increased need for highly efficient, high-fidelity methods for directional cloning. Among the available methods, site-specific recombination-based cloning techniques, which eliminate the use of restriction endonucleases and ligase, have been widely used for high-throughput (HTP) procedures. We have developed a recombination cloning method, which uses truncated recombination sites to clone PCR products directly into destination/expression vectors, thereby bypassing the requirement for first producing an entry clone. Cloning efficiencies in excess of 80% are obtained providing a highly efficient method for directional HTP cloning. PMID:18424799

Transforming the back office with a single keystroke.

PubMed

Kaplan, Charles

2011-09-01

Intelligent data capture is an application that can provide electronic access to data contained in any type of document, including clinical records and financial documents, thereby reducing or eliminating the need for manual data entry. Before implementing this technology, however, healthcare leaders should: Evaluate technology in the context of a business case to ensure a measurable ROI. Communicate with employees throughout the process so they are prepared for and embrace the inevitable changes that will come with automation. Implement the solution in phases, focusing on those document types that can deliver for a safer, less disruptive approach. Achieve maximum benefit to the organization by reengineering business processes to fully leverage technology rather than simply automating existing manual processes.

Pi-CO₂ aqueous post-combustion CO₂ capture: Proof of concept through thermodynamic, hydrodynamic, and gas-lift pump modeling

DOE PAGES

Blount, G.; Gorensek, M.; Hamm, L.; ...

2014-12-31

Partnering in Innovation, Inc. (Pi-Innovation) introduces an aqueous post-combustion carbon dioxide (CO₂) capture system (Pi-CO₂) that offers high market value by directly addressing the primary constraints limiting beneficial re-use markets (lowering parasitic energy costs, reducing delivered cost of capture, eliminating the need for special solvents, etc.). A highly experienced team has completed initial design, modeling, manufacturing verification, and financial analysis for commercial market entry. Coupled thermodynamic and thermal-hydraulic mass transfer modeling results fully support proof of concept. Pi-CO₂ has the potential to lower total cost and risk to levels sufficient to stimulate global demand for CO₂ from local industrial sources.

Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100.

PubMed

Yu, Rosie Z; Kim, Tae-Won; Hong, An; Watanabe, Tanya A; Gaus, Hans J; Geary, Richard S

2007-03-01

The pharmacokinetics of a 2'-O-(2-methoxyethyl)-modified oligonucleotide, ISIS 301012 [targeting human apolipoprotein B-100 (apoB-100)], was characterized in mouse, rat, monkey, and human. Plasma pharmacokinetics following parental administration was similar across species, exhibiting a rapid distribution phase with t(1/2alpha) of several hours and a prolonged elimination phase with t(1/2beta) of days. The prolonged elimination phase represents equilibrium between tissues and circulating drug due to slow elimination from tissues. Absorption was nearly complete following s.c. injection, with bioavailability ranging from 80 to 100% in monkeys. Plasma clearance scaled well across species as a function of body weight alone, and this correlation was improved when corrected for plasma protein binding. In all of the animal models studied, the highest tissue concentrations of ISIS 301012 were observed in kidney and liver. Urinary excretion was less than 3% in monkeys and human in the first 24 h. ISIS 301012 is highly bound to plasma proteins, probably preventing rapid removal by renal filtration. However, following 25 mg/kg s.c. administration in mouse and 5-mg/kg i.v. bolus administration in rat, plasma concentrations of ISIS 301012 exceeded their respective protein binding capacity. Thus, urinary excretion increased to 16% or greater within the first 24 h. Albeit slow, urinary excretion of ISIS 301012 and its shortened metabolites is the ultimate elimination pathway of this compound, as demonstrated by 32% of dose recovered in total excreta by 14 days in a rat mass balance study. The pharmacokinetics of ISIS 301012 in human is predictable from the pharmacokinetics measured in animals. The pharmacokinetic properties of ISIS 301012 provide guidance for clinical development and support infrequent dose administration.

Human Excretion of Bisphenol A: Blood, Urine, and Sweat (BUS) Study

PubMed Central

Genuis, Stephen J.; Beesoon, Sanjay; Birkholz, Detlef; Lobo, Rebecca A.

2012-01-01

Background. Bisphenol A (BPA) is an ubiquitous chemical contaminant that has recently been associated with adverse effects on human health. There is incomplete understanding of BPA toxicokinetics, and there are no established interventions to eliminate this compound from the human body. Using 20 study participants, this study was designed to assess the relative concentration of BPA in three body fluids—blood, urine, and sweat—and to determine whether induced sweating may be a therapeutic intervention with potential to facilitate elimination of this compound. Methods. Blood, urine, and sweat were collected from 20 individuals (10 healthy participants and 10 participants with assorted health problems) and analyzed for various environmental toxicants including BPA. Results. BPA was found to differing degrees in each of blood, urine, and sweat. In 16 of 20 participants, BPA was identified in sweat, even in some individuals with no BPA detected in their serum or urine samples. Conclusions. Biomonitoring of BPA through blood and/or urine testing may underestimate the total body burden of this potential toxicant. Sweat analysis should be considered as an additional method for monitoring bioaccumulation of BPA in humans. Induced sweating appears to be a potential method for elimination of BPA. PMID:22253637

Inactivation and elimination of human enteric viruses by Pacific oysters.

PubMed

McLeod, C; Hay, B; Grant, C; Greening, G; Day, D

2009-12-01

To investigate the comparative elimination of three different human enterically transmitted viruses [i.e. hepatitis A virus (HAV), norovirus (NoV) and poliovirus (PV)] and inactivation of HAV and PV by Pacific oysters. New Zealand grown Pacific oysters (Crassostrea gigas) were allowed to bioaccumulate HAV, NoV and PV. Samples of oyster gut, faeces and pseudofaeces were then analysed by using real-time RT-PCR to determine the amount of viral RNA and cell culture methods to identify changes in the number of plaque forming units. The results suggest that the majority of the PV present in the oyster gut and oyster faeces is noninfectious, while in contrast, most of the HAV detected in the oyster gut are infectious. Depuration experiments identified a large drop in the count of PV in the gut over a 23-h cleansing period, whereas the levels of HAV and NoV did not significantly decrease. Human enterically transmitted viruses are eliminated and inactivated at different rates by Pacific oysters. The research presented in this article has implications for risk management techniques that are used to improve the removal of infectious human enteric viruses from bivalve molluscs.

Neural Connectivity Patterns Underlying Symbolic Number Processing Indicate Mathematical Achievement in Children

ERIC Educational Resources Information Center

Park, Joonkoo; Li, Rosa; Brannon, Elizabeth M.

2014-01-01

In early childhood, humans learn culturally specific symbols for number that allow them entry into the world of complex numerical thinking. Yet little is known about how the brain supports the development of the uniquely human symbolic number system. Here, we use functional magnetic resonance imaging along with an effective connectivity analysis…

NAAHE Special Report: An Annotated Bibliography of Research Relevant to Humane Education.

ERIC Educational Resources Information Center

DeRosa, William

Entries in this annotated bibliography are presented in four sections. The first section includes studies which attempt to evaluate various approaches to humane education, providing educators with general guidelines on which of the approaches have been found to be the most and least effective for teaching young people about animals and animal…

Physics-Based Modeling of Meteor Entry and Breakup

NASA Technical Reports Server (NTRS)

Prabhu, Dinesh K.; Agrawal, Parul; Allen, Gary A., Jr.; Bauschlicher, Charles W., Jr.; Brandis, Aaron M.; Chen, Yih-Kang; Jaffe, Richard L.; Palmer, Grant E.; Saunders, David A.; Stern, Eric C.;

Physics-Based Modeling of Meteor Entry and Breakup

NASA Technical Reports Server (NTRS)

Prabhu, Dinesh K.; Agrawal, Parul; Allen, Gary A.; Brandis, Aaron M.; Chen, Yih-Kanq; Jaffe, Richard L.; Saunders, David A.; Stern, Eric C.; Tauber, Michael E.; Venkatapathy, Ethiraj

2015-01-01

A new research effort at NASA Ames Research Center has been initiated in Planetary Defense, which integrates the disciplines of planetary science, atmospheric entry physics, and physics-based risk assessment. This paper describes work within the new program and is focused on meteor entry and breakup. Over the last six decades significant effort was expended in the US and in Europe to understand meteor entry including ablation, fragmentation and airburst (if any) for various types of meteors ranging from stony to iron spectral types. These efforts have produced primarily empirical mathematical models based on observations. Weaknesses of these models, apart from their empiricism, are reliance on idealized shapes (spheres, cylinders, etc.) and simplified models for thermal response of meteoritic materials to aerodynamic and radiative heating. Furthermore, the fragmentation and energy release of meteors (airburst) is poorly understood. On the other hand, flight of human-made atmospheric entry capsules is well understood. The capsules and their requisite heatshields are designed and margined to survive entry. However, the highest speed Earth entry for capsules is less than 13 km/s (Stardust). Furthermore, Earth entry capsules have never exceeded diameters of 5 m, nor have their peak aerothermal environments exceeded 0.3 atm and 1 kW/cm2. The aims of the current work are: (i) to define the aerothermal environments for objects with entry velocities from 13 to greater than 20 km/s; (ii) to explore various hypotheses of fragmentation and airburst of stony meteors in the near term; (iii) to explore the possibility of performing relevant ground-based tests to verify candidate hypotheses; and (iv) to quantify the energy released in airbursts. The results of the new simulations will be used to anchor said risk assessment analyses. With these aims in mind, state-of-the-art entry capsule design tools are being extended for meteor entries. We describe: (i) applications of current simulation tools to spherical geometries of diameters ranging from 1 to 100 m for an entry velocity of 20 km/s and stagnation pressures ranging from 1 to 100 atm; (ii) the influence of shape and departure of heating environment predictions from those for a simple spherical geometry; (iii) assessment of thermal response models for silica subject to intense radiation; and (iv) results for porosity-driven gross fragmentation of meteors, idealized as a collection of smaller objects. Lessons learned from these simulations will be used to help understand the Chelyabinsk meteor entry up to its first point of fragmentation.

Physics-Based Modeling of Meteor Entry and Breakup

NASA Technical Reports Server (NTRS)

Prabhu, Dinesh K.; Agrawal, Parul; Allen, Gary A., Jr.; Bauschlicher, Charles W., Jr.; Brandis, Aaron M.; Chen, Yih-Kanq; Jaffe, Richard L.; Palmer, Grant E.; Saunders, David A.; Stern, Eric C.;

Human Immunodeficiency Virus Disease Severity, Psychiatric Symptoms, and Functional Outcomes in Perinatally Infected Youth

PubMed Central

Nachman, Sharon; Chernoff, Miriam; Williams, Paige; Hodge, Janice; Heston, Jerry; Gadow, Kenneth D.

2012-01-01

Objective To evaluate associations between human immunodeficiency virus (HIV) disease severity and psychiatric and functional outcomes in youth with perinatal HIV infection. Design Cross-sectional analysis of entry data from an observational, prospective 2-year study. Logistic and linear regression models adjusted for potential confounders were used. Setting Twenty-nine sites of the International Maternal Pediatrics Adolescent AIDS Clinical Trials Group study in the United States and Puerto Rico. Participants Youth aged 6 to 17 years who had HIV infection (N=319). Main Exposures Antiretroviral treatment and perinatal HIV infection. Main Outcome Measures Youth and primary care-givers were administered an extensive battery of measures that assessed psychiatric symptoms; cognitive, social, and academic functioning; and quality of life. Results Characteristics of HIV were a current CD4 percentage of 25% or greater (74% of participants), HIV RNA levels of less than 400 copies/mL (59%), and current highly active antiretroviral therapy (81%). Analyses indicated associations of past and current Centers for Disease Control and Prevention class C designation with less severe attention-deficit/hyperactivity disorder inattention symptoms, older age at nadir CD4 percentage and lower CD4 percentage at study entry with more severe conduct disorder symptoms, higher RNA viral load at study entry with more severe depression symptoms, and lower CD4 percentage at study entry with less severe symptoms of depression. There was little evidence of an association between specific antiretroviral therapy and severity of psychiatric symptoms. A lower nadir CD4 percentage was associated with lower quality of life, worse Wechsler Intelligence Scale for Children Coding Recall scores, and worse social functioning. Conclusion Human immunodeficiency virus illness severity markers are associated with the severity of some psychiatric symptoms and, notably, with cognitive, academic, and social functioning, all of which warrant additional study. Trial Registration clinicaltrials.gov Identifier: NCT00100542 PMID:22312169

Evidence for shear-mediated Ca2+ entry through mechanosensitive cation channels in human platelets and a megakaryocytic cell line.

PubMed

Ilkan, Zeki; Wright, Joy R; Goodall, Alison H; Gibbins, Jonathan M; Jones, Chris I; Mahaut-Smith, Martyn P

2017-06-02

The role of mechanosensitive (MS) Ca 2+ -permeable ion channels in platelets is unclear, despite the importance of shear stress in platelet function and life-threatening thrombus formation. We therefore sought to investigate the expression and functional relevance of MS channels in human platelets. The effect of shear stress on Ca 2+ entry in human platelets and Meg-01 megakaryocytic cells loaded with Fluo-3 was examined by confocal microscopy. Cells were attached to glass coverslips within flow chambers that allowed applications of physiological and pathological shear stress. Arterial shear (1002.6 s -1 ) induced a sustained increase in [Ca 2+ ] i in Meg-01 cells and enhanced the frequency of repetitive Ca 2+ transients by 80% in platelets. These Ca 2+ increases were abrogated by the MS channel inhibitor Grammostola spatulata mechanotoxin 4 (GsMTx-4) or by chelation of extracellular Ca 2+ Thrombus formation was studied on collagen-coated surfaces using DiOC 6 -stained platelets. In addition, [Ca 2+ ] i and functional responses of washed platelet suspensions were studied with Fura-2 and light transmission aggregometry, respectively. Thrombus size was reduced 50% by GsMTx-4, independently of P2X1 receptors. In contrast, GsMTx-4 had no effect on collagen-induced aggregation or on Ca 2+ influx via TRPC6 or Orai1 channels and caused only a minor inhibition of P2X1-dependent Ca 2+ entry. The Piezo1 agonist, Yoda1, potentiated shear-dependent platelet Ca 2+ transients by 170%. Piezo1 mRNA transcripts and protein were detected with quantitative RT-PCR and Western blotting, respectively, in both platelets and Meg-01 cells. We conclude that platelets and Meg-01 cells express the MS cation channel Piezo1, which may contribute to Ca 2+ entry and thrombus formation under arterial shear. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Estimation of dioxin and furan elimination rates with a pharmacokinetic model.

PubMed

Van der Molen, G W; Kooijman, B A; Wittsiepe, J; Schrey, P; Flesch-Janys, D; Slob, W

2000-01-01

Quantitative description of the pharmacokinetics of dioxins and furans in humans can be of great help for the assessment of health risks posed by these compounds. To that the elimination rates of sixteen 2,3,7,8-chlorinated dibenzodioxins and dibenzofurans are estimated from both a longitudinal and a cross-sectional data set using the model of Van der Molen et al. [Van der Molen G.W., Kooijman S.A.L.M., and Slob W. A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD. Fundam Appl Toxicol 1996: 31: 83-94]. In this model the elimination rate is given by the (constant) specific elimination rate multiplied with the ratio between the lipid weight of the liver and total body lipid weight. Body composition, body weight and intake are assumed to depend on age. The elimination rate is, therefore, not constant. For 49-year-old males, the elimination rate estimates range between 0.03 per year for 1,2,3,6,7,8-hexaCDF to 1.0 per year for octaCDF. The elimination rates of the most toxic congeners, 2,3,7,8-tetraCDD, 1,2,3,7,8-pentaCDD, and 2,3,4,7,8-pentaCDF, were estimated at 0.09, 0.06, and 0.07, respectively, based on the cross-sectional data, and 0.11, 0.09, and 0.09 based on the longitudinal data. The elimination rates of dioxins decrease with age between 0.0011 per year for 1,2,3,6,7,8-hexaCDD and 0.0035 per year for 1,2,3,4,6,7,8-heptaCDD. For furans the average decrease is 0.0033 per year. The elimination rates were estimated both from a longitudinal and a cross-sectional data set, and agreed quite well with each other, after taking account of historical changes in average intake levels.

Bisphenol A stimulates human prostate cancer cell migration via remodelling of calcium signalling.

PubMed

Derouiche, Sandra; Warnier, Marine; Mariot, Pascal; Gosset, Pierre; Mauroy, Brigitte; Bonnal, Jean-Louis; Slomianny, Christian; Delcourt, Philippe; Prevarskaya, Natalia; Roudbaraki, Morad

2013-12-01

Bisphenol A (BPA), the principal constituent of reusable water bottles, metal cans, and plastic food containers, has been shown to be involved in human prostate cancer (PCa) cell proliferation. The aim of the present study was to explore the effect of BPA on PCa cell migration and the pathways involved in these processes. Using the transwell technique, we clearly show for the first time that the pre-treatment of the cells with BPA (1-10 nM) induces human PCa cell migration. Using a calcium imaging technique, we show that BPA pre-treatment induces an amplification of Store-Operated Calcium Entry (SOCE) in LNCaP cells. RT-PCR and Western blot experiments allowed the identification of the ion channel proteins which are up-regulated by BPA pre-treatments. These include the Orai1 protein, which is known as an important SOCE actor in various cell systems, including human PCa cells. Using a siRNA strategy, we observed that BPA-induced amplification of SOCE was Orai1-dependent. Interestingly, the BPA-induced PCa cell migration was suppressed when the calcium entry was impaired by the use of SOCE inhibitors (SKF96365, BTP2), or when the extracellular calcium was chelated. Taken together, the results presented here show that BPA induces PCa cells migration via a modulation of the ion channel protein expression involved in calcium entry and in cancer cell migration. The present data provide novel insights into the molecular mechanisms involved in the effects of an environmental factor on cancer cells and suggest both the necessity of preventive measures and the possibility of targeting ion channels in the treatment of PCa cell metastasis.

Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

PubMed Central

Huh, Yeamin; Smith, David E.; Feng, Meihau Rose

2014-01-01

Human clearance prediction for small- and macro-molecule drugs was evaluated and compared using various scaling methods and statistical analysis.Human clearance is generally well predicted using single or multiple species simple allometry for macro- and small-molecule drugs excreted renally.The prediction error is higher for hepatically eliminated small-molecules using single or multiple species simple allometry scaling, and it appears that the prediction error is mainly associated with drugs with low hepatic extraction ratio (Eh). The error in human clearance prediction for hepatically eliminated small-molecules was reduced using scaling methods with a correction of maximum life span (MLP) or brain weight (BRW).Human clearance of both small- and macro-molecule drugs is well predicted using the monkey liver blood flow method. Predictions using liver blood flow from other species did not work as well, especially for the small-molecule drugs. PMID:21892879

Wolbachia wStri Blocks Zika Virus Growth at Two Independent Stages of Viral Replication.

PubMed

Schultz, M J; Tan, A L; Gray, C N; Isern, S; Michael, S F; Frydman, H M; Connor, J H

2018-05-22

Mosquito-transmitted viruses are spread globally and present a great risk to human health. Among the many approaches investigated to limit the diseases caused by these viruses are attempts to make mosquitos resistant to virus infection. Coinfection of mosquitos with the bacterium Wolbachia pipientis from supergroup A is a recent strategy employed to reduce the capacity for major vectors in the Aedes mosquito genus to transmit viruses, including dengue virus (DENV), Chikungunya virus (CHIKV), and Zika virus (ZIKV). Recently, a supergroup B Wolbachia w Stri, isolated from Laodelphax striatellus , was shown to inhibit multiple lineages of ZIKV in Aedes albopictus cells. Here, we show that w Stri blocks the growth of positive-sense RNA viruses DENV, CHIKV, ZIKV, and yellow fever virus by greater than 99.9%. w Stri presence did not affect the growth of the negative-sense RNA viruses LaCrosse virus or vesicular stomatitis virus. Investigation of the stages of the ZIKV life cycle inhibited by w Stri identified two distinct blocks in viral replication. We found a reduction of ZIKV entry into w Stri-infected cells. This was partially rescued by the addition of a cholesterol-lipid supplement. Independent of entry, transfected viral genome was unable to replicate in Wolbachia -infected cells. RNA transfection and metabolic labeling studies suggested that this replication defect is at the level of RNA translation, where we saw a 66% reduction in mosquito protein synthesis in w Stri-infected cells. This study's findings increase the potential for application of w Stri to block additional arboviruses and also identify specific blocks in viral infection caused by Wolbachia coinfection. IMPORTANCE Dengue, Zika, and yellow fever viruses are mosquito-transmitted diseases that have spread throughout the world, causing millions of infections and thousands of deaths each year. Existing programs that seek to contain these diseases through elimination of the mosquito population have so far failed, making it crucial to explore new ways of limiting the spread of these viruses. Here, we show that introduction of an insect symbiont, Wolbachia w Stri, into mosquito cells is highly effective at reducing yellow fever virus, dengue virus, Zika virus, and Chikungunya virus production. Reduction of virus replication was attributable to decreases in entry and a strong block of virus gene expression at the translational level. These findings expand the potential use of Wolbachia w Stri to block viruses and identify two separate steps for limiting virus replication in mosquitos that could be targeted via microbes or other means as an antiviral strategy. Copyright © 2018 Schultz et al.

Observations of Shock Diffusion and Interactions in Supersonic Freestreams with Counterflowing Jets

NASA Technical Reports Server (NTRS)

Daso, Endwell O.; Pritchett, Victor E.; Wang, Ten-See; Blankson, Isiah M.; Auslender, Aaron H.

2006-01-01

One of the technical challenges in long-duration space exploration and interplanetary missions is controlled entry and re-entry into planetary and Earth atmospheres, which requires the dissipation of considerable kinetic energy as the spacecraft decelerates and penetrates the atmosphere. Efficient heat load management of stagnation points and acreage heating remains a technological challenge and poses significant risk, particularly for human missions. An innovative approach using active flow control concept is proposed to significantly modify the external flow field about the spacecraft in planetary atmospheric entry and re-entry in order to mitigate the harsh aerothermal environments, and significantly weaken and disperse the shock-wave system to reduce aerothermal loads and wave drag, as well as improving aerodynamic performance. To explore the potential benefits of this approach, we conducted fundamental experiments in a trisonic blow down wind tunnel to investigate the effects of counterflowing sonic and supersonic jets against supersonic freestreams to gain a better understanding of the flow physics of the interactions of the opposing flows and the resulting shock structure.

The IXV experience, from the mission conception to the flight results

NASA Astrophysics Data System (ADS)

Tumino, G.; Mancuso, S.; Gallego, J.-M.; Dussy, S.; Preaud, J.-P.; Di Vita, G.; Brunner, P.

2016-07-01

The atmospheric re-entry domain is a cornerstone of a wide range of space applications, ranging from reusable launcher stages developments, robotic planetary exploration, human space flight, to innovative applications such as reusable research platforms for in orbit validation of multiple space applications technologies. The Intermediate experimental Vehicle (IXV) is an advanced demonstrator which has performed in-flight experimentation of atmospheric re-entry enabling systems and technologies aspects, with significant advancements on Europe's previous flight experiences, consolidating Europe's autonomous position in the strategic field of atmospheric re-entry. The IXV mission objectives were the design, development, manufacturing, assembling and on-ground to in-flight verification of an autonomous European lifting and aerodynamically controlled reentry system, integrating critical re-entry technologies at system level. Among such critical technologies of interest, special attention was paid to aerodynamic and aerothermodynamics experimentation, including advanced instrumentation for aerothermodynamics phenomena investigations, thermal protections and hot-structures, guidance, navigation and flight control through combined jets and aerodynamic surfaces (i.e. flaps), in particular focusing on the technologies integration at system level for flight, successfully performed on February 11th, 2015.

Complications of Laparoscopy in Connection with Entry Techniques

PubMed Central

2017-01-01

Abstract The anatomy of the human being has not changed. However, technical developments in operating materials and methods call for improvements in surgical procedures as well as the management of complications. A fundamental distinction between any operating method and laparoscopy is that, in the latter, the initial entry is usually performed in blind fashion. Blind entry may result in vessel or organ damage, especially in patients who have undergone previous surgery. One of the difficulties associated with the entry is that the damage may not be identified immediately and then necessitate major abdominal repair. Furthermore, the improvement of surgical instruments and techniques enables the surgeon to perform even major operations by the laparoscopic approach. This is associated with renewed learning curves and a high rate of complications due to vascular, bowel, uterine, or bladder damage. The improvement of surgical techniques must be accompanied by advancements in the management of complications. The aim of this review is to address the risks of laparoscopy as well as their correct and professional management. (J GYNECOL SURG 33:81) PMID:28663686

Nuclear Chk1 prevents premature mitotic entry.

PubMed

Matsuyama, Makoto; Goto, Hidemasa; Kasahara, Kousuke; Kawakami, Yoshitaka; Nakanishi, Makoto; Kiyono, Tohru; Goshima, Naoki; Inagaki, Masaki

2011-07-01

Chk1 inhibits the premature activation of the cyclin-B1-Cdk1. However, it remains controversial whether Chk1 inhibits Cdk1 in the centrosome or in the nucleus before the G2-M transition. In this study, we examined the specificity of the mouse monoclonal anti-Chk1 antibody DCS-310, with which the centrosome was stained. Conditional Chk1 knockout in mouse embryonic fibroblasts reduced nuclear but not centrosomal staining with DCS-310. In Chk1(+/myc) human colon adenocarcinoma (DLD-1) cells, Chk1 was detected in the nucleus but not in the centrosome using an anti-Myc antibody. Through the combination of protein array and RNAi technologies, we identified Ccdc-151 as a protein that crossreacted with DCS-310 on the centrosome. Mitotic entry was delayed by expression of the Chk1 mutant that localized in the nucleus, although forced immobilization of Chk1 to the centrosome had little impact on the timing of mitotic entry. These results suggest that nuclear but not centrosomal Chk1 contributes to correct timing of mitotic entry.

Are we ready for Taenia solium cysticercosis elimination in sub-Saharan Africa?

PubMed

Johansen, Maria Vang; Trevisan, Chiara; Gabriël, Sarah; Magnussen, Pascal; Braae, Uffe Christian

2017-01-01

The World Health Organization announced in November 2014 at the fourth international meeting on 'the control of neglected zoonotic diseases - from advocacy to action', that intervention tools for eliminating Taenia solium taeniosis/cysticercosis (TSTC) are in place. The aim of this work was to elucidate theoretical outcomes of various control options suggested for TSTC elimination in sub-Saharan Africa (SSA) over a 4-year period. Our current knowledge regarding T. solium epidemiology and control primarily builds on studies from Latin America. A simple transmission model - built on data from Latin America - has been used to predict the effect of various interventions such as mass treatment of humans, vaccination and treatment of pigs, and health education of communities, potentially leading to change in bad practices and reducing transmission risks. Based on simulations of the transmission model, even a 4-year integrated One Health approach fails to eliminate TSTC from a small community and in all simulations, the prevalence of human taeniosis and porcine cysticercosis start to rise as soon as the programmes end. Our current knowledge regarding transmission and burden of TSTC in SSA is scarce and while claiming to be tool ready, the selection of diagnostic and surveillance tools, as well as the algorithms and stepwise approaches for control and elimination of TSTC remain major challenges.

Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study.

PubMed

Axelrod, David E; Vedula, Sudeepti; Obaniyi, James

2017-05-01

The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function. A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function. Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug. An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.

Bleeding Disorders Treatment Options

MedlinePlus

... rare bleeding disorders are usually made from human plasma and are treated to eliminate viruses like HIV ... made in the laboratory and not from human plasma, so they carry no risk of infectious disease. ...

Retargeting of Rat Parvovirus H-1PV to Cancer Cells through Genetic Engineering of the Viral Capsid

PubMed Central

Allaume, Xavier; El-Andaloussi, Nazim; Leuchs, Barbara; Bonifati, Serena; Kulkarni, Amit; Marttila, Tiina; Kaufmann, Johanna K.; Nettelbeck, Dirk M.; Kleinschmidt, Jürgen; Rommelaere, Jean

2012-01-01

The rat parvovirus H-1PV is a promising anticancer agent given its oncosuppressive properties and the absence of known side effects in humans. H-1PV replicates preferentially in transformed cells, but the virus can enter both normal and cancer cells. Uptake by normal cells sequesters a significant portion of the administered viral dose away from the tumor target. Hence, targeting H-1PV entry specifically to tumor cells is important to increase the efficacy of parvovirus-based treatments. In this study, we first found that sialic acid plays a key role in H-1PV entry. We then genetically engineered the H-1PV capsid to improve its affinity for human tumor cells. By analogy with the resolved crystal structure of the closely related parvovirus minute virus of mice, we developed an in silico three-dimensional (3D) model of the H-1PV wild-type capsid. Based on this model, we identified putative amino acids involved in cell membrane recognition and virus entry at the level of the 2-fold axis of symmetry of the capsid, within the so-called dimple region. In situ mutagenesis of these residues significantly reduced the binding and entry of H-1PV into permissive cells. We then engineered an entry-deficient viral capsid and inserted a cyclic RGD-4C peptide at the level of its 3-fold axis spike. This peptide binds αvβ3 and αvβ5 integrins, which are overexpressed in cancer cells and growing blood vessels. The insertion of the peptide rescued viral infectivity toward cells overexpressing αvβ5 integrins, resulting in the efficient killing of these cells by the reengineered virus. This work demonstrates that H-1PV can be genetically retargeted through the modification of its capsid, showing great promise for a more efficient use of this virus in cancer therapy. PMID:22258256

Retargeting of rat parvovirus H-1PV to cancer cells through genetic engineering of the viral capsid.

PubMed

Allaume, Xavier; El-Andaloussi, Nazim; Leuchs, Barbara; Bonifati, Serena; Kulkarni, Amit; Marttila, Tiina; Kaufmann, Johanna K; Nettelbeck, Dirk M; Kleinschmidt, Jürgen; Rommelaere, Jean; Marchini, Antonio

2012-04-01

The rat parvovirus H-1PV is a promising anticancer agent given its oncosuppressive properties and the absence of known side effects in humans. H-1PV replicates preferentially in transformed cells, but the virus can enter both normal and cancer cells. Uptake by normal cells sequesters a significant portion of the administered viral dose away from the tumor target. Hence, targeting H-1PV entry specifically to tumor cells is important to increase the efficacy of parvovirus-based treatments. In this study, we first found that sialic acid plays a key role in H-1PV entry. We then genetically engineered the H-1PV capsid to improve its affinity for human tumor cells. By analogy with the resolved crystal structure of the closely related parvovirus minute virus of mice, we developed an in silico three-dimensional (3D) model of the H-1PV wild-type capsid. Based on this model, we identified putative amino acids involved in cell membrane recognition and virus entry at the level of the 2-fold axis of symmetry of the capsid, within the so-called dimple region. In situ mutagenesis of these residues significantly reduced the binding and entry of H-1PV into permissive cells. We then engineered an entry-deficient viral capsid and inserted a cyclic RGD-4C peptide at the level of its 3-fold axis spike. This peptide binds α(v)β(3) and α(v)β(5) integrins, which are overexpressed in cancer cells and growing blood vessels. The insertion of the peptide rescued viral infectivity toward cells overexpressing α(v)β(5) integrins, resulting in the efficient killing of these cells by the reengineered virus. This work demonstrates that H-1PV can be genetically retargeted through the modification of its capsid, showing great promise for a more efficient use of this virus in cancer therapy.

The Phosphatidylserine and Phosphatidylethanolamine Receptor CD300a Binds Dengue Virus and Enhances Infection.

PubMed

Carnec, Xavier; Meertens, Laurent; Dejarnac, Ophélie; Perera-Lecoin, Manuel; Hafirassou, Mohamed Lamine; Kitaura, Jiro; Ramdasi, Rasika; Schwartz, Olivier; Amara, Ali

2016-01-01

Dengue virus (DENV) is the etiological agent of the major human arboviral disease. We previously demonstrated that the TIM and TAM families of phosphatidylserine (PtdSer) receptors involved in the phagocytosis of apoptotic cells mediate DENV entry into target cells. We show here that human CD300a, a recently identified phospholipid receptor, also binds directly DENV particles and enhances viral entry. CD300a facilitates infection of the four DENV serotypes, as well as of other mosquito-borne viruses such as West Nile virus and Chikungunya virus. CD300a acts as an attachment factor that enhances DENV internalization through clathrin-mediated endocytosis. CD300a recognizes predominantly phosphatidylethanolamine (PtdEth) and to a lesser extent PtdSer associated with viral particles. Mutation of residues in the IgV domain critical for phospholipid binding abrogate CD300a-mediated enhancement of DENV infection. Finally, we show that CD300a is expressed at the surface of primary macrophages and anti-CD300a polyclonal antibodies partially inhibited DENV infection of these cells. Overall, these data indicate that CD300a is a novel DENV binding receptor that recognizes PtdEth and PtdSer present on virions and enhance infection. Dengue disease, caused by dengue virus (DENV), has emerged as the most important mosquito-borne viral disease of humans and is a major global health concern. The molecular bases of DENV-host cell interactions during virus entry are poorly understood, hampering the discovery of new targets for antiviral intervention. We recently discovered that the TIM and TAM proteins, two receptor families involved in the phosphatidylserine (PtdSer)-dependent phagocytic removal of apoptotic cells, interact with DENV particles-associated PtdSer through a mechanism that mimics the recognition of apoptotic cells and mediate DENV infection. In this study, we show that CD300a, a novel identified phospholipid receptor, mediates DENV infection. CD300a-dependent DENV infection relies on the direct recognition of phosphatidylethanolamine and to a lesser extent PtdSer associated with viral particles. This study provides novel insights into the mechanisms that mediate DENV entry and reinforce the concept that DENV uses an apoptotic mimicry strategy for viral entry. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Heterogeneous susceptibility of circulating SIV isolate capsids to HIV-interacting factors

PubMed Central

2013-01-01

Background Many species of non-human primates in Africa are naturally infected by simian immunodeficiency viruses (SIV) and humans stand at the forefront of exposure to these viruses in Sub-Saharan Africa. Cross-species transmission and adaptation of SIV to humans have given rise to human immunodeficiency viruses (HIV-1 and HIV-2) on twelve accountable, independent occasions. However, the determinants contributing to a simian-to-human lasting transmission are not fully understood. Following entry, viral cores are released into the cytoplasm and become the principal target of host cellular factors. Here, we evaluated cellular factors likely to be involved in potential new SIV cross-species transmissions. We investigated the interactions of capsids from naturally circulating SIV isolates with both HIV-1 restricting (i.e. TRIM5 proteins) and facilitating (i.e. cyclophilin A and nucleopore-associated Nup358/RanBP2 and Nup153) factors in single-round infectivity assays that reproduce early stages of the viral life-cycle. Results We show that human TRIM5α is unlikely to prevent cross-species transmission of any SIV we tested and observed that the SIV CA-CypA interaction is a widespread but not a universal feature. Moreover, entry in the nucleus of different SIV appeared to follow pathways that do not necessarily recruit Nup358/RanBP2 or Nup153, and this regardless of their interaction with CypA. Nevertheless, we found that, like HIV-1, human-adapted HIV-2 infection was dependent on Nup358/RanBP2 and Nup153 interactions for optimal infection. Furthermore, we found that, unlike HIV CA, SIV CA did not require a direct interaction with the Cyp-like domain of Nup358/RanBP2 to carry out successful infection. Conclusions Circulating SIV present a variety of phenotypes with regard to CA-interacting restricting or facilitating factors. Altogether, we unveiled unidentified pathways for SIV CA, which could also be exploited by HIV in different cellular contexts, to drive entry into the nucleus. Our findings warrant a closer evaluation of other potential defenses against circulating SIV. PMID:23883001

Physician support of HPV vaccination school-entry requirements

PubMed Central

Califano, Sophia; Calo, William A.; Weinberger, Morris; Gilkey, Melissa B.; Brewer, Noel T.

2016-01-01

ABSTRACT School-entry requirements in the US have led to high coverage for several vaccines, but few states and jurisdictions have adopted these policies for human papillomavirus (HPV) vaccination. Because physicians play a key role in advocating for vaccination policies, we assessed physician support of requiring HPV vaccine for school entry and correlates of this support. Participants were a national sample of 775 physicians who provide primary care, including vaccines, to adolescents. Physicians completed an online survey in 2014 that assessed their support for school-entry requirements for HPV vaccination of 11 and 12 y olds. We used multivariable logistic regression to assess correlates of support for these requirements. The majority of physicians (74%) supported some form of school-entry requirements, with or without opt-out provisions. When opt-out provisions were not specified, 47% agreed that laws requiring HPV vaccination for school attendance were a “good idea.” Physicians more often agreed with requirements, without opt-out provisions, if they: had more years in practice (OR=1.49; 95% CI: 1.09-2.04), gave higher quality HPV vaccine recommendations (OR=2.06; 95% CI: 1.45-2.93), believed that having requirements for Tdap, but not HPV, vaccination undermined its importance (OR=3.33; 95% CI: 2.26-4.9), and believed HPV vaccination was as or more important than other adolescent vaccinations (OR=2.30; 95% CI: 1.65-3.18). In conclusion, we found that many physicians supported school-entry requirements for HPV vaccination. More research is needed to investigate the extent to which opt-out provisions might weaken or strengthen physician support of HPV vaccination school-entry requirements. PMID:26900726

Host cell virus entry mediated by Australian bat lyssavirus G envelope glycoprotein occurs through a clathrin-mediated endocytic pathway that requires actin and Rab5.

PubMed

Weir, Dawn L; Laing, Eric D; Smith, Ina L; Wang, Lin-Fa; Broder, Christopher C

2014-02-27

Australian bat lyssavirus (ABLV), a rhabdovirus of the genus Lyssavirus which circulates in both pteropid fruit bats and insectivorous bats in mainland Australia, has caused three fatal human infections, the most recent in February 2013, manifested as acute neurological disease indistinguishable from clinical rabies. Rhabdoviruses infect host cells through receptor-mediated endocytosis and subsequent pH-dependent fusion mediated by their single envelope glycoprotein (G), but the specific host factors and pathways involved in ABLV entry have not been determined. ABLV internalization into HEK293T cells was examined using maxGFP-encoding recombinant vesicular stomatitis viruses (rVSV) that express ABLV G glycoproteins. A combination of chemical and molecular approaches was used to investigate the contribution of different endocytic pathways to ABLV entry. Dominant negative Rab GTPases were used to identify the endosomal compartment utilized by ABLV to gain entry into the host cell cytosol. Here we show that ABLV G-mediated entry into HEK293T cells was significantly inhibited by the dynamin-specific inhibitor dynasore, chlorpromazine, a drug that blocks clathrin-mediated endocytosis, and the actin depolymerizing drug latrunculin B. Over expression of dominant negative mutants of Eps15 and Rab5 also significantly reduced ABLV G-mediated entry into HEK293T cells. Chemical inhibitors of caveolae-dependent endocytosis and macropinocytosis and dominant negative mutants of Rab7 and Rab11 had no effect on ABLV entry. The predominant pathway utilized by ABLV for internalization into HEK293T cells is clathrin-and actin-dependent. The requirement of Rab5 for productive infection indicates that ABLV G-mediated fusion occurs within the early endosome compartment.

Simulating the elimination of sleeping sickness with an agent-based model.

PubMed

Grébaut, Pascal; Girardin, Killian; Fédérico, Valentine; Bousquet, François

2016-01-01

Although Human African Trypanosomiasis is largely considered to be in the process of extinction today, the persistence of human and animal reservoirs, as well as the vector, necessitates a laborious elimination process. In this context, modeling could be an effective tool to evaluate the ability of different public health interventions to control the disease. Using the Cormas ® system, we developed HATSim, an agent-based model capable of simulating the possible endemic evolutions of sleeping sickness and the ability of National Control Programs to eliminate the disease. This model takes into account the analysis of epidemiological, entomological, and ecological data from field studies conducted during the last decade, making it possible to predict the evolution of the disease within this area over a 5-year span. In this article, we first present HATSim according to the Overview, Design concepts, and Details (ODD) protocol that is classically used to describe agent-based models, then, in a second part, we present predictive results concerning the evolution of Human African Trypanosomiasis in the village of Lambi (Cameroon), in order to illustrate the interest of such a tool. Our results are consistent with what was observed in the field by the Cameroonian National Control Program (CNCP). Our simulations also revealed that regular screening can be sufficient, although vector control applied to all areas with human activities could be significantly more efficient. Our results indicate that the current model can already help decision-makers in planning the elimination of the disease in foci. © P. Grébaut et al., published by EDP Sciences, 2016.

Monitoring the elimination of human African trypanosomiasis: Update to 2014

PubMed Central

Priotto, Gerardo; Paone, Massimo; Diarra, Abdoulaye; Grout, Lise; Mattioli, Raffaele C.; Argaw, Daniel

2017-01-01

Background The World Health Organization (WHO) has targeted the elimination of Human African trypanosomiasis (HAT) ‘as a public health problem’ by 2020. The selected indicators of elimination should be monitored every two years, and we provide here a comprehensive update to 2014. The monitoring system is underpinned by the Atlas of HAT. Results With 3,797 reported cases in 2014, the corresponding milestone (5,000 cases) was surpassed, and the 2020 global target of ‘fewer than 2,000 reported cases per year’ seems within reach. The areas where HAT is still a public health problem (i.e. > 1 HAT reported case per 10,000 people per year) have halved in less than a decade, and in 2014 they corresponded to 350 thousand km2. The number and potential coverage of fixed health facilities offering diagnosis and treatment for HAT has expanded, and approximately 1,000 are now operating in 23 endemic countries. The observed trends are supported by sustained surveillance and improved reporting. Discussion HAT elimination appears to be on track. For gambiense HAT, still accounting for the vast majority of reported cases, progress continues unabated in a context of sustained intensity of screening activities. For rhodesiense HAT, a slow-down was observed in the last few years. Looking beyond the 2020 target, innovative tools and approaches will be increasingly needed. Coordination, through the WHO network for HAT elimination, will remain crucial to overcome the foreseeable and unforeseeable challenges that an elimination process will inevitably pose. PMID:28531222

HELICOBACTER PYLORI

EPA Science Inventory

Helicobacter pylori is a pathogenic bacteria which inhabits the human stomach and upper gastrointestinal tract. This encyclopedic entry summarizes the potential role of this organism as a waterborne pathogen. Information is provided on the physiology and morphology of this bacter...

Employee Spirituality in the Workplace: A Cross-Cultural View for the Management of Spiritual Employees.

ERIC Educational Resources Information Center

Lewis, Jeffrey S.; Geroy, Gary D.

2000-01-01

Discusses six entry points to initiate discussion of employee spirituality in management education: cross-cultural management, workplace diversity, leadership, team management, organizational culture, and human resource development. (SK)

Elimination of leprosy as a public health problem by 2000 AD: an epidemiological perspective.

PubMed

Nsagha, Dickson Shey; Bamgboye, Elijah Afolabi; Assob, Jules Clement Nguedia; Njunda, Anna Longdoh; Kamga, Henri Lucien Foumou; Zoung-Kanyi Bissek, Anne-Cécile; Tabah, Earnest Nji; Oyediran, Alain Bankole O O; Njamnshi, Alfred Kongnyu

2011-01-01

Leprosy is caused by Mycobacterium leprae and manifests as damage to the skin and peripheral nerves. The disease is dreaded because it causes deformities, blindness and disfigurement. Worldwide, 2 million people are estimated to be disabled by leprosy. Multidrug therapy is highly effective in curing leprosy, but treating the nerve damage is much more difficult. The World Health Assembly targeted to eliminate leprosy as a public health problem from the world by 2000. The objective of the review was to assess the successes of the leprosy elimination strategy, elimination hurdles and the way forward for leprosy eradication. A structured search was used to identify publications on the elimination strategy. The keywords used were leprosy, elimination and 2000. To identify potential publications, we included papers on leprosy elimination monitoring, special action projects for the elimination of leprosy, modified leprosy elimination campaigns, and the Global Alliance to eliminate leprosy from the following principal data bases: Cochrane data base of systematic reviews, PubMed, Medline, EMBASE, and the Leprosy data base. We also scanned reference lists for important citations. Key leprosy journals including WHO publications were also reviewed. The search identified 63 journal publications on leprosy-related terms that included a form of elimination of which 19 comprehensively tackled the keywords including a book on leprosy elimination. In 1991, the 44th World Health Assembly called for the elimination of leprosy as a public health problem in the world by 2000. Elimination was defined as less than one case of leprosy per 10000-population. Elimination has been made possible by a confluence of several orders of opportunities: the scientific (the natural history of leprosy at the present state of knowledge), technological (multi-drug therapy and the blister pack); political (commitment of governments) and financial (support from NGOs for example the Nippon Foundation that supplies free multi-drug therapy) opportunities. Elimination created the unrealistic expectation that the leprosy problem could be solved by 2000. First, the elimination goal was not feasible in several areas which had high incidence of leprosy. Even if elimination was to be attained, significant numbers of new cases of leprosy would continue to occur and many people with physical imperfections, severe psychological, economic and social problems caused by leprosy would need continuous assistance. Extra-human reservoirs of Mycobacterium leprae, the relationship between leprosy and poverty, prevention of disabilities, lack of a reliable laboratory test to detect subclinical infection and a vaccine are also challenging issues. The evidence base available to inform on leprosy elimination is highly positive with the availability of multi-drug therapy blister packs. There are concerns that leprosy was not the right disease to be targeted for elimination as there are no reliable diagnostic tests to detect subclinical infection including the lack of a vaccine, extra-human reservoirs (monkeys and armadillos), increase in the burden of child cases, no good epidemiological indicator as prevalence instead of incidence is used to measure elimination. Multi-drug therapy treats leprosy very well but there is no proof that it concurrently interrupts transmission. The high social stigma, prevention of disabilities, and the relationship between leprosy and poverty are still major concerns.

Elimination of leukemic cells from human transplants by laser nano-thermolysis

NASA Astrophysics Data System (ADS)

Lapotko, Dmitri; Lukianova, Ekaterina; Potapnev, Michail; Aleinikova, Olga; Oraevsky, Alexander

2006-02-01

We describe novel ex vivo method for elimination of tumor cells from bone marrow and blood, Laser Activated Nano-Thermolysis for Cell Elimination Technology (LANTCET) and propose this method for purging of transplants during treatment of leukemia. Human leukemic cells derived from real patients with different diagnoses (acute lymphoblastic leukemias) were selectively damaged by LANTCET in the experiments by laser-induced micro-bubbles that emerge inside individual specifically-targeted cells around the clusters of light-absorbing gold nanoparticles. Pretreatment of the transplants with diagnosis-specific primary monoclonal antibodies and gold nano-particles allowed the formation of nanoparticle clusters inside leukemic cells only. Electron microscopy found the nanoparticulate clusters inside the cells. Total (99.9%) elimination of leukemic cells targeted with specific antibodies and nanoparticles was achieved with single 10-ns laser pulses with optical fluence of 0.2 - 1.0 J/cm2 at the wavelength of 532 nm without significant damage to normal bone marrow cells in the same transplant. All cells were studied for the damage/viability with several control methods after their irradiation by laser pulses. Presented results have proved potential applicability of developed LANTCET technology for efficient and safe purging (cleaning of residual tumor cells) of human bone marrow and blood transplants. Design of extra-corporeal system was proposed that can process the transplant for one patient for less than an hour with parallel detection and counting residual leukemic cells.

Characterizing Types of Human Mobility to Inform Differential and Targeted Malaria Elimination Strategies in Northeast Cambodia

PubMed Central

Peeters Grietens, Koen; Gryseels, Charlotte; Dierickx, Susan; Bannister-Tyrrell, Melanie; Trienekens, Suzan; Uk, Sambunny; Phoeuk, Pisen; Suon, Sokha; Set, Srun; Gerrets, René; Hoibak, Sarah; Muela Ribera, Joan; Hausmann-Muela, Susanna; Tho, Sochantha; Durnez, Lies; Sluydts, Vincent; d’Alessandro, Umberto; Coosemans, Marc; Erhart, Annette

2015-01-01

Human population movements currently challenge malaria elimination in low transmission foci in the Greater Mekong Subregion. Using a mixed-methods design, combining ethnography (n = 410 interviews), malariometric data (n = 4996) and population surveys (n = 824 indigenous populations; n = 704 Khmer migrants) malaria vulnerability among different types of mobile populations was researched in the remote province of Ratanakiri, Cambodia. Different structural types of human mobility were identified, showing differential risk and vulnerability. Among local indigenous populations, access to malaria testing and treatment through the VMW-system and LLIN coverage was high but control strategies failed to account for forest farmers’ prolonged stays at forest farms/fields (61% during rainy season), increasing their exposure (p = 0.002). The Khmer migrants, with low acquired immunity, active on plantations and mines, represented a fundamentally different group not reached by LLIN-distribution campaigns since they were largely unregistered (79%) and unaware of the local VMW-system (95%) due to poor social integration. Khmer migrants therefore require control strategies including active detection, registration and immediate access to malaria prevention and control tools from which they are currently excluded. In conclusion, different types of mobility require different malaria elimination strategies. Targeting mobility without an in-depth understanding of malaria risk in each group challenges further progress towards elimination. PMID:26593245

Health information system strengthening and malaria elimination in Papua New Guinea.

PubMed

Rosewell, Alexander; Makita, Leo; Muscatello, David; John, Lucy Ninmongo; Bieb, Sibauk; Hutton, Ross; Ramamurthy, Sundar; Shearman, Phil

2017-07-05

The objective of the study was to describe an m-health initiative to strengthen malaria surveillance in a 184-health facility, multi-province, project aimed at strengthening the National Health Information System (NHIS) in a country with fragmented malaria surveillance, striving towards enhanced control, pre-elimination. A remote-loading mobile application and secure online platform for health professionals was created to interface with the new system (eNHIS). A case-based malaria testing register was developed and integrated geo-coded households, villages and health facilities. A malaria programme management dashboard was created, with village-level malaria mapping tools, and statistical algorithms to identify malaria outbreaks. Since its inception in 2015, 160,750 malaria testing records, including village of residence, have been reported to the eNHIS. These case-based, geo-coded malaria data are 100% complete, with a median data entry delay of 9 days from the date of testing. The system maps malaria to the village level in near real-time as well as the availability of treatment and diagnostics to health facility level. Data aggregation, analysis, outbreak detection, and reporting are automated. The study demonstrates that using mobile technologies and GIS in the capture and reporting of NHIS data in Papua New Guinea provides timely, high quality, geo-coded, case-based malaria data required for malaria elimination. The health systems strengthening approach of integrating malaria information management into the eNHIS optimizes sustainability and provides enormous flexibility to cater for future malaria programme needs.

Engineering of Systematic Elimination of a Targeted Chromosome in Human Cells.

PubMed

Sato, Hiroshi; Kato, Hiroki; Yamaza, Haruyoshi; Masuda, Keiji; Nguyen, Huong Thi Nguyen; Pham, Thanh Thi Mai; Han, Xu; Hirofuji, Yuta; Nonaka, Kazuaki

2017-01-01

Embryonic trisomy leads to abortion or congenital genetic disorders in humans. The most common autosomal chromosome abnormalities are trisomy of chromosomes 13, 18, and 21. Although alteration of gene dosage is thought to contribute to disorders caused by extra copies of chromosomes, genes associated with specific disease phenotypes remain unclear. To generate a normal cell from a trisomic cell as a means of etiological analysis or candidate therapy for trisomy syndromes, we developed a system to eliminate a targeted chromosome from human cells. Chromosome 21 was targeted by integration of a DNA cassette in HeLa cells that harbored three copies of chromosome 21. The DNA cassette included two inverted loxP sites and a herpes simplex virus thymidine kinase (HSV-tk) gene. This system causes missegregation of chromosome 21 after expression of Cre recombinase and subsequently enables the selection of cells lacking the chromosome by culturing in a medium that includes ganciclovir (GCV). Cells harboring only two copies of chromosome 21 were efficiently induced by transfection of a Cre expression vector, indicating that this approach is useful for eliminating a targeted chromosome.

Beyond the Poverty of National Security: Toward a Critical Human Security Perspective in Educational Policy

ERIC Educational Resources Information Center

Means, Alexander J.

2014-01-01

This article examines the intersecting logics of human capital and national security underpinning the corporate school reform movement in the United States. Taking a 2012 policy report by the Council on Foreign Relations as an entry point, it suggests that these logics are incoherent not only on their own narrow instrumental terms, but also more…

Induction of proinflammatory cytokines in human lung epithelial cells during Rhodococcus equi infection.

PubMed

Remuzgo-Martínez, Sara; Pilares-Ortega, Lilian; Alvarez-Rodríguez, Lorena; Aranzamendi-Zaldunbide, Maitane; Padilla, Daniel; Icardo, Jose Manuel; Ramos-Vivas, Jose

2013-08-01

Rhodococcus equi is an opportunistic human pathogen associated with immunosuppressed people. While the interaction of R. equi with macrophages has been comprehensively studied, little is known about its interactions with non-phagocytic cells. Here, we characterized the entry process of this bacterium into human lung epithelial cells. The invasion is inhibited by nocodazole and wortmannin, suggesting that the phosphatidylinositol 3-kinase pathway and microtubule cytoskeleton are important for invasion. Pre-incubation of R. equi with a rabbit anti-R. equi polyclonal antiserum resulted in a dramatic reduction in invasion. Also, the invasion process as studied by immunofluorescence and scanning electron microscopy indicates that R. equi make initial contact with the microvilli of the A549 cells, and at the structural level, the entry process was observed to occur via a zipper-like mechanism. Infected lung epithelial cells upregulate the expression of cytokines IL-8 and IL-6 upon infection. The production of these pro-inflammatory cytokines was significantly enhanced in culture supernatants from cells infected with non-mucoid plasmid-less strains when compared with cells infected with mucoid strains. These results demonstrate that human airway epithelial cells produce pro-inflammatory mediators against R. equi isolates.

Mission and Design Sensitivities for Human Mars Landers Using Hypersonic Inflatable Aerodynamic Decelerators

NASA Technical Reports Server (NTRS)

Polsgrove, Tara P.; Thomas, Herbert D.; Collins, Tim; Dwyer Cianciolo, Alicia; Samareh, Jamshid

2017-01-01

Landing humans on Mars is one of NASA's long term goals. The Evolvable Mars Campaign (EMC) is focused on evaluating architectural trade options to define the capabilities and elements needed for a sustainable human presence on the surface of Mars. The EMC study teams have considered a variety of in-space propulsion options and surface mission options. As we seek to better understand how these choices affect the performance of the lander, this work informs and influences requirements for transportation systems to deliver the landers to Mars and enable these missions. This paper presents the effects of mission and vehicle design options on lander mass and performance. Beginning with Earth launch, options include fairing size assumptions, co-manifesting other elements with the lander, and Earth-Moon vicinity operations. Capturing into Mars orbit using either aerocapture or propulsive capture is assessed. For entry, descent, and landing both storable as well as oxygen and methane propellant combinations are considered, engine thrust level is assessed, and sensitivity to landed payload mass is presented. This paper focuses on lander designs using the Hypersonic Inflatable Aerodynamic Decelerators (HIAD), one of several entry system technologies currently considered for human missions.

Retinoic Acid Signalling and the Control of Meiotic Entry in the Human Fetal Gonad

PubMed Central

Kinnell, Hazel L.; Anderson, Richard A.; Saunders, Philippa T. K.

2011-01-01

The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros-derived retinoic acid (RA). Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8–9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARα, β and RXRα, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually-dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may be important in regulating the onset of meiosis in the human fetal ovary, mechanisms other than CYP26B1-mediated metabolism of RA may exist to inhibit the entry of germ cells into meiosis in the human fetal testis. PMID:21674038

Data entry errors and design for model-based tight glycemic control in critical care.

PubMed

Ward, Logan; Steel, James; Le Compte, Aaron; Evans, Alicia; Tan, Chia-Siong; Penning, Sophie; Shaw, Geoffrey M; Desaive, Thomas; Chase, J Geoffrey

2012-01-01

Tight glycemic control (TGC) has shown benefits but has been difficult to achieve consistently. Model-based methods and computerized protocols offer the opportunity to improve TGC quality but require human data entry, particularly of blood glucose (BG) values, which can be significantly prone to error. This study presents the design and optimization of data entry methods to minimize error for a computerized and model-based TGC method prior to pilot clinical trials. To minimize data entry error, two tests were carried out to optimize a method with errors less than the 5%-plus reported in other studies. Four initial methods were tested on 40 subjects in random order, and the best two were tested more rigorously on 34 subjects. The tests measured entry speed and accuracy. Errors were reported as corrected and uncorrected errors, with the sum comprising a total error rate. The first set of tests used randomly selected values, while the second set used the same values for all subjects to allow comparisons across users and direct assessment of the magnitude of errors. These research tests were approved by the University of Canterbury Ethics Committee. The final data entry method tested reduced errors to less than 1-2%, a 60-80% reduction from reported values. The magnitude of errors was clinically significant and was typically by 10.0 mmol/liter or an order of magnitude but only for extreme values of BG < 2.0 mmol/liter or BG > 15.0-20.0 mmol/liter, both of which could be easily corrected with automated checking of extreme values for safety. The data entry method selected significantly reduced data entry errors in the limited design tests presented, and is in use on a clinical pilot TGC study. The overall approach and testing methods are easily performed and generalizable to other applications and protocols. © 2012 Diabetes Technology Society.

The Effect of Ongoing Blood Loss on Human Serum Concentrations of Perfluorinated Acids - Poster Presentation (August 2011)

EPA Science Inventory

In this study, we examined the significance of blood loss as an elimination route of PFAAs in humans, thus indirectly investigating the need for hypotheses other than menstruation to explain the gender differences observed in humans.

Preliminary evidence that abscisic acid improves spatial memory in rats.

PubMed

Qi, Cong-Cong; Ge, Jin-Fang; Zhou, Jiang-Ning

2015-02-01

Abscisic acid (ABA) is a crucial phytohormone that exists in a wide range of animals, including humans, and has multiple bioactivities. As direct derivatives of carotenoids, ABA and retinoic acid (RA) share similar molecular structures, and RA has been reported to improve spatial memory in rodents. To explore the potential effects of ABA on spatial learning and memory in rodents, 20mg/kg ABA was administered to young rats for 6weeks, and its effects on behaviour performance were evaluated through a series of behavioural tests. ABA pharmacokinetic analysis revealed that the exogenous ABA was distributed widely in the rat brain, characterised by rapid absorption and slow elimination. The behavioural tests showed that ABA increased both the duration spent in the target quadrant and the frequency it was entered in the probe test of the Morris water maze (MWM) and decreased the latency to locate the target quadrant. Moreover, ABA decreased the latency to enter the novel arm in the Y-maze test, accompanied by increases in the total entries and distance travelled in the three arms. However, there were no significant differences between the ABA-treated and control rats in the open field test and elevated plus-maze test. These results preliminarily indicate that ABA improves spatial memory in MWM and exploratory activity in Y-maze in young rats. Copyright © 2014 Elsevier Inc. All rights reserved.

Characterization of a recombinant humanized anti-cocaine monoclonal antibody produced from multiple clones for the selection of a master cell bank candidate.

PubMed

Wetzel, Hanna N; Webster, Rose P; Saeed, Fatima O; Kirley, Terence L; Ball, William J; Norman, Andrew B

2017-06-03

We have generated a humanized anti-cocaine monoclonal antibody (mAb), which is at an advanced stage of pre-clinical development. We report here in vitro binding affinity studies, and in vivo pharmacokinetic and efficacy studies of the recombinant mAb. The overall aim was to characterize the recombinant antibody from each of the three highest producing transfected clones and to select one to establish a master cell bank. In mAb pharmacokinetic studies, after injection with h2E2 (120 mg/kg iv) blood was collected from the tail tip of mice over 28 days. Antibody concentrations were quantified using ELISA. The h2E2 concentration as a function of time was fit using a two-compartment pharmacokinetic model. To test in vivo efficacy, mice were injected with h2E2 (120 mg/kg iv), then one hour later injected with an equimolar dose of cocaine. Blood and brain were collected 5 min after cocaine administration. Cocaine concentrations were quantified using LC/MS. The affinity of the antibody for cocaine was determined using a [ 3 H] cocaine binding assay. All three antibodies had long elimination half-lives, 2-5 nM Kd for cocaine, and prevented cocaine's entry into the brain by sequestering it in the plasma. Pharmacokinetic and radioligand binding assays supported designation of the highest producing clone 85 as the master cell bank candidate. Overall, the recombinant h2E2 showed favorable binding properties, pharmacokinetics, and in vivo efficacy. Copyright © 2017 Elsevier Inc. All rights reserved.

AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling.

PubMed

Chen, Jian; Yang, Yi-Feng; Yang, Yu; Zou, Peng; Chen, Jun; He, Yongquan; Shui, Sai-Lan; Cui, Yan-Ru; Bai, Ru; Liang, Ya-Jun; Hu, Yunwen; Jiang, Biao; Lu, Lu; Zhang, Xiaoyan; Liu, Jia; Xu, Jianqing

2018-03-01

Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain-Barré syndrome 1,2 . While progress has been made in understanding the causal link between ZIKV infection and microcephaly 3-9 , the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV 10-22 . Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV. We found, instead, that the presence of AXL attenuated the ZIKV-induced activation of type I interferon (IFN) signalling genes, including several type I IFNs and IFN-stimulating genes. Knocking out type I IFN receptor α chain (IFNAR1) restored the vulnerability of AXL knockout astrocytes to ZIKV infection. Further experiments suggested that AXL regulates the expression of SOCS1, a known type I IFN signalling suppressor, in a STAT1/STAT2-dependent manner. Collectively, our results demonstrate that AXL is unlikely to function as an entry receptor for ZIKV and may instead promote ZIKV infection in human astrocytes by antagonizing type I IFN signalling.

Human MHC-II with Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands-Relation to Rheumatoid Arthritis.

PubMed

Trier, Nicole; Izarzugaza, Jose; Chailyan, Anna; Marcatili, Paolo; Houen, Gunnar

2018-01-21

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder of unknown etiology, which is characterized by inflammation in the synovium and joint damage. Although the pathogenesis of RA remains to be determined, a combination of environmental (e.g., viral infections) and genetic factors influence disease onset. Especially genetic factors play a vital role in the onset of disease, as the heritability of RA is 50-60%, with the human leukocyte antigen (HLA) alleles accounting for at least 30% of the overall genetic risk. Some HLA-DR alleles encode a conserved sequence of amino acids, referred to as the shared epitope (SE) structure. By analyzing the structure of a HLA-DR molecule in complex with Epstein-Barr virus (EBV), the SE motif is suggested to play a vital role in the interaction of MHC II with the viral glycoprotein (gp) 42, an essential entry factor for EBV. EBV has been repeatedly linked to RA by several lines of evidence and, based on several findings, we suggest that EBV is able to induce the onset of RA in predisposed SE-positive individuals, by promoting entry of B-cells through direct contact between SE and gp42 in the entry complex.

Human MHC-II with Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands—Relation to Rheumatoid Arthritis

PubMed Central

Trier, Nicole; Izarzugaza, Jose; Chailyan, Anna; Marcatili, Paolo; Houen, Gunnar

2018-01-01

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder of unknown etiology, which is characterized by inflammation in the synovium and joint damage. Although the pathogenesis of RA remains to be determined, a combination of environmental (e.g., viral infections) and genetic factors influence disease onset. Especially genetic factors play a vital role in the onset of disease, as the heritability of RA is 50–60%, with the human leukocyte antigen (HLA) alleles accounting for at least 30% of the overall genetic risk. Some HLA-DR alleles encode a conserved sequence of amino acids, referred to as the shared epitope (SE) structure. By analyzing the structure of a HLA-DR molecule in complex with Epstein-Barr virus (EBV), the SE motif is suggested to play a vital role in the interaction of MHC II with the viral glycoprotein (gp) 42, an essential entry factor for EBV. EBV has been repeatedly linked to RA by several lines of evidence and, based on several findings, we suggest that EBV is able to induce the onset of RA in predisposed SE-positive individuals, by promoting entry of B-cells through direct contact between SE and gp42 in the entry complex. PMID:29361739

Human Immunodeficiency Virus Playing Hide-and-Seek: Understanding the TFH Cell Reservoir and Proposing Strategies to Overcome the Follicle Sanctuary.

PubMed

Leong, Yew Ann; Atnerkar, Anurag; Yu, Di

2017-01-01

Human immunodeficiency virus (HIV) infects millions of people worldwide, and new cases continue to emerge. Once infected, the virus cannot be cleared by the immune system and causes acquired immunodeficiency syndrome. Combination antiretroviral therapeutic regimen effectively suppresses viral replication and halts disease progression. The treatment, however, does not eliminate the virus-infected cells, and interruption of treatment inevitably leads to viral rebound. The rebound virus originates from a group of virus-infected cells referred to as the cellular reservoir of HIV. Identifying and eliminating the HIV reservoir will prevent viral rebound and cure HIV infection. In this review, we focus on a recently discovered HIV reservoir in a subset of CD4 + T cells called the follicular helper T (T FH ) cells. We describe the potential mechanisms for the emergence of reservoir in T FH cells, and the strategies to target and eliminate this viral reservoir.

IFITM3 Restricts Human Metapneumovirus Infection.

PubMed

McMichael, Temet M; Zhang, Yu; Kenney, Adam D; Zhang, Lizhi; Zani, Ashley; Lu, Mijia; Chemudupati, Mahesh; Li, Jianrong; Yount, Jacob S

2018-06-15

Human metapneumovirus (hMPV) utilizes a bifurcated cellular entry strategy, fusing either with the plasma membrane or, after endocytosis, with the endosome membrane. Whether cellular factors restrict or enhance either entry pathway is largely unknown. We found that the interferon-induced transmembrane protein 3 (IFITM3) inhibits hMPV infection to an extent similar to endocytosis-inhibiting drugs, and an IFITM3 variant that accumulates at the plasma membrane in addition to its endosome localization provided increased virus restriction. Mechanistically, IFITM3 blocks hMPV F protein-mediated membrane fusion, and inhibition of infection was reversed by the membrane destabilizing drug amphotericin B. Conversely, we found that infection by some hMPV strains is enhanced by the endosomal protein Toll-like receptor 7 (TLR7), and that IFITM3 retains the ability to restrict hMPV infection even in cells expressing TLR7. Overall, our results identify IFITM3 as an endosomal restriction factor that limits hMPV infection of cells.

Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment.

PubMed

Sakurai, Yasuteru; Kolokoltsov, Andrey A; Chen, Cheng-Chang; Tidwell, Michael W; Bauta, William E; Klugbauer, Norbert; Grimm, Christian; Wahl-Schott, Christian; Biel, Martin; Davey, Robert A

2015-02-27

Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy. Copyright © 2015, American Association for the Advancement of Science.

Mimicking herpes simplex virus 1 and herpes simplex virus 2 mucosal behavior in a well-characterized human genital organ culture.

PubMed

Steukers, Lennert; Weyers, Steven; Yang, Xiaoyun; Vandekerckhove, Annelies P; Glorieux, Sarah; Cornelissen, Maria; Van den Broeck, Wim; Temmerman, Marleen; Nauwynck, Hans J

2014-07-15

We developed and morphologically characterized a human genital mucosa explant model (endocervix and ectocervix/vagina) to mimic genital herpes infections caused by herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Subsequent analysis of HSV entry receptor expression throughout the menstrual cycle in genital tissues was performed, and the evolution of HSV-1/-2 mucosal spread over time was assessed. Nectin-1 and -2 were expressed in all tissues during the entire menstrual cycle. Herpesvirus entry mediator expression was limited mainly to some connective tissue cells. Both HSV-1 and HSV-2 exhibited a plaque-wise mucosal spread across the basement membrane and induced prominent epithelial syncytia. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Mechanically-Deployed Hypersonic Decelerator and Conformal Ablator Technologies for Mars Missions

NASA Technical Reports Server (NTRS)

Venkatapathy, Ethiraj; Wercinski, Paul F.; Beck, Robin A. S.; Hamm, Kenneth R.; Yount, Bryan C.; Makino, A.; Smith, B.; Gage, P.; Prabhu, D.

2012-01-01

The concept of a mechanically deployable hypersonic decelerator, developed initially for high mass (40 MT) human Mars missions, is currently funded by OCT for technology maturation. The ADEPT (Adaptive, Deployable Entry and Placement Technology) project has broad, game-changing applicability to in situ science missions to Venus, Mars, and the Outer Planets. Combined with maturation of conformal ablator technology (another current OCT investment), the two technologies provide unique low mass mission enabling capabilities otherwise not achievable by current rigid aeroshell or by inflatables. If this abstract is accepted, we will present results that illustrate the mission enabling capabilities of the mechanically deployable architecture for: (1) robotic Mars (Discovery or New Frontiers class) in the near term; (2) alternate approaches to landing MSL-class payloads, without the need for supersonic parachute or lifting entry, in the mid-term; and (3) Heavy mass and human missions to Mars in the long term.

Mechanically-Deployed Hypersonic Decelerator and Conformal Ablator Technologies for Mars Missions

NASA Technical Reports Server (NTRS)

Venkatapathy, E.; Wercinski, P.; Prabhu, D.

2012-01-01

The concept of a mechanically deployable hypersonic decelerator, developed initially for high mass (approximately 40 MT) human Mars missions, is currently funded by OCT for technology maturation. The ADEPT (Adaptive, Deployable Entry and Placement Technology) project has broad, game-changing applicability to in situ science missions to Venus, Mars, and the Outer Planets. Combined with maturation of conformal ablator technology (another current OCT investment), the two technologies provide unique low-mass mission enabling capabilities otherwise not achievable by current rigid aeroshell or by inflatables. If this abstract is accepted, we will present results that illustrate the mission enabling capabilities of the mechanically deployable architecture for: (1) robotic Mars (Discovery or New Frontiers class) in the near term (2) alternate approaches to landing MSL-class payloads, without the need for supersonic parachute or lifting entry, in the mid-term and (3) Heavy mass and human missions to Mars in the long term.

Varied ecosystems need different fire protection

USGS Publications Warehouse

Gutsell, Sheri L.; Johnson, Edward A.; Miyanishi, Kiyoko; Keeley, Jon E.; Dickinson, Matthew; Bridge, Simon R. J.

2001-01-01

Covington states in his Commentary1 that the open ponderosa pine forests of the western United States are "in widespread collapse" because fire suppression by humans has eliminated the low-intensity surface fire regime that maintained the open, park-like structure of these forests. He fears this will lead to an "unprecedented" crown fire regime that will eliminate forests.

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

Tully, Stephen

Electricity access is already well established within the framework of human rights, either as an implicit attribute of a pre-existing right (such as non-discrimination or sustainable development) or explicitly in the context of eliminating discrimination against women. There is also broad acknowledgement by states of the desirability of eliminating energy poverty - for all, but particularly for the rural poor, and women. (author)

A Machine Learning Approach to Evaluating Illness-Induced Religious Struggle

PubMed Central

Glauser, Joshua; Connolly, Brian; Nash, Paul; Grossoehme, Daniel H

2017-01-01

Religious or spiritual struggles are clinically important to health care chaplains because they are related to poorer health outcomes, involving both mental and physical health problems. Identifying persons experiencing religious struggle poses a challenge for chaplains. One potentially underappreciated means of triaging chaplaincy effort are prayers written in chapel notebooks. We show that religious struggle can be identified in these notebooks through instances of negative religious coping, such as feeling anger or abandonment toward God. We built a data set of entries in chapel notebooks and classified them as showing religious struggle, or not. We show that natural language processing techniques can be used to automatically classify the entries with respect to whether or not they reflect religious struggle with as much accuracy as humans. The work has potential applications to triaging chapel notebook entries for further attention from pastoral care staff. PMID:28469429

Tactile Data Entry for Extravehicular Activity

NASA Technical Reports Server (NTRS)

Adams, Richard J.; Olowin, Aaron B.; Hannaford, Blake; Sands, O Scott

2012-01-01

In the task-saturated environment of extravehicular activity (EVA), an astronaut's ability to leverage suit-integrated information systems is limited by a lack of options for data entry. In particular, bulky gloves inhibit the ability to interact with standard computing interfaces such as a mouse or keyboard. This paper presents the results of a preliminary investigation into a system that permits the space suit gloves themselves to be used as data entry devices. Hand motion tracking is combined with simple finger gesture recognition to enable use of a virtual keyboard, while tactile feedback provides touch-based context to the graphical user interface (GUI) and positive confirmation of keystroke events. In human subject trials, conducted with twenty participants using a prototype system, participants entered text significantly faster with tactile feedback than without (p = 0.02). The results support incorporation of vibrotactile information in a future system that will enable full touch typing and general mouse interactions using instrumented EVA gloves.

Paramyxovirus Glycoproteins and the Membrane Fusion Process.

PubMed

Aguilar, Hector C; Henderson, Bryce A; Zamora, J Lizbeth; Johnston, Gunner P

2016-09-01

The family Paramyxoviridae includes many viruses that significantly affect human and animal health. An essential step in the paramyxovirus life cycle is viral entry into host cells, mediated by virus-cell membrane fusion. Upon viral entry, infection results in expression of the paramyxoviral glycoproteins on the infected cell surface. This can lead to cell-cell fusion (syncytia formation), often linked to pathogenesis. Thus membrane fusion is essential for both viral entry and cell-cell fusion and an attractive target for therapeutic development. While there are important differences between viral-cell and cell-cell membrane fusion, many aspects are conserved. The paramyxoviruses generally utilize two envelope glycoproteins to orchestrate membrane fusion. Here, we discuss the roles of these glycoproteins in distinct steps of the membrane fusion process. These findings can offer insights into evolutionary relationships among Paramyxoviridae genera and offer future targets for prophylactic and therapeutic development.

Paramyxovirus Glycoproteins and the Membrane Fusion Process

PubMed Central

Aguilar, Hector C.; Henderson, Bryce A.; Zamora, J. Lizbeth; Johnston, Gunner P.

2016-01-01

The family Paramyxoviridae includes many viruses that significantly affect human and animal health. An essential step in the paramyxovirus life cycle is viral entry into host cells, mediated by virus-cell membrane fusion. Upon viral entry, infection results in expression of the paramyxoviral glycoproteins on the infected cell surface. This can lead to cell-cell fusion (syncytia formation), often linked to pathogenesis. Thus membrane fusion is essential for both viral entry and cell-cell fusion and an attractive target for therapeutic development. While there are important differences between viral-cell and cell-cell membrane fusion, many aspects are conserved. The paramyxoviruses generally utilize two envelope glycoproteins to orchestrate membrane fusion. Here, we discuss the roles of these glycoproteins in distinct steps of the membrane fusion process. These findings can offer insights into evolutionary relationships among Paramyxoviridae genera and offer future targets for prophylactic and therapeutic development. PMID:28138419

Entry, Descent and Landing Systems Analysis: Exploration Feed Forward Internal Peer Review Slide Package

NASA Technical Reports Server (NTRS)

Dwyer Cianciolo, Alicia M. (Editor)

2011-01-01

NASA senior management commissioned the Entry, Descent and Landing Systems Analysis (EDL-SA) Study in 2008 to identify and roadmap the Entry, Descent and Landing (EDL) technology investments that the agency needed to successfully land large payloads at Mars for both robotic and human-scale missions. Year 1 of the study focused on technologies required for Exploration-class missions to land payloads of 10 to 50 mt. Inflatable decelerators, rigid aeroshell and supersonic retro-propulsion emerged as the top candidate technologies. In Year 2 of the study, low TRL technologies identified in Year 1, inflatables aeroshells and supersonic retropropulsion, were combined to create a demonstration precursor robotic mission. This part of the EDL-SA Year 2 effort, called Exploration Feed Forward (EFF), took much of the systems analysis simulation and component model development from Year 1 to the next level of detail.

Entry, Descent and Landing Systems Analysis Study: Phase 2 Report on Exploration Feed-Forward Systems

NASA Technical Reports Server (NTRS)

Dwyer Ciancolo, Alicia M.; Davis, Jody L.; Engelund, Walter C.; Komar, D. R.; Queen, Eric M.; Samareh, Jamshid A.; Way, David W.; Zang, Thomas A.; Murch, Jeff G.; Krizan, Shawn A.;

A dormant internal ribosome entry site controls translation of feline immunodeficiency virus.

PubMed

Camerini, Valentina; Decimo, Didier; Balvay, Laurent; Pistello, Mauro; Bendinelli, Mauro; Darlix, Jean-Luc; Ohlmann, Théophile

2008-04-01

The characterization of internal ribosome entry sites (IRESs) in virtually all lentiviruses prompted us to investigate the mechanism used by the feline immunodeficiency virus (FIV) to produce viral proteins. Various in vitro translation assays with mono- and bicistronic constructs revealed that translation of the FIV genomic RNA occurred both by a cap-dependent mechanism and by weak internal entry of the ribosomes. This weak IRES activity was confirmed in feline cells expressing bicistronic RNAs containing the FIV 5' untranslated region (UTR). Surprisingly, infection of feline cells with FIV, but not human immunodeficiency virus type 1, resulted in a great increase in FIV translation. Moreover, a change in the cellular physiological condition provoked by heat stress resulted in the specific stimulation of expression driven by the FIV 5' UTR while cap-dependent initiation was severely repressed. These results reveal the presence of a "dormant" IRES that becomes activated by viral infection and cellular stress.

Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex

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

Tan, Qiuxiang; Zhu, Ya; Li, Jian

2013-10-21

The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom–resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor–gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity.more » These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.« less

Investigating data entry task performance on a laptop under the impact of vibration: the effect of color.

PubMed

Mallick, Zulquernain

2007-01-01

The last 20 years have seen a tremendous growth in mobile computing and wireless communications and services. An experimental study was conducted to explore the effect of text/background color on a laptop computing system along with variable environmental vibration on operators' data entry task performance in moving automobiles. The operators' performance was measured in terms of the number of characters entered per minute without spaces (NCEPMWS) on a laptop computing system. The subjects were divided into 3 categories, namely, Novices, Intermediates and Experts. Findings suggest a re-evaluation of existing laptop designs taking ergonomics into consideration. It appears that proper selection of text/background color on the laptop coupled with controlled vehicular speed could result in a better quality of interaction between human and laptops and it could also resolve the problem of poor data entry task performance.

Monitoring of heavy metal levels in the major rivers and in residents' blood in Zhenjiang City, China, and assessment of heavy metal elimination via urine and sweat in humans.

PubMed

Sheng, Jianguo; Qiu, Wenhui; Xu, Bentuo; Xu, Hui; Tang, Chong

2016-06-01

The coastal areas of China face great challenges, owing to heavy metal contamination caused by rapid industrialization and urbanization. To our knowledge, this study is the first report of the levels of heavy metals in the major rivers of Zhenjiang, one of the most important cities of the Yangtze River Delta in China. In addition, we measured heavy metal levels in the blood of 76 residents of Zhenjiang. The results suggest that the presence of heavy metals in the blood may threaten human health and the distribution appeared to correspond to most highly populated areas and/or areas with high traffic. We also found that the concentration of heavy metals in human blood showed an accumulation effect with increase in age. Moreover, the levels of most heavy metals were lower in participants who regularly exercised than in those who did not. We studied heavy metal levels in the urine and sweat of another 17 volunteers to monitor the elimination of bioaccumulated heavy metal. Heavy metals were found in the urine and sweat of all the 17 participants and were more concentrated in sweat. Induced micturition and sweating appear to be potential methods for the elimination of heavy metals from the human body.

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

PubMed Central

Kwong, Peter D.; Wyatt, Richard; Robinson, James; Sweet, Raymond W.; Sodroski, Joseph; Hendrickson, Wayne A.

2017-01-01

The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. These interactions initiate a fusion of the viral and cellular membranes. Although gpl20 can elicit virus-neutralizing antibodies, HIV eludes the immune system. We have solved the X-ray crystal structure at 2.5 Å resolution of an HIV-1 gp120 core complexed with a two-domain fragment of human CD4 and an antigen-binding fragment of a neutralizing antibody that blocks chemokine-receptor binding. The structure reveals a cavity-laden CD4-gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change upon CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for immune evasion. Our results provide a framework for understanding the complex biology of HIV entry into cells and should guide efforts to intervene. PMID:9641677

Human Mars EDL Pathfinder Study: Assessment of Technology Development Gaps and Mitigations

NASA Technical Reports Server (NTRS)

Lillard, Randolph; Olejniczak, Joe; Polsgrove, Tara; Cianciolo, Alice Dwyer; Munk, Michelle; Whetsel, Charles; Drake, Bret

2017-01-01

This paper presents the results of a NASA initiated Agency-wide assessment to better characterize the risks and potential mitigation approaches associated with landing human class Entry, Descent, and Landing (EDL) systems on Mars. Due to the criticality and long-lead nature of advancing EDL techniques, it is necessary to determine an appropriate strategy to improve the capability to land large payloads. A key focus of this study was to understand the key EDL risks and with a focus on determining what "must" be tested at Mars. This process identified the various risks and potential risk mitigation strategies along with the key near term technology development efforts required and in what environment those technology demonstrations were best suited. The study identified key risks along with advantages to each entry technology. In addition, it was identified that provided the EDL concept of operations (con ops) minimized large scale transition events, there was no technology requirement for a Mars pre-cursor demonstration. Instead, NASA should take a direct path to a human-scale lander.

The H-PEPSS: an instrument to measure health professionals' perceptions of patient safety competence at entry into practice.

PubMed

Ginsburg, Liane; Castel, Evan; Tregunno, Deborah; Norton, Peter G

2012-08-01

Enhancing competency in patient safety at entry to practice requires introduction and integration of patient safety into health professional education. As efforts to include patient safety in health professional education increase, it is important to capture new health professionals' perspectives of their own patient safety competence at entry to practice. Existing instruments to measure patient safety knowledge, skills and attitudes have been developed largely to examine the impact of specific patient safety curricular initiatives and the psychometric analyses of the instruments used thus far have been exploratory in nature. Confirmatory factor analytic approaches are used to extensively test the Health Professional Education in Patient Safety Survey (H-PEPSS), a newly designed survey rooted in a patient safety competency framework and designed to measure health professionals' self-reported patient safety competence around the time of entry to practice. The H-PEPSS focuses primarily on the socio-cultural aspects of patient safety including culture, teamwork, communication, managing risk and understanding human factors. Results support a parsimonious six-factor measurement model of health professionals' perceptions of patient safety competency. These results support the validity of a reduced version of the H-PEPSS and suggest it can be appropriately used at or near training completion with a variety of health professional groups. Given increased demands for patient safety competency among health professionals at entry to practice and slow, but emerging changes in health professional education, ongoing research to understand the extent of patient safety competency among health professionals around the time of entry to practice will be important.

The H-PEPSS: an instrument to measure health professionals' perceptions of patient safety competence at entry into practice

PubMed Central

Castel, Evan; Tregunno, Deborah; Norton, Peter G

2012-01-01

Background Enhancing competency in patient safety at entry to practice requires introduction and integration of patient safety into health professional education. As efforts to include patient safety in health professional education increase, it is important to capture new health professionals' perspectives of their own patient safety competence at entry to practice. Existing instruments to measure patient safety knowledge, skills and attitudes have been developed largely to examine the impact of specific patient safety curricular initiatives and the psychometric analyses of the instruments used thus far have been exploratory in nature. Methods Confirmatory factor analytic approaches are used to extensively test the Health Professional Education in Patient Safety Survey (H-PEPSS), a newly designed survey rooted in a patient safety competency framework and designed to measure health professionals' self-reported patient safety competence around the time of entry to practice. The H-PEPSS focuses primarily on the socio-cultural aspects of patient safety including culture, teamwork, communication, managing risk and understanding human factors. Results Results support a parsimonious six-factor measurement model of health professionals' perceptions of patient safety competency. These results support the validity of a reduced version of the H-PEPSS and suggest it can be appropriately used at or near training completion with a variety of health professional groups. Conclusions Given increased demands for patient safety competency among health professionals at entry to practice and slow, but emerging changes in health professional education, ongoing research to understand the extent of patient safety competency among health professionals around the time of entry to practice will be important. PMID:22562876

Intersections of Family Homelessness, CPS Involvement, and Race in Alameda County, California

PubMed Central

Shinn, Marybeth

2016-01-01

The homelessness and child protective services (CPS) systems are closely linked. This study examines the patterns and sequence of families’ involvement with homeless shelters and CPS, as well as whether involvement in each system predicts involvement in the other using linked administrative records for 258 families recruited in emergency shelters in Alameda County, California. More than half of families were reported to CPS at some point, but less than one fifth ever had a report substantiated. Reports that were uninvestigated or unfounded increased in the months leading up to shelter entry and spiked immediately afterward, but substantiations and child removals increased only later. Shelter use before study entry was associated with CPS referrals and investigations after study entry, although not with substantiated cases or child removals. However, CPS involvement before study entry was not associated with returns to shelter after study entry. These results imply that an unsubstantiated report of neglect or abuse may serve as an early warning signal for homelessness and that preventive strategies aiming to affect both homeless and child protective systems should focus on reducing homelessness. CPS workers should evaluate families’ housing needs and attempt to link families to appropriate resources. Black families were disproportionately referred to CPS after shelter entry after controlling for other family characteristics, but race was not associated with substantiations of neglect or abuse or with child removals. Findings lend modest support to human decision-making and institutional explanations of racial disproportionalities in CPS involvement, especially for reporters outside of the CPS system. PMID:27318034

Antiviral interactions of combinations of highly potent 2,4(1H,3H)-pyrimidinedione congeners and other anti-HIV agents.

PubMed

Hartman, Tracy L; Yang, Lu; Buckheit, Robert W

2011-12-01

Structure-activity relationship evaluation of seventy-four 2,4(1H,3H)-pyrimidinedione derivatives identified seven lead compounds based on anti-HIV-1 potency, extended range of action to include HIV-2, virus entry inhibition, reverse transcriptase inhibition, and lack of cytotoxicity to human cells. The selected pyrimidinedione congeners are highly active inhibitors of HIV-1 with EC(50) values ranging from 0.6 to 2 nM in CEM-SS cells infected with laboratory derived viruses, 11-20 nM in fresh human PBMCs infected with subtype B (HT/92/599) virus, and 2-7 nM in PBMCs infected with the clinical subtype C (ZA/97/003) virus. Combination antiviral assays were performed using the laboratory adapted RF strain of HIV-1 in CEM-SS cells and with a clade B and C low passage clinical isolate in fresh human peripheral mononuclear cells and the compound interactions were analyzed using MacSynergy II. The seven pyrimidinedione compounds resulted in additive to synergistic interactions in combination with entry and fusion inhibitors, nonnucleoside and nucleoside reverse transcriptase inhibitors, and the protease inhibitors. No evidence of antagonistic antiviral activity or synergistic cytotoxicity was detected with the combinations of compounds tested. The dual mechanism of action of the pyrimidinediones resulting in inhibition of both virus entry and reverse transcription suggests excellent potential of these lead pyrimidinediones as candidates for combination therapy with other approved HIV inhibitors of varying mechanism of action. Copyright © 2011. Published by Elsevier B.V.

Temporal and spatial dynamics underlying capacitative calcium entry in human colonic smooth muscle.

PubMed

Kovac, Jason R; Chrones, Tom; Sims, Stephen M

2008-01-01

Following smooth muscle excitation and contraction, depletion of intracellular Ca(2+) stores activates capacitative Ca(2+) entry (CCE) to replenish stores and sustain cytoplasmic Ca(2+) (Ca(2+)(i)) elevations. The objectives of the present study were to characterize CCE and the Ca(2+)(i) dynamics underlying human colonic smooth muscle contraction by using tension recordings, fluorescent Ca(2+)-indicator dyes, and patch-clamp electrophysiology. The neurotransmitter acetylcholine (ACh) contracted tissue strips and, in freshly isolated colonic smooth muscle cells (SMCs), caused elevation of Ca(2+)(i) as well as activation of nonselective cation currents. To deplete Ca(2+)(i) stores, the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitors thapsigargin and cyclopiazonic acid were added to a Ca(2+)-free bathing solution. Under these conditions, addition of extracellular Ca(2+) (3 mM) elicited increased tension that was inhibited by the cation channel blockers SKF-96365 (10 microM) and lanthanum (100 microM), suggestive of CCE. In a separate series of experiments on isolated SMCs, SERCA inhibition generated a gradual and sustained inward current. When combined with high-speed Ca(2+)-imaging techniques, the CCE-evoked rise of Ca(2+)(i) was associated with inward currents carrying Ca(2+) that were inhibited by SKF-96365. Regional specializations in Ca(2+) influx and handling during CCE were observed. Distinct "hotspot" regions of Ca(2+) rise and plateau were evident in 70% of cells, a feature not previously recognized in smooth muscle. We propose that store-operated Ca(2+) entry occurs in hotspots contributing to localized Ca(2+) elevations in human colonic smooth muscle.

gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes.

PubMed

Braun, L; Ghebrehiwet, B; Cossart, P

2000-04-03

InlB is a Listeria monocytogenes protein that promotes entry of the bacterium into mammalian cells by stimulating tyrosine phosphorylation of the adaptor proteins Gab1, Cbl and Shc, and activation of phosphatidyl- inositol (PI) 3-kinase. Using affinity chromatography and enzyme-linked immunosorbent assay, we demonstrate a direct interaction between InlB and the mammalian protein gC1q-R, the receptor of the globular part of the complement component C1q. Soluble C1q or anti-gC1q-R antibodies impair InlB-mediated entry. Transient transfection of GPC16 cells, which are non-permissive to InlB-mediated entry, with a plasmid-expressing human gC1q-R promotes entry of InlB-coated beads. Furthermore, several experiments indicate that membrane recruitment and activation of PI 3-kinase involve an InlB-gC1q-R interaction and that gC1q-R associates with Gab1 upon stimulation of Vero cells with InlB. Thus, gC1q-R constitutes a cellular receptor involved in InlB-mediated activation of PI 3-kinase and tyrosine phosphorylation of the adaptor protein Gab1. After E-cadherin, the receptor for internalin, gC1q-R is the second identified mammalian receptor promoting entry of L. monocytogenes into mammalian cells.

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

Yesley, M.S.; Ossorio, P.N.

This report updates and expands the second edition of the ELSI Bibliography, published in 1993. The Bibliography and Supplement provides a comprehensive resource for identifying publications on the major topics related to the ethical, legal and social issues (ELSI) of the Human Genome Project. The Bibliography and Supplement are extracted from a database compiled at Los Alamos National Laboratory with the support of the Office of Energy Research, US Department of Energy. The second edition of the ELSI Bibliography was dated May 1993 but included publications added to the database until fall 1993. This Supplement reflects approximately 1,000 entries addedmore » to the database during the past year, bringing the total to approximately 7,000 entries. More than half of the new entries were published in the last year, and the remainder are earlier publications not previously included in the database. Most of the new entries were published in the academic and professional literature. The remainder are press reports from newspapers of record and scientific journals. The topical listing of the second edition has been followed in the Supplement, with a few changes. The topics of Cystic Fibrosis, Huntington`s Disease, and Sickle Cell Anemia have been combined in a single topic, Disorders. Also, all the entries published in the past year are included in a new topic, Publications: September 1993--September 1994, which provides a comprehensive view of recent reporting and commentary on the science and ELSI of genetics.« less

Metrics for the Human Proteome Project 2016: Progress on Identifying and Characterizing the Human Proteome, Including Post-Translational Modifications.

PubMed

Omenn, Gilbert S; Lane, Lydie; Lundberg, Emma K; Beavis, Ronald C; Overall, Christopher M; Deutsch, Eric W

2016-11-04

The HUPO Human Proteome Project (HPP) has two overall goals: (1) stepwise completion of the protein parts list-the draft human proteome including confidently identifying and characterizing at least one protein product from each protein-coding gene, with increasing emphasis on sequence variants, post-translational modifications (PTMs), and splice isoforms of those proteins; and (2) making proteomics an integrated counterpart to genomics throughout the biomedical and life sciences community. PeptideAtlas and GPMDB reanalyze all major human mass spectrometry data sets available through ProteomeXchange with standardized protocols and stringent quality filters; neXtProt curates and integrates mass spectrometry and other findings to present the most up to date authorative compendium of the human proteome. The HPP Guidelines for Mass Spectrometry Data Interpretation version 2.1 were applied to manuscripts submitted for this 2016 C-HPP-led special issue [ www.thehpp.org/guidelines ]. The Human Proteome presented as neXtProt version 2016-02 has 16,518 confident protein identifications (Protein Existence [PE] Level 1), up from 13,664 at 2012-12, 15,646 at 2013-09, and 16,491 at 2014-10. There are 485 proteins that would have been PE1 under the Guidelines v1.0 from 2012 but now have insufficient evidence due to the agreed-upon more stringent Guidelines v2.0 to reduce false positives. neXtProt and PeptideAtlas now both require two non-nested, uniquely mapping (proteotypic) peptides of at least 9 aa in length. There are 2,949 missing proteins (PE2+3+4) as the baseline for submissions for this fourth annual C-HPP special issue of Journal of Proteome Research. PeptideAtlas has 14,629 canonical (plus 1187 uncertain and 1755 redundant) entries. GPMDB has 16,190 EC4 entries, and the Human Protein Atlas has 10,475 entries with supportive evidence. neXtProt, PeptideAtlas, and GPMDB are rich resources of information about post-translational modifications (PTMs), single amino acid variants (SAAVSs), and splice isoforms. Meanwhile, the Biology- and Disease-driven (B/D)-HPP has created comprehensive SRM resources, generated popular protein lists to guide targeted proteomics assays for specific diseases, and launched an Early Career Researchers initiative.

Partner's Resources and Adjusting Working Hours in the Netherlands: Differences over Time, between Levels of Human Capital, and over the Family Cycle

ERIC Educational Resources Information Center

Verbakel, Ellen

2010-01-01

We study to what extent adjustments in labor market participation, defined as employment entry and exit, and as increases and reductions of weekly working hours, depend on resources of the partner. Moreover, we investigate whether the influence of the partner depends on historical period, human capital, and children. We are especially interested…

A Dual Role for the Nonreceptor Tyrosine Kinase Pyk2 during the Intracellular Trafficking of Human Papillomavirus 16.

PubMed

Gottschalk, Elinor Y; Meneses, Patricio I

2015-09-01

The infectious process of human papillomaviruses (HPVs) has been studied considerably, and many cellular components required for viral entry and trafficking continue to be revealed. In this study, we investigated the role of the nonreceptor tyrosine kinase Pyk2 during HPV16 pseudovirion infection of human keratinocytes. We found that Pyk2 is necessary for infection and appears to be involved in the intracellular trafficking of the virus. Small interfering RNA-mediated reduction of Pyk2 resulted in a significant decrease in infection but did not prevent viral entry at the plasma membrane. Pyk2 depletion resulted in altered endolysosomal trafficking of HPV16 and accelerated unfolding of the viral capsid. Furthermore, we observed retention of the HPV16 pseudogenome in the trans-Golgi network (TGN) in Pyk2-depleted cells, suggesting that the kinase could be required for the viral DNA to exit the TGN. While Pyk2 has previously been shown to function during the entry of enveloped viruses at the plasma membrane, the kinase has not yet been implicated in the intracellular trafficking of a nonenveloped virus such as HPV. Additionally, these data enrich the current literature on Pyk2's function in human keratinocytes. In this study, we investigated the role of the nonreceptor tyrosine kinase Pyk2 during human papillomavirus (HPV) infection of human skin cells. Infections with high-risk types of HPV such as HPV16 are the leading cause of cervical cancer and a major cause of genital and oropharyngeal cancer. As a nonenveloped virus, HPV enters cells by interacting with cellular receptors and established cellular trafficking routes to ensure that the viral DNA reaches the nucleus for productive infection. This study identified Pyk2 as a cellular component required for the intracellular trafficking of HPV16 during infection. Understanding the infectious pathways of HPVs is critical for developing additional preventive therapies. Furthermore, this study advances our knowledge of intracellular trafficking processes in keratinocytes. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Single-pilot workload management in entry-level jets.

DOT National Transportation Integrated Search

2013-09-01

Researchers from the NASA Ames Flight Cognition Lab and the FAAs Flight Deck Human Factors Research Laboratory at the Civil Aerospace Medical Institute (CAMI) examined task and workload management by single pilots in Very Light Jets (VLJs), also c...

KENNEDY SPACE CENTER, FLA. - Nine-year-old Sofi Collis is introduced to the media at a press conference. The Siberian-born Arizona resident wrote the winning entry in the Name the Rovers Contest sponsored by NASA and the Lego Co., a Denmark-based toymaker, with collaboration from the Planetary Society, Pasadena, Calif. The names she selected for the Mars Exploration Rovers are "Spirit" and "Opportunity." The third grader's essay was chosen from more than 10,000 American student entries. NASA's twin Mars Exploration Rovers are designed to study the history of water on Mars. These robotic geologists are equipped with a robotic arm, a drilling tool, three spectrometers, and four pairs of cameras that allow them to have a human-like, 3D view of the terrain. Each rover could travel as far as 100 meters in one day to act as Mars scientists' eyes and hands, exploring an environment where humans are not yet able to go. MER-A, with the rover Spirit aboard, is scheduled to launch on June 8 at 2:06 p.m. EDT, with two launch opportunities each day during a launch period that closes on June 24.

NASA Image and Video Library

2003-06-08

KENNEDY SPACE CENTER, FLA. - Nine-year-old Sofi Collis is introduced to the media at a press conference. The Siberian-born Arizona resident wrote the winning entry in the Name the Rovers Contest sponsored by NASA and the Lego Co., a Denmark-based toymaker, with collaboration from the Planetary Society, Pasadena, Calif. The names she selected for the Mars Exploration Rovers are "Spirit" and "Opportunity." The third grader's essay was chosen from more than 10,000 American student entries. NASA's twin Mars Exploration Rovers are designed to study the history of water on Mars. These robotic geologists are equipped with a robotic arm, a drilling tool, three spectrometers, and four pairs of cameras that allow them to have a human-like, 3D view of the terrain. Each rover could travel as far as 100 meters in one day to act as Mars scientists' eyes and hands, exploring an environment where humans are not yet able to go. MER-A, with the rover Spirit aboard, is scheduled to launch on June 8 at 2:06 p.m. EDT, with two launch opportunities each day during a launch period that closes on June 24.

KENNEDY SPACE CENTER, FLA. - Nine-year-old Sofi Collis (left) shares a light moment with NASA Administrator Sean O'Keefe at a press conference. The Siberian-born Arizona resident wrote the winning entry in the Name the Rovers Contest sponsored by NASA and the Lego Co., a Denmark-based toymaker, with collaboration from the Planetary Society, Pasadena, Calif. The names she selected for the Mars Exploration Rovers are "Spirit" and "Opportunity." The third grader's essay was chosen from more than 10,000 American student entries. NASA's twin Mars Exploration Rovers are designed to study the history of water on Mars. These robotic geologists are equipped with a robotic arm, a drilling tool, three spectrometers, and four pairs of cameras that allow them to have a human-like, 3D view of the terrain. Each rover could travel as far as 100 meters in one day to act as Mars scientists' eyes and hands, exploring an environment where humans are not yet able to go. MER-A, with the rover Spirit aboard, is scheduled to launch on June 8 at 2:06 p.m. EDT, with two launch opportunities each day during a launch period that closes on June 24.

NASA Image and Video Library

2003-06-08

KENNEDY SPACE CENTER, FLA. - Nine-year-old Sofi Collis (left) shares a light moment with NASA Administrator Sean O'Keefe at a press conference. The Siberian-born Arizona resident wrote the winning entry in the Name the Rovers Contest sponsored by NASA and the Lego Co., a Denmark-based toymaker, with collaboration from the Planetary Society, Pasadena, Calif. The names she selected for the Mars Exploration Rovers are "Spirit" and "Opportunity." The third grader's essay was chosen from more than 10,000 American student entries. NASA's twin Mars Exploration Rovers are designed to study the history of water on Mars. These robotic geologists are equipped with a robotic arm, a drilling tool, three spectrometers, and four pairs of cameras that allow them to have a human-like, 3D view of the terrain. Each rover could travel as far as 100 meters in one day to act as Mars scientists' eyes and hands, exploring an environment where humans are not yet able to go. MER-A, with the rover Spirit aboard, is scheduled to launch on June 8 at 2:06 p.m. EDT, with two launch opportunities each day during a launch period that closes on June 24.

KENNEDY SPACE CENTER, FLA. - Nine-year-old Sofi Collis (left) is introduced to the media by NASA Administrator Sean O'Keefe at a press conference. The Siberian-born Arizona resident wrote the winning entry in the Name the Rovers Contest sponsored by NASA and the Lego Co., a Denmark-based toymaker, with collaboration from the Planetary Society, Pasadena, Calif. The names she selected for the Mars Exploration Rovers are "Spirit" and "Opportunity." The third grader's essay was chosen from more than 10,000 American student entries. NASA's twin Mars Exploration Rovers are designed to study the history of water on Mars. These robotic geologists are equipped with a robotic arm, a drilling tool, three spectrometers, and four pairs of cameras that allow them to have a human-like, 3D view of the terrain. Each rover could travel as far as 100 meters in one day to act as Mars scientists' eyes and hands, exploring an environment where humans are not yet able to go. MER-A, with the rover Spirit aboard, is scheduled to launch on June 8 at 2:06 p.m. EDT, with two launch opportunities each day during a launch period that closes on June 24.

NASA Image and Video Library

2003-06-08

KENNEDY SPACE CENTER, FLA. - Nine-year-old Sofi Collis (left) is introduced to the media by NASA Administrator Sean O'Keefe at a press conference. The Siberian-born Arizona resident wrote the winning entry in the Name the Rovers Contest sponsored by NASA and the Lego Co., a Denmark-based toymaker, with collaboration from the Planetary Society, Pasadena, Calif. The names she selected for the Mars Exploration Rovers are "Spirit" and "Opportunity." The third grader's essay was chosen from more than 10,000 American student entries. NASA's twin Mars Exploration Rovers are designed to study the history of water on Mars. These robotic geologists are equipped with a robotic arm, a drilling tool, three spectrometers, and four pairs of cameras that allow them to have a human-like, 3D view of the terrain. Each rover could travel as far as 100 meters in one day to act as Mars scientists' eyes and hands, exploring an environment where humans are not yet able to go. MER-A, with the rover Spirit aboard, is scheduled to launch on June 8 at 2:06 p.m. EDT, with two launch opportunities each day during a launch period that closes on June 24.

Child Labor and Environmental Health: Government Obligations and Human Rights

PubMed Central

Amon, Joseph J.; Buchanan, Jane; Cohen, Jane; Kippenberg, Juliane

2012-01-01

The Convention concerning the Prohibition and Immediate Action for the Elimination of the Worst Forms of Child Labour was adopted by the International Labour Organization in 1999. 174 countries around the world have signed or ratified the convention, which requires countries to adopt laws and implement programs to prohibit and eliminate child labor that poses harms to health or safety. Nonetheless, child labor continues to be common in the agriculture and mining sectors, where safety and environmental hazards pose significant risks. Drawing upon recent human rights investigations of child labor in tobacco farming in Kazakhstan and gold mining in Mali, the role of international human rights mechanisms, advocacy with government and private sector officials, and media attention in reducing harmful environmental exposures of child workers is discussed. Human rights-based advocacy in both cases was important to raise attention and help ensure that children are protected from harm. PMID:23316246

A sticky situation: the unexpected stability of malaria elimination

PubMed Central

Smith, David L.; Cohen, Justin M.; Chiyaka, Christinah; Johnston, Geoffrey; Gething, Peter W.; Gosling, Roly; Buckee, Caroline O.; Laxminarayan, Ramanan; Hay, Simon I.; Tatem, Andrew J.

2013-01-01

Malaria eradication involves eliminating malaria from every country where transmission occurs. Current theory suggests that the post-elimination challenges of remaining malaria-free by stopping transmission from imported malaria will have onerous operational and financial requirements. Although resurgent malaria has occurred in a majority of countries that tried but failed to eliminate malaria, a review of resurgence in countries that successfully eliminated finds only four such failures out of 50 successful programmes. Data documenting malaria importation and onwards transmission in these countries suggests malaria transmission potential has declined by more than 50-fold (i.e. more than 98%) since before elimination. These outcomes suggest that elimination is a surprisingly stable state. Elimination's ‘stickiness’ must be explained either by eliminating countries starting off qualitatively different from non-eliminating countries or becoming different once elimination was achieved. Countries that successfully eliminated were wealthier and had lower baseline endemicity than those that were unsuccessful, but our analysis shows that those same variables were at best incomplete predictors of the patterns of resurgence. Stability is reinforced by the loss of immunity to disease and by the health system's increasing capacity to control malaria transmission after elimination through routine treatment of cases with antimalarial drugs supplemented by malaria outbreak control. Human travel patterns reinforce these patterns; as malaria recedes, fewer people carry malaria from remote endemic areas to remote areas where transmission potential remains high. Establishment of an international resource with backup capacity to control large outbreaks can make elimination stickier, increase the incentives for countries to eliminate, and ensure steady progress towards global eradication. Although available evidence supports malaria elimination's stickiness at moderate-to-low transmission in areas with well-developed health systems, it is not yet clear if such patterns will hold in all areas. The sticky endpoint changes the projected costs of maintaining elimination and makes it substantially more attractive for countries acting alone, and it makes spatially progressive elimination a sensible strategy for a malaria eradication endgame. PMID:23798693

Envelope conformational changes induced by human immunodeficiency virus type 1 attachment inhibitors prevent CD4 binding and downstream entry events.

PubMed

Ho, Hsu-Tso; Fan, Li; Nowicka-Sans, Beata; McAuliffe, Brian; Li, Chang-Ben; Yamanaka, Gregory; Zhou, Nannan; Fang, Hua; Dicker, Ira; Dalterio, Richard; Gong, Yi-Fei; Wang, Tao; Yin, Zhiwei; Ueda, Yasutsugu; Matiskella, John; Kadow, John; Clapham, Paul; Robinson, James; Colonno, Richard; Lin, Pin-Fang

2006-04-01

BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1) CD4 attachment inhibitor with demonstrated clinical efficacy. The compound inhibits soluble CD4 (sCD4) binding to the 11 distinct HIV envelope gp120 proteins surveyed. Binding of BMS-488043 and that of sCD4 to gp120 are mutually exclusive, since increased concentrations of one can completely block the binding of the other without affecting the maximal gp120 binding capacity. Similarly, BMS-488043 inhibited virion envelope trimers from binding to sCD4-immunoglobulin G (IgG), with decreasing inhibition as the sCD4-IgG concentration increased, and BMS-488043 blocked the sCD4-induced exposure of the gp41 groove in virions. In both virion binding assays, BMS-488043 was active only when added prior to sCD4. Collectively, these results indicate that obstruction of gp120-sCD4 interactions is the primary inhibition mechanism of this compound and that compound interaction with envelope must precede CD4 binding. By three independent approaches, BMS-488043 was further shown to induce conformational changes within gp120 in both the CD4 and CCR5 binding regions. These changes likely prevent gp120-CD4 interactions and downstream entry events. However, BMS-488043 could only partially inhibit CD4 binding to an HIV variant containing a specific envelope truncation and altered gp120 conformation, despite effectively inhibiting the pseudotyped virus infection. Taken together, BMS-488043 inhibits viral entry primarily through altering the envelope conformation and preventing CD4 binding, and other downstream entry events could also be inhibited as a result of these induced conformational changes.

Impact of Virginia's School-Entry Vaccine Mandate on Human Papillomavirus Vaccination Among 13-17-Year-Old Females.

PubMed

Pierre-Victor, Dudith; Page, Timothy F; Trepka, Mary Jo; Stephens, Dionne P; Li, Tan; Madhivanan, Purnima

2017-03-01

The link between human papillomavirus (HPV) and anogenital cancers is well established in the literature. Many states have passed laws requiring funding for HPV education or vaccination. Mandatory HPV vaccination policies have been considered and passed in several states; yet their effectiveness has not been evaluated. This study sought to assess the impact of Virginia's HPV vaccine mandate for school-entry on HPV vaccine uptake among females aged 13-17 years. Data from the National Immunization Survey-Teen for the 2008-2012 period were used, and 3,203 adolescent females were included in the analysis. We performed difference-in-differences estimation and logistic regression with a policy and period interaction term. Virginia was considered the treatment state, and South Carolina and Tennessee were the comparison states to account for nonpolicy factors that may have affected vaccination rates during the time period considered in the analysis. There was no evidence of an effect of Virginia's HPV vaccine mandate for school-entry on vaccination rates or on physician vaccination recommendation using either the difference-by-differences analysis or the policy and period interaction term in the logistic regression. Physician recommendation was the factor most strongly associated with vaccination in the Virginia-South Carolina analysis (adjusted odds ratio [aOR] = 9.33; 95% confidence interval [CI]: 6.11-14.3) and in the Virginia-Tennessee analysis (aOR = 9.33; 95% CI: 6.11-14.3). Study findings suggest that Virginia's HPV vaccine mandate for school-entry did not lead to a significant increase in HPV vaccination among adolescent females or physician recommendations. However, physician recommendation was the factor most strongly associated with vaccination.

Dissociation of a ferric maltol complex and its subsequent metabolism during absorption across the small intestine of the rat.

PubMed Central

Barrand, M. A.; Callingham, B. A.; Dobbin, P.; Hider, R. C.

1991-01-01

1. The fate and disposition of [59Fe]-ferric [3H]-maltol after intravenous administration were investigated in anaesthetized rats. Immediate dissociation of ferric iron from maltol took place in the circulation even with high doses of ferric maltol (containing 1 mg elemental iron). In plasma samples withdrawn within 1 min of injection and subjected to gel filtration, 59Fe eluted with the high molecular weight proteins whilst the tritium was associated with low molecular weight material. 2. The rates of elimination of 59Fe and of tritium from the plasma and their ultimate fate were very different. The half life for 59Fe in the plasma was around 70 min and 59Fe appeared mainly in the bone marrow and liver. There was an initial rapid exit of tritium from the plasma with a half life of around 12 min. This was followed either by a plateau or by a rise in tritium levels, involving entry of maltol metabolites into the circulation. These metabolites could be recovered in the urine. 3. Entry of 59Fe and of tritium into the blood plasma after intraduodenal administration of [59Fe]-ferric [3H]-maltol was also very different. At low doses of ferric maltol (containing 100 micrograms elemental iron), the tritium appeared in the plasma in highest amounts within seconds and then decreased whilst there was a slow rise in 59Fe levels. At higher doses of ferric maltol (containing 7 mg elemental iron), levels of 59Fe in the plasma were highest at 5 min and then fell whereas tritium levels rose steadily. Mucosal processing of 59Fe prevented further entry of iron at high dose into the circulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1364845

Role of Orai1 and store-operated calcium entry in mouse lacrimal gland signalling and function.

PubMed

Xing, Juan; Petranka, John G; Davis, Felicity M; Desai, Pooja N; Putney, James W; Bird, Gary S

2014-03-01

Lacrimal glands function to produce an aqueous layer, or tear film, that helps to nourish and protect the ocular surface. Lacrimal glands secrete proteins, electrolytes and water, and loss of gland function can result in tear film disorders such as dry eye syndrome, a widely encountered and debilitating disease in ageing populations. To combat these disorders, understanding the underlying molecular signalling processes that control lacrimal gland function will give insight into corrective therapeutic approaches. Previously, in single lacrimal cells isolated from lacrimal glands, we demonstrated that muscarinic receptor activation stimulates a phospholipase C-coupled signalling cascade involving the inositol trisphosphate-dependent mobilization of intracellular calcium and the subsequent activation of store-operated calcium entry (SOCE). Since intracellular calcium stores are finite and readily exhausted, the SOCE pathway is a critical process for sustaining and maintaining receptor-activated signalling. Recent studies have identified the Orai family proteins as critical components of the SOCE channel activity in a wide variety of cell types. In this study we characterize the role of Orai1 in the function of lacrimal glands using a mouse model in which the gene for the calcium entry channel protein, Orai1, has been deleted. Our data demonstrate that lacrimal acinar cells lacking Orai1 do not exhibit SOCE following activation of the muscarinic receptor. In comparison with wild-type and heterozygous littermates, Orai1 knockout mice showed a significant reduction in the stimulated tear production following injection of pilocarpine, a muscarinic receptor agonist. In addition, calcium-dependent, but not calcium-independent exocytotic secretion of peroxidase was eliminated in glands from knockout mice. These studies indicate a critical role for Orai1-mediated SOCE in lacrimal gland signalling and function.

Enhanced store-operated Ca2+ influx and ORAI1 expression in ventricular fibroblasts from human failing heart

PubMed Central

Ross, Gracious R.; Bajwa, Tanvir; Edwards, Stacie; Emelyanova, Larisa; Rizvi, Farhan; Holmuhamedov, Ekhson L.; Werner, Paul; Downey, Francis X.; Tajik, A. Jamil

2017-01-01

ABSTRACT Excessive cardiac fibrosis, characterized by increased collagen-rich extracellular matrix (ECM) deposition, is a major predisposing factor for mechanical and electrical dysfunction in heart failure (HF). The human ventricular fibroblast (hVF) remodeling mechanisms that cause excessive collagen deposition in HF are unclear, although reports suggest a role for intracellular free Ca2+ in fibrosis. Therefore, we determined the association of differences in cellular Ca2+ dynamics and collagen secretion/deposition between hVFs from failing and normal (control) hearts. Histology of left ventricle sections (Masson trichrome) confirmed excessive fibrosis in HF versus normal. In vitro, hVFs from HF showed increased secretion/deposition of soluble collagen in 48 h of culture compared with control [85.9±7.4 µg/106 cells vs 58.5±8.8 µg/106 cells, P<0.05; (Sircol™ assay)]. However, collagen gene expressions (COL1A1 and COL1A2; RT-PCR) were not different. Ca2+ imaging (fluo-3) of isolated hVFs showed no difference in the thapsigargin-induced intracellular Ca2+ release capacity (control 16±1.4% vs HF 17±1.1%); however, Ca2+ influx via store-operated Ca2+ entry/Ca2+ release-activated channels (SOCE/CRAC) was significantly (P≤0.05) greater in HF-hVFs (47±3%) compared with non-failing (35±5%). Immunoblotting for ICRAC channel components showed increased ORAI1 expression in HF-hVFs compared with normal without any difference in STIM1 expression. The Pearson's correlation coefficient for co-localization of STIM1/ORAI1 was significantly (P<0.01) greater in HF (0.5±0.01) than control (0.4±0.01) hVFs. The increase in collagen secretion of HF versus control hVFs was eliminated by incubation of hVFs with YM58483 (10 µM), a selective ICRAC inhibitor, for 48 h (66.78±5.87 µg/106 cells vs 55.81±7.09 µg/106 cells, P=0.27). In conclusion, hVFs from HF have increased collagen secretion capacity versus non-failing hearts and this is related to increase in Ca2+ entry via SOCE and enhanced expression of ORAI, the pore-forming subunit. Therapeutic inhibition of SOCE may reduce the progression of cardiac fibrosis/HF. PMID:28126709

Is the Elimination of Recess in School a Violation of a Child's Basic Human Rights?

ERIC Educational Resources Information Center

Dubroc, Alicia M.

2007-01-01

The elimination of recess in schools across the country is becoming a normal occurrence in many communities, large and small. In each study presented in this content analysis, we find that free time and unstructured play is indeed essential to a child's healthy cognitive development. Article 31 of the United Nations Convention on the Rights of…

A critical review on the survival and elimination of norovirus in food and on food contact surfaces

USDA-ARS?s Scientific Manuscript database

This critical review covers the survival of human norovirus (NoV) in foods and on food contact surfaces as well as the state-of-the-art on the effectiveness of methods to eliminate these viruses. Virus survival studies are reviewed for water, soils and organic wastes, on fomites, hands, fruits and v...

Challenges and needs for China to eliminate rabies.

PubMed

Yin, Wenwu; Dong, Jie; Tu, Changchun; Edwards, John; Guo, Fusheng; Zhou, Hang; Yu, Hongjie; Vong, Sirenda

2013-10-02

In China, rabies is a significant public health concern where dogs remain the main reservoir of disease transmission to humans; rabies-related mortality ranks second in the world.We compiled all published articles and official documents on rabies in mainland China to examine challenges and needs to eliminate rabies in the country. The Chinese authorities have identified rabies as a priority, recognized rabies control in dogs as key to control rabies in humans and required intersectoral collaborations. Efforts have been made to respond effectively to the latest re-emergence of rabies, which peaked in 2007 with >3,300 cases. Despite these outcomes and the increasing volume of publications and regulations in the recent years, our review points to some major information gaps to improve rabies control activities and envisage elimination program. An emphasis on laboratory or pathogen-associated and basic epidemiology research in the literature has contrasted with the absence of information to monitor various systems in humans and animals (e.g. quality of surveillance, response and post-exposure prophylaxis). Information is also lacking to appropriately inform policymakers (e.g. economic disease burden, impact of policies) and assist program managers (e.g. comprehensive and strategic guidance for cost-effective prevention and control activities, public education and dog population management).In conclusion, strategic planning is needed to provide a sense of direction, demonstrate feasibility of elimination in China, and develop a research agenda, addressing country's operational needs and constraints. The planning should be a multisectoral effort.

Challenges and needs for China to eliminate rabies

PubMed Central

2013-01-01

In China, rabies is a significant public health concern where dogs remain the main reservoir of disease transmission to humans; rabies-related mortality ranks second in the world. We compiled all published articles and official documents on rabies in mainland China to examine challenges and needs to eliminate rabies in the country. The Chinese authorities have identified rabies as a priority, recognized rabies control in dogs as key to control rabies in humans and required intersectoral collaborations. Efforts have been made to respond effectively to the latest re-emergence of rabies, which peaked in 2007 with >3,300 cases. Despite these outcomes and the increasing volume of publications and regulations in the recent years, our review points to some major information gaps to improve rabies control activities and envisage elimination program. An emphasis on laboratory or pathogen-associated and basic epidemiology research in the literature has contrasted with the absence of information to monitor various systems in humans and animals (e.g. quality of surveillance, response and post-exposure prophylaxis). Information is also lacking to appropriately inform policymakers (e.g. economic disease burden, impact of policies) and assist program managers (e.g. comprehensive and strategic guidance for cost-effective prevention and control activities, public education and dog population management). In conclusion, strategic planning is needed to provide a sense of direction, demonstrate feasibility of elimination in China, and develop a research agenda, addressing country’s operational needs and constraints. The planning should be a multisectoral effort. PMID:24088366

Bone Metabolism of the Patient with a Malignant Melanoma during the Entry Examination and the Check-up of Whole-body Bone Scintigraphy.

PubMed

Weissensteiner, Jaroslav; Babušíková, Eva

Malignant melanoma is a malignancy located predominantly in the skin and the incidence of melanoma increases. We compared the markers of bone metabolism - osteocalcin (OC), beta-carboxyterminal cross-linked telopeptide of type I collagen (β-CrossLaps, β-CTx) and tumour marker - human epididymis protein 4 (HE4) in the serum with finding during the entry examination and the check-up of whole-body bone scintigraphy of the patient with a malignant melanoma. Serum concentrations of OC, β-CTx, HE4 were determined in 1 patient (female, age 64 years) with malignant melanoma and correlated with the presence of equivocal bone metastases detected by whole-body bone scintigraphy (the entry examination and check-up after 6 months). Concentrations of bone metabolism markers decreased during six months and we observed progress in bone metastases. The change of the markers levels during the entry examination and the check-up of the whole-body bone scintigraphy with equivocal finding of bone metastases could be a sign of a possible initiating progression of malignant melanoma despite a clinically negative finding that does not prove the progression of the disease.

Platelet activation suppresses HIV-1 infection of T cells

PubMed Central

2013-01-01

Background Platelets, anucleate cell fragments abundant in human blood, can capture HIV-1 and platelet counts have been associated with viral load and disease progression. However, the impact of platelets on HIV-1 infection of T cells is unclear. Results We found that platelets suppress HIV-1 spread in co-cultured T cells in a concentration-dependent manner. Platelets containing granules inhibited HIV-1 spread in T cells more efficiently than degranulated platelets, indicating that the granule content might exert antiviral activity. Indeed, supernatants from activated and thus degranulated platelets suppressed HIV-1 infection. Infection was inhibited at the stage of host cell entry and inhibition was independent of the viral strain or coreceptor tropism. In contrast, blockade of HIV-2 and SIV entry was less efficient. The chemokine CXCL4, a major component of platelet granules, blocked HIV-1 entry and neutralization of CXCL4 in platelet supernatants largely abrogated their anti-HIV-1 activity. Conclusions Release of CXCL4 by activated platelets inhibits HIV-1 infection of adjacent T cells at the stage of virus entry. The inhibitory activity of platelet-derived CXCL4 suggests a role of platelets in the defense against infection by HIV-1 and potentially other pathogens. PMID:23634812

Platelet activation suppresses HIV-1 infection of T cells.

PubMed

Solomon Tsegaye, Theodros; Gnirß, Kerstin; Rahe-Meyer, Niels; Kiene, Miriam; Krämer-Kühl, Annika; Behrens, Georg; Münch, Jan; Pöhlmann, Stefan

2013-05-01

Platelets, anucleate cell fragments abundant in human blood, can capture HIV-1 and platelet counts have been associated with viral load and disease progression. However, the impact of platelets on HIV-1 infection of T cells is unclear. We found that platelets suppress HIV-1 spread in co-cultured T cells in a concentration-dependent manner. Platelets containing granules inhibited HIV-1 spread in T cells more efficiently than degranulated platelets, indicating that the granule content might exert antiviral activity. Indeed, supernatants from activated and thus degranulated platelets suppressed HIV-1 infection. Infection was inhibited at the stage of host cell entry and inhibition was independent of the viral strain or coreceptor tropism. In contrast, blockade of HIV-2 and SIV entry was less efficient. The chemokine CXCL4, a major component of platelet granules, blocked HIV-1 entry and neutralization of CXCL4 in platelet supernatants largely abrogated their anti-HIV-1 activity. Release of CXCL4 by activated platelets inhibits HIV-1 infection of adjacent T cells at the stage of virus entry. The inhibitory activity of platelet-derived CXCL4 suggests a role of platelets in the defense against infection by HIV-1 and potentially other pathogens.

Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors.

PubMed

Wu, Chien-Huang; Wang, Chuan-Jen; Chang, Chun-Ping; Cheng, Yung-Chi; Song, Jen-Shin; Jan, Jiing-Jyh; Chou, Ming-Chen; Ke, Yi-Yu; Ma, Jing; Wong, Ying-Chieh; Hsieh, Tsung-Chih; Tien, Yun-Chen; Gullen, Elizabeth A; Lo, Chen-Fu; Cheng, Chia-Yi; Liu, Yu-Wei; Sadani, Amit A; Tsai, Chia-Hua; Hsieh, Hsin-Pang; Tsou, Lun K; Shia, Kak-Shan

2015-02-12

Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound 24 complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound 24 showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4(+)/CD34(+) stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function.

Parametric entry corridors for lunar/Mars aerocapture missions

NASA Technical Reports Server (NTRS)

Ling, Lisa M.; Baseggio, Franco M.; Fuhry, Douglas P.

1991-01-01

Parametric atmospheric entry corridor data are presented for Earth and Mars aerocapture. Parameter ranges were dictated by the range of mission designs currently envisioned as possibilities for the Human Exploration Initiative (HEI). This data, while not providing a means for exhaustive evaluation of aerocapture performance, should prove to be a useful aid for preliminary mission design and evaluation. Entry corridors are expressed as ranges of allowable vacuum periapse altitude of the planetary approach hyperbolic orbit, with chart provided for conversion to an approximate flight path angle corridor at entry interface (125 km altitude). The corridor boundaries are defined by open-loop aerocapture trajectories which satisfy boundary constraints while utilizing the full aerodynamic control capability of the vehicle (i.e., full lift-up or full lift-down). Parameters examined were limited to those of greatest importance from an aerocapture performance standpoint, including the approach orbit hyperbolic excess velocity, the vehicle lift to drag ratio, maximum aerodynamic load factor limit, and the apoapse of the target orbit. The impact of the atmospheric density bias uncertainties are also included. The corridor data is presented in graphical format, and examples of the utilization of these graphs for mission design and evaluation are included.

Identification of a D-amino acid decapeptide HIV-1 entry inhibitor

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

Boggiano, Cesar; Jiang Shibo; Lu Hong

2006-09-08

Entry of human immunodeficiency virus type 1 (HIV-1) virion into host cells involves three major steps, each being a potential target for the development of entry inhibitors: gp120 binding to CD4, gp120-CD4 complex interacting with a coreceptor, and gp41 refolding to form a six-helix bundle. Using a D-amino acid decapeptide combinatorial library, we identified peptide DC13 as having potent HIV-1 fusion inhibitory activity, and effectively inhibiting infection by several laboratory-adapted and primary HIV-1 strains. While DC13 did not block binding of gp120 to CD4, nor disrupt the gp41 six-helix bundle formation, it effectively blocked the binding of an anti-CXCR4 monoclonalmore » antibody and chemokine SDF-1{alpha} to CXCR4-expressing cells. However, because R5-using primary viruses were also neutralized, the antiviral activity of DC13 implies additional mode(s) of action. These results suggest that DC13 is a useful HIV-1 coreceptor antagonist for CXCR4 and, due to its biostability and simplicity, may be of value for developing a new class of HIV-1 entry inhibitors.« less

Nonnative forest insects and pathogens in the United States: Impacts and policy options.

PubMed

Lovett, Gary M; Weiss, Marissa; Liebhold, Andrew M; Holmes, Thomas P; Leung, Brian; Lambert, Kathy Fallon; Orwig, David A; Campbell, Faith T; Rosenthal, Jonathan; McCullough, Deborah G; Wildova, Radka; Ayres, Matthew P; Canham, Charles D; Foster, David R; LaDeau, Shannon L; Weldy, Troy

2016-07-01

We review and synthesize information on invasions of nonnative forest insects and diseases in the United States, including their ecological and economic impacts, pathways of arrival, distribution within the United States, and policy options for reducing future invasions. Nonnative insects have accumulated in United States forests at a rate of ~2.5 per yr over the last 150 yr. Currently the two major pathways of introduction are importation of live plants and wood packing material such as pallets and crates. Introduced insects and diseases occur in forests and cities throughout the United States, and the problem is particularly severe in the Northeast and Upper Midwest. Nonnative forest pests are the only disturbance agent that has effectively eliminated entire tree species or genera from United States forests within decades. The resulting shift in forest structure and species composition alters ecosystem functions such as productivity, nutrient cycling, and wildlife habitat. In urban and suburban areas, loss of trees from streets, yards, and parks affects aesthetics, property values, shading, stormwater runoff, and human health. The economic damage from nonnative pests is not yet fully known, but is likely in the billions of dollars per year, with the majority of this economic burden borne by municipalities and residential property owners. Current policies for preventing introductions are having positive effects but are insufficient to reduce the influx of pests in the face of burgeoning global trade. Options are available to strengthen the defenses against pest arrival and establishment, including measures taken in the exporting country prior to shipment, measures to ensure clean shipments of plants and wood products, inspections at ports of entry, and post-entry measures such as quarantines, surveillance, and eradication programs. Improved data collection procedures for inspections, greater data accessibility, and better reporting would support better evaluation of policy effectiveness. Lack of additional action places the nation, local municipalities, and property owners at high risk of further damaging and costly invasions. Adopting stronger policies to reduce establishments of new forest insects and diseases would shift the major costs of control to the source and alleviate the economic burden now borne by homeowners and municipalities. © 2016 by the Ecological Society of America.

HPVdb: a data mining system for knowledge discovery in human papillomavirus with applications in T cell immunology and vaccinology

PubMed Central

Zhang, Guang Lan; Riemer, Angelika B.; Keskin, Derin B.; Chitkushev, Lou; Reinherz, Ellis L.; Brusic, Vladimir

2014-01-01

High-risk human papillomaviruses (HPVs) are the causes of many cancers, including cervical, anal, vulvar, vaginal, penile and oropharyngeal. To facilitate diagnosis, prognosis and characterization of these cancers, it is necessary to make full use of the immunological data on HPV available through publications, technical reports and databases. These data vary in granularity, quality and complexity. The extraction of knowledge from the vast amount of immunological data using data mining techniques remains a challenging task. To support integration of data and knowledge in virology and vaccinology, we developed a framework called KB-builder to streamline the development and deployment of web-accessible immunological knowledge systems. The framework consists of seven major functional modules, each facilitating a specific aspect of the knowledgebase construction process. Using KB-builder, we constructed the Human Papillomavirus T cell Antigen Database (HPVdb). It contains 2781 curated antigen entries of antigenic proteins derived from 18 genotypes of high-risk HPV and 18 genotypes of low-risk HPV. The HPVdb also catalogs 191 verified T cell epitopes and 45 verified human leukocyte antigen (HLA) ligands. Primary amino acid sequences of HPV antigens were collected and annotated from the UniProtKB. T cell epitopes and HLA ligands were collected from data mining of scientific literature and databases. The data were subject to extensive quality control (redundancy elimination, error detection and vocabulary consolidation). A set of computational tools for an in-depth analysis, such as sequence comparison using BLAST search, multiple alignments of antigens, classification of HPV types based on cancer risk, T cell epitope/HLA ligand visualization, T cell epitope/HLA ligand conservation analysis and sequence variability analysis, has been integrated within the HPVdb. Predicted Class I and Class II HLA binding peptides for 15 common HLA alleles are included in this database as putative targets. HPVdb is a knowledge-based system that integrates curated data and information with tailored analysis tools to facilitate data mining for HPV vaccinology and immunology. To our best knowledge, HPVdb is a unique data source providing a comprehensive list of HPV antigens and peptides. Database URL: http://cvc.dfci.harvard.edu/hpv/ PMID:24705205

HPVdb: a data mining system for knowledge discovery in human papillomavirus with applications in T cell immunology and vaccinology.

PubMed

Zhang, Guang Lan; Riemer, Angelika B; Keskin, Derin B; Chitkushev, Lou; Reinherz, Ellis L; Brusic, Vladimir

2014-01-01

High-risk human papillomaviruses (HPVs) are the causes of many cancers, including cervical, anal, vulvar, vaginal, penile and oropharyngeal. To facilitate diagnosis, prognosis and characterization of these cancers, it is necessary to make full use of the immunological data on HPV available through publications, technical reports and databases. These data vary in granularity, quality and complexity. The extraction of knowledge from the vast amount of immunological data using data mining techniques remains a challenging task. To support integration of data and knowledge in virology and vaccinology, we developed a framework called KB-builder to streamline the development and deployment of web-accessible immunological knowledge systems. The framework consists of seven major functional modules, each facilitating a specific aspect of the knowledgebase construction process. Using KB-builder, we constructed the Human Papillomavirus T cell Antigen Database (HPVdb). It contains 2781 curated antigen entries of antigenic proteins derived from 18 genotypes of high-risk HPV and 18 genotypes of low-risk HPV. The HPVdb also catalogs 191 verified T cell epitopes and 45 verified human leukocyte antigen (HLA) ligands. Primary amino acid sequences of HPV antigens were collected and annotated from the UniProtKB. T cell epitopes and HLA ligands were collected from data mining of scientific literature and databases. The data were subject to extensive quality control (redundancy elimination, error detection and vocabulary consolidation). A set of computational tools for an in-depth analysis, such as sequence comparison using BLAST search, multiple alignments of antigens, classification of HPV types based on cancer risk, T cell epitope/HLA ligand visualization, T cell epitope/HLA ligand conservation analysis and sequence variability analysis, has been integrated within the HPVdb. Predicted Class I and Class II HLA binding peptides for 15 common HLA alleles are included in this database as putative targets. HPVdb is a knowledge-based system that integrates curated data and information with tailored analysis tools to facilitate data mining for HPV vaccinology and immunology. To our best knowledge, HPVdb is a unique data source providing a comprehensive list of HPV antigens and peptides. Database URL: http://cvc.dfci.harvard.edu/hpv/.

An expanding toolkit for preclinical pre-erythrocytic malaria vaccine development: bridging traditional mouse malaria models and human trials

PubMed Central

Steel, Ryan WJ; Kappe, Stefan HI; Sack, Brandon K

2016-01-01

Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts. PMID:27855488

An expanding toolkit for preclinical pre-erythrocytic malaria vaccine development: bridging traditional mouse malaria models and human trials.

PubMed

Steel, Ryan Wj; Kappe, Stefan Hi; Sack, Brandon K

2016-12-01

Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts.

Analysis of Effectiveness of Phoenix Entry Reaction Control System

NASA Technical Reports Server (NTRS)

Dyakonov, Artem A.; Glass, Christopher E.; Desai, Prasun, N.; VanNorman, John W.

2008-01-01

Interaction between the external flowfield and the reaction control system (RCS) thruster plumes of the Phoenix capsule during entry has been investigated. The analysis covered rarefied, transitional, hypersonic and supersonic flight regimes. Performance of pitch, yaw and roll control authority channels was evaluated, with specific emphasis on the yaw channel due to its low nominal yaw control authority. Because Phoenix had already been constructed and its RCS could not be modified before flight, an assessment of RCS efficacy along the trajectory was needed to determine possible issues and to make necessary software changes. Effectiveness of the system at various regimes was evaluated using a hybrid DSMC-CFD technique, based on DSMC Analysis Code (DAC) code and General Aerodynamic Simulation Program (GASP), the LAURA (Langley Aerothermal Upwind Relaxation Algorithm) code, and the FUN3D (Fully Unstructured 3D) code. Results of the analysis at hypersonic and supersonic conditions suggest a significant aero-RCS interference which reduced the efficacy of the thrusters and could likely produce control reversal. Very little aero-RCS interference was predicted in rarefied and transitional regimes. A recommendation was made to the project to widen controller system deadbands to minimize (if not eliminate) the use of RCS thrusters through hypersonic and supersonic flight regimes, where their performance would be uncertain.

Histopathological changes induced by malathion in the gills of bluegill Lepomis macrochirus

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

Richmonds, C.; Dutta, H.M.

1989-07-01

Malathion is a widely used broad spectrum organophosphorus insecticide. Its wide use provides many occasions for its entry into aquatic environments. The presence of this chemical in the aquatic environment would adversely affect many non-target species like fish. About 50 to 90% of the absorbed malathion can be eliminated in one to three days by the fish. About 25% of malathion remained in river water after 2 wk, and 10% remained after 4 wk from the time of its entry. Respiratory distress is one of the early symptoms of pesticide poisoning. These toxicants appear to cause a loss of adhesionmore » between the epithelial cells and the underlying pillar cell system, accompanied by a collapse of the structural integrity of the secondary lamellae. Gills are important in respiration as well as osmoregulation of the fish. Therefore it was decided to study the effects of malathion on the gills of bluegill sunfish, Lepomis macrochirus. Bluegills were selected for this study due to the following reasons: (1) Bluegills are more sensitive to malathion when compared to fathead minnows and goldfish. (2) They are important both as edible and game fish. (3) They are easily available and easy to maintain in the laboratory.« less

Aerodynamic Characteristics and Control Effectiveness of the HL-20 Lifting Body Configuration at Mach 10 in Air

NASA Technical Reports Server (NTRS)

Scallion, William I.

1999-01-01

A 0.0196-scale model of the HL-20 lifting-body, one of several configurations proposed for future crewed spacecraft, was tested in the Langley 31-Inch Mach 10 Tunnel. The purpose of the tests was to determine the effectiveness of fin-mounted elevons, a lower surface flush-mounted body flap, and a flush-mounted yaw controller at hypersonic speeds. The nominal angle-of-attack range, representative of hypersonic entry, was 2 deg to 41 deg, the sideslip angles were 0 deg, 2 deg, and -2 deg, and the test Reynolds number was 1.06 x 10 E6 based on model reference length. The aerodynamic, longitudinal, and lateral control effectiveness along with surface oil flow visualizations are presented and discussed. The configuration was longitudinally and laterally stable at the nominal center of gravity. The primary longitudinal control, the fin-mounted elevons, could not trim the model to the desired entry angle of attack of 30 deg. The lower surface body flaps were effective for roll control and the associated adverse yawing moment was eliminated by skewing the body flap hinge lines. A yaw controller, flush-mounted on the lower surface, was also effective, and the associated small rolling moment was favorable.