Rejuvenation of Human Cardiac Progenitor Cells With Pim-1 Kinase

PubMed Central

Mohsin, Sadia; Khan, Mohsin; Nguyen, Jonathan; Alkatib, Monique; Siddiqi, Sailay; Hariharan, Nirmala; Wallach, Kathleen; Monsanto, Megan; Gude, Natalie; Dembitsky, Walter; Sussman, Mark A.

2014-01-01

Rationale Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPCs) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in patients with heart failure constrain the proliferation, survival, and regenerative capacity of hCPCs. Rejuvenation of senescent hCPCs will improve the outcome of regenerative therapy for a substantial patient population possessing functionally impaired stem cells. Objective Reverse phenotypic and functional senescence of hCPCs by ex vivo modification with Pim-1. Methods and Results C-kit–positive hCPCs were isolated from heart biopsy samples of patients undergoing left ventricular assist device implantation. Growth kinetics, telomere lengths, and expression of cell cycle regulators showed significant variation between hCPC isolated from multiple patients. Telomere length was significantly decreased in hCPC with slow-growth kinetics concomitant with decreased proliferation and upregulation of senescent markers compared with hCPC with fast-growth kinetics. Desirable youthful characteristics were conferred on hCPCs by genetic modification using Pim-1 kinase, including increases in proliferation, telomere length, survival, and decreased expression of senescence markers. Conclusions Senescence characteristics of hCPCs are ameliorated by Pim-1 kinase resulting in rejuvenation of phenotypic and functional properties. hCPCs show improved cellular properties resulting from Pim-1 modification, but benefits were more pronounced in hCPC with slow-growth kinetics relative to hCPC with fast-growth kinetics. With the majority of patients with heart failure presenting advanced age, infirmity, and impaired regenerative capacity, the use of Pim-1 modification should be incorporated into cell-based therapeutic approaches to broaden inclusion criteria and address limitations associated with the senescent phenotype of aged hCPC. PMID:24044948

Cell and gene therapy for severe heart failure patients: The time and place for Pim-1 Kinase

PubMed Central

Siddiqi, Sailay; Sussman, Mark A

2014-01-01

Regenerative therapy in severe heart failure patients presents a challenging set of circumstances including a damaged myocardial environment that accelerates senescence in myocytes and cardiac progenitor cells. Failing myocardium suffers from deterioration of contractile function coupled with impaired regenerative potential that drives the heart toward decompensation. Efficacious regenerative cell therapy for severe heart failure requires disruption of this vicious circle that can be accomplished by alteration of the compromised myocyte phenotype and rejuvenation of progenitor cells. This review focuses upon potential for Pim-1 kinase to mitigate chronic heart failure by improving myocyte quality through preservation of mitochondrial integrity, prevention of hypertrophy and inhibition of apoptosis. In addition, cardiac progenitors engineered with Pim-1 possess enhanced regenerative potential, making Pim-1 an important player in future treatment of severe heart failure. PMID:23984924

[Effects of Pim-1 inhibitor on mouse model of inflammatory bowel disease induced by TNBS].

PubMed

Ou, Rong; Shen, Yueming; Zeng, Ya; Zou, Lingzhi; Jiang, Na; Xu, Meihua

2018-05-28

To explore the role of Pim-1 in the pathology of inflammatory bowel disease and the potential effect of Pim-1 inhibitor on treating such disease.
 Methods: Forty-five BALB/c mice were randomly divided into 5 groups (n=9): A normal control group, a inflammatory bowel disease group, two different dose of Pim-1 inhibitor treatment groups, and steroidhormone treatment group. The model of inflammatory bowel disease was induced by intracolonic administration of 2, 4, 6-trinitrobenzenestdfonic acid (TNBS) and ethanol mixture. Mice were treated with Pim-1 inhibitor [intraperitoneal inject, 5 or 10 mg/(kg.d)] for 5 days and prednisone (intragastric administration, 0.1 mg/d) for 5 days. The DAI, colon length, gross score and pathological grade were evaluated. The expressions of T cell master transcription factors T-box expressed in T cells (T-bet), GATA binding protein 3 (GATA-3), RA orphan receptorγ (RORγt) and forkhead box P3 (Foxp3) were measured by Real-time PCR and Western blot, respectively.
 Results: Pim-1 inhibitor and prednisone showed therapeutic effect on acute TNBS colitis in vivo. GATA3 and RORγt were significantly up-regulated in acute TNBS colitis (P<0.05). In contrast, the expression of Foxp3 was suppressed in the inflammatory bowel disease group, whereas it did not cause any significant change in T-bet expression (P>0.05). Administration of Pim-1 inhibitor and prednisone resulted in suppression of GATA3, RORγt expression, and the increase of Foxp3 expression (P<0.05). Administration of Pim-1 inhibitor and prednisone resulted in inhibition of T-bet mRNA expression (P<0.05), but only prednisone could inhibit T-bet protein expression (P>0.05).
 Conclusion: Pim-1 inhibitor significantly suppresses Th2- and Th17-type immune responses. Furthermore, Pim-1 inhibitor could induce T-cell differentiation towards a Treg phenotype. Pim-1 inhibitor has therapeutic effect on acute TNBS colitis.

PIMS-Universal Payload Information Management

NASA Technical Reports Server (NTRS)

Elmore, Ralph; McNair, Ann R. (Technical Monitor)

2002-01-01

As the overall manager and integrator of International Space Station (ISS) science payloads and experiments, the Payload Operations Integration Center (POIC) at Marshall Space Flight Center had a critical need to provide an information management system for exchange and management of ISS payload files as well as to coordinate ISS payload related operational changes. The POIC's information management system has a fundamental requirement to provide secure operational access not only to users physically located at the POIC, but also to provide collaborative access to remote experimenters and International Partners. The Payload Information Management System (PIMS) is a ground based electronic document configuration management and workflow system that was built to service that need. Functionally, PIMS provides the following document management related capabilities: 1. File access control, storage and retrieval from a central repository vault. 2. Collect supplemental data about files in the vault. 3. File exchange with a PMS GUI client, or any FTP connection. 4. Files placement into an FTP accessible dropbox for pickup by interfacing facilities, included files transmitted for spacecraft uplink. 5. Transmission of email messages to users notifying them of new version availability. 6. Polling of intermediate facility dropboxes for files that will automatically be processed by PIMS. 7. Provide an API that allows other POIC applications to access PIMS information. Functionally, PIMS provides the following Change Request processing capabilities: 1. Ability to create, view, manipulate, and query information about Operations Change Requests (OCRs). 2. Provides an adaptable workflow approval of OCRs with routing through developers, facility leads, POIC leads, reviewers, and implementers. Email messages can be sent to users either involving them in the workflow process or simply notifying them of OCR approval progress. All PIMS document management and OCR workflow controls are

A potential therapeutic target for FLT3-ITD AML: PIM1 Kinase

PubMed Central

Fathi, Amir T.; Arowojolu, Omotayo; Swinnen, Ian; Sato, Takashi; Rajkhowa, Trivikram; Small, Donald; Marmsater, Fredrik; Robinson, John E.; Gross, Stefan David; Martinson, Matthew; Allen, Shelley; Kallan, Nicholas C.; Levis, Mark

2011-01-01

Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) mutation have a poor prognosis, and FLT3 inhibitors are now under clinical investigation. PIM1, a serine/threonine kinase, is up-regulated in FLT3-ITD AML and may be involved in FLT3-mediated leukemogenesis. We employed a PIM1 inhibitor, AR00459339 (Array Biopharma Inc.), to investigate the effect of PIM1 inhibition in FLT3-mutant AML. Like FLT3 inhibitors, AR00459339 was preferentially cytotoxic to FLT3-ITD cells, as demonstrated in the MV4-11, Molm-14, and TF/ITD cell lines, as well as 12 FLT3-ITD primary samples. Unlike FLT3 inhibitors, AR00459339 did not suppress phosphorylation of FLT3, but did promote the de-phosphorylation of downstream FLT3 targets, STAT5, AKT, and BAD. Combining AR00459339 with a FLT3 inhibitor resulted in additive to mildly synergistic cytotoxic effects. AR00459339 was cytotoxic to FLT3-ITD samples from patients with secondary resistance to FLT3 inhibitors, suggesting a novel benefit to combining these agents. We conclude that PIM1 appears to be closely associated with FLT3 signaling, and that inhibition of PIM1 may hold therapeutic promise, either as monotherapy, or by overcoming resistance to FLT3 inhibitors. PMID:21802138

EBNA3C Augments Pim-1 Mediated Phosphorylation and Degradation of p21 to Promote B-Cell Proliferation

PubMed Central

Banerjee, Shuvomoy; Lu, Jie; Cai, Qiliang; Sun, Zhiguo; Jha, Hem Chandra; Robertson, Erle S.

2014-01-01

Epstein–Barr virus (EBV), a ubiquitous human herpesvirus, can latently infect the human population. EBV is associated with several types of malignancies originating from lymphoid and epithelial cell types. EBV latent antigen 3C (EBNA3C) is essential for EBV-induced immortalization of B-cells. The Moloney murine leukemia provirus integration site (PIM-1), which encodes an oncogenic serine/threonine kinase, is linked to several cellular functions involving cell survival, proliferation, differentiation, and apoptosis. Notably, enhanced expression of Pim-1 kinase is associated with numerous hematological and non-hematological malignancies. A higher expression level of Pim-1 kinase is associated with EBV infection, suggesting a crucial role for Pim-1 in EBV-induced tumorigenesis. We now demonstrate a molecular mechanism which reveals a direct role for EBNA3C in enhancing Pim-1 expression in EBV-infected primary B-cells. We also showed that EBNA3C is physically associated with Pim-1 through its amino-terminal domain, and also forms a molecular complex in B-cells. EBNA3C can stabilize Pim-1 through abrogation of the proteasome/Ubiquitin pathway. Our results demonstrate that EBNA3C enhances Pim-1 mediated phosphorylation of p21 at the Thr145 residue. EBNA3C also facilitated the nuclear localization of Pim-1, and promoted EBV transformed cell proliferation by altering Pim-1 mediated regulation of the activity of the cell-cycle inhibitor p21/WAF1. Our study demonstrated that EBNA3C significantly induces Pim-1 mediated proteosomal degradation of p21. A significant reduction in cell proliferation of EBV-transformed LCLs was observed upon stable knockdown of Pim-1. This study describes a critical role for the oncoprotein Pim-1 in EBV-mediated oncogenesis, as well as provides novel insights into oncogenic kinase-targeted therapeutic intervention of EBV-associated cancers. PMID:25121590

Removal of aniline from air and water by polymers of intrinsic microporosity (PIM-1) electrospun ultrafine fibers.

PubMed

Satilmis, Bekir; Uyar, Tamer

2018-04-15

This research aims to investigate the possibility of electrospun fibers from Polymers of Intrinsic Microporosity (PIM-1) as an alternative adsorbent for aniline removal from both air and aqueous solution. Adsorption properties of electrospun PIM-1 fibers were compared with powder and film form of PIM-1. While electrospun PIM-1 nanofibrous mat can adsorb 871 mg g -1 aniline from air, it can also adsorb 78 ± 5.4 mg g -1 aniline from aqueous environment when 50 mg L -1 aniline solution is used. The experimental maximum adsorption capacity of electrospun PIM-1 fibers was found as (q e ) 138 mg g -1 . Langmuir and Freundlich isotherm models have been studied and Langmuir model found more appropriate for aniline adsorption on electrospun PIM-1 fibers. The study reveals that self-standing electrospun fibrous mat of PIM-1 has shown potential to be used as an efficient adsorbent material for the adsorption of VOCs from air and aqueous system thanks to its fast kinetic and high adsorption capacity. Copyright © 2018 Elsevier Inc. All rights reserved.

Pim-1L Protects Cell Surface-Resident ABCA1 From Lysosomal Degradation in Hepatocytes and Thereby Regulates Plasma High-Density Lipoprotein Level.

PubMed

Katsube, Akira; Hayashi, Hisamitsu; Kusuhara, Hiroyuki

2016-12-01

ATP-binding cassette transporter A1 (ABCA1) exerts an atheroprotective action through the biogenesis of high-density lipoprotein in hepatocytes and prevents the formation of foam cells from macrophages. Controlling ABCA1 is a rational approach to improving atherosclerotic cardiovascular disease. Although much is known about the regulatory mechanism of ABCA1 synthesis, the molecular mechanism underpinning its degradation remains to be clearly described. ABCA1 possesses potential sites of phosphorylation by serine/threonine-protein kinase Pim-1 (Pim-1). Pim-1 depletion decreased the expression of cell surface-resident ABCA1 (csABCA1) and apolipoprotein A-I-mediated [ 3 H]cholesterol efflux in the human hepatoma cell line HepG2, but not in peritoneal macrophages from mice. In vitro kinase assay, immunoprecipitation, and immunocytochemistry suggested phosphorylation of csABCA1 by the long form of Pim-1 (Pim-1L). Cell surface biotinylation indicated that Pim-1L inhibited lysosomal degradation of csABCA1 involving the liver X receptor β, which interacts with csABCA1 and thereby protects it from ubiquitination and subsequent lysosomal degradation. Cell surface coimmunoprecipitation with COS-1 cells expressing extracellularly hemagglutinin-tagged ABCA1 showed that Pim-1L-mediated phosphorylation of csABCA1 facilitated the interaction between csABCA1 and liver X receptor β and thereby stabilized the csABCA1-Pim-1L complex. Mice deficient in Pim-1 kinase activity showed lower expression of ABCA1 in liver plasma membranes and lower plasma high-density lipoprotein levels than control mice. Pim-1L protects hepatic csABCA1 from lysosomal degradation by facilitating the physical interaction between csABCA1 and liver X receptor β and subsequent stabilization of the csABCA1-Pim-1L complex and thereby regulates the circulating level of high-density lipoprotein. Our findings may aid the development of high-density lipoprotein-targeted therapy. © 2016 American Heart Association

Synthesis and Transport Properties of Novel MOF/PIM-1/MOF Sandwich Membranes for Gas Separation

PubMed Central

Fuoco, Alessio; Khdhayyer, Muhanned R.; Attfield, Martin P.; Esposito, Elisa; Jansen, Johannes C.; Budd, Peter M.

2017-01-01

Metal-organic frameworks (MOFs) were supported on polymer membrane substrates for the fabrication of composite polymer membranes based on unmodified and modified polymer of intrinsic microporosity (PIM-1). Layers of two different MOFs, zeolitic imidazolate framework-8 (ZIF-8) and Copper benzene tricarboxylate ((HKUST-1), were grown onto neat PIM-1, amide surface-modified PIM-1 and hexamethylenediamine (HMDA) -modified PIM-1. The surface-grown crystalline MOFs were characterized by a combination of several techniques, including powder X-ray diffraction, infrared spectroscopy and scanning electron microscopy to investigate the film morphology on the neat and modified PIM-1 membranes. The pure gas permeabilities of He, H2, O2, N2, CH4, CO2 were studied to understand the effect of the surface modification on the basic transport properties and evaluate the potential use of these membranes for industrially relevant gas separations. The pure gas transport was discussed in terms of permeability and selectivity, highlighting the effect of the MOF growth on the diffusion coefficients of the gas in the new composite polymer membranes. The results confirm that the growth of MOFs on polymer membranes can enhance the selectivity of the appropriately functionalized PIM-1, without a dramatic decrease of the permeability. PMID:28208658

Mixed Matrix Membranes of Boron Icosahedron and Polymers of Intrinsic Microporosity (PIM-1) for Gas Separation

PubMed Central

Khan, Muntazim Munir; Shishatskiy, Sergey; Filiz, Volkan

2018-01-01

This work reports on the preparation and gas transport performance of mixed matrix membranes (MMMs) based on the polymer of intrinsic microporosity (PIM-1) and potassium dodecahydrododecaborate (K2B12H12) as inorganic particles (IPs). The effect of IP loading on the gas separation performance of these MMMs was investigated by varying the IP content (2.5, 5, 10 and 20 wt %) in a PIM-1 polymer matrix. The derived MMMs were characterized by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), single gas permeation tests and sorption measurement. The PIM1/K2B12H12 MMMs show good dispersion of the IPs (from 2.5 to 10 wt %) in the polymer matrix. The gas permeability of PIM1/K2B12H12 MMMs increases as the loading of IPs increases (up to 10 wt %) without sacrificing permselectivity. The sorption isotherm in PIM-1 and PIM1/K2B12H12 MMMs demonstrate typical dual-mode sorption behaviors for the gases CO2 and CH4. PMID:29301312

Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase.

PubMed

Fischer, Kimberlee M; Cottage, Christopher T; Wu, Weitao; Din, Shabana; Gude, Natalie A; Avitabile, Daniele; Quijada, Pearl; Collins, Brett L; Fransioli, Jenna; Sussman, Mark A

2009-11-24

Despite numerous studies demonstrating the efficacy of cellular adoptive transfer for therapeutic myocardial regeneration, problems remain for donated cells with regard to survival, persistence, engraftment, and long-term benefits. This study redresses these concerns by enhancing the regenerative potential of adoptively transferred cardiac progenitor cells (CPCs) via genetic engineering to overexpress Pim-1, a cardioprotective kinase that enhances cell survival and proliferation. Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32 weeks to assess cardiac function and engraftment of Pim-1 CPCs with echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 showed increased proliferation and expression of markers consistent with cardiogenic lineage commitment after dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produced greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32 weeks after delivery. Salutary effects include reduction of infarct size, greater number of c-kit(+) cells, and increased vasculature in the damaged region. Myocardial repair is significantly enhanced by genetic engineering of CPCs with Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell-based therapeutic approaches.

The PIM kinases in hematological cancers.

PubMed

Alvarado, Yesid; Giles, Francis J; Swords, Ronan T

2012-02-01

The PIM genes represent a family of proto-oncogenes that encode three different serine/threonine protein kinases (PIM1, PIM2 and PIM3) with essential roles in the regulation of signal transduction cascades, which promote cell survival, proliferation and drug resistance. PIM kinases are overexpressed in several hematopoietic tumors and support in vitro and in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. PIM kinases do not have an identified regulatory domain, which means that these proteins are constitutively active once transcribed. They appear to be critical downstream effectors of important oncoproteins and, when overexpressed, can mediate drug resistance to available agents, such as rapamycin. Recent crystallography studies reveal that, unlike other kinases, they possess a hinge region, which creates a unique binding pocket for ATP, offering a target for an increasing number of potent small-molecule PIM kinase inhibitors. Preclinical studies in models of various hematologic cancers indicate that these novel agents show promising activity and some of them are currently being evaluated in a clinical setting. In this review, we profile the PIM kinases as targets for therapeutics in hematologic malignancies.

The putative oncogene Pim-1 in the mouse: its linkage and variation among t haplotypes.

PubMed

Nadeau, J H; Phillips, S J

1987-11-01

Pim-1, a putative oncogene involved in T-cell lymphomagenesis, was mapped between the pseudo-alpha globin gene Hba-4ps and the alpha-crystallin gene Crya-1 on mouse chromosome 17 and therefore within the t complex. Pim-1 restriction fragment variants were identified among t haplotypes. Analysis of restriction fragment sizes obtained with 12 endonucleases demonstrated that the Pim-1 genes in some t haplotypes were indistinguishable from the sizes for the Pim-1b allele in BALB/c inbred mice. There are now three genes, Pim-1, Crya-1 and H-2 I-E, that vary among independently derived t haplotypes and that have indistinguishable alleles in t haplotypes and inbred strains. These genes are closely linked within the distal inversion of the t complex. Because it is unlikely that these variants arose independently in t haplotypes and their wild-type homologues, we propose that an exchange of chromosomal segments, probably through double crossingover, was responsible for indistinguishable Pim-1 genes shared by certain t haplotypes and their wild-type homologues. There was, however, no apparent association between variant alleles of these three genes among t haplotypes as would be expected if a single exchange introduced these alleles into t haplotypes. If these variant alleles can be shown to be identical to the wild-type allele, then lack of association suggests that multiple exchanges have occurred during the evolution of the t complex.

Can foreign proteins imported into yeast mitochondria interfere with PIM1p protease and/or chaperone function?

PubMed

Saveliev, A S; Kovaleva, I E; Novikova, L A; Isaeva, L V; Luzikov, V N

1999-03-15

When studying the fate of mammalian apocytochrome P450scc (apo-P450scc) imported in small amounts into isolated yeast mitochondria, we found that it undergoes degradation, this process being retarded if recipient mitochondria are preloaded in vivo (to about 0.2% of total organelle protein) with a fusion protein composed of mammalian adrenodoxin reductase and adrenodoxin (AdR-Ad); in parallel we observed aggregation of apo-P450scc. These effects suggest some overload of Pim1p protease and/or mtHsp70 system by AdR-Ad, as both of them are involved in the degradation of apo-P450scc (see Savel'ev et al. J. Biol. Chem. 273, 20596-20602, 1998). However, under the same conditions AdR-Ad was not able to impede the import of proteins into mitochondria and the development of the mitochondrial respiratory machinery in yeast, the processes requiring the mtHsp70 system and Pim1p, respectively. These data imply that chaperones and Pim1p protease prefer their natural targets in mitochondria to imported foreign proteins. Copyright 1999 Academic Press.

Latency in Visionic Systems: Test Methods and Requirements

NASA Technical Reports Server (NTRS)

Bailey, Randall E.; Arthur, J. J., III; Williams, Steven P.; Kramer, Lynda J.

2005-01-01

A visionics device creates a pictorial representation of the external scene for the pilot. The ultimate objective of these systems may be to electronically generate a form of Visual Meteorological Conditions (VMC) to eliminate weather or time-of-day as an operational constraint and provide enhancement over actual visual conditions where eye-limiting resolution may be a limiting factor. Empirical evidence has shown that the total system delays or latencies including the imaging sensors and display systems, can critically degrade their utility, usability, and acceptability. Definitions and measurement techniques are offered herein as common test and evaluation methods for latency testing in visionics device applications. Based upon available data, very different latency requirements are indicated based upon the piloting task, the role in which the visionics device is used in this task, and the characteristics of the visionics cockpit display device including its resolution, field-of-regard, and field-of-view. The least stringent latency requirements will involve Head-Up Display (HUD) applications, where the visionics imagery provides situational information as a supplement to symbology guidance and command information. Conversely, the visionics system latency requirement for a large field-of-view Head-Worn Display application, providing a Virtual-VMC capability from which the pilot will derive visual guidance, will be the most stringent, having a value as low as 20 msec.

PIM-1 as a Solution-Processable “Molecular Basket” for CO 2 Capture from Dilute Sources

DOE PAGES

Pang, Simon H.; Jue, Melinda L.; Leisen, Johannes; ...

2015-12-07

Here, rising atmospheric CO 2 levels have triggered recent research into the science of amine materials supported on hard, porous materials such as mesoporous silica or alumina. While such materials can give high CO 2 uptakes and good sorption kinetics, they are difficult to utilize in practical applications due to difficulty in contacting large volumes of CO 2-laden gases with powder materials without significant pressure drops or sorbent attrition. Here, we describe a simple approach based on the impregnation of a permanently microporous polymer, PIM-1, with poly(ethylene imine) (PEI), removing the need for use of the hard oxide. PEI/PIM-1 compositesmore » demonstrate comparable performance to more traditionally studied oxide sorbents, with the benefit that PIM-1 is soluble in common solvents, making it eminently more viable for processing into morphologies that can facilitate heat and mass transfer and fabrication into low pressure drop contactors. In addition to adsorption studies performed on a variety of PEI/PIM-1 architectures, spin diffusion NMR studies were performed to suggest that PEI is well-dispersed within the PIM-1, allowing for rapid CO 2 adsorption.« less

Inhibition of PIM1 kinase attenuates inflammation-induced pro-labour mediators in human foetal membranes in vitro.

PubMed

Lim, Ratana; Barker, Gillian; Lappas, Martha

2017-06-01

Does proviral integration site for Moloney murine leukaemic virus (PIM)1 kinase play a role in regulating the inflammatory processes of human labour and delivery? PIM1 kinase plays a critical role in foetal membranes in regulating pro-inflammatory and pro-labour mediators. Infection and inflammation have strong causal links to preterm delivery by stimulating pro-inflammatory cytokines and collagen degrading enzymes, which can lead to rupture of membranes. PIM1 has been shown to have a role in immune regulation and inflammation in non-gestational tissues; however, its role has not been explored in the field of human labour. PIM1 expression was analysed in myometrium and/or foetal membranes obtained at term and preterm (n = 8-9 patients per group). Foetal membranes, freshly isolated amnion cells and primary myometrial cells were used to investigate the effect of PIM1 inhibition on pro-labour mediators (n = 5 patients per treatment group). Foetal membranes, from term and preterm, were obtained from non-labouring and labouring women, and from preterm pre-labour rupture of membranes (PPROM) (n = 9 per group). Amnion was collected from women with and without preterm chorioamnionitis (n = 8 per group). Expression of PIM1 kinase was determined by qRT-PCR and western blotting. To determine the effect of PIM1 kinase inhibition on the expression of pro-inflammatory and pro-labour mediators induced by bacterial products lipopolysaccharide (LPS) (10 μg/ml) and flagellin (1 μg/ml) and pro-inflammatory cytokine tumour necrosis factor (TNF) (10 ng/ml), chemical inhibitors SMI-4a (20 μM) and AZD1208 (50 μM) were used in foetal membrane explants and siRNA against PIM1 was used in primary amnion cells. Statistical significance was set at P < 0.05. PIM1 expression was significantly increased in foetal membranes after spontaneous term labour compared to no labour at term and in amnion with preterm chorioamnionitis compared to preterm with no chorioamnionitis. There was no

Membranes of Polymers of Intrinsic Microporosity (PIM-1) Modified by Poly(ethylene glycol).

PubMed

Bengtson, Gisela; Neumann, Silvio; Filiz, Volkan

2017-06-05

Until now, the leading polymer of intrinsic microporosity PIM-1 has become quite famous for its high membrane permeability for many gases in gas separation, linked, however, to a rather moderate selectivity. The combination with the hydrophilic and low permeable poly(ethylene glycol) (PEG) and poly(ethylene oxides) (PEO) should on the one hand reduce permeability, while on the other hand enhance selectivity, especially for the polar gas CO₂ by improving the hydrophilicity of the membranes. Four different paths to combine PIM-1 with PEG or poly(ethylene oxide) and poly(propylene oxide) (PPO) were studied: physically blending, quenching of polycondensation, synthesis of multiblock copolymers and synthesis of copolymers with PEO/PPO side chain. Blends and new, chemically linked polymers were successfully formed into free standing dense membranes and measured in single gas permeation of N₂, O₂, CO₂ and CH₄ by time lag method. As expected, permeability was lowered by any substantial addition of PEG/PEO/PPO regardless the manufacturing process and proportionally to the added amount. About 6 to 7 wt % of PEG/PEO/PPO added to PIM-1 halved permeability compared to PIM-1 membrane prepared under similar conditions. Consequently, selectivity from single gas measurements increased up to values of about 30 for CO₂/N₂ gas pair, a maximum of 18 for CO₂/CH₄ and 3.5 for O₂/N₂.

PIM kinases as therapeutic targets against advanced melanoma

PubMed Central

Shannan, Batool; Watters, Andrea; Chen, Quan; Mollin, Stefan; Dörr, Markus; Meggers, Eric; Xu, Xiaowei; Gimotty, Phyllis A.; Perego, Michela; Li, Ling; Benci, Joseph; Krepler, Clemens; Brafford, Patricia; Zhang, Jie; Wei, Zhi; Zhang, Gao; Liu, Qin; Yin, Xiangfan; Nathanson, Katherine L.; Herlyn, Meenhard; Vultur, Adina

2016-01-01

Therapeutic strategies for the treatment of metastatic melanoma show encouraging results in the clinic; however, not all patients respond equally and tumor resistance still poses a challenge. To identify novel therapeutic targets for melanoma, we screened a panel of structurally diverse organometallic inhibitors against human-derived normal and melanoma cells. We observed that a compound that targets PIM kinases (a family of Ser/Thr kinases) preferentially inhibited melanoma cell proliferation, invasion, and viability in adherent and three-dimensional (3D) melanoma models. Assessment of tumor tissue from melanoma patients showed that PIM kinases are expressed in pre- and post-treatment tumors, suggesting PIM kinases as promising targets in the clinic. Using knockdown studies, we showed that PIM1 contributes to melanoma cell proliferation and tumor growth in vivo; however, the presence of PIM2 and PIM3 could also influence the outcome. The inhibition of all PIM isoforms using SGI-1776 (a clinically-available PIM inhibitor) reduced melanoma proliferation and survival in preclinical models of melanoma. This was potentiated in the presence of the BRAF inhibitor PLX4720 and in the presence of PI3K inhibitors. Our findings suggest that PIM inhibitors provide promising additions to the targeted therapies available to melanoma patients. PMID:27448973

Performance Information Management System (PIMS) Communication

DTIC Science & Technology

1993-12-31

34AD-A284 851 AD MIPR NO. MIPR 92MM2501 TITLE: Performance Information Management System (PIMS) Communication PRINCIPAL INVESTIGATOR: Kathryn P...93 . . ..- F •nal,. 12/1/91 - 12/31/93- ...... . ..... PIMS-Performance Information Management System Communications 92MM2501 Kathryn P. Winter Navy

How Do Organic Vapors Swell Ultrathin Films of Polymer of Intrinsic Microporosity PIM-1?

PubMed

Ogieglo, Wojciech; Rahimi, Khosorov; Rauer, Sebastian Bernhard; Ghanem, Bader; Ma, Xiaohua; Pinnau, Ingo; Wessling, Matthias

2017-07-27

Dynamic sorption of ethanol and toluene vapor into ultrathin supported films of polymer of intrinsic microporosity PIM-1 down to a thickness of 6 nm are studied with a combination of in situ spectroscopic ellipsometry and in situ X-ray reflectivity. Both ethanol and toluene significantly swell the PIM-1 matrix and, at the same time, induce persistent structural relaxations of the frozen-in glassy PIM-1 morphology. For ethanol below 20 nm, three effects were identified. First, the swelling magnitude at high vapor pressures is reduced by about 30% as compared to that of thicker films. Second, at low penetrant activities (below 0.3p/p 0 ), films below 20 nm are able to absorb slightly more penetrant as compared with thicker films despite a similar swelling magnitude. Third, for the ultrathin films, the onset of the dynamic penetrant-induced glass transition P g has been found to shift to higher values, indicating higher resistance to plasticization. All of these effects are consistent with a view where immobilization of the superglassy PIM-1 at the substrate surface leads to an arrested, even more rigid, and plasticization-resistant, yet still very open, microporous structure. PIM-1 in contact with the larger and more condensable toluene shows very complex, heterogeneous swelling dynamics, and two distinct penetrant-induced relaxation phenomena, probably associated with the film outer surface and the bulk, are detected. Following the direction of the penetrant's diffusion, the surface seems to plasticize earlier than the bulk, and the two relaxations remain well separated down to 6 nm film thickness, where they remarkably merge to form just a single relaxation.

Pim-1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer

DTIC Science & Technology

2007-10-01

submitted to the Journal of Biological Chemistry . BODY We will outline our progress through reference to the specific aims described above. The first... Chemistry (see manuscript in appendix). The goal of specific aim #2 was to define pathways through which the PIM1 kinase could activate NFkB...or with three other flavonoids , has been determined. We have also shown that quercetagetin is able to inhibit the activity of the PIM1 kinase in

Cytoplasmic Irradiation Induces Metabolic Shift in Human Small Airway Epithelial Cells via Activation of Pim-1 Kinase.

PubMed

Wu, Jinhua; Zhang, Qin; Wuu, Yen-Ruh; Zou, Sirui; Hei, Tom K

2017-04-01

The unique cellular and molecular consequences of cytoplasmic damage caused by ionizing radiation were studied using a precision microbeam irradiator. Our results indicated that targeted cytoplasmic irradiation induced metabolic shift from an oxidative to glycolytic phenotype in human small airway epithelial cells (SAE). At 24 h postirradiation, there was an increase in the mRNA expression level of key glycolytic enzymes as well as lactate secretion in SAE cells. Using RNA-sequencing analysis to compare genes that were responsive to cytoplasmic versus nuclear irradiation, we found a glycolysis related gene, Pim-1, was significantly upregulated only in cytoplasmic irradiated SAE cells. Inhibition of Pim-1 activity using the selective pharmaceutic inhibitor Smi-4a significantly reduced the level of lactate production and glucose uptake after cytoplasmic irradiation. In addition, Pim-1 also inhibited AMPK activity, which is a well-characterized negative regulator of glycolysis. Distinct from the glycolysis induced by cytoplasmic irradiation, targeted nuclear irradiation also induced a transient and minimal increase in glycolysis that correlated with increased expression of Hif-1α. In an effort to explore the underline mechanism, we found that inhibition of mitochondria fission using the cell-permeable inhibitor mdivi-1 suppressed the induction of Pim-1, thus confirming Pim-1 upregulation as a downstream effect of mitochondrial dysfunction. Our data show and, for the first time, that cytoplasmic irradiation mediate expression level of Pim-1, which lead to glycolytic shift in SAE cells. Additionally, since glycolysis is frequently linked to cancer cell metabolism, our findings further suggest a role of cytoplasmic damage in promoting neoplastic changes.

Cytoplasmic Irradiation Induces Metabolic Shift in Human Small Airway Epithelial Cells via Activation of Pim-1 Kinase

PubMed Central

Wu, Jinhua; Zhang, Qin; Wuu, Yen-Ruh; Zou, Sirui; Hei, Tom K.

2017-01-01

The unique cellular and molecular consequences of cytoplasmic damage caused by ionizing radiation were studied using a precision microbeam irradiator. Our results indicated that targeted cytoplasmic irradiation induced metabolic shift from an oxidative to glycolytic phenotype in human small airway epithelial cells (SAE). At 24 h postirradiation, there was an increase in the mRNA expression level of key glycolytic enzymes as well as lactate secretion in SAE cells. Using RNA-sequencing analysis to compare genes that were responsive to cytoplasmic versus nuclear irradiation, we found a glycolysis related gene, Pim-1, was significantly upregulated only in cytoplasmic irradiated SAE cells. Inhibition of Pim-1 activity using the selective pharmaceutic inhibitor Smi-4a significantly reduced the level of lactate production and glucose uptake after cytoplasmic irradiation. In addition, Pim-1 also inhibited AMPK activity, which is a well-characterized negative regulator of glycolysis. Distinct from the glycolysis induced by cytoplasmic irradiation, targeted nuclear irradiation also induced a transient and minimal increase in glycolysis that correlated with increased expression of Hif-1α. In an effort to explore the underline mechanism, we found that inhibition of mitochondria fission using the cell-permeable inhibitor mdivi-1 suppressed the induction of Pim-1, thus confirming Pim-1 upregulation as a downstream effect of mitochondrial dysfunction. Our data show and, for the first time, that cytoplasmic irradiation mediate expression level of Pim-1, which lead to glycolytic shift in SAE cells. Additionally, since glycolysis is frequently linked to cancer cell metabolism, our findings further suggest a role of cytoplasmic damage in promoting neoplastic changes. PMID:28170315

Increased expression of activated pSTAT3 and PIM-1 in the pulmonary vasculature of experimental congenital diaphragmatic hernia.

PubMed

Hofmann, Alejandro D; Takahashi, Toshiaki; Duess, Johannes; Gosemann, Jan-Hendrik; Puri, Prem

2015-06-01

Signal transducer and activator of transcription (STAT) protein family (STAT1-6) regulates diverse cellular processes. Recently, the isoform STAT3 has been implicated to play a central role in the pathogenesis of pulmonary hypertension (PH). In human PH activated STAT3 (pSTAT3) was shown to directly trigger expression of the provirus integration site for Moloney murine leukemia virus (Pim-1), which promotes proliferation and resistance to apoptosis in SMCs. We designed this study to investigate the hypothesis that pSTAT3 and Pim-1 pulmonary vascular expression is increased in nitrofen-induced CDH. Pregnant rats were exposed to nitrofen or vehicle on D9.5. Fetuses were sacrificed on D21 and divided into nitrofen (n=16) and control group (n=16). QRT-PCR, western blotting, and confocal-immunofluorescence were performed to determine pulmonary gene and protein expression levels of pSTAT3 and Pim-1. Pulmonary Pim-1 gene expression was significantly increased in the CDH group compared to controls. Western blotting and confocal-microscopy confirmed increased pulmonary protein expression of Pim-1 and increased activation of pSTAT3 in CDH lungs compared to controls. Markedly increased gene and protein expression of Pim-1 and activated pSTAT3 in the pulmonary vasculature of nitrofen-induced CDH lungs suggest that pSTAT3 and Pim-1 are important mediators of PH in nitrofen-induced CDH. Copyright © 2015. Published by Elsevier Inc.

An introduction to the new Productivity Information Management System (PIMS)

NASA Technical Reports Server (NTRS)

Hull, R.

1982-01-01

The productivity information management system (PIMS), is described. The main objective of this computerized system is to enable management scientists to interactively explore data concerning DSN operations, maintenance and repairs, to develop and verify models for management planning. The PIMS will provide a powerful set of tools for iteratively manipulating data sets in a wide variety of ways. The initial version of PIMS will be a small scale pilot system. The following topics are discussed: (1) the motivation for developing PIMS; (2) various data sets which will be integrated by PIMS; (3) overall design of PIMS; and (4) how PIMS will be used. A survey of relevant databases concerning DSN operations at Goldstone is also included.

Structure-based design of novel quinoxaline-2-carboxylic acids and analogues as Pim-1 inhibitors.

PubMed

Oyallon, Bruno; Brachet-Botineau, Marie; Logé, Cédric; Bonnet, Pascal; Souab, Mohamed; Robert, Thomas; Ruchaud, Sandrine; Bach, Stéphane; Berthelot, Pascal; Gouilleux, Fabrice; Viaud-Massuard, Marie-Claude; Denevault-Sabourin, Caroline

2018-05-11

We identified a new series of quinoxaline-2-carboxylic acid derivatives, targeting the human proviral integration site for Moloney murine leukemia virus-1 (HsPim-1) kinase. Seventeen analogues were synthesized providing useful insight into structure-activity relationships studied. Docking studies realized in the ATP pocket of HsPim-1 are consistent with an unclassical binding mode of these inhibitors. The lead compound 1 was able to block HsPim-1 enzymatic activity at nanomolar concentrations (IC 50 of 74 nM), with a good selectivity profile against a panel of mammalian protein kinases. In vitro studies on the human chronic myeloid leukemia cell line KU812 showed an antitumor activity at micromolar concentrations. As a result, compound 1 represents a promising lead for the design of novel anticancer targeted therapies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold.

PubMed

Song, Ji-Yoon; Marszalek, Jaroslaw; Craig, Elizabeth Anne

2012-06-26

Fe-S clusters are critical prosthetic groups for proteins involved in various critical biological processes. Before being transferred to recipient apo-proteins, Fe-S clusters are assembled on the highly conserved scaffold protein Isu, the abundance of which is regulated posttranslationally on disruption of the cluster biogenesis system. Here we report that Isu is degraded by the Lon-type AAA+ ATPase protease of the mitochondrial matrix, Pim1. Nfs1, the cysteine desulfurase responsible for providing sulfur for cluster formation, is required for the increased Isu stability occurring after disruption of cluster formation on or transfer from Isu. Physical interaction between the Isu and Nfs1 proteins, not the enzymatic activity of Nfs1, is the important factor in increased stability. Analysis of several conditions revealed that high Isu levels can be advantageous or disadvantageous, depending on the physiological condition. During the stationary phase, elevated Isu levels were advantageous, resulting in prolonged chronological lifespan. On the other hand, under iron-limiting conditions, high Isu levels were deleterious. Compared with cells expressing normal levels of Isu, such cells grew poorly and exhibited reduced activity of the heme-containing enzyme ferric reductase. Our results suggest that modulation of the degradation of Isu by the Pim1 protease is a regulatory mechanism serving to rapidly help balance the cell's need for critical iron-requiring processes under changing environmental conditions.

Hierarchical Control on Polyene Macrolide Biosynthesis: PimR Modulates Pimaricin Production via the PAS-LuxR Transcriptional Activator PimM

PubMed Central

Santos-Aberturas, Javier; Vicente, Cláudia M.; Payero, Tamara D.; Martín-Sánchez, Lara; Cañibano, Carmen; Martín, Juan F.; Aparicio, Jesús F.

2012-01-01

Control of polyene macrolide production in Streptomyces natalensis is mediated by the transcriptional activator PimR. This regulator combines an N-terminal domain corresponding to the Streptomyces antibiotic regulatory protein (SARP) family of transcriptional activators with a C-terminal half homologous to guanylate cyclases and large ATP-binding regulators of the LuxR family. The PimR SARP domain (PimRSARP) was expressed in Escherichia coli as a glutathione S-transferase (GST)–fused protein. Electrophoretic mobility shift assays showed that GST-PimRSARP binds a single target, the intergenic region between the regulatory genes pimR and pimMs in the pimaricin cluster. The PimRSARP-binding site was investigated by DNaseI protection studies, revealing that it contains three heptameric direct repeats adjusting to the consensus 5′-CGGCAAG-3′. Transcription start points of pimM and pimR promoters were identified by 5′-RACE, revealing that unlike other SARPs, PimRSARP does not interact with the -35 region of its target promoter. Quantitative transcriptional analysis of these regulatory genes on mutants on each of them has allowed the identification of the pimM promoter as the transcriptional target for PimR. Furthermore, the constitutive expression of pimM restored pimaricin production in a pimaricin-deficient strain carrying a deletion mutant of pimR. These results reveal that PimR exerts its positive effect on pimaricin production by controlling pimM expression level, a regulator whose gene product activates transcription from eight different promoters of pimaricin structural genes directly. PMID:22693644

[Effect of ginsenoside Rg3 on Pim-3 and Bad proteins in human pancreatic cancer cell line PANC-1].

PubMed

Jian, Jie; Hu, Zhi-Fang; Huang, Yuan

2009-05-01

Ginsenoside Rg3 is a traditional Chinese medicine monomer which possesses anticancer effects. This study was to investigate the effects of ginsenoside Rg3 on Pim-3 and phosphorylated Bad (pBad) proteins, pBad (Ser112) and pBad (Ser136) in human pancreatic cancer cell line PANC-1. PANC-1 cells were exposed to 10, 20, 40 and 80 micromol/L ginsenoside Rg3 for 24 h. A short hairpin RNA (shRNA) of Pim-3 was cloned and inserted into a eukaryotic expression vector pSilencer 3.1-H1 Neo to construct pSilencer 3.1-H1 Neo-Pim-3. pSilencer 3.1-H1 Neo-Pim-3 was then transfected into PANC-1 cells. Cell proliferation was measured by MTT assay; cell apoptosis was observed under an invert microscope and measured by flow cytometry with Annexin V/PI staining; protein expressions of Pim-3, Bad, pBad (Ser112) and pBad (Ser136) were measured by Western blot. The inhibitory rates of 10, 20, 40 and 80 micromol/L ginsenoside Rg3 on PANC-1 cells were 20.2%, 33.4%, 52.8% and 65.3%, respectively. Typical morphological changes in apoptosis were induced by ginsenoside Rg3. The apoptotic rate of PANC-1 cells was significantly higher in the ginsenoside Rg3 treatment group (80 micromol/L) than in the control group (12.2% vs. 3.3%, P<0.05). Ginsenoside Rg3 had no influence on the total Bad protein expression, but decreased both Pim-3 and pBad (Ser112) expressions in a dose-dependent manner. pBad (Ser136) was not expressed in PANC-1 cells. Compared with the control group, the percentages of early and total apoptotic cells were significantly increased in PANC-1 cells transfected with pim-3-shRNA [(11.5+/-3.7)% vs. (5.8+/-2.2)%,P<0.01;(20.8+/-2.6)% vs.(13.0+/-4.1)%,P<0.05], while the expressions of pim-3 and pBad (Ser112) were both decreased. The anti-tumor effect of ginsenoside Rg3 may be associated with the decrease of Pim-3 and pBad (Ser112).

SGI-1776, an imidazo pyridazine compound, inhibits the proliferation of ovarian cancer cells by inactivating Pim-1.

PubMed

Xie, Jing; Bai, Jun

2014-07-01

To investigate the antitumor effect of SGI-1776 on human ovarian cancer HO-8910 cells and its molecular mechanism. HO-8910 cells were cultured in vitro, and the proliferation inhibitory effects of SGI- 1776 were determined by MTT assay and colony formation assay. The effect of SGI-1776 on the distribution of cell cycle phase was observed by flow cytometry with propidium iodide (PI) staining. The inhibition rate of migration and invasion were valued by transwell cell assay. Multiple molecular techniques, such as ELISA, Western blot, siRNA and cDNA transfection were used to explore the molecular mechanism. SGI-1776 presented dramatic anti-tumor activity against HO-8910 cells in vitro, inhibited the cells proliferation and colony formation, and attenuated the migration and invasion in a dosedependent manner, accompanied by cell cycle arrest in G1 phase. SGI-1776 caused the proliferation inhibition with concomitant decrease in Pim-1 kinase activity, down-regulated the expression of Pim-1 protein and and its downstream genes, such as CDK6, pCDK6, CDK4, pCDK4, CDK2 and pCDK2, and increased the expression of P21 and P27. Down-regulation expression of Pim-1 by siRNA followed SGI-1776 treatment resulted in enhanced cell proliferation inhibition rate and attenuated migration/invasion. Up-regulation of Pim-1 by cDNA transfection attenuated SGI- 1776-induced cell proliferation inhibition and its migration/invasion. Pim-1 mediates the biological effect of SGI-1776 in human ovarian cancer HO-8910 cells, suggesting Pim-1 might be a novel target for human ovarian cancer.

3D-QSAR and virtual screening studies of thiazolidine-2,4-dione analogs: Validation of experimental inhibitory potencies towards PIM-1 kinase

NASA Astrophysics Data System (ADS)

Asati, Vivek; Bharti, Sanjay Kumar; Budhwani, Ashok Kumar

2017-04-01

The proviral insertion site in moloney murine leukemia virus (PIM) is a family of serine/threonine kinase of Ca2+-calmodulin-dependent protein kinase (CAMK) group which is responsible for the activation and regulation of cellular transcription and translation. The three isoforms of PIM kinase (PIM-1, PIM-2 and PIM-3) share high homology and functional idleness are widely expressed and involved in a variety of biological processes including cell survival, proliferation, differentiation and apoptosis. Altered expression of PIM-1 kinase correlated with hematologic malignancies and solid tumors. In the present study, atom-based 3D-QSAR, docking and virtual screening studies have been performed on a series of thiazolidine-2,4-dione derivatives as PIM-1 kinase inhibitors. 3D-QSAR and docking approach has shortlisted the most active thiazolidine-2,4-dione derivatives such as 28, 31, 33 and 35 with the incorporation of more than one structural feature in a single molecule. External validations by various parameters and molecular docking studies at the active site of PIM-1 kinase have proved the reliability of the developed 3D-QSAR model. The generated pharmacophore (AADHR.33) from 3D-QSAR study was used for screening of drug like compounds from ZINC database, where ZINC15056464 and ZINC83292944 showed potential binding affinities at the active site amino acid residues (LYS67, GLU171, ASP128 and ASP186) of PIM-1 kinase.

Eco-friendly synthesis of novel cyanopyridine derivatives and their anticancer and PIM-1 kinase inhibitory activities.

PubMed

Abouzid, Khaled A M; Al-Ansary, Ghada H; El-Naggar, Abeer M

2017-07-07

Targeting Pim-1 kinase recently proved to be profitable for conquering cancer proliferation. In the current study, we report the design, synthesis and biological evaluation of two novel series of 2-amino cyanopyridine series (5a-g) and 2-oxocyanopyridine series (6a-g) targeting Pim-1 kinase. All of the newly synthesized compounds were evaluated for their in vitro anticancer activity against a panel of three cell lines, namely, the liver cancer cell line (HepG2), the colon cancer cell line (HCT-116) and the breast cancer cell line (MCF-7). Most of the compounds showed good to moderate anti-proliferative activity against HepG2 and HCT-116 cell lines while only few compounds showed significant cytotoxic activity against MCF-7 cell line. Further, the Pim-1 kinase inhibitory activity for the two series was evaluated where most of the tested compounds showed marked Pim-1 kinase inhibitory activity (26%-89%). Moreover, determination of the IC 50 values unraveled very potent molecules in the submicromolar range where compound 6c possessed an IC 50 value of 0.94 μM. Moreover, apoptosis studies were conducted on the most potent compound 6c to evaluate the proapoptotic potential of our compounds. Interestingly, it induced the level of active caspase 3 and boosted the Bax/Bcl2 ratio 22704 folds in comparison to the control. Finally, a molecular docking study was conducted to reveal the probable interaction with the Pim-1 kinase active site. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells.

PubMed

Chen, Lisa S; Redkar, Sanjeev; Bearss, David; Wierda, William G; Gandhi, Varsha

2009-11-05

Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compounds, SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concentration-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-X(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 reduction.

Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells

PubMed Central

Chen, Lisa S.; Redkar, Sanjeev; Bearss, David; Wierda, William G.

2009-01-01

Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compounds, SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concentration-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-XL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 reduction. PMID:19734450

Identification of novel inhibitors for Pim-1 kinase using pharmacophore modeling based on a novel method for selecting pharmacophore generation subsets

NASA Astrophysics Data System (ADS)

Shahin, Rand; Swellmeen, Lubna; Shaheen, Omar; Aboalhaija, Nour; Habash, Maha

2016-01-01

Targeting Proviral integration-site of murine Moloney leukemia virus 1 kinase, hereafter called Pim-1 kinase, is a promising strategy for treating different kinds of human cancer. Headed for this a total list of 328 formerly reported Pim-1 kinase inhibitors has been explored and divided based on the pharmacophoric features of the most active molecules into 10 subsets projected to represent potential active binding manners accessible to ligands within the binding pocket of Pim-1 kinase. Discovery Studio 4.1 (DS 4.1) was employed to detect potential pharmacophoric active binding manners anticipated by Pim-1 Kinase inhibitors. The pharmacophoric models were then allowed to compete within Quantitative Structure Activity Relationship (QSAR) framework with other 2D descriptors. Accordingly Genetic algorithm and multiple linear regression investigation were engaged to find the finest QSAR equation that has the best predictive power r 262 2 = 0.70, F = 119.14, r LOO 2 = 0.693, r PRESS 2 against 66 external test inhibitors = 0.71 q2 = 0.55. Three different pharmacophores appeared in the successful QSAR equation this represents three different binding modes for inhibitors within the Pim-1 kinase binding pocket. Pharmacophoric models were later used to screen compounds within the National Cancer Institute database. Several low micromolar Pim-1 Kinase inhibitors were captured. The most potent hits show IC50 values of 0.77 and 1.03 µM. Also, upon analyzing the successful QSAR Equation we found that some polycyclic aromatic electron-rich structures namely 6-Chloro-2-methoxy-acridine can be considered as putative hits for Pim-1 kinase inhibition.

Anomalies in the low frequency vibrational density of states for a polymer with intrinsic microporosity - the Boson peak of PIM-1.

PubMed

Zorn, Reiner; Yin, Huajie; Lohstroh, Wiebke; Harrison, Wayne; Budd, Peter M; Pauw, Brian R; Böhning, Martin; Schönhals, Andreas

2018-01-17

Polymers with intrinsic microporosity are promising candidates for the active separation layer in gas separation membranes. Here, the vibrational density of states (VDOS) for PIM-1, the prototypical polymer with intrinsic microporosity, is investigated by means of inelastic neutron scattering. The results are compared to data measured for a more conventional high-performance polyimide used in gas separation membranes (Matrimid). The measured data show the characteristic low frequency excess contribution to VDOS above the Debye sound wave level, generally known as the Boson peak in glass-forming materials. In comparison to the Boson peak of Matrimid, that of PIM-1 is shifted to lower frequencies. This shift is discussed considering the microporous, sponge-like structure of PIM-1 as providing a higher compressibility at the molecular scale than for conventional polymers. For an annealed PIM-1 sample, the Boson peak shifts to higher frequencies in comparison to the un-annealed sample. These changes in the VDOS of the annealed PIM-1 sample are related to changes in the microporous structure as confirmed by X-ray scattering.

Hit to lead evaluation of 1,2,3-triazolo[4,5-b]pyridines as PIM kinase inhibitors.

PubMed

Pastor, Joaquín; Oyarzabal, Julen; Saluste, Gustavo; Alvarez, Rosa María; Rivero, Virginia; Ramos, Francisco; Cendón, Elena; Blanco-Aparicio, Carmen; Ajenjo, Nuria; Cebriá, Antonio; Albarrán, M I; Cebrián, David; Corrionero, Ana; Fominaya, Jesús; Montoya, Guillermo; Mazzorana, Marco

2012-02-15

PIM kinases have become targets of interest due to their association with biochemical mechanisms affecting survival, proliferation and cytokine production. 1,2,3-Triazolo[4,5-b]pyridines were identified as PIM inhibitors applying a scaffold hopping approach. Initial exploration around this scaffold and X-ray crystallographic data are hereby described. Copyright © 2012 Elsevier Ltd. All rights reserved.

Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

PubMed Central

Santio, Niina M.; Eerola, Sini K.; Paatero, Ilkka; Yli-Kauhaluoma, Jari; Anizon, Fabrice; Moreau, Pascale; Tuomela, Johanna; Härkönen, Pirkko; Koskinen, Päivi J.

2015-01-01

Background and methods Pim family proteins are oncogenic kinases implicated in several types of cancer and involved in regulation of cell proliferation, survival as well as motility. Here we have investigated the ability of Pim kinases to promote metastatic growth of prostate cancer cells in two xenograft models for human prostate cancer. We have also evaluated the efficacy of Pim-selective inhibitors to antagonize these effects. Results We show here that tumorigenic growth of both subcutaneously and orthotopically inoculated prostate cancer xenografts is enhanced by stable overexpression of either Pim-1 or Pim-3. Moreover, Pim-overexpressing orthotopic prostate tumors are highly invasive and able to migrate not only to the nearby prostate-draining lymph nodes, but also into the lungs to form metastases. When the xenografted mice are daily treated with the Pim-selective inhibitor DHPCC-9, both the volumes as well as the metastatic capacity of the tumors are drastically decreased. Interestingly, the Pim-promoted metastatic growth of the orthotopic xenografts is associated with enhanced angiogenesis and lymphangiogenesis. Furthermore, forced Pim expression also increases phosphorylation of the CXCR4 chemokine receptor, which may enable the tumor cells to migrate towards tissues such as the lungs that express the CXCL12 chemokine ligand. Conclusions Our results indicate that Pim overexpression enhances the invasive properties of prostate cancer cells in vivo. These effects can be reduced by the Pim-selective inhibitor DHPCC-9, which can reach tumor tissues without serious side effects. Thus, Pim-targeting therapies with DHPCC-9-like compounds may help to prevent progression of local prostate carcinomas to fatally metastatic malignancies. PMID:26075720

Metabolic Dysfunction Consistent with Premature Aging Results from Deletion of Pim Kinases

PubMed Central

Din, Shabana; Konstandin, Mathias H; Johnson, Bevan; Emathinger, Jacqueline; Völkers, Mirko; Toko, Haruhiro; Collins, Brett; Ormachea, Lucy; Samse, Kaitlen; Kubli, Dieter A; De La Torre, Andrea; Kraft, Andrew S; Gustafsson, Asa B; Kelly, Daniel P; Sussman, Mark A

2014-01-01

Rationale The senescent cardiac phenotype is accompanied by changes in mitochondrial function and biogenesis causing impairment in energy provision. The relationship between myocardial senescence and Pim kinases deserves attention since Pim-1 kinase is cardioprotective, in part, by preservation of mitochondrial integrity. Study of the pathological effects resulting from genetic deletion of all Pim kinase family members could provide important insight regarding cardiac mitochondrial biology and the aging phenotype. Objective Demonstrate myocardial senescence is promoted by loss of Pim leading to premature aging and aberrant mitochondrial function. Methods and Results Cardiac myocyte senescence was evident at three months of age in Pim Triple KnockOut (PTKO) mice, where all three isoforms of Pim kinase family members are genetically deleted. Cellular hypertrophic remodeling and fetal gene program activation was followed by heart failure at six months in PTKO mice. Metabolic dysfunction is an underlying cause of cardiac senescence and instigates a decline in cardiac function. Altered mitochondrial morphology is evident consequential to Pim deletion together with decreased ATP levels and increased phosphorylated AMPK, exposing an energy deficiency in PTKO mice. Expression of the genes encoding master regulators of mitochondrial biogenesis, PPARγ coactivator-1 (PGC-1) α and β were diminished in PTKO hearts, as were downstream targets included in mitochondrial energy transduction, including fatty acid oxidation. Reversal of the dysregulated metabolic phenotype was observed by overexpressing c-Myc, a downstream target of Pim kinases. Conclusion Pim kinases prevent premature cardiac aging and maintain a healthy pool of functional mitochondria leading to efficient cellular energetics. PMID:24916111

Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia.

PubMed

Chen, Lisa S; Redkar, Sanjeev; Taverna, Pietro; Cortes, Jorge E; Gandhi, Varsha

2011-07-21

Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-x(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment.

Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia

PubMed Central

Chen, Lisa S.; Redkar, Sanjeev; Taverna, Pietro; Cortes, Jorge E.

2011-01-01

Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-xL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment. PMID:21628411

Pre-clinical evidence of PIM kinase inhibitor activity in BCR-ABL1 unmutated and mutated Philadelphia chromosome-positive (Ph+) leukemias

PubMed Central

Curi, Dany A.; Beauchamp, Elspeth M.; Blyth, Gavin T.; Arslan, Ahmet Dirim; Donato, Nicholas J.; Giles, Francis J.; Altman, Jessica K.; Platanias, Leonidas C.

2015-01-01

We investigated the efficacy of targeting the PIM kinase pathway in Philadelphia chromosome-positive (Ph+) leukemias. We provide evidence that inhibition of PIM, with the pan-PIM inhibitor SGI-1776, results in suppression of classic PIM effectors and also elements of the mTOR pathway, suggesting interplay between PIM and mTOR signals. Our data demonstrate that PIM inhibition enhances the effects of imatinib mesylate on Ph+ leukemia cells. We also found that PIM inhibition results in suppression of leukemic cell proliferation and induction of apoptosis of Ph+ leukemia cells, including those resistant to imatinib mesylate. Importantly, inhibition of PIM results in enhanced suppression of primary leukemic progenitors from patients with CML. Altogether these findings suggest that pharmacological PIM targeting may provide a unique therapeutic approach for the treatment of Ph+ leukemias. PMID:26375673

Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1

PubMed Central

Thomas, Maren; Lange-Grünweller, Kerstin; Hartmann, Dorothee; Golde, Lara; Schlereth, Julia; Streng, Dennis; Aigner, Achim; Grünweller, Arnold; Hartmann, Roland K.

2013-01-01

The human polycistronic miRNA cluster miR-17-92 is frequently overexpressed in hematopoietic malignancies and cancers. Its transcription is in part controlled by an E2F-regulated host gene promoter. An intronic A/T-rich region directly upstream of the miRNA coding region also contributes to cluster expression. Our deletion analysis of the A/T-rich region revealed a strong dependence on c-Myc binding to the functional E3 site. Yet, constructs lacking the 5′-proximal ~1.3 kb or 3′-distal ~0.1 kb of the 1.5 kb A/T-rich region still retained residual specific promoter activity, suggesting multiple transcription start sites (TSS) in this region. Furthermore, the protooncogenic kinase, Pim-1, its phosphorylation target HP1γ and c-Myc colocalize to the E3 region, as inferred from chromatin immunoprecipitation. Analysis of pri-miR-17-92 expression levels in K562 and HeLa cells revealed that silencing of E2F3, c-Myc or Pim-1 negatively affects cluster expression, with a synergistic effect caused by c-Myc/Pim-1 double knockdown in HeLa cells. Thus, we show, for the first time, that the protooncogene Pim-1 is part of the network that regulates transcription of the human miR-17-92 cluster. PMID:23749113

Pim kinases are upregulated during Epstein-Barr virus infection and enhance EBNA2 activity

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

Rainio, Eeva-Marja; Turku Graduate School of Biomedical Sciences, 20520 Turku; Ahlfors, Helena

Latent Epstein-Barr virus (EBV) infection is strongly associated with B-cell proliferative diseases such as Burkitt's lymphoma. Here we show that the oncogenic serine/threonine kinases Pim-1 and Pim-2 enhance the activity of the viral transcriptional activator EBNA2. During EBV infection of primary B-lymphocytes, the mRNA expression levels of pim genes, especially of pim-2, are upregulated and remain elevated in latently infected B-cell lines. Thus, EBV-induced upregulation of Pim kinases and Pim-stimulated EBNA2 transcriptional activity may contribute to the ability of EBV to immortalize B-cells and predispose them to malignant growth.

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

PubMed

Liu, Jing; Qu, Xinyu; Shao, Liwei; Hu, Yuan; Yu, Xin; Lan, Peixiang; Guo, Qie; Han, Qiuju; Zhang, Jian; Zhang, Cai

2018-03-04

Melanoma is the deadliest form of commonly encountered skin cancer, and has fast propagating and highly invasive characteristics. Pim-3, a highly expressed oncogene in melanoma, is a highly conserved serine/threonine kinase with various biological activities, such as proliferation-accelerating and anti-apoptosis effects on cancer progression. However, whether Pim-3 regulates melanoma metastasis has not been determined. Here, we constructed a Pim-3-silencing short hairpin RNA (sh-Pim-3), a TLR7-stimulating ssRNA and a dual-function vector containing a sh-Pim-3 and a ssRNA, and transfected them into the B16F10 melanoma cell line to investigate the effects of Pim-3 on migration and invasion in melanoma. We found that sh-Pim-3 inhibited B16F10 cell migration and invasion in vitro. In a tumor-bearing mouse model, sh-Pim-3 significantly downregulated pulmonary metastasis of B16F10 melanoma cell in vivo. Mechanistically, sh-Pim-3 inhibited metastasis by regulating the expression of genes related to epithelial-mesenchymal transition (EMT). Further study revealed that by promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), Pim-3 induced the expression of Slug, Snail, and ZEB1, which enhanced EMT-related changes and induced melanoma migration and invasion. Our study suggests that Pim-3 is a potential effective target for melanoma therapy.

Accelerated Evolution of PAK3- and PIM1-like Kinase Gene Families in the Zebra Finch, Taeniopygia guttata

PubMed Central

Kong, Lesheng; Lovell, Peter V.; Heger, Andreas; Mello, Claudio V.; Ponting, Chris P.

2010-01-01

Genes encoding protein kinases tend to evolve slowly over evolutionary time, and only rarely do they appear as recent duplications in sequenced vertebrate genomes. Consequently, it was a surprise to find two families of kinase genes that have greatly and recently expanded in the zebra finch (Taeniopygia guttata) lineage. In contrast to other amniotic genomes (including chicken) that harbor only single copies of p21-activated serine/threonine kinase 3 (PAK3) and proviral integration site 1 (PIM1) genes, the zebra finch genome appeared at first to additionally contain 67 PAK3-like (PAK3L) and 51 PIM1-like (PIM1L) protein kinase genes. An exhaustive analysis of these gene models, however, revealed most to be incomplete, owing to the absence of terminal exons. After reprediction, 31 PAK3L genes and 10 PIM1L genes remain, and all but three are predicted, from the retention of functional sites and open reading frames, to be enzymatically active. PAK3L, but not PIM1L, gene sequences show evidence of recurrent episodes of positive selection, concentrated within structures spatially adjacent to N- and C-terminal protein regions that have been discarded from zebra finch PAK3L genes. At least seven zebra finch PAK3L genes were observed to be expressed in testis, whereas two sequences were found transcribed in the brain, one broadly including the song nuclei and the other in the ventricular zone and in cells resembling Bergmann's glia in the cerebellar Purkinje cell layer. Two PIM1L sequences were also observed to be expressed with broad distributions in the zebra finch brain, one in both the ventricular zone and the cerebellum and apparently associated with glial cells and the other showing neuronal cell expression and marked enrichment in midbrain/thalamic nuclei. These expression patterns do not correlate with zebra finch-specific features such as vocal learning. Nevertheless, our results show how ancient and conserved intracellular signaling molecules can be co

Targeting PIM kinase as a therapeutic strategy in human hepatoblastoma

PubMed Central

Stafman, Laura L.; Mruthyunjayappa, Smitha; Waters, Alicia M.; Garner, Evan F.; Aye, Jamie M.; Stewart, Jerry E.; Yoon, Karina J.; Whelan, Kimberly; Mroczek-Musulman, Elizabeth; Beierle, Elizabeth A.

2018-01-01

Increasing incidence coupled with poor prognosis and treatments that are virtually unchanged over the past 20 years have made the need for the development of novel therapeutics for hepatoblastoma imperative. PIM kinases have been implicated as drivers of tumorigenesis in multiple cancers, including hepatocellular carcinoma. We hypothesized that PIM kinases, specifically PIM3, would play a role in hepatoblastoma tumorigenesis and that PIM kinase inhibition would affect hepatoblastoma in vitro and in vivo. Parameters including cell survival, proliferation, motility, and apoptosis were assessed in human hepatoblastoma cells following PIM3 knockdown with siRNA or treatment with the PIM inhibitor AZD1208. An in vivo model of human hepatoblastoma was utilized to study the effects of PIM inhibition alone and in combination with cisplatin. PIM kinases were found to be present in the human hepatoblastoma cell line, HuH6, and in a human hepatoblastoma patient-derived xenograft, COA67. PIM3 knockdown or inhibition with AZD1208 decreased cell survival, attachment independent growth, and motility. Additionally, inhibition of tumor growth was observed in a hepatoblastoma xenograft model in mice treated with AZD1208. Combination therapy with AZD1208 and cisplatin resulted in a significant increase in animal survival when compared to either treatment alone. The current studies showed that PIM kinase inhibition decreased human hepatoblastoma tumorigenicity both in vitro and in vivo, implying that PIM inhibitors may be useful as a novel therapeutic for children with hepatoblastoma.

PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression.

PubMed

Horiuchi, Dai; Camarda, Roman; Zhou, Alicia Y; Yau, Christina; Momcilovic, Olga; Balakrishnan, Sanjeev; Corella, Alexandra N; Eyob, Henok; Kessenbrock, Kai; Lawson, Devon A; Marsh, Lindsey A; Anderton, Brittany N; Rohrberg, Julia; Kunder, Ratika; Bazarov, Alexey V; Yaswen, Paul; McManus, Michael T; Rugo, Hope S; Werb, Zena; Goga, Andrei

2016-11-01

Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.

Latency Requirements for Head-Worn Display S/EVS Applications

NASA Technical Reports Server (NTRS)

Bailey, Randall E.; Trey Arthur, J. J., III; Williams, Steven P.

2004-01-01

NASA s Aviation Safety Program, Synthetic Vision Systems Project is conducting research in advanced flight deck concepts, such as Synthetic/Enhanced Vision Systems (S/EVS), for commercial and business aircraft. An emerging thrust in this activity is the development of spatially-integrated, large field-of-regard information display systems. Head-worn or helmet-mounted display systems are being proposed as one method in which to meet this objective. System delays or latencies inherent to spatially-integrated, head-worn displays critically influence the display utility, usability, and acceptability. Research results from three different, yet similar technical areas flight control, flight simulation, and virtual reality are collectively assembled in this paper to create a global perspective of delay or latency effects in head-worn or helmet-mounted display systems. Consistent definitions and measurement techniques are proposed herein for universal application and latency requirements for Head-Worn Display S/EVS applications are drafted. Future research areas are defined.

Latency requirements for head-worn display S/EVS applications

NASA Astrophysics Data System (ADS)

Bailey, Randall E.; Arthur, Jarvis J., III; Williams, Steven P.

2004-08-01

NASA's Aviation Safety Program, Synthetic Vision Systems Project is conducting research in advanced flight deck concepts, such as Synthetic/Enhanced Vision Systems (S/EVS), for commercial and business aircraft. An emerging thrust in this activity is the development of spatially-integrated, large field-of-regard information display systems. Head-worn or helmet-mounted display systems are being proposed as one method in which to meet this objective. System delays or latencies inherent to spatially-integrated, head-worn displays critically influence the display utility, usability, and acceptability. Research results from three different, yet similar technical areas - flight control, flight simulation, and virtual reality - are collectively assembled in this paper to create a global perspective of delay or latency effects in head-worn or helmet-mounted display systems. Consistent definitions and measurement techniques are proposed herein for universal application and latency requirements for Head-Worn Display S/EVS applications are drafted. Future research areas are defined.

The novel anti-adipogenic effect and mechanisms of action of SGI-1776, a Pim-specific inhibitor, in 3T3-L1 adipocytes.

PubMed

Park, Yu-Kyoung; Hong, Victor Sukbong; Lee, Tae-Yoon; Lee, Jinho; Choi, Jong-Soon; Park, Dong-Soon; Park, Gi-Young; Jang, Byeong-Churl

2016-01-01

The proviral integration site for moloney murine leukemia virus (Pim) kinases, consisting of Pim-1, Pim-2 and Pim-3, belongs to a family of serine/threonine kinases that are involved in controlling cell growth and differentiation. Pim kinases are emerging as important mediators of adipocyte differentiation. SGI-1776, an inhibitor of Pim kinases, is widely used to assess the physiological roles of Pim kinases, particularly cell functions. In the present study, we examined the effects of SGI-1776 on adipogenesis. The anti‑adipogenic effect of SGI‑1776 was measured by Oil Red O staining and AdipoRed assays. The effect of SGI‑1776 on the growth of 3T3‑L1 adipocytes was determined by cell count analysis. The effects of SGI‑1776 on the protein and mRNA expression of adipogenesis-related proteins and adipokines in 3T3‑L1 adipocytes were also evaluated by western blot analysis and RT‑PCR, respectively. Notably, SGI-1776 markedly inhibited lipid accumulation during the differentiation of 3T3-L1 preadipocytes into adipocytes. On a mechanistic level, SGI-1776 inhibited not only the expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ) and fatty acid synthase (FAS), but also the phosphorylation of signal transducer and activator of transcription-3 (STAT-3). Moreover, SGI-1776 decreased the expression of adipokines, including the expression of leptin and regulated on activation, normal T cell expressed and secreted (RANTES) during adipocyte differentiation. These findings demonstrate that SGI-1776 inhibits adipogenesis by downregulating the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS and STAT-3.

Performance Information Management System (PIMS) Communication

DTIC Science & Technology

1992-10-15

AD-A267 040 AD 14IPR NO: 92M•2501 TITLE: PERFORMANCE INFORMATION MANAGEMENT SYSTEM (PIMS) COMMUNICATION V G ,c¶• PRINCIPAL INVESTIGATOR: Kathryn P...Performance Information Management System (PIMS) MIPR No. Communication 92MM2501 6. AUTHOR(S) Kathryn P. Winter 7. PERFORMING ORGANIZATION NAME(S) AND

Transcription and translation are primary targets of Pim kinase inhibitor SGI-1776 in mantle cell lymphoma

PubMed Central

Yang, Qingshan; Chen, Lisa S.; Neelapu, Sattva S.; Miranda, Roberto N.; Medeiros, L. Jeffrey

2012-01-01

Proviral integration site for Moloney murine leukemia virus (Pim) kinases are serine/threonine/tyrosine kinases and oncoproteins that promote tumor progression. Three isoforms of Pim kinases have been identified and are known to phosphorylate numerous substrates, with regulatory functions in transcription, translation, cell cycle, and survival pathways. These kinases are involved in production, proliferation, and survival of normal B cells and are overexpressed in B-cell malignancies such as mantle cell lymphoma (MCL). SGI-1776 is a small mol-ecule and Pim kinase inhibitor with selectivity for Pim-1. We hypothesize that Pim kinase function can be inhibited by SGI-1776 in MCL and that inhibition of phosphorylation of downstream substrates will disrupt transcriptional, translational, and cell cycle processes and promote cell death. SGI-1776 treatment in 4 MCL cell lines resulted in apoptosis induction. Phosphorylation of transcription (c-Myc) and translation targets (4E-BP1), tested in Jeko-1 and Mino, was declined. Consistent with these data, Mcl-1 and cyclin D1 protein levels were decreased. Importantly, similar to cell line data, MCL primary cells but not normal cells showed similar inhibition of substrate phosphorylation and cytotoxicity from SGI-1776 treatment. Genetic knockdown of Pim-1/Pim-2 affected similar proteins in MCL cell lines. Collectively these data demonstrate Pim kinases as therapeutic targets in MCL. PMID:22955922

Transcription and translation are primary targets of Pim kinase inhibitor SGI-1776 in mantle cell lymphoma.

PubMed

Yang, Qingshan; Chen, Lisa S; Neelapu, Sattva S; Miranda, Roberto N; Medeiros, L Jeffrey; Gandhi, Varsha

2012-10-25

Proviral integration site for Moloney murine leukemia virus (Pim) kinases are serine/threonine/tyrosine kinases and oncoproteins that promote tumor progression. Three isoforms of Pim kinases have been identified and are known to phosphorylate numerous substrates, with regulatory functions in transcription, translation, cell cycle, and survival pathways. These kinases are involved in production, proliferation, and survival of normal B cells and are overexpressed in B-cell malignancies such as mantle cell lymphoma (MCL). SGI-1776 is a small molecule and Pim kinase inhibitor with selectivity for Pim-1. We hypothesize that Pim kinase function can be inhibited by SGI-1776 in MCL and that inhibition of phosphorylation of downstream substrates will disrupt transcriptional, translational, and cell cycle processes and promote cell death. SGI-1776 treatment in 4 MCL cell lines resulted in apoptosis induction. Phosphorylation of transcription (c-Myc) and translation targets (4E-BP1), tested in Jeko-1 and Mino, was declined. Consistent with these data, Mcl-1 and cyclin D1 protein levels were decreased. Importantly, similar to cell line data, MCL primary cells but not normal cells showed similar inhibition of substrate phosphorylation and cytotoxicity from SGI-1776 treatment. Genetic knockdown of Pim-1/Pim-2 affected similar proteins in MCL cell lines. Collectively these data demonstrate Pim kinases as therapeutic targets in MCL.

In vivo Knock-down of the HSV-1 Latency-Associated Transcript Reduces Reactivation from Latency.

PubMed

Watson, Zachary L; Washington, Shannan D; Phelan, Dane M; Lewin, Alfred S; Tuli, Sonal S; Schultz, Gregory S; Neumann, Donna M; Bloom, David C

2018-06-06

During Herpes Simplex Virus (HSV) latency, most viral genes are silenced with the exception of one region of the genome encoding the latency-associated transcript (LAT). This long non-coding RNA was originally described as having a role in enhancing HSV-1 reactivation. However, subsequent evidence showing that the LAT blocked apoptosis and promoted efficient establishment of latency suggested that its effects on reactivation were secondary to establishment. Here, we utilize an Adeno-associated Virus (AAV) vector to deliver a LAT-targeting hammerhead ribozyme to HSV-1-infected neurons of rabbits after the establishment of HSV-1 latency. The rabbits were then induced to reactivate latent HSV-1. Using this model, we show that decreasing LAT levels in neurons following the establishment of latency reduced the ability of the virus to reactivate. This demonstrates that the HSV-1 LAT RNA has a role in reactivation that is independent of its function in establishment of latency. In addition these results suggest the potential of AAV vectors expressing LAT-targeting ribozymes as a potential therapy for recurrent HSV disease such as herpes stromal keratitis, a leading cause of infectious blindness. Importance Herpes Simplex Virus (HSV) establishes a life long infection and remains dormant (latent) in our nerve cells. Occasionally HSV reactivates to cause disease, with HSV-1 typically causing cold sores whereas HSV-2 is the most common cause of genital herpes. The details of how HSV reactivates are largely unknown. Most of HSV's genes are silent during latency with the exception of RNAs made from the latency-associated transcript (LAT) region. While viruses that make less LAT do not reactivate efficiently, these viruses also do not establish latency as efficiently. Here we deliver a ribozyme that can degrade the LAT to the nerve cells of latently infected rabbits using a gene therapy vector. We show that this treatment blocks reactivation in the majority of the rabbits. This

Knockdown of Pim-3 suppresses the tumorigenicity of glioblastoma by regulating cell cycle and apoptosis.

PubMed

Quan, J; Zhou, L; Qu, J

2015-03-09

Products of the Pim (the proviral integration site for the Moloney murine leukemia virus) family of proto—oncogenes possess serine/threonine kinase activity and belong to the Ca2+/calmodulin—dependent protein kinase group. Pim—3, a member of the Pim family is closely linked to the development of a variety of tumors. However, the role of Pim—3 in human glioblastoma remains unknown. In this study, we elucidated the role of Pim—3 in the growth and apoptosis of glioblastoma cells. Western blotting was used for determination of protein levels, and shRNA was used for Pim—3 knockdown. The MTT assay was used to evaluate cell proliferation and flow cytometry was used to determine cell cycle status and the number of apoptotic cells. A mouse xenograft model was established by injecting nude mice with Pim—3—depleted glioblastoma cells in order to determine tumor growth in vivo. We demonstrated that Pim—3 was highly expressed in human glioblastoma cell lines. We also found that knockdown of Pim—3 by specific shRNA slowed decreased proliferation, induced cell cycle arrest in the G0/G1 phase, and increased apoptosis in glioblastoma cells. Pim—3 knockdown potently inhibited the growth of subcutaneously implanted glioblastoma cells in vivo. We further revealed that Pim—3 knockdown induced growth inhibition by reducing the levels of the anti—apoptotic protein Bcl—xl and cell cycle regulatory proteins, including cyclin D1 and Cdc25C, and increasing the levels of the pro—apoptotic protein Bax.

Pim-1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer

DTIC Science & Technology

2006-10-01

flavonoids , has been determined. We have also shown that quercetagetin is able to inhibit the activity of the PIM1 kinase in prostate cancer cells...Adventist University, Collegedale, TN 1967-1971, B.A. (biology, chemistry ) Loma Linda University, Loma Linda, CA 1971-1975, M.D

Rheological behavior of magnetic powder mixtures for magnetic PIM

NASA Astrophysics Data System (ADS)

Kim, Sung Hun; Kim, See Jo; Park, Seong Jin; Mun, Jun Ho; Kang, Tae Gon; Park, Jang Min

2012-06-01

Powder injection molding (PIM) is a promising manufacturing technology for the net-shape production of small, complex, and precise metal or ceramic components. In order to manufacture high quality magnets using PIM, the magneto-rheological (MR) properties of the PIM feedstock, i.e. magnetic powder-binder mixture, should be investigated experimentally and theoretically. The current research aims at comprehensive understanding of the rheological characteristics of the PIM feedstock. The feedstock used in the experiment consists of strontium ferrite powder and paraffin wax. Steady and oscillatory shear tests have been carried out using a plate-and-plate rheometer, under the influence of a uniform magnetic field applied externally. Rheological properties of the PIM feedstock have been measured and characterized for various conditions by changing the temperature, the powder fraction and the magnetic flux density.

Mixed-Penetrant Sorption in Ultrathin Films of Polymer of Intrinsic Microporosity PIM-1.

PubMed

Ogieglo, Wojciech; Furchner, Andreas; Ghanem, Bader; Ma, Xiaohua; Pinnau, Ingo; Wessling, Matthias

2017-11-02

Mixed-penetrant sorption into ultrathin films of a superglassy polymer of intrinsic microporosity (PIM-1) was studied for the first time by using interference-enhanced in situ spectroscopic ellipsometry. PIM-1 swelling and the concurrent changes in its refractive index were determined in ultrathin (12-14 nm) films exposed to pure and mixed penetrants. The penetrants included water, n-hexane, and ethanol and were chosen on the basis of their significantly different penetrant-penetrant and penetrant-polymer affinities. This allowed studying microporous polymer responses at diverse ternary compositions and revealed effects such as competition for the sorption sites (for water/n-hexane or ethanol/n-hexane) or enhancement in sorption of typically weakly sorbing water in the presence of more highly sorbing ethanol. The results reveal details of the mutual sorption effects which often complicate comprehension of glassy polymers' behavior in applications such as high-performance membranes, adsorbents, or catalysts. Mixed-penetrant effects are typically very challenging to study directly, and their understanding is necessary owing to a broadly recognized inadequacy of simple extrapolations from measurements in a pure component environment.

Initial Kernel Timing Using a Simple PIM Performance Model

NASA Technical Reports Server (NTRS)

Katz, Daniel S.; Block, Gary L.; Springer, Paul L.; Sterling, Thomas; Brockman, Jay B.; Callahan, David

2005-01-01

This presentation will describe some initial results of paper-and-pencil studies of 4 or 5 application kernels applied to a processor-in-memory (PIM) system roughly similar to the Cascade Lightweight Processor (LWP). The application kernels are: * Linked list traversal * Sun of leaf nodes on a tree * Bitonic sort * Vector sum * Gaussian elimination The intent of this work is to guide and validate work on the Cascade project in the areas of compilers, simulators, and languages. We will first discuss the generic PIM structure. Then, we will explain the concepts needed to program a parallel PIM system (locality, threads, parcels). Next, we will present a simple PIM performance model that will be used in the remainder of the presentation. For each kernel, we will then present a set of codes, including codes for a single PIM node, and codes for multiple PIM nodes that move data to threads and move threads to data. These codes are written at a fairly low level, between assembly and C, but much closer to C than to assembly. For each code, we will present some hand-drafted timing forecasts, based on the simple PIM performance model. Finally, we will conclude by discussing what we have learned from this work, including what programming styles seem to work best, from the point-of-view of both expressiveness and performance.

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

PubMed Central

Allen, Sariah J.; Rhode-Kurnow, Antje; Mott, Kevin R.; Jiang, Xianzhi; Carpenter, Dale; Rodriguez-Barbosa, J. Ignacio; Jones, Clinton; Wechsler, Steven L.; Ware, Carl F.

2014-01-01

Herpesvirus entry mediator (HVEM) is one of several cell surface proteins herpes simplex virus (HSV) uses for attachment/entry. HVEM regulates cellular immune responses and can also increase cell survival. Interestingly, latency-associated transcript (LAT), the only viral gene consistently expressed during neuronal latency, enhances latency and reactivation by promoting cell survival and by helping the virus evade the host immune response. However, the mechanisms of these LAT activities are not well understood. We show here for the first time that one mechanism by which LAT enhances latency and reactivation appears to be by upregulating HVEM expression. HSV-1 latency/reactivation was significantly reduced in Hvem−/− mice, indicating that HVEM plays a significant role in HSV-1 latency/reactivation. Furthermore, LAT upregulated HVEM expression during latency in vivo and also when expressed in vitro in the absence of other viral factors. This study suggests a mechanism whereby LAT upregulates HVEM expression potentially through binding of two LAT small noncoding RNAs to the HVEM promoter and that the increased HVEM then leads to downregulation of immune responses in the latent microenvironment and increased survival of latently infected cells. Thus, one of the mechanisms by which LAT enhances latency/reactivation appears to be through increasing expression of HVEM. PMID:24307582

Inhibition of oncogenic Pim-3 kinase modulates transformed growth and chemosensitizes pancreatic cancer cells to gemcitabine

PubMed Central

Xu, Dapeng; Cobb, Michael G.; Gavilano, Lily; Witherspoon, Sam M.; Williams, Daniel; White, Catherine D.; Taverna, Pietro; Bednarski, Brian K.; Kim, Hong Jin; Baldwin, Albert S.; Baines, Antonio T.

2013-01-01

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 5-year survival rate of only 6%. Although the cytosine analog gemcitabine is the drug commonly used to treat PDAC, chemoresistance unfortunately renders the drug ineffective. Thus, strategies that can decrease this resistance will be essential for improving the dismal outcome of patients suffering from this disease. We previously observed that oncogenic Pim-1 kinase was aberrantly expressed in PDAC tissues and cell lines and was responsible for radioresistance. Furthermore, members of the Pim family have been shown to reduce the efficacy of chemotherapeutic drugs in cancer. Therefore, we attempted to evaluate the role of Pim-3 in chemoresistance of PDAC cells. We were able to confirm upregulation of the Pim-3 oncogene in PDAC tissues and cell lines vs. normal samples. Biological consequences of inhibiting Pim-3 expression with shRNA-mediated suppression included decreases in anchorage-dependent growth, invasion through Matrigel and chemoresistance to gemcitabine as measured by caspase-3 activity. Additionally, we were able to demonstrate that Pim-1 and Pim-3 play overlapping but non-identical roles as it relates to gemcitabine sensitivity of pancreatic cancer cells. To further support the role of Pim-3 suppression in sensitizing PDAC cells to gemcitabine, we used the pharmacological Pim kinase inhibitor SGI-1776. Treatment of PDAC cells with SGI-1776 resulted in decreased phosphorylation of the proapoptotic protein Bad and cell cycle changes. When SGI-1776 was combined with gemcitabine, there was a greater decrease in cell viability in the PDAC cells vs. cells treated with either of the drugs separately. These results suggest combining drug therapies that inhibit Pim kinases, such as Pim-3, with chemotherapeutic agents, to aid in decreasing chemoresistance in pancreatic cancer. PMID:23760491

Experiments on PIM in Support of the Development of IVA Technology for Radiography at AWE

NASA Astrophysics Data System (ADS)

Clough, Stephen G.; Thomas, Kenneth J.; Williamson, Mark C.; Phillips, Martin J.; Smith, Ian D.; Bailey, Vernon L.; Kishi, Hiroshi J.; Maenchen, John E.; Johnson, David L.

2002-12-01

The PIM machine has been designed and constructed at AWE as part of a program to investigate IVA technology for radiographic applications. PIM, as originally constructed, was a prospective single module of a 14 MV, 100 kA, ten module machine. The design of such a machine is a primary goal of the program as several are required to provide multi-axis radiography in a new Hydrodynamics Research Facility (HRF). Another goal is to design lower voltage machines (ranging from 1 to 5 MV) utilizing PIM style components. The original PIM machine consisted of a single inductive cavity pulsed by a 10 ohm water dielectric Blumlein pulse forming line (PFL) charged by a Marx generator. These components successfully achieved their design voltages and data on the prepulse was obtained showing it to be worse than expected. This information provided a basis for design work on the 14 MV HRF IVA, carried out by Titan-PSD, resulting in a proposal for a prepulse switch, a prototype of which should be installed on PIM by the end of this year. The original single, coaxial switch used to initiate the Blumlein has been replaced by a prototype laser triggered switching arrangement, also designed by Titan-PSD, which it was desired to test prior to its eventual use in the HRF. Despite problems with the laser, which will necessitate further experiments, it was determined that laser triggering with low jitter was occurring. A split oil co-ax feed has now been used to install a second cavity, in parallel with the first, on the PIM Blumlein. This two cavity configuration provides a prototype for future radiographic machines operating at up to 3 MV and a test facility for diode research.

Photodynamic immune modulation (PIM)

NASA Astrophysics Data System (ADS)

North, John R.; Hunt, David W. C.; Simkin, Guillermo O.; Ratkay, Leslie G.; Chan, Agnes H.; Lui, Harvey; Levy, Julia G.

1999-09-01

Photodynamic Therapy (PDT) is accepted for treatment of superficial and lumen-occluding tumors in regions accessible to activating light and is now known to be effective in closure of choroidal neovasculature in Age Related Macular Degeneration. PDT utilizes light absorbing drugs (photosensitizers) that generate the localized formation of reactive oxygen species after light exposure. In a number of systems, PDT has immunomodulatory effects; Photodynamic Immune Modulation (PIM). Using low- intensity photodynamic regimens applied over a large body surface area, progression of mouse autoimmune disease could be inhibited. Further, this treatment strongly inhibited the immunologically- medicated contact hypersensitivity response to topically applied chemical haptens. Immune modulation appears to result from selective targeting of activated T lymphocytes and reduction in immunostimulation by antigen presenting cells. Psoriasis, an immune-mediated skin condition, exhibits heightened epidermal cell proliferation, epidermal layer thickening and plaque formation at different body sites. In a recent clinical trial, approximately one-third of patients with psoriasis and arthritis symptoms (psoriatic arthritis) displayed a significant clinical improvement in several psoriasis-related parameters after four weekly whole-body PIM treatments with verteporfin. The safety profile was favorable. The capacity of PIM to influence other human immune disorders including rheumatoid arthritis is under extensive evaluation.

Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes.

PubMed

Mumenthaler, Shannon M; Ng, Patricia Y B; Hodge, Amanda; Bearss, David; Berk, Gregory; Kanekal, Sarath; Redkar, Sanjeev; Taverna, Pietro; Agus, David B; Jain, Anjali

2009-10-01

The serine/threonine family of Pim kinases function as oncogenes and have been implicated in prostate cancer progression, particularly in hormone-refractory prostate disease, as a result of their antiapoptotic function. In this study, we used a pharmacologic inhibitor targeting the Pim family members, SGI-1776, to determine whether modulation of Pim kinase activity could alter prostate cancer cell survival and modulate chemotherapy resistance. Extensive biochemical characterization of SGI-1776 confirmed its specificity for the three isoforms of the Pim family. Treatment of prostate cancer cells with SGI-1776 resulted in a dose-dependent reduction in phosphorylation of known Pim kinase substrates that are involved in cell cycle progression and apoptosis (p21(Cip1/WAF1) and Bad). Consequently, SGI-1776 compromised overall cell viability by inducing G(1) cell cycle arrest and triggering apoptosis. Overexpression of recombinant Pim-1 markedly increased sensitivity of SGI-1776-mediated prostate cancer cell apoptosis and p21(Cip1/WAF1) phosphorylation inhibition, reinforcing the specificity of SGI-1776. An additional cytotoxic effect was observed when SGI-1776 was combined with taxane-based chemotherapy agents. SGI-1776 was able to reduce cell viability in a multidrug resistance 1 protein-based taxane-refractory prostate cancer cell line. In addition, SGI-1776 treatment was able to resensitize chemoresistant cells to taxane-based therapies by inhibiting multidrug resistance 1 activity and inducing apoptosis. These findings support the idea that inhibiting Pim kinases, in combination with a chemotherapeutic agent, could play an important role in prostate cancer treatment by targeting the clinical problem of chemoresistance.

Tutorial: Reactive high power impulse magnetron sputtering (R-HiPIMS)

NASA Astrophysics Data System (ADS)

Anders, André

2017-05-01

High Power Impulse Magnetron Sputtering (HiPIMS) is a coating technology that combines magnetron sputtering with pulsed power concepts. By applying power in pulses of high amplitude and a relatively low duty cycle, large fractions of sputtered atoms and near-target gases are ionized. In contrast to conventional magnetron sputtering, HiPIMS is characterized by self-sputtering or repeated gas recycling for high and low sputter yield materials, respectively, and both for most intermediate materials. The dense plasma in front of the target has the dual function of sustaining the discharge and providing plasma-assistance to film growth, affecting the microstructure of growing films. Many technologically interesting thin films are compound films, which are composed of one or more metals and a reactive gas, most often oxygen or nitrogen. When reactive gas is added, non-trivial consequences arise for the system because the target may become "poisoned," i.e., a compound layer forms on the target surface affecting the sputtering yield and the yield of secondary electron emission and thereby all other parameters. It is emphasized that the target state depends not only on the reactive gas' partial pressure (balanced via gas flow and pumping) but also on the ion flux to the target, which can be controlled by pulse parameters. This is a critical technological opportunity for reactive HiPIMS (R-HiPIMS). The scope of this tutorial is focused on plasma processes and mechanisms of operation and only briefly touches upon film properties. It introduces R-HiPIMS in a systematic, step-by-step approach by covering sputtering, magnetron sputtering, reactive magnetron sputtering, pulsed reactive magnetron sputtering, HiPIMS, and finally R-HiPIMS. The tutorial is concluded by considering variations of R-HiPIMS known as modulated pulsed power magnetron sputtering and deep-oscillation magnetron sputtering and combinations of R-HiPIMS with superimposed dc magnetron sputtering.

Discovery of novel Pim-1 kinase inhibitors by a hierarchical multistage virtual screening approach based on SVM model, pharmacophore, and molecular docking.

PubMed

Ren, Ji-Xia; Li, Lin-Li; Zheng, Ren-Lin; Xie, Huan-Zhang; Cao, Zhi-Xing; Feng, Shan; Pan, You-Li; Chen, Xin; Wei, Yu-Quan; Yang, Sheng-Yong

2011-06-27

In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors.

Up-regulation of Pim-3 in Chronic Obstructive Pulmonary Disease (COPD) patients and its potential therapeutic role in COPD rat modeling.

PubMed

Yang, Cheng; Li, Li; Guo, Junhua; Zhang, Weiqiang; Zhu, Wenbiao; Rao, Xinhui; Huang, Wenjie

2017-04-01

Pim-3 belongs to the PIM kinase family and plays an important role in promoting inflammation, which is essential in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Immunohistochemistry (IHC), western blot, and RT-PCR analyses were performed to assess the expression of Pim-3 in both COPD and healthy lung tissue samples. SMA (Smooth Muscle Actin) and Cyclin D1 expression were detected by IHC. We also constructed animal models for the control, COPD, and Pim-3 inhibition groups, in order to analyze the effects of Pim-3 inhibition on COPD, and the role of Pim-3 in the p38 pathway. Compared with normal lung tissue, Pim-3 mRNA and protein were up-regulated in COPD tissue. Expression of Cyclin D1 and SMA were also up-regulated in the COPD group. In the animal model experiment, we found that suppression of Pim-3 decreased Pim-3, Cyclin D1, and SMA expression, as well as ameliorated lung damage in COPD patients. The inhibition of Pim-3 also resulted in the suppression of the p38 pathway. Our study suggests that up-regulation of Pim-3 successfully accelerated COPD development, and aggravated lung damage. The molecular mechanism of Pim-3 in COPD might be related to the p38 pathway, and is correlated with Cyclin D1 and SMA expression. Copyright © 2017 Elsevier GmbH. All rights reserved.

Downregulation of microRNA-33a promotes cyclin-dependent kinase 6, cyclin D1 and PIM1 expression and gastric cancer cell proliferation

PubMed Central

WANG, YUDONG; ZHOU, XINLIANG; SHAN, BAOEN; HAN, JING; WANG, FEIFEI; FAN, XIAOJIE; LV, YALEI; CHANG, LIANG; LIU, WEI

2015-01-01

Although microRNA-33 (miR-33) family members are known to be involved in the regulation and balancing of cholesterol metabolism, fatty acid oxidation and insulin signaling, their functions in carcinogenesis are controversial and the underlying mechanisms have remained elusive. Gastric cancer is the fourth most common malignancy in the world; however, the dysregulation and function of miR-33 family members in gastric cancer have not been extensively studied. The present study reported that a miR-33 family member, miR-33a, was significantly downregulated in gastric cancer tissues and gastric cancer cell lines. Of note, the expression of miR-33a was inversely correlated with pathological differentiation and metastasis as well as gastric cancer biomarker CA199. A cell-counting kit-8 assay showed that transfection of the SGC-7901 gastric cell line with miR-33a-overexpression plasmid inhibited the capability of the cells to proliferate. Furthermore, overexpression of miR-33a led to cell cycle arrest of SGC-7901 cells in G1 phase. In addition, a luciferase reporter assay showed that miR-33a directly targeted cyclin-dependent kinase 6 (CDK6), cyclin D1 (CCND1) and serine/threonine kinase PIM-1. In gastric cancer specimens, the reduced expression of miR-33a was associated with increased expression of CDK-6, CCND1 and PIM1. However, only PIM1 expression was significantly increased in cancer tissues compared with that in their adjacent tissues. The present study revealed that miR-33a was downregulated in gastric cancer tissues and cell lines, while forced overexpression of miR-33a decreased CDK-6, CCND1 and PIM1 expression to inhibit gastric cancer cell proliferation by causing G1 phase arrest. miR-33a overexpression may therefore resemble an efficient strategy for gastric cancer therapy. PMID:26352175

Overcoming Resistance to Inhibitors of the Akt Protein Kinase by Modulation of the Pim Kinase Pathway

DTIC Science & Technology

2017-01-01

regulated by Pim and what is the outcome of treating animals with Pim inhibitors. To explore these tasks we first stained human tumor and normal samples ...Sepharose beads. The beads were incubated with 100 ng of purified Pim-1 proteins at 37 °C for 30 minutes. Samples were analyzed by immunoblot assays using...secreted by these cells using novel technology, develop potential urine biomarkers of treatment success. 1R21 CA178324-01A1 (Kraft, PI) 06/01/15

Tutorial: Reactive high power impulse magnetron sputtering (R-HiPIMS)

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

Anders, André

High Power Impulse Magnetron Sputtering (HiPIMS) is a coating technology that combines magnetron sputtering with pulsed power concepts. Furthermore, by applying power in pulses of high amplitude and a relatively low duty cycle, large fractions of sputtered atoms and near-target gases are ionized. In contrast to conventional magnetron sputtering, HiPIMS is characterized by self-sputtering or repeated gas recycling for high and low sputter yield materials, respectively, and both for most intermediate materials. The dense plasma in front of the target has the dual function of sustaining the discharge and providing plasma-assistance to film growth, affecting the microstructure of growing films.more » Many technologically interesting thin films are compound films, which are composed of one or more metals and a reactive gas, most often oxygen or nitrogen. When reactive gas is added, non-trivial consequences arise for the system because the target may become “poisoned,” i.e., a compound layer forms on the target surface affecting the sputtering yield and the yield of secondary electron emission and thereby all other parameters. It is emphasized that the target state depends not only on the reactive gas' partial pressure (balanced via gas flow and pumping) but also on the ion flux to the target, which can be controlled by pulse parameters. This is a critical technological opportunity for reactive HiPIMS (R-HiPIMS). The scope of this tutorial is focused on plasma processes and mechanisms of operation and only briefly touches upon film properties. It introduces R-HiPIMS in a systematic, step-by-step approach by covering sputtering, magnetron sputtering, reactive magnetron sputtering, pulsed reactive magnetron sputtering, HiPIMS, and finally R-HiPIMS. The tutorial is concluded by considering variations of R-HiPIMS known as modulated pulsed power magnetron sputtering and deep-oscillation magnetron sputtering and combinations of R-HiPIMS with superimposed dc magnetron

Tutorial: Reactive high power impulse magnetron sputtering (R-HiPIMS)

DOE PAGES

Anders, André

2017-03-21

High Power Impulse Magnetron Sputtering (HiPIMS) is a coating technology that combines magnetron sputtering with pulsed power concepts. Furthermore, by applying power in pulses of high amplitude and a relatively low duty cycle, large fractions of sputtered atoms and near-target gases are ionized. In contrast to conventional magnetron sputtering, HiPIMS is characterized by self-sputtering or repeated gas recycling for high and low sputter yield materials, respectively, and both for most intermediate materials. The dense plasma in front of the target has the dual function of sustaining the discharge and providing plasma-assistance to film growth, affecting the microstructure of growing films.more » Many technologically interesting thin films are compound films, which are composed of one or more metals and a reactive gas, most often oxygen or nitrogen. When reactive gas is added, non-trivial consequences arise for the system because the target may become “poisoned,” i.e., a compound layer forms on the target surface affecting the sputtering yield and the yield of secondary electron emission and thereby all other parameters. It is emphasized that the target state depends not only on the reactive gas' partial pressure (balanced via gas flow and pumping) but also on the ion flux to the target, which can be controlled by pulse parameters. This is a critical technological opportunity for reactive HiPIMS (R-HiPIMS). The scope of this tutorial is focused on plasma processes and mechanisms of operation and only briefly touches upon film properties. It introduces R-HiPIMS in a systematic, step-by-step approach by covering sputtering, magnetron sputtering, reactive magnetron sputtering, pulsed reactive magnetron sputtering, HiPIMS, and finally R-HiPIMS. The tutorial is concluded by considering variations of R-HiPIMS known as modulated pulsed power magnetron sputtering and deep-oscillation magnetron sputtering and combinations of R-HiPIMS with superimposed dc magnetron

HTLV-1 Tax activates HIV-1 transcription in latency models.

PubMed

Geddes, Victor Emmanuel Viana; José, Diego Pandeló; Leal, Fabio E; Nixon, Douglas F; Tanuri, Amilcar; Aguiar, Renato Santana

2017-04-01

HIV-1 latency is a major obstacle to HIV-1 eradication. Coinfection with HTLV-1 has been associated with faster progression to AIDS. HTLV-1 encodes the transactivator Tax which can activate both HTLV-1 and HIV-1 transcription. Here, we demonstrate that Tax activates HIV transcription in latent CD4 + T cells. Tax promotes the activation of P-TEFb, releasing CDK9 and Cyclin T1 from inactive forms, promoting transcription elongation and reactivation of latent HIV-1. Tax mutants lacking interaction with the HIV-1-LTR promoter were not able to activate P-TEFb, with no subsequent activation of latent HIV. In HIV-infected primary resting CD4 + T cells, Tax-1 reactivated HIV-1 transcription up to five fold, confirming these findings in an ex vivo latency model. Finally, our results confirms that HTLV-1/Tax hijacks cellular partners, promoting HIV-1 transcription, and this interaction should be further investigated in HIV-1 latency studies in patients with HIV/HTLV-1 co-infection. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxaliplatin antagonizes HIV-1 latency by activating NF-κB without causing global T cell activation

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

Zhu, Xiaoli; Liu, Sijie; Wang, Pengfei

Highlights: • The chemotherapeutic drug oxaliplatin reactivates latent HIV-1 in this cell line model of HIV-1 latency. • Reactivation is synergized when oxaliplatin is used in combination with valproic acid. • Oxaliplatin reactivates latent HIV-1 through activation of NF-kB and does not induce T cell activation. - Abstract: Reactivation of latent HIV-1 is a promising strategy for the clearance of the viral reservoirs. Because of the limitations of current agents, identification of new latency activators is urgently required. Using an established model of HIV-1 latency, we examined the effect of Oxaliplatin on latent HIV-1 reactivation. We showed that Oxaliplatin, alonemore » or in combination with valproic acid (VPA), was able to reactivate HIV-1 without inducing global T cell activation. We also provided evidence that Oxaliplatin reactivated HIV-1 expression by inducing nuclear factor kappa B (NF-κB) nuclear translocation. Our results indicated that Oxaliplatin could be a potential drug candidate for anti-latency therapies.« less

Hit to lead account of the discovery of a new class of inhibitors of Pim kinases and crystallographic studies revealing an unusual kinase binding mode.

PubMed

Qian, Kevin; Wang, Lian; Cywin, Charles L; Farmer, Bennett T; Hickey, Eugene; Homon, Carol; Jakes, Scott; Kashem, Mohammed A; Lee, George; Leonard, Scott; Li, Jun; Magboo, Ronald; Mao, Wang; Pack, Edward; Peng, Charlene; Prokopowicz, Anthony; Welzel, Morgan; Wolak, John; Morwick, Tina

2009-04-09

A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.

HTMT-class Latency Tolerant Parallel Architecture for Petaflops Scale Computation

NASA Technical Reports Server (NTRS)

Sterling, Thomas; Bergman, Larry

2000-01-01

semiconductor logic. Wave Division Multiplexing optical communications can approach a peak per fiber bandwidth of 1 Tbps and the new Data Vortex network topology employing this technology can connect tens of thousands of ports providing a bi-section bandwidth on the order of a Petabyte per second with latencies well below 100 nanoseconds, even under heavy loads. Processor-in-Memory (PIM) technology combines logic and memory on the same chip exposing the internal bandwidth of the memory row buffers at low latency. And holographic storage photorefractive storage technologies provide high-density memory with access a thousand times faster than conventional disk technologies. Together these technologies enable a new class of shared memory system architecture with a peak performance in the range of a Petaflops but size and power requirements comparable to today's largest Teraflops scale systems. To achieve high-sustained performance, HTMT combines an advanced multithreading processor architecture with a memory-driven coarse-grained latency management strategy called "percolation", yielding high efficiency while reducing the much of the parallel programming burden. This paper will present the basic system architecture characteristics made possible through this series of advanced technologies and then give a detailed description of the new percolation approach to runtime latency management.

The Plasma Instrument for Magnetic Sounding (PIMS) on The Europa Clipper Mission

NASA Astrophysics Data System (ADS)

Westlake, Joseph H.; McNutt, Ralph L.; Kasper, Justin C.; Case, Anthony W.; Grey, Matthew P.; Kim, Cindy K.; Battista, Corina C.; Rymer, Abigail; Paty, Carol S.; Jia, Xianzhe; Stevens, Michael L.; Khurana, Krishan; Kivelson, Margaret G.; Slavin, James A.; Korth, Haje H.; Smith, Howard T.; Krupp, Norbert; Roussos, Elias; Saur, Joachim

2016-10-01

The Europa Clipper mission is equipped with a sophisticated suite of 9 instruments to study Europa's interior and ocean, geology, chemistry, and habitability from a Jupiter orbiting spacecraft. The Plasma Instrument for Magnetic Sounding (PIMS) on Europa Clipper is a Faraday Cup based plasma instrument whose heritage dates back to the Voyager spacecraft. PIMS will measure the plasma that populates Jupiter's magnetosphere and Europa's ionosphere. The science goals of PIMS are to: 1) estimate the ocean salinity and thickness by determining Europa's magnetic induction response, corrected for plasma contributions; 2) assess mechanisms responsible for weathering and releasing material from Europa's surface into the atmosphere and ionosphere; and 3) understand how Europa influences its local space environment and Jupiter's magnetosphere and vice versa.Europa is embedded in a complex Jovian magnetospheric plasma, which rotates with the tilted planetary field and interacts dynamically with Europa's ionosphere affecting the magnetic induction signal. Plasma from Io's temporally varying torus diffuses outward and mixes with the charged particles in Europa's own torus producing highly variable plasma conditions at Europa. PIMS works in conjunction with the Interior Characterization of Europa using Magnetometry (ICEMAG) investigation to probe Europa's subsurface ocean. This investigation exploits currents induced in Europa's interior by the moon's exposure to variable magnetic fields in the Jovian system to infer properties of Europa's subsurface ocean such as its depth, thickness, and conductivity. This technique was successfully applied to Galileo observations and demonstrated that Europa indeed has a subsurface ocean. While these Galileo observations contributed to the renewed interest in Europa, due to limitations in the observations the results raised major questions that remain unanswered. PIMS will greatly refine our understanding of Europa's global liquid ocean by

The Plasma Instrument for Magnetic Sounding (PIMS) onboard the Europa Clipper Mission

NASA Astrophysics Data System (ADS)

Westlake, Joseph H.; McNutt, Ralph L.; Kasper, Justin C.; Rymer, Abigail; Case, Anthony; Battista, Corina; Cochrane, Corey; Coren, David; Crew, Alexander; Grey, Matthew; Jia, Xianzhe; Khurana, Krishan; Kim, Cindy; Kivelson, Margaret G.; Korth, Haje; Krupp, Norbert; Paty, Carol; Roussos, Elias; Stevens, Michael; Slavin, James A.; Smith, Howard T.; Saur, Joachim

2017-10-01

Europa is embedded in a complex Jovian magnetospheric plasma, which rotates with the tilted planetary field and interacts dynamically with Europa’s ionosphere affecting the magnetic induction signal. Plasma from Io’s temporally varying torus diffuses outward and mixes with the charged particles in Europa’s own torus producing highly variable plasma conditions. Onboard the Europa Clipper spacecraft the Plasma Instrument for Magnetic Sounding (PIMS) works in conjunction with the Interior Characterization of Europa using Magnetometry (ICEMAG) investigation to probe Europa’s subsurface ocean. This investigation exploits currents induced in Europa’s interior by the moon’s exposure to variable magnetic fields in the Jovian system to infer properties of Europa’s subsurface ocean such as its depth, thickness, and conductivity. This technique was successfully applied to Galileo observations and demonstrated that Europa indeed has a subsurface ocean. While these Galileo observations contributed to the renewed interest in Europa, due to limitations in the observations the results raised major questions that remain unanswered. PIMS will greatly refine our understanding of Europa’s global liquid ocean by accounting for contributions to the magnetic field from plasma currents.The Europa Clipper mission is equipped with a sophisticated suite of 9 instruments to study Europa's interior and ocean, geology, chemistry, and habitability from a Jupiter orbiting spacecraft. PIMS on Europa Clipper is a Faraday Cup based plasma instrument whose heritage dates back to the Voyager spacecraft. PIMS will measure the plasma that populates Jupiter’s magnetosphere and Europa’s ionosphere. The science goals of PIMS are to: 1) estimate the ocean salinity and thickness by determining Europa’s magnetic induction response, corrected for plasma contributions; 2) assess mechanisms responsible for weathering and releasing material from Europa’s surface into the atmosphere and

The Plasma Instrument for Magnetic Sounding (PIMS) on The Europa Clipper Mission

NASA Astrophysics Data System (ADS)

Westlake, J. H.; McNutt, R. L., Jr.; Kasper, J. C.; Battista, C.; Case, A. W.; Cochrane, C.; Grey, M.; Jia, X.; Kivelson, M.; Kim, C.; Korth, H.; Khurana, K. K.; Krupp, N.; Paty, C. S.; Roussos, E.; Rymer, A. M.; Stevens, M. L.; Slavin, J. A.; Smith, H. T.; Saur, J.; Coren, D.

2017-12-01

The Europa Clipper mission is equipped with a sophisticated suite of 9 instruments to study Europa's interior and ocean, geology, chemistry, and habitability from a Jupiter orbiting spacecraft. The Plasma Instrument for Magnetic Sounding (PIMS) on Europa Clipper is a Faraday Cup based plasma instrument whose heritage dates back to the Voyager spacecraft. PIMS will measure the plasma that populates Jupiter's magnetosphere and Europa's ionosphere. The science goals of PIMS are to: 1) estimate the ocean salinity and thickness by determining Europa's magnetic induction response, corrected for plasma contributions; 2) assess mechanisms responsible for weathering and releasing material from Europa's surface into the atmosphere and ionosphere; and 3) understand how Europa influences its local space environment and Jupiter's magnetosphere and vice versa. Europa is embedded in a complex Jovian magnetospheric plasma, which rotates with the tilted planetary field and interacts dynamically with Europa's ionosphere affecting the magnetic induction signal. Plasma from Io's temporally varying torus diffuses outward and mixes with the charged particles in Europa's own torus producing highly variable plasma conditions at Europa. PIMS works in conjunction with the Interior Characterization of Europa using Magnetometry (ICEMAG) investigation to probe Europa's subsurface ocean. This investigation exploits currents induced in Europa's interior by the moon's exposure to variable magnetic fields in the Jovian system to infer properties of Europa's subsurface ocean such as its depth, thickness, and conductivity. This technique was successfully applied to Galileo observations and demonstrated that Europa indeed has a subsurface ocean. While these Galileo observations contributed to the renewed interest in Europa, due to limitations in the observations the results raised major questions that remain unanswered. PIMS will greatly refine our understanding of Europa's global liquid ocean by

FLT3-ITD induces expression of Pim kinases through STAT5 to confer resistance to the PI3K/Akt pathway inhibitors on leukemic cells by enhancing the mTORC1/Mcl-1 pathway.

PubMed

Okada, Keigo; Nogami, Ayako; Ishida, Shinya; Akiyama, Hiroki; Chen, Cheng; Umezawa, Yoshihiro; Miura, Osamu

2018-02-06

FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells. These cooperative effects were enhanced or inhibited by knock down of mTOR or expression of its activated mutant, respectively. Overexpression of Mcl-1 conferred the resistance on 32D/ITD cells to combined inhibition of the PI3K/Akt pathway and Pim kinases, while the Mcl-1-specific BH3 mimetic A-1210477 conquered the resistance of MV4-11 cells to GDC-0941. Furthermore, overexpression of Pim-1 in 32D/TKD enhanced the mTORC1/Mcl-1 pathway and partially protected it from the PI3K/Akt inhibitors or the FLT3 inhibitor gilteritinib to confer the resistance to PI3K/Akt inhibitors. Finally, AZD1208 and GDC-0941 cooperatively inhibited the mTORC1/Mcl-1 pathway and reduced viable cell numbers of primary AML cells from some FLT3-ITD positive cases. Thus, Pim kinases may protect the mTORC1/4EBP1/Mcl-1 pathway to confer the resistance to the PI3K/Akt inhibitors on FLT3-ITD cells and represent promising therapeutic targets.

Potentially inappropriate medicines in elderly hospitalised patients according to the EU(7)-PIM list, STOPP version 2 criteria and comprehensive protocol.

PubMed

Mucalo, Iva; Hadžiabdić, Maja Ortner; Brajković, Andrea; Lukić, Sonja; Marić, Patricia; Marinović, Ivana; Bačić-Vrca, Vesna

2017-08-01

The aim of this study was to measure the prevalence of potentially inappropriate medications (PIMs) by using the EU(7)-PIM list, STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions) version 2 criteria and the new comprehensive protocol. This prospective study involved a sample of 276 consecutive elderly patients discharged from the university teaching hospital. Age, gender, diagnoses, medication history and medicines at discharge were recorded. The main outcome measure was the prevalence of PIMs according to each set of criteria: EU(7)-PIM list, STOPP version 2 criteria and comprehensive protocol. The median patient age (range) was 74 (65-92) years. The median number of prescribed medications was 7 (1-17). STOPP identified 393 PIMs affecting 190 patients (69%), EU(7)-PIM list identified 330 PIMs in 184 patients (66.7%) whilst the comprehensive protocol identified 134 PIMs in 102 patients (37%). STOPP version 2 criteria identified significantly more PIMs per patient than the other two protocols (p < 0.001). Gender (p = 0.002), glomerular filtration rate (p = 0.039) and number of comorbidities (p = 0.001) were associated with the proportion of PIMs for the STOPP version 2 criteria only. A very high PIM prevalence at discharge was reported suggesting the urgent need for actions to reduce them. STOPP version 2 criteria identified significantly more PIMs than the EU(7)-PIM list and the comprehensive protocol and was found as a more sensitive tool for PIM detection.

RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia.

PubMed

Hospital, M-A; Jacquel, A; Mazed, F; Saland, E; Larrue, C; Mondesir, J; Birsen, R; Green, A S; Lambert, M; Sujobert, P; Gautier, E-F; Salnot, V; Le Gall, M; Decroocq, J; Poulain, L; Jacque, N; Fontenay, M; Kosmider, O; Récher, C; Auberger, P; Mayeux, P; Bouscary, D; Sarry, J-E; Tamburini, J

2018-03-01

Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.

The influence of superimposed DC current on electrical and spectroscopic characteristics of HiPIMS discharge

NASA Astrophysics Data System (ADS)

Zuo, Xiao; Chen, Rende; Liu, Jingzhou; Ke, Peiling; Wang, Aiying

2018-01-01

The electrical characteristics and spectroscopic properties have been comprehensively investigated in a DC superimposed high power impulse magnetron sputtering (DC-HiPIMS) deposition system in this paper. The influence of superimposed DC current on the variation of target and substrate current waveforms, active species and electron temperatures with pulse voltages are focused. The peak target currents in DC-HiPIMS are lower than in HiPIMS. The time scales of the two main discharge processes like ionization and gas rarefaction in DC-HiPIMS are analyzed. When the pulse voltage is higher than 600 V, the gas rarefaction effect becomes apparent. Overall, the ionization process is found to be dominant in the initial ˜100 μs during each pulse. The active species of Ar and Cr in DC-HiPIMS are higher than in HiPIMS unless that the pulse voltage reaches 900 V. However, the ionization degree in HiPIMS exceeds that in DC-HiPIMS at around 600 V. The electron temperature calculated by modified Boltzmann plot method based on corona model has a precipitous increase from 0.87 to 25.0 eV in HiPIMS, but varies mildly after the introduction of the superimposed DC current. Additionally, the current from plasma flowing to the substrate is improved when a DC current is superimposed with HiPIMS.

Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation.

PubMed

Kapoor, Shivani; Natarajan, Karthika; Baldwin, Patrick R; Doshi, Kshama A; Lapidus, Rena G; Mathias, Trevor J; Scarpa, Mario; Trotta, Rossana; Davila, Eduardo; Kraus, Manfred; Huszar, Dennis; Tron, Adriana E; Perrotti, Danilo; Baer, Maria R

2018-01-01

Purpose: fms -like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G 1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234-47. ©2017 AACR . ©2017 American Association for Cancer Research.

PIMS: Memristor-Based Processing-in-Memory-and-Storage.

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

Cook, Jeanine

Continued progress in computing has augmented the quest for higher performance with a new quest for higher energy efficiency. This has led to the re-emergence of Processing-In-Memory (PIM) ar- chitectures that offer higher density and performance with some boost in energy efficiency. Past PIM work either integrated a standard CPU with a conventional DRAM to improve the CPU- memory link, or used a bit-level processor with Single Instruction Multiple Data (SIMD) control, but neither matched the energy consumption of the memory to the computation. We originally proposed to develop a new architecture derived from PIM that more effectively addressed energymore » efficiency for high performance scientific, data analytics, and neuromorphic applications. We also originally planned to implement a von Neumann architecture with arithmetic/logic units (ALUs) that matched the power consumption of an advanced storage array to maximize energy efficiency. Implementing this architecture in storage was our original idea, since by augmenting storage (in- stead of memory), the system could address both in-memory computation and applications that accessed larger data sets directly from storage, hence Processing-in-Memory-and-Storage (PIMS). However, as our research matured, we discovered several things that changed our original direc- tion, the most important being that a PIM that implements a standard von Neumann-type archi- tecture results in significant energy efficiency improvement, but only about a O(10) performance improvement. In addition to this, the emergence of new memory technologies moved us to propos- ing a non-von Neumann architecture, called Superstrider, implemented not in storage, but in a new DRAM technology called High Bandwidth Memory (HBM). HBM is a stacked DRAM tech- nology that includes a logic layer where an architecture such as Superstrider could potentially be implemented.« less

PIM1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer

DTIC Science & Technology

2008-10-31

2007) C«t Pr. T«K:J1 r. 587-605 CaUtr«M, F. I . |200S> Oil . te- Tx\\u< 35.443-582 I ..-:tiatr.-ir, C.Iixo;, X. Cfitniti t,B<nor V..Dcrtgovsu, V,Chat...control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. I . REPORT DATE (DD-MM-YYYY) 31-10-2008 2. REPORT TYPE Annual 3. DATES COVERED...reporting period a number of studies were undertaken to characterize Fig. 4. Modulation of docetaxel cell kill by enforced expression of pim-1 cDNAs. 1 i

The EU(7)-PIM list: a list of potentially inappropriate medications for older people consented by experts from seven European countries.

PubMed

Renom-Guiteras, Anna; Meyer, Gabriele; Thürmann, Petra A

2015-07-01

The aim of the study was to develop a European list of potentially inappropriate medications (PIM) for older people, which can be used for the analysis and comparison of prescribing patterns across European countries and for clinical practice. A preliminary PIM list was developed, based on the German PRISCUS list of potentially inappropriate medications and other PIM lists from the USA, Canada and France. Thirty experts on geriatric prescribing from Estonia, Finland, France, the Netherlands, Spain and Sweden participated; eight experts performed a structured expansion of the list, suggesting further medications; twenty-seven experts participated in a two-round Delphi survey assessing the appropriateness of drugs and suggesting dose adjustments and therapeutic alternatives. Finally, twelve experts completed a brief final survey to decide upon issues requiring further consensus. Experts reached a consensus that 282 chemical substances or drug classes from 34 therapeutic groups are PIM for older people; some PIM are restricted to a certain dose or duration of use. The PIM list contains suggestions for dose adjustments and therapeutic alternatives. The European Union (EU)(7)-PIM list is a screening tool, developed with participation of experts from seven European countries, that allows identification and comparison of PIM prescribing patterns for older people across European countries. It can also be used as a guide in clinical practice, although it does not substitute the decision-making process of individualised prescribing for older people. Further research is needed to investigate the feasibility and applicability and, finally, the clinical benefits of the newly developed list.

Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells

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

Chen, Xiang-Yuan; Wang, Zhen; Li, Bei

Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevatedmore » the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer. - Highlights: • This is first study to demonstrate that Pim-3 is endogenously induced by ionizing radiation in pancreatic cancer cells, and Pim-3 overexpression enhanced radioresistance of pancreatic cancer cells both in vitro and in vivo. • This is first study to provide evidence that radioresistance induced by Pim-3 is mainly attributed to Pim-3 induces activation of ATM, which subsequently activates checkpoint 1, leading to amplification of DNA repair through cell cycle arrest and DNA repair pathways. • This is first study to indicate that targeting Pim-3 may be a promising strategy to provide better treatment efficacy in combination with radiotherapy in human

Reversal of Latency as Part of a Cure for HIV-1.

PubMed

Rasmussen, Thomas Aagaard; Tolstrup, Martin; Søgaard, Ole Schmeltz

2016-02-01

Here, the use of pharmacological agents to reverse HIV-1 latency will be explored as a therapeutic strategy towards a cure. However, while clinical trials of latency-reversing agents LRAs) have demonstrated their ability to increase production of latent HIV-1, such interventions have not had an effect on the size of the latent HIV-1 reservoir. Plausible explanations for this include insufficient host immune responses against virus-expressing cells, the presence of escape mutations in archived virus, or an insufficient scale of latency reversal. Importantly, these early studies of LRAs were primarily designed to investigate their ability to perturb the state of HIV-1 latency; using the absence of an impact on the size of the HIV-1 reservoir to discard their potential inclusion in curative strategies would be erroneous and premature. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prescribing potentially inappropriate medication (PIM) in Germany's elderly as indicated by the PRISCUS list. An analysis based on regional claims data.

PubMed

Schubert, Ingrid; Küpper-Nybelen, Jutta; Ihle, Peter; Thürmann, Petra

2013-07-01

The aim of this study was to estimate the prevalence of potentially inappropriate medication (PIM) in the elderly as indicated by Germany's recently published list (PRISCUS) and to assess factors independently associated with PIM prescribing, both overall and separately for therapeutic groups. Claims data analysis (Health Insurance Sample AOK Hesse/KV Hesse, 18.75% random sample of insurants from AOK Hesse, Germany) is used in the study. The study population is composed of 73,665 insurants >64 years of age continuously insured in the last quarter of 2009 and either continuously insured or deceased in 2010. Prevalence estimates are standardized to the population of Germany (31 December 2010). The variables age, sex, polypharmacy, hospital stay and nursing care are assessed for their independent association with general PIM prescription and among 11 therapeutic subgroups using multivariate logistic regression analysis. In 2010, 22.0% of the elderly received at least one PIM prescription (men: 18.3%, women: 24.8%). The highest PIM prevalence was observed for antidepressants (6.5%), antihypertensives (3.8%) and antiarrhythmic drugs (3.5%). Amitriptyline, tetrazepam, doxepin, acetyldigoxin, doxazosin and etoricoxib were the most frequently prescribed PIMs. Multivariate analyses indicate that women (OR 1.39; 95% CI: 1.34-1.44) and persons with extreme polypharmacy (≥10 vs. <5 drugs: OR 5.16; 95% CI: 4.87-5.47) were at higher risk for receiving a PRISCUS-PIM. Risk analysis for therapeutic groups shows divergent associations. PRISCUS-PIMs are widely used. Educational programs should focus on drugs with high treatment prevalence and call professionals' attention to those elderly patients who are at special risk for inappropriate medication. Copyright © 2013 John Wiley & Sons, Ltd.

Synthesis and biological investigation of PIM mimics carrying biotin or a fluorescent label for cellular imaging.

PubMed

Front, Sophie; Bourigault, Marie-Laure; Rose, Stéphanie; Noria, Ségueni; Quesniaux, Valérie F J; Martin, Olivier R

2013-01-16

Phosphatidyl inositol mannosides (PIMs) are constituents of the mycobacterial cell wall; these glycolipids are known to exhibit potent inhibitory activity toward the LPS-induced production of cytokines by macrophages, and therefore have potential as anti-inflammatory agents. Recently, heterocyclic analogues of PIMs in which the inositol is replaced by a piperidine (aza-PIM mimics) or a tetrahydropyran moiety (oxa-PIM mimics) have been prepared by short synthetic sequences and shown to retain the biological activity of the parent PIM structures. In this investigation, the aza-PIM analogue was used as a convenient scaffold to link biotin or a fluorescent label (tetramethyl-rhodamine) by way of an aminocaproyl spacer, with the goal of using these conjugates for intracellular localization and for the study of the mechanism of their antiinflammatory action. The synthesis of these compounds is reported, as well as the evaluation of their activities as inhibitors of LPS-induced cytokine production by macrophages (TNFα, IL12p40); preliminary investigations by FACS and confocal microscopy indicated that PIM-biotin conjugate binds to macrophage membranes with rapid kinetics.

Initial Testing (Stage 1) of SGI-1776, a PIM1 Kinase Inhibitor, by the Pediatric Preclinical Testing Program

PubMed Central

Batra, Vandana; Maris, John M.; Kang, Min H.; Reynolds, C. Patrick; Houghton, Peter J.; Alexander, Denise; Kolb, E. Anders; Gorlick, Richard; Keir, Stephen T.; Carol, Hernan; Lock, Richard; Billups, Catherine A.; Smith, Malcolm A.

2011-01-01

The PIM kinase inhibitor, SGI-1776, was tested against the PPTP in vitro (1.0 nM to 10 μM) and in vivo panels (148 mg/kg daily x 5 days for 3 weeks). SGI-1776 exhibited cytotoxic activity in vitro with a median relative IC50 of 3.1 μM. SGI-1776 induced significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. SGI-1776 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induced complete responses of subcutaneous MV4;11 (B myeloid leukemia). PMID:22052829

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

PubMed Central

Pourchet, Aldo; Modrek, Aram S.; Placantonakis, Dimitris G.; Mohr, Ian; Wilson, Angus C.

2017-01-01

Herpes simplex virus 1 (HSV-1) uses latency in peripheral ganglia to persist in its human host, however, recurrent reactivation from this reservoir can cause debilitating and potentially life-threatening disease. Most studies of latency use live-animal infection models, but these are complex, multilayered systems and can be difficult to manipulate. Infection of cultured primary neurons provides a powerful alternative, yielding important insights into host signaling pathways controlling latency. However, small animal models do not recapitulate all aspects of HSV-1 infection in humans and are limited in terms of the available molecular tools. To address this, we have developed a latency model based on human neurons differentiated in culture from an NIH-approved embryonic stem cell line. The resulting neurons are highly permissive for replication of wild-type HSV-1, but establish a non-productive infection state resembling latency when infected at low viral doses in the presence of the antivirals acyclovir and interferon-α. In this state, viral replication and expression of a late viral gene marker are not detected but there is an accumulation of the viral latency-associated transcript (LAT) RNA. After a six-day establishment period, antivirals can be removed and the infected cultures maintained for several weeks. Subsequent treatment with sodium butyrate induces reactivation and production of new infectious virus. Human neurons derived from stem cells provide the appropriate species context to study this exclusively human virus with the potential for more extensive manipulation of the progenitors and access to a wide range of preexisting molecular tools. PMID:28594343

Biological Effects of the Pim Kinase Inhibitor, SGI-1776, in Multiple Myeloma

PubMed Central

Cervantes-Gomez, Fabiola; Chen, Lisa S.; Orlowski, Robert Z.; Gandhi, Varsha

2013-01-01

Pim kinases are constitutively active serine/threonine/tyrosine kinases that are overexpressed in hematological malignancies such as multiple myeloma. Pim kinase substrates are involved in transcription, protein translation, cell proliferation, and apoptosis. SGI-1776 is a potent Pim kinase inhibitor that has proven to be cytotoxic to leukemia and lymphoma cells. Based on this background, we hypothesized that SGI-1776 treatment would result in myeloma cytotoxicity. To test this, myeloma cell lines and primary CD138+ cells from myeloma patients were treated with SGI-1776 in a dose- and time-dependent manner and effect on cell death and proliferation, induction of autophagy, as wells as changes in cell cycle profile were measured. SGI-1776 treatment resulted in limited apoptosis in cell lines (mean 30%) and CD138+ cells (<10%) as assessed by Annexin-V/PI. Limited effect was observed in cell cycle profile or growth in cell lines. However, DNA synthesis was decreased by 70% at 3 μM (all time points) in U266 though this was not observed in MM.1S. In accordance, immunoblot analyses revealed no change in transcription (c-Myc and H3), or apoptotic (Bad) proteins that are substrates of Pim kinases. In contrast, autophagy, as assessed by acridine orange staining, was induced with SGI-1776 treatment in both cell lines (U266 25-70%; MM.1S 8-52%) and CD138+ cells (19-21%). Immunoblot analyses of autophagy LC3b marker and translation initiation proteins (phospho p70S6K and 4E-BP1) corroborated autophagy induction. These data indicate that SGI-1776 treatment in myeloma cell lines and CD138+ myeloma cells elicits its deleterious effects through inhibition of translation and induction of autophagy. PMID:23988451

Biological effects of the Pim kinase inhibitor, SGI-1776, in multiple myeloma.

PubMed

Cervantes-Gomez, Fabiola; Chen, Lisa S; Orlowski, Robert Z; Gandhi, Varsha

2013-09-01

Pim kinases are constitutively active serine/threonine/tyrosine kinases that are overexpressed in hematological malignancies such as multiple myeloma. Pim kinase substrates are involved in transcription, protein translation, cell proliferation, and apoptosis. SGI-1776 is a potent Pim kinase inhibitor that has proven to be cytotoxic to leukemia and lymphoma cells. Based on this background, we hypothesized that SGI-1776 treatment would result in myeloma cytotoxicity. To test this, myeloma cell lines and primary CD138(+) cells from myeloma patients were treated with SGI-1776 in a dose- and time-dependent manner, and effect on cell death and proliferation, induction of autophagy, and changes in cell cycle profile were measured. SGI-1776 treatment resulted in limited apoptosis in cell lines (mean 30%) and CD138(+) cells (< 10%) assessed using Annexin-V/propidium iodide. Limited effect was observed in cell cycle profile or growth in cell lines. However, DNA synthesis was decreased by 70% at 3 μM (all time points) in U266 though this was not observed in MM.1S. In accordance, immunoblot analyses revealed no change in transcription (c-Myc and H3), or apoptotic (Bad) proteins that are substrates of Pim kinases. In contrast, autophagy, assessed using acridine orange staining, was induced with SGI-1776 treatment in both cell lines (U266, 25%-70%; MM.1S, 8%-52%) and CD138(+) cells (19%-21%). Immunoblot analyses of the autophagy LC3b marker and translation initiation proteins (phospho-p70S6K and 4E-BP1) corroborated autophagy induction. These data indicate that SGI-1776 treatment in myeloma cell lines and CD138(+) myeloma cells elicits its deleterious effects through inhibition of translation and induction of autophagy. Copyright © 2013 Elsevier Inc. All rights reserved.

Targeting PIM kinase enhances the activity of sunitinib in renal cell carcinoma.

PubMed

Mahalingam, D; Espitia, C M; Medina, E C; Esquivel, J A; Kelly, K R; Bearss, D; Choy, G; Taverna, P; Carew, J S; Giles, F J; Nawrocki, S T

2011-11-08

Upregulation of PIM kinase expression has been reported in many malignancies, suggesting that inhibition of PIM kinase activity may be an attractive therapeutic strategy. We hypothesised that inhibition of PIM kinase activity with SGI-1776, a novel small molecule inhibitor of PIM kinase activity, would reduce the viability of renal cell carcinoma (RCC) cells and enhance the activity of sunitinib. Immunoblotting, qRT-PCR, and gene expression arrays were carried out to identify genes modulated by SGI-1776 treatment. The anticancer activity of SGI-1776 and sunitinib was determined by viability and apoptosis assays and in tumour xenografts in vivo. Treatment with SGI-1776 led to a decrease in phosphorylated and total c-Myc levels, which resulted in the modulation of c-Myc target genes. SGI-1776 in combination with sunitinib induced a further reduction in c-Myc levels, which was associated with enhanced anticancer activity. siRNA-mediated knockdown of c-Myc demonstrated that its expression has a key role in regulating the sensitivity to the combination of SGI-1776 and sunitinib. Importantly, the combination significantly reduced tumour burden in two RCC xenograft models compared with single-agent therapy and was very well tolerated. These data indicate that targeting PIM kinase signalling is a promising treatment strategy for RCC. 2011 Cancer Research UK

Primary display latency criteria based on flying qualities and performance data

NASA Technical Reports Server (NTRS)

Funk, John D., Jr.; Beck, Corin P.; Johns, John B.

1993-01-01

With a pilots' increasing use of visual cue augmentation, much requiring extensive pre-processing, there is a need to establish criteria for new avionics/display design. The timeliness and synchronization of the augmented cues is vital to ensure the performance quality required for precision mission task elements (MTEs) where augmented cues are the primary source of information to the pilot. Processing delays incurred while transforming sensor-supplied flight information into visual cues are unavoidable. Relationships between maximum control system delays and associated flying qualities levels are documented in MIL-F-83300 and MIL-F-8785. While cues representing aircraft status may be just as vital to the pilot as prompt control response for operations in instrument meteorological conditions, presently, there are no specification requirements on avionics system latency. To produce data relating avionics system latency to degradations in flying qualities, the Navy conducted two simulation investigations. During the investigations, flying qualities and performance data were recorded as simulated avionics system latency was varied. Correlated results of the investigation indicates that there is a detrimental impact of latency on flying qualities. Analysis of these results and consideration of key factors influencing their application indicate that: (1) Task performance degrades and pilot workload increases as latency is increased. Inconsistency in task performance increases as latency increases. (2) Latency reduces the probability of achieving Level 1 handling qualities with avionics system latency as low as 70 ms. (3) The data suggest that the achievement of desired performance will be ensured only at display latency values below 120 ms. (4) These data also suggest that avoidance of inadequate performance will be ensured only at display latency values below 150 ms.

Mapping of the Pim-1 oncogene in mouse t-haplotypes and its use to define the relative map positions of the tcl loci t0(t6) and tw12 and the marker tf (tufted).

PubMed

Ark, B; Gummere, G; Bennett, D; Artzt, K

1991-06-01

Pim-1 is an oncogene activated in mouse T-cell lymphomas induced by Moloney and AKR mink cell focus (MCF) viruses. Pim-1 was previously mapped to chromosome 17 by somatic cell hybrids, and subsequently to the region between the hemoglobin alpha-chain pseudogene 4 (Hba-4ps) and the alpha-crystalline gene (Crya-1) by Southern blot analysis of DNA obtained from panels of recombinant inbred strains. We have now mapped Pim-1 more accurately in t-haplotypes by analysis of recombinant t-chromosomes. The recombinants were derived from Tts6tf/t12 parents backcrossed to + tf/ + tf, and scored for recombination between the loci of T and tf. For simplicity all t-complex lethal genes properly named tcl-tx are shortened to tx. The Pim-1 gene was localized 0.6 cM proximal to the tw12 lethal gene, thus placing the Pim-1 gene 5.2 cM distal to the H-2 region in t-haplotypes. Once mapped, the Pim-1 gene was used as a marker for further genetic analysis of t-haplotypes. tw12 is so close to tf that even with a large number of recombinants it was not possible to determine whether it is proximal or distal to tf. Southern blot analysis of DNA from T-tf recombinants with a separation of tw12 and tf indicated that tw12 is proximal to tf. The mapping of two allelic t-lethals, t0 and t6 with respect to tw12 and tf has also been a problem.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-latency primate vestibuloocular responses during translation

NASA Technical Reports Server (NTRS)

Angelaki, D. E.; McHenry, M. Q.

1999-01-01

Short-lasting, transient head displacements and near target fixation were used to measure the latency and early response gain of vestibularly evoked eye movements during lateral and fore-aft translations in rhesus monkeys. The latency of the horizontal eye movements elicited during lateral motion was 11.9 +/- 5.4 ms. Viewing distance-dependent behavior was seen as early as the beginning of the response profile. For fore-aft motion, latencies were different for forward and backward displacements. Latency averaged 7.1 +/- 9.3 ms during forward motion (same for both eyes) and 12.5 +/- 6.3 ms for the adducting eye (e.g., left eye during right fixation) during backward motion. Latencies during backward motion were significantly longer for the abducting eye (18.9 +/- 9.8 ms). Initial acceleration gains of the two eyes were generally larger than unity but asymmetric. Specifically, gains were consistently larger for abducting than adducting eye movements. The large initial acceleration gains tended to compensate for the response latencies such that the early eye movement response approached, albeit consistently incompletely, that required for maintaining visual acuity during the movement. These short-latency vestibuloocular responses could complement the visually generated optic flow responses that have been shown to exhibit much longer latencies.

Repressive LTR nucleosome positioning by the BAF complex is required for HIV latency.

PubMed

Rafati, Haleh; Parra, Maribel; Hakre, Shweta; Moshkin, Yuri; Verdin, Eric; Mahmoudi, Tokameh

2011-11-01

Persistence of a reservoir of latently infected memory T cells provides a barrier to HIV eradication in treated patients. Several reports have implicated the involvement of SWI/SNF chromatin remodeling complexes in restricting early steps in HIV infection, in coupling the processes of integration and remodeling, and in promoter/LTR transcription activation and repression. However, the mechanism behind the seemingly contradictory involvement of SWI/SNF in the HIV life cycle remains unclear. Here we addressed the role of SWI/SNF in regulation of the latent HIV LTR before and after transcriptional activation. We determined the predicted nucleosome affinity of the LTR sequence and found a striking reverse correlation when compared to the strictly positioned in vivo LTR nucleosomal structure; sequences encompassing the DNase hypersensitive regions displayed the highest nucleosome affinity, while the strictly positioned nucleosomes displayed lower affinity for nucleosome formation. To examine the mechanism behind this reverse correlation, we used a combinatorial approach to determine DNA accessibility, histone occupancy, and the unique recruitment and requirement of BAF and PBAF, two functionally distinct subclasses of SWI/SNF at the LTR of HIV-infected cells before and after activation. We find that establishment and maintenance of HIV latency requires BAF, which removes a preferred nucleosome from DHS1 to position the repressive nucleosome-1 over energetically sub-optimal sequences. Depletion of BAF resulted in de-repression of HIV latency concomitant with a dramatic alteration in the LTR nucleosome profile as determined by high resolution MNase nucleosomal mapping. Upon activation, BAF was lost from the HIV promoter, while PBAF was selectively recruited by acetylated Tat to facilitate LTR transcription. Thus BAF and PBAF, recruited during different stages of the HIV life cycle, display opposing function on the HIV promoter. Our data point to the ATP-dependent BRG1

Pim-2 activates API-5 to inhibit the apoptosis of hepatocellular carcinoma cells through NF-kappaB pathway.

PubMed

Ren, Ke; Zhang, Wei; Shi, Yujun; Gong, Jianping

2010-06-01

Pim-2 is proved to be relevant to the tumorigenesis of hepatocellular carcinoma (HCC), but the mechanism is unclear. We studied the relationship among Pim-2, NF-kappaB and API-5. In our experiment, expression level of the three factors and phosphorylation level of API-5, as well as NF-kappaB activity, were detected in HCC tissues and the nontumorous controls. Then Pim-2 gene was transfected into nontumorous liver cells L02, and Pim-2 SiRNA was transfected into hepatoblastoma cell line HepG2. Parthenolide was added as NF-kappaB inhibitor. The same detections as above were repeated in the cells, along with the apoptosis analysis. We found the levels of Pim-2, NF-kappaB and API-5, as well as NF-kappaB activity, were significantly higher in HCC tissues. Pim-2 level was increased in L02 cells after the transfection of Pim-2 gene, but decreased in HepG2 cells after the transfection of Pim-2 SiRNA. The levels of NF-kappaB and API-5, as well as NF-kappaB activity and API-5 phosphorylation level, were in accordance with Pim-2 level, but could be reversed by Parthenolide. Cell apoptosis rates were negatively correlated with API-5 phosphorylation level. Therefore, we infer that Pim-2 could activate API-5 to inhibit the apoptosis of liver cells, and NF-kappaB is the key regulator.

Influence of Herpes Simplex Virus 1 Latency-Associated Transcripts on the Establishment and Maintenance of Latency in the ROSA26R Reporter Mouse Model

PubMed Central

Nicoll, M. P.; Proença, J. T.; Connor, V.

2012-01-01

Herpes simplex virus 1 (HSV-1) can establish life-long latent infection in sensory neurons, from which periodic reactivation can occur. During latency, viral gene expression is largely restricted to the latency-associated transcripts (LATs). While not essential for any phase of latency, to date the LATs have been shown to increase the efficiency of both establishment and reactivation of latency in small-animal models. We sought to investigate the role of LAT expression in the frequency of latency establishment within the ROSA26R reporter mouse model utilizing Cre recombinase-encoding recombinant viruses harboring deletions of the core LAT promoter (LAP) region. HSV-1 LAT expression was observed to influence the number of latently infected neurons in trigeminal but not dorsal root ganglia. Furthermore, the relative frequencies of latency establishment of LAT-positive and LAT-negative viruses are influenced by the inoculum dose following infection of the mouse whisker pads. Finally, analysis of the infected cell population at two latent time points revealed a relative loss of latently infected cells in the absence of LAT expression. We conclude that the HSV-1 LATs facilitate the long-term stability of the latent cell population within the infected host and that interpretation of LAT establishment phenotypes is influenced by infection methodology. PMID:22696655

Initial testing (stage 1) of SGI-1776, a PIM1 kinase inhibitor, by the pediatric preclinical testing program.

PubMed

Batra, Vandana; Maris, John M; Kang, Min H; Reynolds, C Patrick; Houghton, Peter J; Alexander, Denise; Kolb, E Anders; Gorlick, Richard; Keir, Stephen T; Carol, Hernan; Lock, Richard; Billups, Catherine A; Smith, Malcolm A

2012-10-01

The PIM kinase inhibitor, SGI-1776, was tested against the PPTP in vitro (1.0 nM-10 µM) and in vivo panels (148 mg/kg daily × 5 days for 3 weeks). SGI-1776 exhibited cytotoxic activity in vitro with a median relative IC(50) of 3.1 µM. SGI-1776 induced significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. SGI-1776 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induced complete responses of subcutaneous MV4;11 (B myeloid leukemia). Copyright © 2011 Wiley Periodicals, Inc.

MicroRNA-101-3p suppresses cell proliferation, invasion and enhances chemotherapeutic sensitivity in salivary gland adenoid cystic carcinoma by targeting Pim-1

PubMed Central

Liu, Xiao-Yu; Liu, Zhi-Jian; He, Hong; Zhang, Chen; Wang, Yun-Long

2015-01-01

MicroRNAs (miRNAs) play critical roles in carcinogenesis and tumor progression. Recent research has revealed miR-101-3p as an important regulator in several cancers. Nevertheless, its function in salivary gland Adenoid cystic carcinoma (ACC), a relatively rare malignance with poor long-term survival rate arisen in head and neck region, remain unknown. In this study, down-regulated miR-101-3p expression was detected in ACC tissues and ACC cell lines with high potential for metastasis. Ectopic expression of miR-101-3p significantly repressed the invasion, proliferation, colony formation, and formation of nude mice xenografts and induced potent apoptosis in ACC cell lines. The provirus integration site for Moloney murine leukemia virus 1 (Pim-1) oncogene was subsequently confirmed as a direct target gene of miR-101-3p in ACC. Functional restoration assays revealed that miR-101-3p inhibits cell growth and invasion by directly decreasing Pim-1 expression. Protein levels of Survivin, Cyclin D1 and β-catenin were also down-regulated by miR-101-3p. miR-101-3p enhanced the sensitivity of cisplatin in ACC cell lines. Taken together, our results demonstrate that the novel miR-101-3p/Pim-1 axis provides excellent insights into the carcinogenesis and tumor progression of ACC and may be a promising therapeutic target for this type of cancer. PMID:26693056

Targeting PIM kinase enhances the activity of sunitinib in renal cell carcinoma

PubMed Central

Mahalingam, D; Espitia, C M; Medina, E C; Esquivel, J A; Kelly, K R; Bearss, D; Choy, G; Taverna, P; Carew, J S; Giles, F J; Nawrocki, S T

2011-01-01

Background: Upregulation of PIM kinase expression has been reported in many malignancies, suggesting that inhibition of PIM kinase activity may be an attractive therapeutic strategy. We hypothesised that inhibition of PIM kinase activity with SGI-1776, a novel small molecule inhibitor of PIM kinase activity, would reduce the viability of renal cell carcinoma (RCC) cells and enhance the activity of sunitinib. Methods: Immunoblotting, qRT–PCR, and gene expression arrays were carried out to identify genes modulated by SGI-1776 treatment. The anticancer activity of SGI-1776 and sunitinib was determined by viability and apoptosis assays and in tumour xenografts in vivo. Results: Treatment with SGI-1776 led to a decrease in phosphorylated and total c-Myc levels, which resulted in the modulation of c-Myc target genes. SGI-1776 in combination with sunitinib induced a further reduction in c-Myc levels, which was associated with enhanced anticancer activity. siRNA-mediated knockdown of c-Myc demonstrated that its expression has a key role in regulating the sensitivity to the combination of SGI-1776 and sunitinib. Importantly, the combination significantly reduced tumour burden in two RCC xenograft models compared with single-agent therapy and was very well tolerated. Conclusion: These data indicate that targeting PIM kinase signalling is a promising treatment strategy for RCC. PMID:22015557

Varicella zoster virus latency

PubMed Central

Eshleman, Emily; Shahzad, Aamir; Cohrs, Randall J

2011-01-01

Primary infection by varicella zoster virus (VZV) typically results in childhood chickenpox, at which time latency is established in the neurons of the cranial nerve, dorsal root and autonomic ganglia along the entire neuraxis. During latency, the histone-associated virus genome assumes a circular episomal configuration from which transcription is epigenetically regulated. The lack of an animal model in which VZV latency and reactivation can be studied, along with the difficulty in obtaining high-titer cell-free virus, has limited much of our understanding of VZV latency to descriptive studies of ganglia removed at autopsy and analogy to HSV-1, the prototype alphaherpesvirus. However, the lack of miRNA, detectable latency-associated transcript and T-cell surveillance during VZV latency highlight basic differences between the two neurotropic herpesviruses. This article focuses on VZV latency: establishment, maintenance and reactivation. Comparisons are made with HSV-1, with specific attention to differences that make these viruses unique human pathogens. PMID:21695042

Spi1 GTPase interacts with RCC1 to maintain interdependency of cell cycle events.

PubMed

Matsumoto, T; Beach, D

1991-01-01

A mutant which can enter mitosis at any cell cycle stage has been isolated and characterized in fission yeast. The pim1 (premature initiation of mitosis) mutant prearrested at G1/S can develop a mitotic spindle and has tightly condensed chromosomes upon shift to the restrictive temperature. pim1-induced mitosis requires maturation promoting factor (MPF) activity, but not the essential mitotic inducer, cdc25. The pim1+ gene encodes a homolog of regulator of chromosome condensation 1 (RCC1), a regulator of onset of mitosis in mammalian cells. A multicopy suppressor of pim1, spi1, was isolated, and found to encode a 25 kDa GTPase. The primary sequence of the spi1 GTPase shows extensive identity (80%) to human TC4, whose function is unknown. The spi1/TC4 GTPase defines a novel class in the "ras-like" GTPase family, which is distinct from ras, rho, or ypt. Disruption of the spi1+ gene causes genomic instability in a heterozygous diploid. These genetic data suggest that pim1+ and spi1+ interact to coordinate correct entry into mitosis. Immunological experiments demonstrate that the pim1+ and spi1+ products are physically associated. Mutation in the pim1 gene results in lowered affinity of the protein for the spi1 protein in vitro, which may explain why high dosages of the spi1 protein can rescue the pim1 mutant in vivo. The pim1/spi1 complex dissociates in the presence of Mg2+ and GTP. The current data suggests that pim1+ acts as a GTP exchanger for the spi1 GTPase.

Pim-2 protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced apoptosis via downregulation of Bim expression.

PubMed

Xu, Yan; Xing, Yawei; Xu, Yanjie; Huang, Chahua; Bao, Huihui; Hong, Kui; Cheng, Xiaoshu

2016-12-01

We know that silencing Bim, a pro-apoptosis protein, significantly attenuates glucose and oxygen-deprived induced apoptosis in cardiomyocytes. However, the mechanisms underlying the regulation of the Bim activation in the heart have remained unknown. Pim-2 is one of three Pim serine/threonine kinase family members thought to be involved in cell survival and proliferation. H9c2 cardiomyocytes were subjected to a hypoxia/reoxygenation (H/R) condition in vitro, mimicking ischemic/reperfusion injury in vivo. H/R augmented the expression of Bim, Cyt C, and Pim-2 and induced H9c2 cell apoptosis. Overexpression of Pim-2 attenuated apoptosis which induced by H/R in H9c2 cells, via downregulation of Bim and Cyt C expression. Silencing of Pim-2 promoted H/R-induced apoptosis via upregulation of Bim and Cyt C expression. Co-IP revealed the interaction between Pim-2 and Bim protein, with Bim Ser 65 phosphorylated by Pim-2. Furthermore, blocking proteasome activity by MG132 prevented Bim degradation, and Bim S65A mutation could reverse the anti-apoptotic role of Pim-2 which induced by H/R. These data demonstrated that Pim-2 is a novel Bim-interacting protein, which negatively regulates Bim degradation and protects H9c2 cardiomyocytes from H/R-induced apoptosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Combination of PIM and JAK2 inhibitors synergistically suppresses cell proliferation and overcomes drug resistance of myeloproliferative neoplasms

PubMed Central

Greco, Rita; Li, Zhifang; Sun, Fangxian; Barberis, Claude; Tabart, Michel; Patel, Vinod; Schio, Laurent; Hurley, Raelene; Chen, Bo; Cheng, Hong; Lengauer, Christoph; Pollard, Jack; Watters, James; Garcia-Echeverria, Carlos; Wiederschain, Dmitri; Adrian, Francisco; Zhang, JingXin

2014-01-01

Inhibitors of JAK2 kinase are emerging as an important treatment modality for myeloproliferative neoplasms (MPN). However, similar to other kinase inhibitors, resistance to JAK2 inhibitors may eventually emerge through a variety of mechanisms. Effective drug combination is one way to enhance therapeutic efficacy and combat resistance against JAK2 inhibitors. To identify potential combination partners for JAK2 compounds in MPN cell lines, we performed pooled shRNA screen targeting 5,000 genes in the presence or absence of JAK2 blockade. One of the top hits identified was MYC, an oncogenic transcription factor that is difficult to inhibit directly, but could be targeted by modulation of upstream regulatory elements such as kinases. We demonstrate herein that PIM kinase inhibitors efficiently suppress MYC protein levels in MPN cell lines. Overexpression of MYC restores the viability of PIM inhibitor-treated cells, revealing causal relationship between MYC down-regulation and cell growth inhibition by PIM compounds. Combination of various PIM inhibitors with a JAK2 inhibitor results in significant synergistic growth inhibition of multiple MPN cancer cell lines and induction of apoptosis. Mechanistic studies revealed strong downregulation of phosphorylated forms of S6 and 4EBP1 by JAK2/PIM inhibitor combination treatment. Finally, such combination was effective in eradicating in vitro JAK2 inhibitor-resistant MPN clones, where MYC is consistently up-regulated. These findings demonstrate that simultaneous suppression of JAK2 and PIM kinase activity by small molecule inhibitors is more effective than either agent alone in suppressing MPN cell growth. Our data suggest that JAK2 and PIM combination might warrant further investigation for the treatment of JAK2-driven hematologic malignancies. PMID:24830942

PIMS sequencing extension: a laboratory information management system for DNA sequencing facilities

PubMed Central

2011-01-01

Background Facilities that provide a service for DNA sequencing typically support large numbers of users and experiment types. The cost of services is often reduced by the use of liquid handling robots but the efficiency of such facilities is hampered because the software for such robots does not usually integrate well with the systems that run the sequencing machines. Accordingly, there is a need for software systems capable of integrating different robotic systems and managing sample information for DNA sequencing services. In this paper, we describe an extension to the Protein Information Management System (PIMS) that is designed for DNA sequencing facilities. The new version of PIMS has a user-friendly web interface and integrates all aspects of the sequencing process, including sample submission, handling and tracking, together with capture and management of the data. Results The PIMS sequencing extension has been in production since July 2009 at the University of Leeds DNA Sequencing Facility. It has completely replaced manual data handling and simplified the tasks of data management and user communication. Samples from 45 groups have been processed with an average throughput of 10000 samples per month. The current version of the PIMS sequencing extension works with Applied Biosystems 3130XL 96-well plate sequencer and MWG 4204 or Aviso Theonyx liquid handling robots, but is readily adaptable for use with other combinations of robots. Conclusions PIMS has been extended to provide a user-friendly and integrated data management solution for DNA sequencing facilities that is accessed through a normal web browser and allows simultaneous access by multiple users as well as facility managers. The system integrates sequencing and liquid handling robots, manages the data flow, and provides remote access to the sequencing results. The software is freely available, for academic users, from http://www.pims-lims.org/. PMID:21385349

PIMS sequencing extension: a laboratory information management system for DNA sequencing facilities.

PubMed

Troshin, Peter V; Postis, Vincent Lg; Ashworth, Denise; Baldwin, Stephen A; McPherson, Michael J; Barton, Geoffrey J

2011-03-07

Facilities that provide a service for DNA sequencing typically support large numbers of users and experiment types. The cost of services is often reduced by the use of liquid handling robots but the efficiency of such facilities is hampered because the software for such robots does not usually integrate well with the systems that run the sequencing machines. Accordingly, there is a need for software systems capable of integrating different robotic systems and managing sample information for DNA sequencing services. In this paper, we describe an extension to the Protein Information Management System (PIMS) that is designed for DNA sequencing facilities. The new version of PIMS has a user-friendly web interface and integrates all aspects of the sequencing process, including sample submission, handling and tracking, together with capture and management of the data. The PIMS sequencing extension has been in production since July 2009 at the University of Leeds DNA Sequencing Facility. It has completely replaced manual data handling and simplified the tasks of data management and user communication. Samples from 45 groups have been processed with an average throughput of 10000 samples per month. The current version of the PIMS sequencing extension works with Applied Biosystems 3130XL 96-well plate sequencer and MWG 4204 or Aviso Theonyx liquid handling robots, but is readily adaptable for use with other combinations of robots. PIMS has been extended to provide a user-friendly and integrated data management solution for DNA sequencing facilities that is accessed through a normal web browser and allows simultaneous access by multiple users as well as facility managers. The system integrates sequencing and liquid handling robots, manages the data flow, and provides remote access to the sequencing results. The software is freely available, for academic users, from http://www.pims-lims.org/.

Paladin Integrated Management (PIM)

DTIC Science & Technology

2013-12-01

46:35 UNCLASSIFIED 4 Mission and Description The M109 Family of Vehicles (FOV) 155-millimeter / 39-caliber Self-Propelled Howitzer ( SPH ) provides...Teams, and Stryker Brigade Combat Teams. The M109 FOV Carrier Ammunition Tracked (CAT) provides armored ammunition supply support to the SPH ...fielded versions of the Army’s SPH and CAT. The Paladin Integrated Management (PIM) SPH and CAT will replace the M109A6 Paladin and M992A2 FAASV

Self-Assessment of Practice Performance: Development of the ABIM Practice Improvement Module (PIM[superscript SM])

ERIC Educational Resources Information Center

Duffy, F. Daniel; Lynn, Lorna A.; Didura, Halyna; Hess, Brian; Caverzagie, Kelly; Grosso, Louis; Lipner, Rebecca A.; Holmboe, Eric S.

2008-01-01

Background: Quality measurement and improvement in practice are requirements for Maintenance of Certification by the American Board of Medical Specialties boards and a component of many pay for performance programs. Objective: To describe the development of the American Board of Internal Medicine (ABIM) Practice Improvement Module (PIM[superscript…

Low-energy ion irradiation in HiPIMS to enable anatase TiO2 selective growth

NASA Astrophysics Data System (ADS)

Cemin, Felipe; Tsukamoto, Makoto; Keraudy, Julien; Antunes, Vinícius Gabriel; Helmersson, Ulf; Alvarez, Fernando; Minea, Tiberiu; Lundin, Daniel

2018-06-01

High power impulse magnetron sputtering (HiPIMS) has already demonstrated great potential for synthesizing the high-energy crystalline phase of titanium dioxide (rutile TiO2) due to large quantities of highly energetic ions present in the discharge. In this work, it is shown that the metastable anatase phase can also be obtained by HiPIMS. The required deposition conditions have been identified by systematically studying the phase formation, microstructure and chemical composition as a function of mode of target operation as well as of substrate temperature, working pressure, and peak current density. It is found that films deposited in the metal and transition modes are predominantly amorphous and contain substoichiometric TiO x compounds, while in compound mode they are well-crystallized and present only O2‑ ions bound to Ti4+, i.e. pure TiO2. Anatase TiO2 films are obtained for working pressures between 1 and 2 Pa, a peak current density of ~1 A cm‑2 and deposition temperatures lower than 300 °C. Rutile is favored at lower pressures (<1 Pa) and higher peak current densities (>2 A cm‑2), while amorphous films are obtained at higher pressures (5 Pa). Microstructural characterization of selected films is also presented.

HIV-1 transcription and latency: an update

PubMed Central

2013-01-01

Combination antiretroviral therapy, despite being potent and life-prolonging, is not curative and does not eradicate HIV-1 infection since interruption of treatment inevitably results in a rapid rebound of viremia. Reactivation of latently infected cells harboring transcriptionally silent but replication-competent proviruses is a potential source of persistent residual viremia in cART-treated patients. Although multiple reservoirs may exist, the persistence of resting CD4+ T cells carrying a latent infection represents a major barrier to eradication. In this review, we will discuss the latest reports on the molecular mechanisms that may regulate HIV-1 latency at the transcriptional level, including transcriptional interference, the role of cellular factors, chromatin organization and epigenetic modifications, the viral Tat trans-activator and its cellular cofactors. Since latency mechanisms may also operate at the post-transcriptional level, we will consider inhibition of nuclear RNA export and inhibition of translation by microRNAs as potential barriers to HIV-1 gene expression. Finally, we will review the therapeutic approaches and clinical studies aimed at achieving either a sterilizing cure or a functional cure of HIV-1 infection, with a special emphasis on the most recent pharmacological strategies to reactivate the latent viruses and decrease the pool of viral reservoirs. PMID:23803414

PIM kinase inhibition presents a novel targeted therapy against triple-negative breast tumors with elevated MYC expression

PubMed Central

Horiuchi, Dai; Camarda, Roman; Zhou, Alicia Y.; Yau, Christina; Momcilovic, Olga; Balakrishnan, Sanjeev; Corella, Alexandra N.; Eyob, Henok; Kessenbrock, Kai; Lawson, Devon A.; Marsh, Lindsey A.; Anderton, Brittany N.; Rohrberg, Julia; Kunder, Ratika; Bazarov, Alexey V.; Yaswen, Paul; McManus, Michael T.; Rugo, Hope S.; Werb, Zena; Goga, Andrei

2017-01-01

Triple-negative breast cancer (TNBC), which lacks the expression of the estrogen, progesterone, and HER2 receptors, represents the breast cancer subtype with the poorest outcome1. No targeted therapy is available against this subtype due to lack of validated molecular targets. We previously reported that MYC signaling is disproportionally elevated in triple-negative (TN) tumors compared to receptor-positive (RP) tumors2. MYC is an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes3. Direct inhibition of oncogenic MYC transcriptional activity has remained challenging4,5. The present study conducted an shRNA screen against all kinases to uncover novel MYC-dependent synthetic lethal combinations, and identified PIM1, a non-essential kinase. Here we demonstrate that PIM1 expression was elevated in TN tumors and was associated with poor prognosis in patients with hormone and HER2 receptor-negative tumors. Small molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic breast cancer models by inhibiting oncogenic transcriptional activity of MYC while simultaneously restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that exhibit elevated MYC expression. PMID:27775705

Time of flight in MUSE at PIM1 at Paul Scherrer Institute

NASA Astrophysics Data System (ADS)

Lin, Wan; Gilman, Ronald; MUSE Collaboration

2016-09-01

The MUSE experiment at PIM1 at Paul Scherrer Institute in Villigen, Switzerland, measures elastic scattering of electrons and muons from a liquid hydrogen target. The intent of the experiment is to deduce whether the radius of the proton is the same when determined from the two different particle types. Precision timing is an important aspect of the experiment, used to determine particle types, reaction types, and beam momentum. Here we present results for a test setup measuring time of flight between prototypes of two detector systems to be used in the experiment, compared to Geant4 simulations. The results demonstrate time of flight resolution better than 100 ps, and beam momentum determination at the level of a few tenths of a percent. Douglass Project for Rutgers Women in Math, Science & Engineering, National Science Foundation Grant 1306126 to Rutgers University.

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

PubMed Central

Moss, Charles Randall; Whitehurst, Christopher B.; Moody, Cary A.

2015-01-01

ABSTRACT As a herpesvirus, Epstein-Barr virus (EBV) establishes a latent infection that can periodically undergo reactivation, resulting in lytic replication and the production of new infectious virus. Latent membrane protein-1 (LMP1), the principal viral oncoprotein, is a latency-associated protein implicated in regulating viral reactivation and the maintenance of latency. We recently found that LMP1 hijacks the SUMO-conjugating enzyme Ubc9 via its C-terminal activating region-3 (CTAR3) and induces the sumoylation of cellular proteins. Because protein sumoylation can promote transcriptional repression, we hypothesized that LMP1-induced protein sumoylation induces the repression of EBV lytic promoters and helps maintain the viral genome in its latent state. We now show that with inhibition of LMP1-induced protein sumoylation, the latent state becomes less stable or leakier in EBV-transformed lymphoblastoid cell lines. The cells are also more sensitive to viral reactivation induced by irradiation, which results in the increased production and release of infectious virus, as well as increased susceptibility to ganciclovir treatment. We have identified a target of LMP1-mediated sumoylation that contributes to the maintenance of latency in this context: KRAB-associated protein-1 (KAP1). LMP1 CTAR3-mediated sumoylation regulates the function of KAP1. KAP1 also binds to EBV OriLyt and immediate early promoters in a CTAR3-dependent manner, and inhibition of sumoylation processes abrogates the binding of KAP1 to these promoters. These data provide an additional line of evidence that supports our findings that CTAR3 is a distinct functioning regulatory region of LMP1 and confirm that LMP1-induced sumoylation may help stabilize the maintenance of EBV latency. IMPORTANCE Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) plays an important role in the maintenance of viral latency. Previously, we documented that LMP1 targets cellular proteins to be modified by a

Coregulatory Interactions among CD8α Dendritic Cells, the Latency-Associated Transcript, and Programmed Death 1 Contribute to Higher Levels of Herpes Simplex Virus 1 Latency

PubMed Central

Mott, Kevin R.; Allen, Sariah J.; Zandian, Mandana

2014-01-01

ABSTRACT The latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1), CD8α+ dendritic cells (DCs), and programmed death 1 (PD-1) have all been implicated in the HSV-1 latency-reactivation cycle. It is not known, however, whether an interaction between LAT and CD8α+ DCs regulates latency and T-cell exhaustion. To address this question, we used LAT-expressing [LAT(+)] and LAT-negative [LAT(−)] viruses. Depletion of DCs in mice ocularly infected with LAT(+) virus resulted in a reduction in the number of T cells expressing PD-1 in the trigeminal ganglia (TG), whereas depletion of DCs in mice similarly infected with LAT(−) virus did not alter PD-1 expression. CD8α+ DCs, but not CD4+ DCs, infected with LAT(+) virus had higher levels of ICP0, ICP4, thymidine kinase (TK), and PD-1 ligand 1 (PD-L1) transcripts than those infected with LAT(−) virus. Coculture of infected bone marrow (BM)-derived DCs from wild-type (WT) mice, but not infected DCs from CD8α−/− mice, with WT naive T cells contributed to an increase in PD-1 expression. Transfer of bone marrow from WT mice but not CD8α−/− mice to recipient Rag1−/− mice increased the number of latent viral genomes in reconstituted mice infected with the LAT(+) virus. Collectively, these data indicated that a reduction in latency correlated with a decline in the levels of CD8α+ DCs and PD-1 expression. In summary, our results demonstrate an interaction among LAT, PD-1, and CD11c CD8α+ cells that regulates latency in the TG of HSV-1-infected mice. IMPORTANCE Very little is known regarding the interrelationship of LAT, PD-1, and CD8α+ DCs and how such interactions might contribute to relative numbers of latent viral genomes. We show here that (i) in both in vivo and in vitro studies, deficiency of CD8α+ DCs significantly reduced T-cell exhaustion in the presence of LAT(+) virus but not LAT(−) virus; (ii) HSV-1 infectivity was significantly lower in LAT(−)-infected DCs than in their LAT

Repressive LTR Nucleosome Positioning by the BAF Complex Is Required for HIV Latency

PubMed Central

Hakre, Shweta; Moshkin, Yuri; Verdin, Eric; Mahmoudi, Tokameh

2011-01-01

Persistence of a reservoir of latently infected memory T cells provides a barrier to HIV eradication in treated patients. Several reports have implicated the involvement of SWI/SNF chromatin remodeling complexes in restricting early steps in HIV infection, in coupling the processes of integration and remodeling, and in promoter/LTR transcription activation and repression. However, the mechanism behind the seemingly contradictory involvement of SWI/SNF in the HIV life cycle remains unclear. Here we addressed the role of SWI/SNF in regulation of the latent HIV LTR before and after transcriptional activation. We determined the predicted nucleosome affinity of the LTR sequence and found a striking reverse correlation when compared to the strictly positioned in vivo LTR nucleosomal structure; sequences encompassing the DNase hypersensitive regions displayed the highest nucleosome affinity, while the strictly positioned nucleosomes displayed lower affinity for nucleosome formation. To examine the mechanism behind this reverse correlation, we used a combinatorial approach to determine DNA accessibility, histone occupancy, and the unique recruitment and requirement of BAF and PBAF, two functionally distinct subclasses of SWI/SNF at the LTR of HIV-infected cells before and after activation. We find that establishment and maintenance of HIV latency requires BAF, which removes a preferred nucleosome from DHS1 to position the repressive nucleosome-1 over energetically sub-optimal sequences. Depletion of BAF resulted in de-repression of HIV latency concomitant with a dramatic alteration in the LTR nucleosome profile as determined by high resolution MNase nucleosomal mapping. Upon activation, BAF was lost from the HIV promoter, while PBAF was selectively recruited by acetylated Tat to facilitate LTR transcription. Thus BAF and PBAF, recruited during different stages of the HIV life cycle, display opposing function on the HIV promoter. Our data point to the ATP-dependent BRG1

Reduced evolutionary rates in HIV-1 reveal extensive latency periods among replicating lineages.

PubMed

Immonen, Taina T; Leitner, Thomas

2014-10-16

HIV-1 can persist for the duration of a patient's life due in part to its ability to hide from the immune system, and from antiretroviral drugs, in long-lived latent reservoirs. Latent forms of HIV-1 may also be disproportionally involved in transmission. Thus, it is important to detect and quantify latency in the HIV-1 life cycle. We developed a novel molecular clock-based phylogenetic tool to investigate the prevalence of HIV-1 lineages that have experienced latency. The method removes alternative sources that may affect evolutionary rates, such as hypermutation, recombination, and selection, to reveal the contribution of generation-time effects caused by latency. Our method was able to recover latent lineages with high specificity and sensitivity, and low false discovery rates, even on relatively short branches on simulated phylogenies. Applying the tool to HIV-1 sequences from 26 patients, we show that the majority of phylogenetic lineages have been affected by generation-time effects in every patient type, whether untreated, elite controller, or under effective or failing treatment. Furthermore, we discovered extensive effects of latency in sequence data (gag, pol, and env) from reservoirs as well as in the replicating plasma population. To better understand our phylogenetic findings, we developed a dynamic model of virus-host interactions to investigate the proportion of lineages in the actively replicating population that have ever been latent. Assuming neutral evolution, our dynamic modeling showed that under most parameter conditions, it is possible for a few activated latent viruses to propagate so that in time, most HIV-1 lineages will have been latent at some time in their past. These results suggest that cycling in and out of latency plays a major role in the evolution of HIV-1. Thus, no aspect of HIV-1 evolution can be fully understood without considering latency - including treatment, drug resistance, immune evasion, transmission, and pathogenesis.

Tricyclic Benzo[cd]azulenes Selectively Inhibit Activities of Pim Kinases and Restrict Growth of Epstein-Barr Virus-Transformed Cells

PubMed Central

Santio, Niina M.; Arnaudova, Ralica; Eerola, Sini K.; Rainio, Eeva-Marja; Aumüller, Ingo B.; Yli-Kauhaluoma, Jari; Koskinen, Päivi J.

2013-01-01

Oncogenic Pim family kinases are often overexpressed in human hematopoietic malignancies as well as in solid tumours. These kinases contribute to tumorigenesis by promoting cell survival and by enhancing resistance against chemotherapy and radiation therapy. Furthermore, we have recently shown that they increase the metastatic potential of adherent cancer cells. Here we describe identification of tricyclic benzo[cd]azulenes and their derivatives as effective and selective inhibitors of Pim kinases. These compounds inhibit Pim autophosphorylation and abrogate the anti-apoptotic effects of Pim kinases. They also reduce cancer cell motility and suppress proliferation of lymphoblastoid cell lines infected and immortalized by the Epstein-Barr virus. Thus, these novel Pim-selective inhibitors provide promising compounds for both research and therapeutic purposes. PMID:23405147

Photo-physics study of a styrylquinoline as inhibitor of Pim-1 kinase: Solvent and concentration effects

NASA Astrophysics Data System (ADS)

Lamhasni, Taibi; Barbache, Sara; Ait Lyazidi, Saadia; Haddad, Mustapha; Hnach, Mohamed; Desmaële, Didier

2018-03-01

7-Nicotinoyl-styrylquinoline (MB96) displays an antiviral activity on HIV-1 infected CEM cell lines and is a promising inhibitor of the serine/threonine-protein Pim-1 kinase. By means of UV-vis spectroscopy supported by theoretical calculations this styrylquinoline is shown to exist in different conformations: the s-trans planar conformation along with other twisted ones with respect to the torsion around the single bond between the quinoline and the phenylethenyl appendage. Hydrogen bonding interactions with the solvent shift the skeleton of the MB96 towards the planar form, enhancing conjugation of π-electrons between the quinoline and the catechol parts, while self-association process seems furthering this planar conformation.

Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells.

PubMed

Lee, Miso; Lee, Kyung-Hun; Min, Ahrum; Kim, Jeongeun; Kim, Seongyeong; Jang, Hyemin; Lim, Jee Min; Kim, So Hyeon; Ha, Dong-Hyeon; Jeong, Won Jae; Suh, Koung Jin; Yang, Yae-Won; Kim, Tae Yong; Oh, Do-Youn; Bang, Yung-Jue; Im, Seock-Ah

2018-06-06

Pim kinases are highly conserved serine/threonine kinases, and different expression patterns of each isoform (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancers, including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effects of AZD1208 as a single agent and in combination with an Akt inhibitor in gastric cancer cells. The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assays. The underlying mechanism was also examined by western blotting, immunofluorescence assay, and cell cycle analysis. AZD1208 treatment decreased gastric cancer cell proliferation rates and induced autophagy only in long-term culture systems. Light chain 3B (LC3B), a marker of autophagy, was increased in sensitive cells in a dose-dependent manner with AZD1208 treatment, which suggested that the growth inhibition effect of AZD1208 was achieved through autophagy, not apoptosis. Moreover, we found that cells damaged by Pim inhibition were repaired by activation of the DNA damage repair pathway, which promoted cell survival and led the cells to become resistant to AZD1208. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines. Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. Moreover, the combination of AZD1208 with an Akt inhibitor showed synergistic antitumor effects through regulation of the DNA damage repair pathway.

PIM Pedagogy: Toward a Loosely Unified Model for Teaching and Studying Comics and Graphic Novels

ERIC Educational Resources Information Center

Carter, James B.

2015-01-01

The article debuts and explains "PIM" pedagogy, a construct for teaching comics at the secondary- and post-secondary levels and for deep reading/studying comics. The PIM model for considering comics is actually based in major precepts of education studies, namely constructivist foundations of learning, and loosely unifies constructs…

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

PubMed Central

Doshi, Kshama A.; Trotta, Rossana; Natarajan, Karthika; Rassool, Feyruz V.; Tron, Adriana E.; Huszar, Dennis; Perrotti, Danilo; Baer, Maria R.

2016-01-01

Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD. PMID:27374090

Enhanced properties of tungsten thin films deposited with a novel HiPIMS approach

NASA Astrophysics Data System (ADS)

Velicu, Ioana-Laura; Tiron, Vasile; Porosnicu, Corneliu; Burducea, Ion; Lupu, Nicoleta; Stoian, George; Popa, Gheorghe; Munteanu, Daniel

2017-12-01

Despite the tremendous potential for industrial use of tungsten (W), very few studies have been reported so far on controlling and tailoring the properties of W thin films obtained by physical vapor deposition techniques and, even less, for those deposited by High Power Impulse Magnetron Sputtering (HiPIMS). This study presents results on the deposition process and properties characterization of nanocrystalline W thin films deposited on silicon and molybdenum substrates (100 W average sputtering power) by conventional dc magnetron sputtering (dcMS) and HiPIMS techniques. Topological, structural, mechanical and tribological properties of the deposited thin films were investigated. It was found that in HiPIMS, both deposition process and coatings properties may be optimized by using an appropriate magnetic field configuration and pulsing design. Compared to the other deposited samples, the W films grown in multi-pulse (5 × 3 μs) HiPIMS assisted by an additional magnetic field, created with a toroidal-shaped permanent magnet placed in front of the magnetron cathode, show significantly enhanced properties, such as: smoother surfaces, higher homogeneity and denser microstructure, higher hardness and Young's modulus values, better adhesion to the silicon substrate and lower coefficient of friction. Mechanical behaviour and structural changes are discussed based on plasma diagnostics results.

The effect of changing the magnetic field strength on HiPIMS deposition rates

NASA Astrophysics Data System (ADS)

Bradley, J. W.; Mishra, A.; Kelly, P. J.

2015-06-01

The marked difference in behaviour between HiPIMS and conventional dc or pulsed-dc magnetron sputtering discharges with changing magnetic field strengths is demonstrated through measurements of deposition rate. To provide a comparison between techniques the same circular magnetron was operated in the three excitation modes at a fixed average power of 680 W and a pressure of 0.54 Pa in the non-reactive sputtering of titanium. The total magnetic field strength B at the cathode surface in the middle of the racetrack was varied from 195 to 380 G. DC and pulsed-dc discharges show the expected behaviour that deposition rates fall with decreasing B (here by ~25-40%), however the opposite trend is observed in HiPIMS with deposition rates rising by a factor of 2 over the same decrease in B. These observations are understood from the stand point of the different composition and transport processes of the depositing metal flux between the techniques. In HiPIMS, this flux is largely ionic and slow post-ionized sputtered particles are subject to strong back attraction to the target by a retarding plasma potential structure ahead of them. The height of this potential barrier is known to increase with increasing B. From a simple phenomenological model of the sputtered particles fluxes, and using the measured deposition rates from the different techniques as inputs, the combined probabilities of ionization, α, and back attraction, β, of the metal species in HiPIMS has been calculated. There is a clear fall in αβ (from ~0.9 to ~0.7) with decreasing B-field strengths, we argue primarily due to a weakening of electrostatic ion back attraction, so leading to higher deposition rates. The results indicate that careful design of magnetron field strengths should be considered to optimise HiPIMS deposition rates.

Rabbit and Mouse Models of HSV-1 Latency, Reactivation, and Recurrent Eye Diseases

PubMed Central

Webre, Jody M.; Hill, James M.; Nolan, Nicole M.; Clement, Christian; McFerrin, Harris E.; Bhattacharjee, Partha S.; Hsia, Victor; Neumann, Donna M.; Foster, Timothy P.; Lukiw, Walter J.; Thompson, Hilary W.

2012-01-01

The exact mechanisms of HSV-1 establishment, maintenance, latency, reactivation, and also the courses of recurrent ocular infections remain a mystery. Comprehensive understanding of the HSV-1 disease process could lead to prevention of HSV-1 acute infection, reactivation, and more effective treatments of recurrent ocular disease. Animal models have been used for over sixty years to investigate our concepts and hypotheses of HSV-1 diseases. In this paper we present descriptions and examples of rabbit and mouse eye models of HSV-1 latency, reactivation, and recurrent diseases. We summarize studies in animal models of spontaneous and induced HSV-1 reactivation and recurrent disease. Numerous stimuli that induce reactivation in mice and rabbits are described, as well as factors that inhibit viral reactivation from latency. The key features, advantages, and disadvantages of the mouse and rabbit models in relation to the study of ocular HSV-1 are discussed. This paper is pertinent but not intended to be all inclusive. We will give examples of key papers that have reported novel discoveries related to the review topics. PMID:23091352

A qualitative study on personal information management (PIM) in clinical and basic sciences faculty members of a medical university in Iran

PubMed Central

Sedghi, Shahram; Abdolahi, Nida; Azimi, Ali; Tahamtan, Iman; Abdollahi, Leila

2015-01-01

Background: Personal Information Management (PIM) refers to the tools and activities to save and retrieve personal information for future uses. This study examined the PIM activities of faculty members of Iran University of Medical Sciences (IUMS) regarding their preferred PIM tools and four aspects of acquiring, organizing, storing and retrieving personal information. Methods: The qualitative design was based on phenomenology approach and we carried out 37 interviews with clinical and basic sciences faculty members of IUMS in 2014. The participants were selected using a random sampling method. All interviews were recorded by a digital voice recorder, and then transcribed, codified and finally analyzed using NVivo 8 software. Results: The use of PIM electronic tools (e-tools) was below expectation among the studied sample and just 37% had reasonable knowledge of PIM e-tools such as, external hard drivers, flash memories etc. However, all participants used both paper and electronic devices to store and access information. Internal mass memories (in Laptops) and flash memories were the most used e-tools to save information. Most participants used "subject" (41.00%) and "file name" (33.7 %) to save, organize and retrieve their stored information. Most users preferred paper-based rather than electronic tools to keep their personal information. Conclusion: Faculty members had little knowledge about PIM techniques and tools. Those who organized personal information could easier retrieve the stored information for future uses. Enhancing familiarity with PIM tools and training courses of PIM tools and techniques are suggested. PMID:26793648

Handling qualities effects of display latency

NASA Technical Reports Server (NTRS)

King, David W.

1993-01-01

Display latency is the time delay between aircraft response and the corresponding response of the cockpit displays. Currently, there is no explicit specification for allowable display lags to ensure acceptable aircraft handling qualities in instrument flight conditions. This paper examines the handling qualities effects of display latency between 70 and 400 milliseconds for precision instrument flight tasks of the V-22 Tiltrotor aircraft. Display delay effects on the pilot control loop are analytically predicted through a second order pilot crossover model of the V-22 lateral axis, and handling qualities trends are evaluated through a series of fixed-base piloted simulation tests. The results show that the effects of display latency for flight path tracking tasks are driven by the stability characteristics of the attitude control loop. The data indicate that the loss of control damping due to latency can be simply predicted from knowledge of the aircraft's stability margins, control system lags, and required control bandwidths. Based on the relationship between attitude control damping and handling qualities ratings, latency design guidelines are presented. In addition, this paper presents a design philosophy, supported by simulation data, for using flight director display augmentation to suppress the effects of display latency for delays up to 300 milliseconds.

Extraction of Gold(III) from Hydrochloric Acid Solutions with a PVC-based Polymer Inclusion Membrane (PIM) Containing Cyphos(®) IL 104.

PubMed

Bonggotgetsakul, Ya Ya Nutchapurida; Cattrall, Robert W; Kolev, Spas D

2015-12-08

Poly(vinyl chloride) (PVC) based polymer inclusion membranes (PIMs), with different concentrations of Cyphos® IL 104 as the membrane extractant/carrier, were studied for their ability to extract Au(III) from hydrochloric acid solutions. Some of the PIMs also contained one of the following plasticizers or modifiers: 2-nitrophenyloctyl ether, dioctylphthalate, 1-dodecanol, 1-tetradecanol, or tri(2-ethylhexyl) phosphate. The best performance, in terms of extraction rate and amount of Au(III) extracted, was exhibited by a PIM consisting of 25 wt% Cyphos(®) IL 104, 5 wt% 1-dodecanol, and 70 wt% PVC. An almost complete back-extraction of the Au(III) extracted from this membrane was achieved by using a 0.10 mol L(-1) Na₂SO₃ receiver solution at pH 8. The stoichiometry of the extracted Au(III)/Cyphos® IL 104 adduct was determined as [P]⁺ [AuCl₄](-) H⁺ [PO₂](-) where [P]⁺ and [PO₂](-) represent trihexyl(tetradecyl) phosphonium and bis(2,4,4-trimethylpentyl) phosphinate ions, respectively. Back-extraction of Au(III) is suggested to occur by reduction of Au(III) to Au(I), with the formation of the species [Au(SO₃)₂](3-) in the aqueous receiver solution. Loss of 1-dodecanol from the newly developed PIM to the aqueous solutions in contact with it was observed, which indicated that this membrane was suitable for single use in the efficient recovery of Au(III) from hydrochloric acid solutions of electronic scrap or recycled jewelry.

A review comparing cathodic arcs and high power impulse magnetron sputtering (HiPIMS)

DOE PAGES

Anders, André

2014-09-02

In this study, high power impulse magnetron sputtering (HiPIMS) has been in the center of attention over the last years as it is an emerging physical vapor deposition (PVD) technology that combines advantages of magnetron sputtering with various forms of energetic deposition of films such as ion plating and cathodic arc plasma deposition. It should not come at a surprise that many extension and variations of HiPIMS make use, intentionally or unintentionally, of previously discovered approaches to film processing such as substrate surface preparation by metal ion sputtering and phased biasing for film texture and stress control. Therefore, in thismore » review, an overview is given on some historical developments and features of cathodic arc and HiPIMS plasmas, showing commonalities and differences. To limit the scope, emphasis is put on plasma properties, as opposed to surveying the vast literature on specific film materials and their properties.« less

Trade-off between synergy and efficacy in combinations of HIV-1 latency-reversing agents.

PubMed

Gupta, Vipul; Dixit, Narendra M

2018-02-01

Eradicating HIV-1 infection is difficult because of the reservoir of latently infected cells that gets established soon after infection, remains hidden from antiretroviral drugs and host immune responses, and retains the capacity to reignite infection following the cessation of treatment. Drugs called latency-reversing agents (LRAs) are being developed to reactivate latently infected cells and render them susceptible to viral cytopathicity or immune killing. Whereas individual LRAs have failed to induce adequate reactivation, pairs of LRAs have been identified recently that act synergistically and hugely increase reactivation levels compared to individual LRAs. The maximum synergy achievable with LRA pairs is of clinical importance, as it would allow latency-reversal with minimal drug exposure. Here, we employed stochastic simulations of HIV-1 transcription and translation in latently infected cells to estimate this maximum synergy. We incorporated the predominant mechanisms of action of the two most promising classes of LRAs, namely, protein kinase C agonists and histone deacetylase inhibitors, and quantified the activity of individual LRAs in the two classes by mapping our simulations to corresponding in vitro experiments. Without any adjustable parameters, our simulations then quantitatively captured experimental observations of latency-reversal when the LRAs were used in pairs. Performing simulations representing a wide range of drug concentrations, we estimated the maximum synergy achievable with these LRA pairs. Importantly, we found with all the LRA pairs we considered that concentrations yielding the maximum synergy did not yield the maximum latency-reversal. Increasing concentrations to increase latency-reversal compromised synergy, unravelling a trade-off between synergy and efficacy in LRA combinations. The maximum synergy realizable with LRA pairs would thus be restricted by the desired level of latency-reversal, a constrained optimum we elucidated with

Exploring New Potentials of Blogs for Learning: Can Children Use Blogs for Personal Information Management (PIM)?

ERIC Educational Resources Information Center

Yeo, Hwan-Ik; Lee, Yekyung Lisa

2014-01-01

This study explores the use of blogs for personal information management (PIM) as a learning tool that could bring increased efficiency and academic self-efficacy for carrying out learning tasks. In order to identify the uses and effects of using blogs for PIM by children, a control group that used personal spaces within the class website and an…

Avoiding and tolerating latency in large-scale next-generation shared-memory multiprocessors

NASA Technical Reports Server (NTRS)

Probst, David K.

1993-01-01

A scalable solution to the memory-latency problem is necessary to prevent the large latencies of synchronization and memory operations inherent in large-scale shared-memory multiprocessors from reducing high performance. We distinguish latency avoidance and latency tolerance. Latency is avoided when data is brought to nearby locales for future reference. Latency is tolerated when references are overlapped with other computation. Latency-avoiding locales include: processor registers, data caches used temporally, and nearby memory modules. Tolerating communication latency requires parallelism, allowing the overlap of communication and computation. Latency-tolerating techniques include: vector pipelining, data caches used spatially, prefetching in various forms, and multithreading in various forms. Relaxing the consistency model permits increased use of avoidance and tolerance techniques. Each model is a mapping from the program text to sets of partial orders on program operations; it is a convention about which temporal precedences among program operations are necessary. Information about temporal locality and parallelism constrains the use of avoidance and tolerance techniques. Suitable architectural primitives and compiler technology are required to exploit the increased freedom to reorder and overlap operations in relaxed models.

Monitoring data transfer latency in CMS computing operations

DOE PAGES

Bonacorsi, Daniele; Diotalevi, Tommaso; Magini, Nicolo; ...

2015-12-23

During the first LHC run, the CMS experiment collected tens of Petabytes of collision and simulated data, which need to be distributed among dozens of computing centres with low latency in order to make efficient use of the resources. While the desired level of throughput has been successfully achieved, it is still common to observe transfer workflows that cannot reach full completion in a timely manner due to a small fraction of stuck files which require operator intervention.For this reason, in 2012 the CMS transfer management system, PhEDEx, was instrumented with a monitoring system to measure file transfer latencies, andmore » to predict the completion time for the transfer of a data set. The operators can detect abnormal patterns in transfer latencies while the transfer is still in progress, and monitor the long-term performance of the transfer infrastructure to plan the data placement strategy.Based on the data collected for one year with the latency monitoring system, we present a study on the different factors that contribute to transfer completion time. As case studies, we analyze several typical CMS transfer workflows, such as distribution of collision event data from CERN or upload of simulated event data from the Tier-2 centres to the archival Tier-1 centres. For each workflow, we present the typical patterns of transfer latencies that have been identified with the latency monitor.We identify the areas in PhEDEx where a development effort can reduce the latency, and we show how we are able to detect stuck transfers which need operator intervention. Lastly, we propose a set of metrics to alert about stuck subscriptions and prompt for manual intervention, with the aim of improving transfer completion times.« less

Monitoring data transfer latency in CMS computing operations

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

Bonacorsi, Daniele; Diotalevi, Tommaso; Magini, Nicolo

During the first LHC run, the CMS experiment collected tens of Petabytes of collision and simulated data, which need to be distributed among dozens of computing centres with low latency in order to make efficient use of the resources. While the desired level of throughput has been successfully achieved, it is still common to observe transfer workflows that cannot reach full completion in a timely manner due to a small fraction of stuck files which require operator intervention.For this reason, in 2012 the CMS transfer management system, PhEDEx, was instrumented with a monitoring system to measure file transfer latencies, andmore » to predict the completion time for the transfer of a data set. The operators can detect abnormal patterns in transfer latencies while the transfer is still in progress, and monitor the long-term performance of the transfer infrastructure to plan the data placement strategy.Based on the data collected for one year with the latency monitoring system, we present a study on the different factors that contribute to transfer completion time. As case studies, we analyze several typical CMS transfer workflows, such as distribution of collision event data from CERN or upload of simulated event data from the Tier-2 centres to the archival Tier-1 centres. For each workflow, we present the typical patterns of transfer latencies that have been identified with the latency monitor.We identify the areas in PhEDEx where a development effort can reduce the latency, and we show how we are able to detect stuck transfers which need operator intervention. Lastly, we propose a set of metrics to alert about stuck subscriptions and prompt for manual intervention, with the aim of improving transfer completion times.« less

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

PubMed Central

2009-01-01

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway. PMID:19961595

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation.

PubMed

Kennedy, Peter G E; Rovnak, Joel; Badani, Hussain; Cohrs, Randall J

2015-07-01

Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing

Ocular HSV-1: Is the Cornea a Reservoir for Viral Latency or a Fast Pit Stop?

PubMed Central

Kennedy, David P.; Clement, Christian; Arceneaux, Richard L.; Bhattacharjee, Partha S.; Huq, Tashfin S.; Hill, James M.

2010-01-01

Purpose To present a review supporting and refuting evidence from mouse, rabbit, non-human primate, and human studies of herpes simplex virus type 1 (HSV-1) concerning corneal latency. Methods More than 50 research papers on HSV-1 published in peer-reviewed journals were examined. Results Infectious HSV-1 has been found in mouse denervated tissues and in tissues with negative cultures from the corresponding ganglion. However, the different mouse strains have shown varied responses to different strains of HSV, making it difficult to relate such findings to humans. Rabbit studies provide excellent evidence for HSV-1 corneal latency including data on HSV-1 migration from the cornea into the corneoscleral rim and on the distribution of HSV-1 DNA in the cornea. However, the available methods for the detection of infectious HSV-1 may not be sensitive enough to detect low-level infection. Infectious HSV-1 has been successfully isolated from the tears of non-human primates in the absence of detectable corneal lesions. The recurrence of corneal ulcers in non-human primates before the appearance of infectious HSV-1 in tears suggests that the origin of the HSV-1 is the cornea, rather than the TG. Human studies presented evidence of both ganglion and corneal latency. Conclusion Understanding HSV-1 disease progression and the possibility of corneal latency could lead to more effective treatments for herpetic keratitis. However, it is unlikely that operational latency in the cornea will be definitively proven unless a new method with higher sensitivity for the detection of infectious virus is developed. PMID:21304287

EOS Data Products Latency and Reprocessing Evaluation

NASA Astrophysics Data System (ADS)

Ramapriyan, H. K.; Wanchoo, L.

2012-12-01

NASA's Earth Observing System (EOS) Data and Information System (EOSDIS) program has been processing, archiving, and distributing EOS data since the launch of Terra platform in 1999. The EOSDIS Distributed Active Archive Centers (DAACs) and Science-Investigator-led Processing Systems (SIPSs) are generating over 5000 unique products with a daily average volume of 1.7 Petabytes. Initially EOSDIS had requirements to make process data products within 24 hours of receiving all inputs needed for generating them. Thus, generally, the latency would be slightly over 24 and 48 hours after satellite data acquisition, respectively, for Level 1 and Level 2 products. Due to budgetary constraints these requirements were relaxed, with the requirement being to avoid a growing backlog of unprocessed data. However, the data providers have been generating these products in as timely a manner as possible. The reduction in costs of computing hardware has helped considerably. It is of interest to analyze the actual latencies achieved over the past several years in processing and inserting the data products into the EOSDIS archives for the users to support various scientific studies such as land processes, oceanography, hydrology, atmospheric science, cryospheric science, etc. The instrument science teams have continuously evaluated the data products since the launches of EOS satellites and improved the science algorithms to provide high quality products. Data providers have periodically reprocessed the previously acquired data with these improved algorithms. The reprocessing campaigns run for an extended time period in parallel with forward processing, since all data starting from the beginning of the mission need to be reprocessed. Each reprocessing activity involves more data than the previous reprocessing. The historical record of the reprocessing times would be of interest to future missions, especially those involving large volumes of data and/or computational loads due to

Involvement of histone methyltransferase GLP in HIV-1 latency through catalysis of H3K9 dimethylation

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

Ding, Donglin; Qu, Xiying; Li, Lin

Understanding the mechanism of HIV-1 latency is crucial to eradication of the viral reservoir in HIV-1-infected individuals. However, the role of histone methyltransferase (HMT) G9a-like protein (GLP) in HIV-1 latency is still unclear. In the present work, we established four clonal cell lines containing HIV-1 vector. We found that the integration sites of most clonal cell lines favored active gene regions. However, we also observed hypomethylation of CpG of HIV 5′LTR in all four clonal cell lines. Additionally, 5′-deoxy-5′-methylthioadenosine (MTA), a broad-spectrum histone methyltransferase inhibitor, was used to examine the role of histone methylation in HIV-1 latency. MTA was foundmore » to decrease the level of H3K9 dimethylation, causing reactivation of latent HIV-1 in C11 cells. GLP knockdown by small interfering RNA clearly induced HIV-1 LTR expression. Results suggest that GLP may play a significant role in the maintenance of HIV-1 latency by catalyzing dimethylation of H3K9. - Highlights: ► We have established an in vitro model of HIV-1 latency. ► The integration sites of most clonal cell lines favor in active gene regions. ► Hypomethylation occurs in CpG islands of HIV 5′LTR in all four clonal cell lines. ► MTA can reactivate latent HIV-1 by decreasing the level of H3K9 me2 in C11 cells. ► HMT GLP may play a significant role in the maintenance of HIV-1 latency.« less

The Protein Information Management System (PiMS): a generic tool for any structural biology research laboratory

PubMed Central

Morris, Chris; Pajon, Anne; Griffiths, Susanne L.; Daniel, Ed; Savitsky, Marc; Lin, Bill; Diprose, Jonathan M.; Wilter da Silva, Alan; Pilicheva, Katya; Troshin, Peter; van Niekerk, Johannes; Isaacs, Neil; Naismith, James; Nave, Colin; Blake, Richard; Wilson, Keith S.; Stuart, David I.; Henrick, Kim; Esnouf, Robert M.

2011-01-01

The techniques used in protein production and structural biology have been developing rapidly, but techniques for recording the laboratory information produced have not kept pace. One approach is the development of laboratory information-management systems (LIMS), which typically use a relational database schema to model and store results from a laboratory workflow. The underlying philosophy and implementation of the Protein Information Management System (PiMS), a LIMS development specifically targeted at the flexible and unpredictable workflows of protein-production research laboratories of all scales, is described. PiMS is a web-based Java application that uses either Postgres or Oracle as the underlying relational database-management system. PiMS is available under a free licence to all academic laboratories either for local installation or for use as a managed service. PMID:21460443

The Protein Information Management System (PiMS): a generic tool for any structural biology research laboratory.

PubMed

Morris, Chris; Pajon, Anne; Griffiths, Susanne L; Daniel, Ed; Savitsky, Marc; Lin, Bill; Diprose, Jonathan M; da Silva, Alan Wilter; Pilicheva, Katya; Troshin, Peter; van Niekerk, Johannes; Isaacs, Neil; Naismith, James; Nave, Colin; Blake, Richard; Wilson, Keith S; Stuart, David I; Henrick, Kim; Esnouf, Robert M

2011-04-01

The techniques used in protein production and structural biology have been developing rapidly, but techniques for recording the laboratory information produced have not kept pace. One approach is the development of laboratory information-management systems (LIMS), which typically use a relational database schema to model and store results from a laboratory workflow. The underlying philosophy and implementation of the Protein Information Management System (PiMS), a LIMS development specifically targeted at the flexible and unpredictable workflows of protein-production research laboratories of all scales, is described. PiMS is a web-based Java application that uses either Postgres or Oracle as the underlying relational database-management system. PiMS is available under a free licence to all academic laboratories either for local installation or for use as a managed service.

Zebra Alphaherpesviruses (EHV-1 and EHV-9): Genetic Diversity, Latency and Co-Infections.

PubMed

Abdelgawad, Azza; Damiani, Armando; Ho, Simon Y W; Strauss, Günter; Szentiks, Claudia A; East, Marion L; Osterrieder, Nikolaus; Greenwood, Alex D

2016-09-20

Alphaherpesviruses are highly prevalent in equine populations and co-infections with more than one of these viruses' strains frequently diagnosed. Lytic replication and latency with subsequent reactivation, along with new episodes of disease, can be influenced by genetic diversity generated by spontaneous mutation and recombination. Latency enhances virus survival by providing an epidemiological strategy for long-term maintenance of divergent strains in animal populations. The alphaherpesviruses equine herpesvirus 1 (EHV-1) and 9 (EHV-9) have recently been shown to cross species barriers, including a recombinant EHV-1 observed in fatal infections of a polar bear and Asian rhinoceros. Little is known about the latency and genetic diversity of EHV-1 and EHV-9, especially among zoo and wild equids. Here, we report evidence of limited genetic diversity in EHV-9 in zebras, whereas there is substantial genetic variability in EHV-1. We demonstrate that zebras can be lytically and latently infected with both viruses concurrently. Such a co-occurrence of infection in zebras suggests that even relatively slow-evolving viruses such as equine herpesviruses have the potential to diversify rapidly by recombination. This has potential consequences for the diagnosis of these viruses and their management in wild and captive equid populations.

Minimizing Input-to-Output Latency in Virtual Environment

NASA Technical Reports Server (NTRS)

Adelstein, Bernard D.; Ellis, Stephen R.; Hill, Michael I.

2009-01-01

A method and apparatus were developed to minimize latency (time delay ) in virtual environment (VE) and other discrete- time computer-base d systems that require real-time display in response to sensor input s. Latency in such systems is due to the sum of the finite time requi red for information processing and communication within and between sensors, software, and displays.

Improved UT1 Predictions through Low-Latency VLBI Observations

DTIC Science & Technology

2010-03-14

J Geod (2010) 84:399–402 DOI 10.1007/s00190-010-0372-8 SHORT NOTE Improved UT1 predictions through low-latency VLBI observations Brian Luzum · Axel...polar motion and nutation on UT1 determinations from VLBI Intensive obser- vations. J Geod 82(12):863. doi:10.1007/s00190-008-0212-2 Ray JR, Carter WE...Behrend D (2007) The International VLBI Service for Geodesy and Astrometry (IVS): current capabilities and future prospects. J Geod 81(6–8):479. doi

Composite targets in HiPIMS plasmas: Correlation of in-vacuum XPS characterization and optical plasma diagnostics

NASA Astrophysics Data System (ADS)

Layes, Vincent; Monje, Sascha; Corbella, Carles; Schulz-von der Gathen, Volker; von Keudell, Achim; de los Arcos, Teresa

2017-05-01

In-vacuum characterization of magnetron targets after High Power Impulse Magnetron Sputtering (HiPIMS) has been performed by X-ray photoelectron spectroscopy (XPS). Al-Cr composite targets (circular, 50 mm diameter) mounted in two different geometries were investigated: an Al target with a small Cr disk embedded at the racetrack position and a Cr target with a small Al disk embedded at the racetrack position. The HiPIMS discharge and the target surface composition were characterized in parallel for low, intermediate, and high power conditions, thus covering both the Ar-dominated and the metal-dominated HiPIMS regimes. The HiPIMS plasma was investigated using optical emission spectroscopy and fast imaging using a CCD camera; the spatially resolved XPS surface characterization was performed after in-vacuum transfer of the magnetron target to the XPS chamber. This parallel evaluation showed that (i) target redeposition of sputtered species was markedly more effective for Cr atoms than for Al atoms; (ii) oxidation at the target racetrack was observed even though the discharge ran in pure Ar gas without O2 admixture, the oxidation depended on the discharge power and target composition; and (iii) a bright emission spot fixed on top of the inserted Cr disk appeared for high power conditions.

T-18, a stemonamide synthetic intermediate inhibits Pim kinase activity and induces cell apoptosis, acting as a potent anticancer drug.

PubMed

Wang, Zhen; Li, Xing-Min; Shang, Kun; Zhang, Peng; Wang, Chao-Fu; Xin, Yu-Hu; Zhou, Lu; Li, Ying-Yi

2013-03-01

Pim-3 kinase has been shown to be aberrantly expressed in premalignant and malignant lesions of endoderm-derived organs such as the liver, pancreas, colon and stomach. Pim-3 kinase inactivates the Bad protein, a proapoptotic molecule, and improves the expression of Bcl-xL, an antiapoptotic molecule, to promote cell proliferation. Thus, blocking Pim-3 kinase activity may be a new strategy for the treatment of pancreatic cancer. In this study, we screened low molecular compounds and observed that the stemonamide synthetic intermediate, T-18, potently inhibited Pim kinase activity. Moreover, T-18 inhibited the proliferation of human pancreatic, as well as that of hepatocellular and colon cancer cells in vitro. It also induced the apoptosis of human pancreatic carcinoma cells in vitro by decreasing the levels of phospho-Ser112-Bad; the levels of Pim-3 kinase and total Bad protein were not altered. Furthermore, T-18 inhibited the growth of human pancreatic cancer cells in nude mice without apparent adverse effects when the tumor was palpable. These observations indicate that stemonamide synthetic intermediates may be novel drugs for the treatment of gastrointestinal cancers, particularly pancreatic cancer.

Establishment of HSV1 Latency in Immunodeficient Mice Facilitates Efficient In Vivo Reactivation

PubMed Central

Ramakrishna, Chandran; Ferraioli, Adrianna; Calle, Aleth; Nguyen, Thanh K.; Openshaw, Harry; Lundberg, Patric S.; Lomonte, Patrick; Cantin, Edouard M.

2015-01-01

The establishment of latent infections in sensory neurons is a remarkably effective immune evasion strategy that accounts for the widespread dissemination of life long Herpes Simplex Virus type 1 (HSV1) infections in humans. Periodic reactivation of latent virus results in asymptomatic shedding and transmission of HSV1 or recurrent disease that is usually mild but can be severe. An in-depth understanding of the mechanisms regulating the maintenance of latency and reactivation are essential for developing new approaches to block reactivation. However, the lack of a reliable mouse model that supports efficient in vivo reactivation (IVR) resulting in production of infectious HSV1 and/or disease has hampered progress. Since HSV1 reactivation is enhanced in immunosuppressed hosts, we exploited the antiviral and immunomodulatory activities of IVIG (intravenous immunoglobulins) to promote survival of latently infected immunodeficient Rag mice. Latently infected Rag mice derived by high dose (HD), but not low dose (LD), HSV1 inoculation exhibited spontaneous reactivation. Following hyperthermia stress (HS), the majority of HD inoculated mice developed HSV1 encephalitis (HSE) rapidly and synchronously, whereas for LD inoculated mice reactivated HSV1 persisted only transiently in trigeminal ganglia (Tg). T cells, but not B cells, were required to suppress spontaneous reactivation in HD inoculated latently infected mice. Transfer of HSV1 memory but not OVA specific or naïve T cells prior to HS blocked IVR, revealing the utility of this powerful Rag latency model for studying immune mechanisms involved in control of reactivation. Crossing Rag mice to various knockout strains and infecting them with wild type or mutant HSV1 strains is expected to provide novel insights into the role of specific cellular and viral genes in reactivation, thereby facilitating identification of new targets with the potential to block reactivation. PMID:25760441

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

PubMed Central

Kennedy, Peter G. E.; Rovnak, Joel; Badani, Hussain

2015-01-01

Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an ‘end-less’ state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is

Protein Profiling Identifies mTOR Pathway Modulation and Cytostatic Effects of Pim Kinase Inhibitor, AZD1208, in Acute Myeloid Leukemia

PubMed Central

Chen, Lisa S.; Yang, Ji-Yeon; Liang, Han; Cortes, Jorge E.; Gandhi, Varsha

2017-01-01

Pim kinases phosphorylate and regulate a number of key AML cell survival proteins, and Pim inhibitors have recently entered clinical trial for hematological malignancies. AZD1208 is a small molecule pan-Pim kinase inhibitor and AZD1208 treatment resulted in growth inhibition and cell size reduction in AML cell lines including FLT3-WT (OCI-AML-3, KG-1a, MOLM-16) and FLT3-ITD mutated (MOLM-13, MV-4-11). There was limited apoptosis induction (<10% increase) in the AML cell lines evaluated with up to 3 μM AZD1208 for 24h, suggesting that growth inhibition is not through apoptosis induction. Using reverse phase protein array (RPPA) and immunoblot analysis, we identified that AZD1208 resulted in suppression of mTOR signaling, including inhibition of protein phosphorylation of mTOR(Ser2448), p70S6K(Thr389), S6(Ser235/236) and 4E-BP1(Ser65). Consistent with mTOR inhibition, there was also a reduction in protein synthesis that correlated with cell size reduction and growth inhibition with AZD1208; our study provide insights into the mechanism of AZD1208. PMID:27054578

Earlier Visual N1 Latencies in Expert Video-Game Players: A Temporal Basis of Enhanced Visuospatial Performance?

PubMed Central

Latham, Andrew J.; Patston, Lucy L. M.; Westermann, Christine; Kirk, Ian J.; Tippett, Lynette J.

2013-01-01

Increasing behavioural evidence suggests that expert video game players (VGPs) show enhanced visual attention and visuospatial abilities, but what underlies these enhancements remains unclear. We administered the Poffenberger paradigm with concurrent electroencephalogram (EEG) recording to assess occipital N1 latencies and interhemispheric transfer time (IHTT) in expert VGPs. Participants comprised 15 right-handed male expert VGPs and 16 non-VGP controls matched for age, handedness, IQ and years of education. Expert VGPs began playing before age 10, had a minimum 8 years experience, and maintained playtime of at least 20 hours per week over the last 6 months. Non-VGPs had little-to-no game play experience (maximum 1.5 years). Participants responded to checkerboard stimuli presented to the left and right visual fields while 128-channel EEG was recorded. Expert VGPs responded significantly more quickly than non-VGPs. Expert VGPs also had significantly earlier occipital N1s in direct visual pathways (the hemisphere contralateral to the visual field in which the stimulus was presented). IHTT was calculated by comparing the latencies of occipital N1 components between hemispheres. No significant between-group differences in electrophysiological estimates of IHTT were found. Shorter N1 latencies may enable expert VGPs to discriminate attended visual stimuli significantly earlier than non-VGPs and contribute to faster responding in visual tasks. As successful video-game play requires precise, time pressured, bimanual motor movements in response to complex visual stimuli, which in this sample began during early childhood, these differences may reflect the experience and training involved during the development of video-game expertise, but training studies are needed to test this prediction. PMID:24058667

Earlier visual N1 latencies in expert video-game players: a temporal basis of enhanced visuospatial performance?

PubMed

Latham, Andrew J; Patston, Lucy L M; Westermann, Christine; Kirk, Ian J; Tippett, Lynette J

2013-01-01

Increasing behavioural evidence suggests that expert video game players (VGPs) show enhanced visual attention and visuospatial abilities, but what underlies these enhancements remains unclear. We administered the Poffenberger paradigm with concurrent electroencephalogram (EEG) recording to assess occipital N1 latencies and interhemispheric transfer time (IHTT) in expert VGPs. Participants comprised 15 right-handed male expert VGPs and 16 non-VGP controls matched for age, handedness, IQ and years of education. Expert VGPs began playing before age 10, had a minimum 8 years experience, and maintained playtime of at least 20 hours per week over the last 6 months. Non-VGPs had little-to-no game play experience (maximum 1.5 years). Participants responded to checkerboard stimuli presented to the left and right visual fields while 128-channel EEG was recorded. Expert VGPs responded significantly more quickly than non-VGPs. Expert VGPs also had significantly earlier occipital N1s in direct visual pathways (the hemisphere contralateral to the visual field in which the stimulus was presented). IHTT was calculated by comparing the latencies of occipital N1 components between hemispheres. No significant between-group differences in electrophysiological estimates of IHTT were found. Shorter N1 latencies may enable expert VGPs to discriminate attended visual stimuli significantly earlier than non-VGPs and contribute to faster responding in visual tasks. As successful video-game play requires precise, time pressured, bimanual motor movements in response to complex visual stimuli, which in this sample began during early childhood, these differences may reflect the experience and training involved during the development of video-game expertise, but training studies are needed to test this prediction.

On the influence of latency estimation on dynamic group communication using overlays

NASA Astrophysics Data System (ADS)

Vik, Knut-Helge; Griwodz, Carsten; Halvorsen, Pål

2009-01-01

Distributed interactive applications tend to have stringent latency requirements and some may have high bandwidth demands. Many of them have also very dynamic user groups for which all-to-all communication is needed. In online multiplayer games, for example, such groups are determined through region-of-interest management in the application. We have investigated a variety of group management approaches for overlay networks in earlier work and shown that several useful tree heuristics exist. However, these heuristics require full knowledge of all overlay link latencies. Since this is not scalable, we investigate the effects that latency estimation techqniues have ton the quality of overlay tree constructions. We do this by evaluating one example of our group management approaches in Planetlab and examing how latency estimation techqniues influence their quality. Specifically, we investigate how two well-known latency estimation techniques, Vivaldi and Netvigator, affect the quality of tree building.

Proviral Latency, Persistent Human Immunodeficiency Virus Infection, and the Development of Latency Reversing Agents

PubMed Central

Archin, Nancie M.

2017-01-01

Abstract Quiescent proviral genomes that persist during human immunodeficiency virus type 1 (HIV-1) infection despite effective antiretroviral therapy (ART) can fuel rebound viremia after ART interruption and is a central obstacle to the cure of HIV infection. The induction of quiescent provirus is the goal of a new class of potential therapeutics, latency reversing agents (LRAs). The discovery, development, and testing of HIV LRAs is a key part of current efforts to develop latency reversal and viral clearance strategies to eradicate established HIV infection. The development of LRAs is burdened by many uncertainties that make drug discovery difficult. The biology of HIV latency is complex and incompletely understood. Potential targets for LRAs are host factors, and the potential toxicities of host-directed therapies in individuals that are otherwise clinically stable may be unacceptable. Assays to measure latency reversal and assess the effectiveness of potential therapeutics are complex and incompletely validated. Despite these obstacles, novel LRAs are under development and beginning to enter combination testing with viral clearance strategies. It is hoped that the steady advances in the development of LRAs now being paired with emerging immunotherapeutics to clear persistently infected cells will soon allow measurable clinical advances toward an HIV cure. PMID:28520964

Communication latencies of wireless devices suitable for time-critical messaging to anesthesia providers.

PubMed

Epstein, Richard H; Dexter, Franklin; Rothman, Brian

2013-04-01

Rapid and reliable methods of text communication to mobile anesthesia care providers are important to patient care and to efficient operating room management. Anesthesia departments are implementing automated methods to send text messages to mobile devices for abnormal vital signs, clinical recommendations, quality of care, and compliance or billing issues. The most time-critical communications determine maximum acceptable latencies. We studied the reliability of several alphanumeric messaging systems to identify an appropriate technology for such use. Latencies between message initiation and delivery to 3 alphanumeric paging devices were measured over weeks. Two devices used Internet pathways outside the hospital's local network with an external paging vendor (SkyTel). The third device used only the internal hospital network (Zetron). Sequential cell phone text page latencies were examined for lag-1 autocorrelation using the runs test, with results binned by hour and by day. Message latencies subsequently were batched in successive 1-week bins for calculation of the mean and 99th percentiles of latencies. We defined acceptance criteria as a mean latency <30 seconds and no more than 1 in 200 pages (0.5%) having a latency longer than 100 seconds. Cell phone texting was used as a positive control to assure that the analysis was appropriate, because such devices have (known) poor reliability during high network activity. There was substantial correlation among latencies for sequential cell phone text messages when binned by hours (P < 0.0001), but not by days (P = 0.61). The 2 devices using Internet pathways outside the hospital's network demonstrated unacceptable performance, with 1.3% and 33% of latencies exceeding 100 seconds, respectively. The device dependent only on the internal network had a mean latency of 8 seconds, with 100% of 40,200 pages having latencies <100 seconds. The findings suggest that the network used was the deciding factor. Developers of

Potential role for a B-catenin coactivator (high mobility group AT-hook 1 protein) during the latency-reactivation cycle of bovine herpesverus 1

USDA-ARS?s Scientific Manuscript database

The latency-related (LR)-RNA encoded by bovine herpes virus 1 (BoHV-1) is abundantly expressed in latently infected sensory neurons. Although the LR gene encodes several products, ORF2 appears to play a dominant role during the latency-reactivation cycle because a mutant virus containing stop codons...

[Analysis for the association between genetic polymorphisms of XRCC1, XPD, XRCC3, CCND1 and the latency of the occupational chronic benzene poisoning].

PubMed

Xu, Jian-ning; Huang, Hui-long; Wang, Quan-kai; Wang, Ya-wen; Yang, Min; Zheng, Yu-xin

2007-03-01

To explore the association between genetic polymorphisms of XRCC1, XPD, XRCC3 and CCND1 and latency of occupational chronic benzene poisoning. 80 patients diagnosed with occupational chronic benzene poisoning were investigated. PCR-RFLP was applied to detect the single nucleotide polymorphisms of C26304T, G27466A, G28152A, G36189A of XRCC1, C22541A, C23591T, A35931C of XPD, C18067T of XRCC3 and G870A of CCND1. Their relationship with the latency of chronic benzene poisoning was analyzed by Kaplan-Meier method. The association of XRCC1 G27466A subgroup with the latency of chronic benzene poisoning was observed, as well as that of CCDN1G870A subgroup. The benzene-exposed workers with XRCC1 27466G/G homozygous wild genotype developed chronic benzene poisoning 6.9 years later than those had homozygous (27466A/A) or heterozygous (27466G/A) mutant alleles. On the other hand, the latency developing chronic benzene poisoning was longer in workers with homozygous (CCND1 870A/A) or heterozygous (CCND1 870G/A) mutant alleles than in those carrying 870G/G homozygous wild genotype (14.9 vs. 8.7 years). The polymorphisms of XRCC1 and CCND1 potentially modify the latency of the chronic benzene poisoning among workers exposed to benzene.

Identification of two small RNAs within the first 1.5-kb of the herpes simplex virus type 1-encoded latency-associated transcript.

PubMed

Peng, Weiping; Vitvitskaia, Olga; Carpenter, Dale; Wechsler, Steven L; Jones, Clinton

2008-01-01

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is abundantly expressed in latently infected neurons. In the rabbit or mouse ocular models of infection, expression of the first 1.5 kb of LAT coding sequences is sufficient for and necessary for wild-type levels of spontaneous reactivation from latency. The antiapoptosis functions of LAT, which maps to the same 1.5 kb of LAT, are important for the latency-reactivation cycle because replacement of LAT with other antiapoptosis genes (the baculovirus IAP gene or the bovine herpesvirus type 1 latency-related gene) restores wild-type levels of reactivation to a LAT null mutant. A recent study identified a micro-RNA within LAT that can inhibit apoptosis (Gupta et al, Nature 442: 82-85). In this study, the authors analyzed the first 1.5 kb of LAT for additional small RNAs that may have regulatory functions. Two LAT-specific small RNAs were detected in productively infected human neuroblastoma cells within the first 1.5 kb of LAT, in a region that is important for inhibiting apoptosis. Although these small RNAs possess extensive secondary structure and a stem-loop structure, bands migrating near 23 bases were not detected suggesting these small RNAs are not true micro-RNAs. Both of the small LAT-specific RNAs have the potential to base pair with the ICP4 mRNA. These two small LAT RNAs may play a role in the latency-reactivation cycle by reducing apoptosis and/or by reducing ICP4 RNA expression.

Industrial WSN Based on IR-UWB and a Low-Latency MAC Protocol

NASA Astrophysics Data System (ADS)

Reinhold, Rafael; Underberg, Lisa; Wulf, Armin; Kays, Ruediger

2016-07-01

Wireless sensor networks for industrial communication require high reliability and low latency. As current wireless sensor networks do not entirely meet these requirements, novel system approaches need to be developed. Since ultra wideband communication systems seem to be a promising approach, this paper evaluates the performance of the IEEE 802.15.4 impulse-radio ultra-wideband physical layer and the IEEE 802.15.4 Low Latency Deterministic Network (LLDN) MAC for industrial applications. Novel approaches and system adaptions are proposed to meet the application requirements. In this regard, a synchronization approach based on circular average magnitude difference functions (CAMDF) and on a clean template (CT) is presented for the correlation receiver. An adapted MAC protocol titled aggregated low latency (ALL) MAC is proposed to significantly reduce the resulting latency. Based on the system proposals, a hardware prototype has been developed, which proves the feasibility of the system and visualizes the real-time performance of the MAC protocol.

Development of performance indicators for municipal solid waste management (PIMS): A review.

PubMed

Sanjeevi, V; Shahabudeen, P

2015-12-01

The aim of this paper is to review papers on municipal solid waste management (SWM) systems, especially on performance indicators (PIs), and suggest practical methods to manage the same by administrators. Worldwide, about 4 billion metric tons of solid waste (SW) is generated annually; the management of SW across cities is increasingly getting more complex and the funds available for providing service to citizens are shrinking. Analysis of the non-technical research papers shows that focus areas on SW can be grouped into 18 types, one being PIs. Historically, PIs for municipal SWM (PIMS) commenced with the publication of guidelines by various government agencies, starting in 1969. This was followed by a few benchmarking studies, commencing in 1998, by various international institutions. Many published comparative studies also disseminated good practices across the cities. From the 1990s onwards, research work started defining PIMS. These initiatives by various researchers took multiple dimensions and are reviewed in this paper. In almost all studies, the PIMS is measured in terms of investment decisions, public acceptance levels, social participation and environmental needs. The multiple indicators are complex, however, and managers of cities need simple tools to use. To make it simple, five-factor PIs are arrived at, considering simplicity and covering all the factors. A research agenda is outlined for future directions in the areas of cost reduction, citizens' services, citizen involvement and environmental impact. © The Author(s) 2015.

Characterization of graded TiC layers deposited by HiPIMS method

NASA Astrophysics Data System (ADS)

Bohovicova, Jana; Bonova, Lucia; Halanda, Juraj; Ivan, Jozef; Mesko, Marcel; Advanced Technologies Research Institute Team; Institute of Electronic; Photonic Team

2016-09-01

An advanced yet recent development of sputter technique is high power impulse magnetron sputtering (HiPIMS), in which short, energetic pulses are applied to the target, leading to a formation of an ultra-dense plasma in front of the cathode, that provide a high degree of ionization of sputtered material, and consequently enable to control the energy and the direction of the deposition flux. This gives a possibility to alter composition and microstructure in a controlled manner, enables the optimization of TiC for tribological applications. The aim of this work is to link physical phenomena in transient HiPIMS discharges to microstructural and compositional properties of graded TiC thin films. It was found that Ti bottom layer is contamination free. Compared to the direct current magnetron sputtering films, we observed an element specific reduction of impurities measured by ERDA by a factor 3 for N, 4 for H and by a factor of 20 for O. The high purity of Ti layer is partly explained by gas rarefaction and the cleaning effect of the bombarding ions. Graphitization degree of carbon top layer was elucidated by Raman spectroscopy. The compositional effects are correlated with differences in the film microstructure revealed by SEM, XRD and TEM analysis. This work was supported by VEGA, Project No. 1/0503/15 and APVV, Project No. 15-0168.

Low-latency situational awareness for UxV platforms

NASA Astrophysics Data System (ADS)

Berends, David C.

2012-06-01

Providing high quality, low latency video from unmanned vehicles through bandwidth-limited communications channels remains a formidable challenge for modern vision system designers. SRI has developed a number of enabling technologies to address this, including the use of SWaP-optimized Systems-on-a-Chip which provide Multispectral Fusion and Contrast Enhancement as well as H.264 video compression. Further, the use of salience-based image prefiltering prior to image compression greatly reduces output video bandwidth by selectively blurring non-important scene regions. Combined with our customization of the VLC open source video viewer for low latency video decoding, SRI developed a prototype high performance, high quality vision system for UxV application in support of very demanding system latency requirements and user CONOPS.

Identification of herpes simplex virus type 1 proteins encoded within the first 1.5 kb of the latency-associated transcript.

PubMed

Henderson, Gail; Jaber, Tareq; Carpenter, Dale; Wechsler, Steven L; Jones, Clinton

2009-09-01

Expression of the first 1.5 kb of the latency-associated transcript (LAT) that is encoded by herpes simplex virus type 1 (HSV-1) is sufficient for wild-type (wt) levels of reactivation from latency in small animal models. Peptide-specific immunoglobulin G (IgG) was generated against open reading frames (ORFs) that are located within the first 1.5 kb of LAT coding sequences. Cells stably transfected with LAT or trigeminal ganglionic neurons of mice infected with a LAT expressing virus appeared to express the L2 or L8 ORF. Only L2 ORF expression was readily detected in trigeminal ganglionic neurons of latently infected mice.

HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies

PubMed Central

Battistini, Angela; Sgarbanti, Marco

2014-01-01

The major obstacle towards HIV-1 eradication is the life-long persistence of the virus in reservoirs of latently infected cells. In these cells the proviral DNA is integrated in the host’s genome but it does not actively replicate, becoming invisible to the host immune system and unaffected by existing antiviral drugs. Rebound of viremia and recovery of systemic infection that follows interruption of therapy, necessitates life-long treatments with problems of compliance, toxicity, and untenable costs, especially in developing countries where the infection hits worst. Extensive research efforts have led to the proposal and preliminary testing of several anti-latency compounds, however, overall, eradication strategies have had, so far, limited clinical success while posing several risks for patients. This review will briefly summarize the more recent advances in the elucidation of mechanisms that regulates the establishment/maintenance of latency and therapeutic strategies currently under evaluation in order to eradicate HIV persistence. PMID:24736215

Combination of Pim kinase inhibitor SGI-1776 and bendamustine in B-cell lymphoma.

PubMed

Yang, Qingshan; Chen, Lisa S; Neelapu, Sattva S; Gandhi, Varsha

2013-09-01

SGI-1776 is a small-molecule Pim kinase inhibitor that primarily targets c-MYC-driven transcription and cap-dependent translation in mantle cell lymphoma (MCL) cells. Bendamustine is an alkylating chemotherapeutic agent approved for use in B-cell lymphoma that is known to induce DNA damage and initiate response to repair. Our studies were conducted in MCL cell lines JeKo-1 and Mino, as well as primary B-cell lymphoma samples of MCL and splenic marginal zone lymphoma (SMZL), where we treated cells with SGI-1776 and bendamustine. We measured levels of cellular apoptosis, macromolecule synthesis inhibition, and DNA damage induced by drug treatments. Both SGI-1776 and bendamustine effectively induced apoptosis as single agents, and when used in combination, an additive effect in cell killing was observed in MCL cell lines JeKo-1 and Mino, as well as in MCL and SMZL primary cells. As expected, SGI-1776 was effective in inducing a decrease of global RNA and protein synthesis, and bendamustine significantly inhibited DNA synthesis and generated a DNA damage response. When used in combination, the effects were intensified in DNA, RNA, and protein synthesis inhibition compared with single-agent treatments. These data provide a foundation and suggest the feasibility of using Pim kinase inhibitors in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma. Copyright © 2013 Elsevier Inc. All rights reserved.

Latency correction of event-related potentials between different experimental protocols

NASA Astrophysics Data System (ADS)

Iturrate, I.; Chavarriaga, R.; Montesano, L.; Minguez, J.; Millán, JdR

2014-06-01

Objective. A fundamental issue in EEG event-related potentials (ERPs) studies is the amount of data required to have an accurate ERP model. This also impacts the time required to train a classifier for a brain-computer interface (BCI). This issue is mainly due to the poor signal-to-noise ratio and the large fluctuations of the EEG caused by several sources of variability. One of these sources is directly related to the experimental protocol or application designed, and may affect the amplitude or latency of ERPs. This usually prevents BCI classifiers from generalizing among different experimental protocols. In this paper, we analyze the effect of the amplitude and the latency variations among different experimental protocols based on the same type of ERP. Approach. We present a method to analyze and compensate for the latency variations in BCI applications. The algorithm has been tested on two widely used ERPs (P300 and observation error potentials), in three experimental protocols in each case. We report the ERP analysis and single-trial classification. Main results. The results obtained show that the designed experimental protocols significantly affect the latency of the recorded potentials but not the amplitudes. Significance. These results show how the use of latency-corrected data can be used to generalize the BCIs, reducing the calibration time when facing a new experimental protocol.

PIM-Check: development of an international prescription-screening checklist designed by a Delphi method for internal medicine patients

PubMed Central

Desnoyer, Aude; Blanc, Anne-Laure; Pourcher, Valérie; Besson, Marie; Fonzo-Christe, Caroline; Desmeules, Jules; Perrier, Arnaud; Bonnabry, Pascal; Samer, Caroline; Guignard, Bertrand

2017-01-01

Objectives Potentially inappropriate medication (PIM) occurs frequently and is a well-known risk factor for adverse drug events, but its incidence is underestimated in internal medicine. The objective of this study was to develop an electronic prescription-screening checklist to assist residents and young healthcare professionals in PIM detection. Design Five-step study involving selection of medical domains, literature review and 17 semistructured interviews, a two-round Delphi survey, a forward/back-translation process and an electronic tool development. Setting 22 University and general hospitals from Canada, Belgium, France and Switzerland. Participants 40 physicians and 25 clinical pharmacists were involved in the study. Agreement with the checklist statements and their usefulness for healthcare professional training were evaluated using two 6-point Likert scales (ranging from 0 to 5). Primary and secondary outcome measures Agreement and usefulness ratings were defined as: >65% of the experts giving the statement a rating of 4 or 5, during the first Delphi-round and >75% during the second. Results 166 statements were generated during the first two steps. Mean agreement and usefulness ratings were 4.32/5 (95% CI 4.28 to 4.36) and 4.11/5 (4.07 to 4.15), respectively, during the first Delphi-round and 4.53/5 (4.51 to 4.56) and 4.36/5 (4.33 to 4.39) during the second (p<0.001). The final checklist includes 160 statements in 17 medical domains and 56 pathologies. An algorithm of approximately 31 000 lines was developed including comorbidities and medications variables to create the electronic tool. Conclusion PIM-Check is the first electronic prescription-screening checklist designed to detect PIM in internal medicine. It is intended to help young healthcare professionals in their clinical practice to detect PIM, to reduce medication errors and to improve patient safety. PMID:28760793

Resident T Cells are Unable to Control HSV-1 Activity in the Brain Ependymal Region During Latency1

PubMed Central

Menendez, Chandra M.; Jinkins, Jeremy K.; Carr, Daniel J.J.

2016-01-01

Herpes simplex virus type 1 (HSV-1) is one of the leading etiologies of sporadic viral encephalitis. Early anti-viral intervention is crucial to the survival of herpes simplex encephalitis patients; however, many survivors suffer from long-term neurological deficits. It is currently understood that HSV-1 establishes a latent infection within sensory peripheral neurons throughout the life of the host. However, the tissue residence of latent virus, other than in sensory neurons, and the potential pathogenic consequences of latency remain enigmatic. In the present study, we characterized the lytic and latent infection of HSV-1 in the central nervous system in comparison to the peripheral nervous system following ocular infection in mice. We utilized RT-PCR to detect latency associated transcripts and HSV-1 lytic cycle genes within the brain stem, the ependyma (EP), containing the limbic and cortical areas which also harbor neural progenitor cells, in comparison to the trigeminal ganglia. Unexpectedly, HSV-1 lytic genes, usually identified during acute infection, are uniquely expressed in the EP 60 days post infection when animals are no longer suffering from encephalitis. An inflammatory response was also mounted in the EP by the maintenance of resident memory T cells. However, EP T cells were incapable of controlling HSV-1 infection ex-vivo and secreted less IFN-γ which correlated with expression of a variety of exhaustion-related inhibitory markers. Collectively our data suggest that the persistent viral lytic gene expression during latency is the cause of the chronic inflammatory response leading to the exhaustion of the resident T cells in the EP. PMID:27357149

Data latency and the user community

NASA Astrophysics Data System (ADS)

Escobar, V. M.; Brown, M. E.; Carroll, M.

2013-12-01

The community using NASA Earth science observations in applications has grown significantly, with increasing sophistication to serve national interests. The National Research Council's Earth Science Decadal Survey report stated that the planning for applied and operational considerations in the missions should accompany the acquisition of new knowledge about Earth (NRC, 2007). This directive has made product applications at NASA an integral part of converting the data collected into actionable knowledge that can be used to inform policy. However, successfully bridging scientific research with operational decision making in different application areas requires looking into user data requirements and operational needs. This study was conducted to determine how users are incorporating NASA data into applications and operational processes. The approach included a review of published materials, direct interviews with mission representatives, and an online professional review, which was distributed to over 6000 individuals. We provide a complete description of the findings with definitions and explanations of what goes into measuring latency as well as how users and applications utilize NASA data products. We identified 3 classes of users: operational (need data in 3 hours or less), near real time (need data within a day of acquisition), and scientific users (need highest quality data, time independent). We also determined that most users with applications are interested in specific types of products that may come from multiple missions. These users will take the observations when they are available, however the observations may have additional applications value if they are available either by a certain time of day or within a period of time after acquisition. NASA has supported the need for access to low latency data on an ad-hoc basis and more substantively in stand-alone systems such as the MODIS Rapid Response system and more recently with LANCE. The increased level

Latency reversal and viral clearance to cure HIV-1

PubMed Central

Margolis, David M.; Garcia, J. Victor; Hazuda, Daria J.; Haynes, Barton F.

2016-01-01

Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication—a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society. PMID:27463679

The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency

PubMed Central

Mousseau, Guillaume; Kessing, Cari F.; Fromentin, Rémi; Trautmann, Lydie; Chomont, Nicolas

2015-01-01

ABSTRACT Antiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4+ T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production. Here we show that the Tat inhibitor didehydro-cortistatin A (dCA), unlike other antiretrovirals, reduces residual levels of viral transcription in several models of HIV latency, breaks the Tat-mediated transcriptional feedback loop, and establishes a nearly permanent state of latency, which greatly diminishes the capacity for virus reactivation. Importantly, treatment with dCA induces inactivation of viral transcription even after its removal, suggesting that the HIV promoter is epigenetically repressed. Critically, dCA inhibits viral reactivation upon CD3/CD28 or prostratin stimulation of latently infected CD4+ T cells from HIV-infected subjects receiving suppressive ART. Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs. PMID:26152583

Optical and Gravimetric Partitioning of Coastal Ocean Suspended Particulate Inorganic Matter (PIM)

NASA Astrophysics Data System (ADS)

Stavn, R. H.; Zhang, X.; Falster, A. U.; Gray, D. J.; Rick, J. J.; Gould, R. W., Jr.

2016-02-01

Recent work on the composition of suspended particulates of estuarine and coastal waters increases our capabilities to investigate the biogeochemal processes occurring in these waters. The biogeochemical properties associated with the particulates involve primarily sorption/desorption of dissolved matter onto the particle surfaces, which vary with the types of particulates. Therefore, the breakdown into chemical components of suspended matter will greatly expand the biogeochemistry of the coastal ocean region. The gravimetric techniques for these studies are here expanded and refined. In addition, new optical inversions greatly expand our capabilities to study spatial extent of the components of suspended particulate matter. The partitioning of a gravimetric PIM determination into clay minerals and amorphous silica is aided by electron microprobe analysis. The amorphous silica is further partitioned into contributions by detrital material and by the tests of living diatoms based on an empirical formula relating the chlorophyll content of cultured living diatoms in log phase growth to their frustules determined after gravimetric analysis of the ashed diatom residue. The optical inversion of composition of suspended particulates is based on the entire volume scattering function (VSF) measured in the field with a Multispectral Volume Scattering Meter and a LISST 100 meter. The VSF is partitioned into an optimal combination of contributions by particle subpopulations, each of which is uniquely represented by a refractive index and a log-normal size distribution. These subpopulations are aggregated to represent the two components of PIM using the corresponding refractive indices and sizes which also yield a particle size distribution for the two components. The gravimetric results of partitioning PIM into clay minerals and amorphous silica confirm the optical inversions from the VSF.

Test Operations Procedure (TOP) 02-2-546 Teleoperated Unmanned Ground Vehicle (UGV) Latency Measurements

DTIC Science & Technology

2017-01-11

discrete system components or measurements of latency in autonomous systems. 15. SUBJECT TERMS Unmanned Ground Vehicles, Basic Video Latency, End-to... discrete system components or measurements of latency in autonomous systems. 1.1 Basic Video Latency. Teleoperation latency, or lag, describes

The molecular basis of herpes simplex virus latency

PubMed Central

Nicoll, Michael P; Proença, João T; Efstathiou, Stacey

2012-01-01

Herpes simplex virus type 1 is a neurotropic herpesvirus that establishes latency within sensory neurones. Following primary infection, the virus replicates productively within mucosal epithelial cells and enters sensory neurones via nerve termini. The virus is then transported to neuronal cell bodies where latency can be established. Periodically, the virus can reactivate to resume its normal lytic cycle gene expression programme and result in the generation of new virus progeny that are transported axonally back to the periphery. The ability to establish lifelong latency within the host and to periodically reactivate to facilitate dissemination is central to the survival strategy of this virus. Although incompletely understood, this review will focus on the mechanisms involved in the regulation of latency that centre on the functions of the virus-encoded latency-associated transcripts (LATs), epigenetic regulation of the latent virus genome and the molecular events that precipitate reactivation. This review considers current knowledge and hypotheses relating to the mechanisms involved in the establishment, maintenance and reactivation herpes simplex virus latency. PMID:22150699

Long-latency auditory evoked potentials with verbal and nonverbal stimuli.

PubMed

Oppitz, Sheila Jacques; Didoné, Dayane Domeneghini; Silva, Débora Durigon da; Gois, Marjana; Folgearini, Jordana; Ferreira, Geise Corrêa; Garcia, Michele Vargas

2015-01-01

Long-latency auditory evoked potentials represent the cortical activity related to attention, memory, and auditory discrimination skills. Acoustic signal processing occurs differently between verbal and nonverbal stimuli, influencing the latency and amplitude patterns. To describe the latencies of the cortical potentials P1, N1, P2, N2, and P3, as well as P3 amplitude, with different speech stimuli and tone bursts, and to classify them in the presence and absence of these data. A total of 30 subjects with normal hearing were assessed, aged 18-32 years old, matched by gender. Nonverbal stimuli were used (tone burst; 1000Hz - frequent and 4000Hz - rare); and verbal (/ba/ - frequent; /ga/, /da/, and /di/ - rare). Considering the component N2 for tone burst, the lowest latency found was 217.45ms for the BA/DI stimulus; the highest latency found was 256.5ms. For the P3 component, the shortest latency with tone burst stimuli was 298.7 with BA/GA stimuli, the highest, was 340ms. For the P3 amplitude, there was no statistically significant difference among the different stimuli. For latencies of components P1, N1, P2, N2, P3, there were no statistical differences among them, regardless of the stimuli used. There was a difference in the latency of potentials N2 and P3 among the stimuli employed but no difference was observed for the P3 amplitude. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Adaptive and Innate Transforming Growth Factor β Signaling Impact Herpes Simplex Virus 1 Latency and Reactivation▿

PubMed Central

Allen, Sariah J.; Mott, Kevin R.; Wechsler, Steven L.; Flavell, Richard A.; Town, Terrence; Ghiasi, Homayon

2011-01-01

Innate and adaptive immunity play important protective roles by combating herpes simplex virus 1 (HSV-1) infection. Transforming growth factor β (TGF-β) is a key negative cytokine regulator of both innate and adaptive immune responses. Yet, it is unknown whether TGF-β signaling in either immune compartment impacts HSV-1 replication and latency. We undertook genetic approaches to address these issues by infecting two different dominant negative TGF-β receptor type II transgenic mouse lines. These mice have specific TGF-β signaling blockades in either T cells or innate cells. Mice were ocularly infected with HSV-1 to evaluate the effects of restricted innate or adaptive TGF-β signaling during acute and latent infections. Limiting innate cell but not T cell TGF-β signaling reduced virus replication in the eyes of infected mice. On the other hand, blocking TGF-β signaling in either innate cells or T cells resulted in decreased latency in the trigeminal ganglia of infected mice. Furthermore, inhibiting TGF-β signaling in T cells reduced cell lysis and leukocyte infiltration in corneas and trigeminal ganglia during primary HSV-1 infection of mice. These findings strongly suggest that TGF-β signaling, which generally functions to dampen immune responses, results in increased HSV-1 latency. PMID:21880769

SUN2 Modulates HIV-1 Infection and Latency through Association with Lamin A/C To Maintain the Repressive Chromatin.

PubMed

Sun, Wei-Wei; Jiao, Shi; Sun, Li; Zhou, Zhaocai; Jin, Xia; Wang, Jian-Hua

2018-05-01

The postintegrational latency of HIV-1 is characterized by reversible silencing of long terminal repeat (LTR)-driven transcription of the HIV genome. It is known that the formation of repressive chromatin at the 5'-LTR of HIV-1 proviral DNA impedes viral transcription by blocking the recruitment of positive transcription factors. How the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. Elucidation of which chromatin reassembly factor mediates the reorganization of chromatin is likely to facilitate the understanding of the host's modulation of HIV-1 transcription and latency. Here we revealed that "Sad1 and UNC84 domain containing 2" (SUN2), an inner nuclear membrane protein, maintained the repressive chromatin and inhibited HIV LTR-driven transcription of proviral DNA through an association with lamin A/C. Specifically, lamin A/C tethered SUN2 to the nucleosomes 1 and 2 of the HIV-1 5'-LTR to block the initiation and elongation of HIV-1 transcription. SUN2 knockdown converted chromatin to an active form and thus enhanced the phosphorylation of RNA polymerase II and its recruitment to the 5'-LTR HIV-1 proviral DNA, leading to reactivation of HIV-1 from latency. Conversely, the exogenous factors such as tumor necrosis factor alpha (TNF-α) induced reactivation, and the replication of HIV-1 led to the disassociation between SUN2 and lamin A/C, suggesting that disruption of the association between SUN2 and lamin A/C to convert the repressive chromatin to the active form might be a prerequisite for the initiation of HIV-1 transcription and replication. Together, our findings indicate that SUN2 is a novel chromatin reassembly factor that helps to maintain chromatin in a repressive state and consequently inhibits HIV-1 transcription. IMPORTANCE Despite the successful use of scores of antiretroviral drugs, HIV latency poses a major impediment to virus eradication. Elucidation of the mechanism of latency facilitates the discovery of new

MicroRNA-155 Reinforces HIV Latency*

PubMed Central

Ruelas, Debbie S.; Chan, Jonathan K.; Oh, Eugene; Heidersbach, Amy J.; Hebbeler, Andrew M.; Chavez, Leonard; Verdin, Eric; Rape, Michael; Greene, Warner C.

2015-01-01

The presence of a small number of infected but transcriptionally dormant cells currently thwarts a cure for the more than 35 million individuals infected with HIV. Reactivation of these latently infected cells may result in three fates: 1) cell death due to a viral cytopathic effect, 2) cell death due to immune clearance, or 3) a retreat into latency. Uncovering the dynamics of HIV gene expression and silencing in the latent reservoir will be crucial for developing an HIV-1 cure. Here we identify and characterize an intracellular circuit involving TRIM32, an HIV activator, and miR-155, a microRNA that may promote a return to latency in these transiently activated reservoir cells. Notably, we demonstrate that TRIM32, an E3 ubiquitin ligase, promotes reactivation from latency by directly modifying IκBα, leading to a novel mechanism of NF-κB induction not involving IκB kinase activation. PMID:25873391

Current views on HIV-1 latency, persistence, and cure.

PubMed

Melkova, Zora; Shankaran, Prakash; Madlenakova, Michaela; Bodor, Josef

2017-01-01

HIV-1 infection cannot be cured as it persists in latently infected cells that are targeted neither by the immune system nor by available therapeutic approaches. Consequently, a lifelong therapy suppressing only the actively replicating virus is necessary. The latent reservoir has been defined and characterized in various experimental models and in human patients, allowing research and development of approaches targeting individual steps critical for HIV-1 latency establishment, maintenance, and reactivation. However, additional mechanisms and processes driving the remaining low-level HIV-1 replication in the presence of the suppressive therapy still remain to be identified and targeted. Current approaches toward HIV-1 cure involve namely attempts to reactivate and purge HIV latently infected cells (so-called "shock and kill" strategy), as well as approaches involving gene therapy and/or gene editing and stem cell transplantation aiming at generation of cells resistant to HIV-1. This review summarizes current views and concepts underlying different approaches aiming at functional or sterilizing cure of HIV-1 infection.

Latency reversal and viral clearance to cure HIV-1.

PubMed

Margolis, David M; Garcia, J Victor; Hazuda, Daria J; Haynes, Barton F

2016-07-22

Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication--a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society. Copyright © 2016, American Association for the Advancement of Science.

Telemetry System Data Latency

DTIC Science & Technology

2017-07-13

ec o n d s Data Rate TELEMETRY SYSTEM DATA LATENCY 15 of 31 Document: JT3-AFC-SRPT-17172-0005 Revision...250 So ft w ar e D ec o m L at en cy N T im es G re at er T h an D xD ec o m L at en cy Data Rate TELEMETRY SYSTEM DATA LATENCY 16 of...20.0 30.0 40.0 50.0 60.0 70.0 M ill is ec o n d s Data Rate TELEMETRY SYSTEM DATA LATENCY 17 of 31 Document:

Short- and long-latency auditory evoked potentials in individuals with vestibular dysfunction.

PubMed

Santos Filha, Valdete Alves Valentins Dos; Bruckmann, Mirtes; Garcia, Michele Vargas

2018-01-01

Purpose Evaluate the auditory pathway at the brainstem and cortical levels in individuals with peripheral vestibular dysfunction. Methods The study sample was composed 19 individuals aged 20-80 years that presented exam results suggestive of Peripheral Vestibular Disorder (PVD) or Vestibular Dysfunction (VD). Participants underwent evaluation of the auditory pathway through Brainstem Auditory Evoked Potentials (BAEP) (short latency) and P1, N1, P2, N2, and P300 cortical potentials (long latency). Results Nine individuals presented diagnosis of VD and 10 participants were diagnosed with PVD. The overall average of the long latency potentials of the participants was within the normal range, whereas an increased mean was observed in the short latency of waves III and V of the left ear, as well as in the I - III interpeak interval of both ears. Association of the auditory potentials with VD and PVD showed statistically significant correlation only in the III - V interpeak interval of the right ear for short latency. Comparison between the long and short latencies in the groups showed differences between VD and PVD, but without statistical significance. Conclusion No statistically significant correlation was observed between VD/PVD and the auditory evoked potentials; however, for the long latency potentials, individuals with VD presented higher latency in P1, N1, P2, and N2, where as participants with PVD showed higher latency in P300. In the short latency potentials, there was an increase in the absolute latencies in the VD group and in the interpeak intervals in the PVD group.

Risk factors for the prescription of potentially inappropriate medication (PIM) in the elderly : an analysis of sickness fund routine claims data from Germany.

PubMed

Stock, Stephanie; Redaelli, Marcus; Simic, Dusan; Siegel, Martin; Henschel, Frank

2014-10-01

Elderly people are especially prone to suffer adverse drug reactions (ADR). Main reasons for the higher vulnerability of the elderly to ADR are changes in metabolism as i.e. slower renal clearance and polypharmacie which often results from multimorbidity. To prevent ADR careful prescription with special consideration of these aspects is warranted. To help physicians avoid drugs which are especially likely to cause ADR lists have been developed following the consensus method process. For Germany this list is called the PRISCUS list. It was developed based on a literature review, review of international lists such as the American Beers list, and a consensus process based on a Delphi survey. It contains 83 drugs from 18 classes which are classified as potentially inapropriate medication (PIM). It also lists alternatives for each PIM. If a drug is registered with the PRISCUS list this does not mean automatically that it is contraindicated in the elderly but that special caution should be excercised in prescribing the drug, alternatives should be considered and the patient carefully monitored.Prescription rates for PIMs in Germany in the elderly is pretty much stable at around 23% with only a small decline in the past years. Also, more than 5% of all prescriptions in the elderly are PIM prescriptions. Physicians specially trained in geriatrics tend to prescribe less PIMs compared to other physicians.

Cumulative latency advance underlies fast visual processing in desynchronized brain state

PubMed Central

Wang, Xu-dong; Chen, Cheng; Zhang, Dinghong; Yao, Haishan

2014-01-01

Fast sensory processing is vital for the animal to efficiently respond to the changing environment. This is usually achieved when the animal is vigilant, as reflected by cortical desynchronization. However, the neural substrate for such fast processing remains unclear. Here, we report that neurons in rat primary visual cortex (V1) exhibited shorter response latency in the desynchronized state than in the synchronized state. In vivo whole-cell recording from the same V1 neurons undergoing the two states showed that both the resting and visually evoked conductances were higher in the desynchronized state. Such conductance increases of single V1 neurons shorten the response latency by elevating the membrane potential closer to the firing threshold and reducing the membrane time constant, but the effects only account for a small fraction of the observed latency advance. Simultaneous recordings in lateral geniculate nucleus (LGN) and V1 revealed that LGN neurons also exhibited latency advance, with a degree smaller than that of V1 neurons. Furthermore, latency advance in V1 increased across successive cortical layers. Thus, latency advance accumulates along various stages of the visual pathway, likely due to a global increase of membrane conductance in the desynchronized state. This cumulative effect may lead to a dramatic shortening of response latency for neurons in higher visual cortex and play a critical role in fast processing for vigilant animals. PMID:24347634

Cumulative latency advance underlies fast visual processing in desynchronized brain state.

PubMed

Wang, Xu-dong; Chen, Cheng; Zhang, Dinghong; Yao, Haishan

2014-01-07

Fast sensory processing is vital for the animal to efficiently respond to the changing environment. This is usually achieved when the animal is vigilant, as reflected by cortical desynchronization. However, the neural substrate for such fast processing remains unclear. Here, we report that neurons in rat primary visual cortex (V1) exhibited shorter response latency in the desynchronized state than in the synchronized state. In vivo whole-cell recording from the same V1 neurons undergoing the two states showed that both the resting and visually evoked conductances were higher in the desynchronized state. Such conductance increases of single V1 neurons shorten the response latency by elevating the membrane potential closer to the firing threshold and reducing the membrane time constant, but the effects only account for a small fraction of the observed latency advance. Simultaneous recordings in lateral geniculate nucleus (LGN) and V1 revealed that LGN neurons also exhibited latency advance, with a degree smaller than that of V1 neurons. Furthermore, latency advance in V1 increased across successive cortical layers. Thus, latency advance accumulates along various stages of the visual pathway, likely due to a global increase of membrane conductance in the desynchronized state. This cumulative effect may lead to a dramatic shortening of response latency for neurons in higher visual cortex and play a critical role in fast processing for vigilant animals.

PIM-Check: development of an international prescription-screening checklist designed by a Delphi method for internal medicine patients.

PubMed

Desnoyer, Aude; Blanc, Anne-Laure; Pourcher, Valérie; Besson, Marie; Fonzo-Christe, Caroline; Desmeules, Jules; Perrier, Arnaud; Bonnabry, Pascal; Samer, Caroline; Guignard, Bertrand

2017-07-31

Potentially inappropriate medication (PIM) occurs frequently and is a well-known risk factor for adverse drug events, but its incidence is underestimated in internal medicine. The objective of this study was to develop an electronic prescription-screening checklist to assist residents and young healthcare professionals in PIM detection. Five-step study involving selection of medical domains, literature review and 17 semistructured interviews, a two-round Delphi survey, a forward/back-translation process and an electronic tool development. 22 University and general hospitals from Canada, Belgium, France and Switzerland. 40 physicians and 25 clinical pharmacists were involved in the study.Agreement with the checklist statements and their usefulness for healthcare professional training were evaluated using two 6-point Likert scales (ranging from 0 to 5). Agreement and usefulness ratings were defined as: >65% of the experts giving the statement a rating of 4 or 5, during the first Delphi-round and >75% during the second. 166 statements were generated during the first two steps. Mean agreement and usefulness ratings were 4.32/5 (95% CI 4.28 to 4.36) and 4.11/5 (4.07 to 4.15), respectively, during the first Delphi-round and 4.53/5 (4.51 to 4.56) and 4.36/5 (4.33 to 4.39) during the second (p<0.001). The final checklist includes 160 statements in 17 medical domains and 56 pathologies. An algorithm of approximately 31 000 lines was developed including comorbidities and medications variables to create the electronic tool. PIM-Check is the first electronic prescription-screening checklist designed to detect PIM in internal medicine. It is intended to help young healthcare professionals in their clinical practice to detect PIM, to reduce medication errors and to improve patient safety. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Reduced atomic shadowing in HiPIMS: Role of the thermalized metal ions

NASA Astrophysics Data System (ADS)

Oliveira, João Carlos; Ferreira, Fábio; Anders, André; Cavaleiro, Albano

2018-03-01

In magnetron sputtering, the ability to tailor film properties depends primarily on the control of the flux of particles impinging on the growing film. Among deposition mechanisms, the shadowing effect leads to the formation of a rough surface and a porous, columnar microstructure. Re-sputtered species may be re-deposited in the valleys of the films surface and thereby contribute to a reduction of roughness and to fill the underdense regions. Both effects are non-local and they directly compete to shape the final properties of the deposited films. Additional control of the bombarding flux can be obtained by ionizing the sputtered flux, because ions can be controlled with respect to their energy and impinging direction, such as in High-Power Impulse Magnetron Sputtering (HiPIMS). In this work, the relation between ionization of the sputtered species and thin film properties is investigated in order to identify the mechanisms which effectively influence the shadowing effect in Deep Oscillation Magnetron Sputtering (DOMS), a variant of HiPIMS. The properties of two Cr films deposited using the same averaged target power by d.c. magnetron sputtering and DOMS have been compared. Additionally, the angle distribution of the Cr species impinging on the substrate was simulated using Monte Carlo-based programs while the energy distribution of the energetic particles bombarding the substrate was evaluated by energy-resolved mass analysis. It was found that the acceleration of the thermalized chromium ions at the substrate sheath in DOMS significantly reduces the high angle component of their impinging angle distribution and, thus, efficiently reduces atomic shadowing. Therefore, a high degree of ionization in HiPIMS results in almost shadowing effect-free film deposition and allows us to deposit dense and compact films without the need of high energy particle bombardment during growth.

Consistent latencies of vestibular evoked myogenic potentials.

PubMed

Wang, Shou-Jen; Yeh, Te-Huei; Chang, Chun-Hsiang; Young, Yi-Ho

2008-12-01

This study investigated the association between neck length and vestibular evoked myogenic potential (VEMP) latencies in healthy children, adolescents, and adults to elucidate when VEMP latencies reach consistent levels. Findings of VEMP tests in 14 healthy children, seven healthy adolescents, and 14 healthy adults were analyzed for correlations with neck length, which was measured as the distance of a line dropping vertically from the mastoid tip to the horizontal plane passing through the clavicle. All healthy children, adolescents, and adults exhibited present VEMP responses. Children, adolescents, and adults significantly differed in p13 latency, n23 latency, and p13-n23 interval. According to receiver operating characteristic curve analysis, the optimal cutoff values of p13 and n23 latencies between children and adults were 12.6 and 19.8 msec, respectively. Because the odds ratio of p13 latency was less than that of n23 latency, n23 latency was used to discriminate VEMP latencies between children and adults. Accordingly, a cutoff value of 15.3 cm for neck length was proposed as a criterion for predicting VEMP latency within the adult range. Consequently, a positive correlation between neck length and VEMP latency was observed when neck length was <15.3 cm, while above which level one need not account for neck length in evaluating VEMP latency. The intra-subject variability of norms can be enhanced if the normative data for VEMP characteristic parameters take structural variance into account. This study suggests that the adult range of VEMP latencies can be anticipated if neck length is >15.3 cm.

The Human Immunodeficiency Virus 1 ASP RNA promotes viral latency by recruiting the Polycomb Repressor Complex 2 and promoting nucleosome assembly

PubMed Central

Zapata, Juan C.; Campilongo, Federica; Barclay, Robert A.; DeMarino, Catherine; Iglesias-Ussel, Maria D.; Kashanchi, Fatah; Romerio, Fabio

2017-01-01

Various epigenetic marks at the HIV-1 5′LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), thus promoting nucleosome assembly and suppressing gene expression. We found that an HIV-1 antisense transcript expressed from the 3′LTR and encoding the antisense protein ASP promotes proviral latency. Expression of ASP RNA reduced HIV-1 replication in Jurkat cells. Moreover, ASP RNA expression promoted the establishment and maintenance of HIV-1 latency in Jurkat E4 cells. We show that this transcript interacts with and recruits PRC2 to the HIV-1 5′LTR, increasing accumulation of the suppressive epigenetic mark H3K27me3, while reducing RNA Polymerase II and thus proviral transcription. Altogether, our results suggest that the HIV-1 ASP transcript promotes epigenetic silencing of the HIV-1 5′LTR and proviral latency through the PRC2 pathway. PMID:28340355

Scaling to Nanotechnology Limits with the PIMS Computer Architecture and a new Scaling Rule

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

Debenedictis, Erik P.

2015-02-01

We describe a new approach to computing that moves towards the limits of nanotechnology using a newly formulated sc aling rule. This is in contrast to the current computer industry scali ng away from von Neumann's original computer at the rate of Moore's Law. We extend Moore's Law to 3D, which l eads generally to architectures that integrate logic and memory. To keep pow er dissipation cons tant through a 2D surface of the 3D structure requires using adiabatic principles. We call our newly proposed architecture Processor In Memory and Storage (PIMS). We propose a new computational model that integratesmore » processing and memory into "tiles" that comprise logic, memory/storage, and communications functions. Since the programming model will be relatively stable as a system scales, programs repr esented by tiles could be executed in a PIMS system built with today's technology or could become the "schematic diagram" for implementation in an ultimate 3D nanotechnology of the future. We build a systems software approach that offers advantages over and above the technological and arch itectural advantages. Firs t, the algorithms may be more efficient in the conventional sens e of having fewer steps. Second, the algorithms may run with higher power efficiency per operation by being a better match for the adiabatic scaling ru le. The performance analysis based on demonstrated ideas in physical science suggests 80,000 x improvement in cost per operation for the (arguably) gene ral purpose function of emulating neurons in Deep Learning.« less

Latency-Based and Psychophysiological Measures of Sexual Interest Show Convergent and Concurrent Validity.

PubMed

Ó Ciardha, Caoilte; Attard-Johnson, Janice; Bindemann, Markus

2018-04-01

Latency-based measures of sexual interest require additional evidence of validity, as do newer pupil dilation approaches. A total of 102 community men completed six latency-based measures of sexual interest. Pupillary responses were recorded during three of these tasks and in an additional task where no participant response was required. For adult stimuli, there was a high degree of intercorrelation between measures, suggesting that tasks may be measuring the same underlying construct (convergent validity). In addition to being correlated with one another, measures also predicted participants' self-reported sexual interest, demonstrating concurrent validity (i.e., the ability of a task to predict a more validated, simultaneously recorded, measure). Latency-based and pupillometric approaches also showed preliminary evidence of concurrent validity in predicting both self-reported interest in child molestation and viewing pornographic material containing children. Taken together, the study findings build on the evidence base for the validity of latency-based and pupillometric measures of sexual interest.

Combination of Pim kinase inhibitor, SGI-1776, with bendamustine in B-cell lymphoma

PubMed Central

Yang, Qingshan; Chen, Lisa S; Neelapu, Sattva S.; Gandhi, Varsha

2013-01-01

SGI-1776 is a small molecule Pim kinase inhibitor that primarily targets c-Myc-driven transcription and cap-dependent translation in mantle cell lymphoma (MCL) cells. Bendamustine is an alkylating chemotherapeutic agent approved for use in B-cell lymphoma that is known to induce DNA damage and to initiate response to repair. We hypothesized that while each drug leads to the effects as stated above, combination of these drugs will enhance SGI-1776-induced inhibition of global transcription and translation processes, while promoting bendamustine-triggered decrease of DNA synthesis and DNA damage response in B-cell lymphoma. Both SGI-1776 and bendamustine as single agents effectively induced apoptosis and when used in combination, additive effect in cell killing was observed in MCL cell lines, JeKo-1 and Mino, as well as MCL and splenic marginal zone lymphoma (a type of B-cell lymphoma) primary cells. As expected, SGI-1776 was effective in inducing decrease of global RNA and protein synthesis, while bendamustine significantly inhibited DNA synthesis and generated DNA damage response. When used in combination, effects were intensified in DNA, RNA and protein syntheses compared to single agent treatments. Together, these data provided foundation and suggested feasibility of using Pim kinase inhibitor in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma. PMID:24290221

Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency

PubMed Central

Archin, Nancie M.; Kirchherr, Jennifer L.; Sung, Julia A.M.; Clutton, Genevieve; Sholtis, Katherine; Xu, Yinyan; Allard, Brigitte; Stuelke, Erin; Kashuba, Angela D.; Kuruc, Joann D.; Gay, Cynthia L.; Goonetilleke, Nilu

2017-01-01

BACKGROUND. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency. METHODS. In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell–associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals. RESULTS. Serial VOR exposures separated by 72 hours most often resulted in an increase in cell-associated HIV RNA within circulating resting CD4+ T cells. VOR was well tolerated by all participants. However, despite serial reversal of latency over 1 month of VOR dosing, we did not observe a measurable decrease (>0.3 log10) in the frequency of latent infection within resting CD4+ T cells. CONCLUSIONS. These findings outline parameters for the experimental use of VOR to clear latent infection. Latency reversal can be achieved by VOR safely and repeatedly, but effective depletion of persistent HIV infection will require additional advances. In addition to improvements in latency reversal, these advances may include the sustained induction of potent antiviral immune responses capable of recognizing and clearing the rare cells in which HIV latency has been reversed. TRIAL REGISTRATION. Clinicaltrials.gov NCT01319383. FUNDING. NIH grants U01 AI095052, AI50410, and P30 CA016086 and National Center for Advancing Translational Sciences grant KL2 TR001109. PMID:28714868

Multiple sleep latency measures in narcolepsy and behaviourally induced insufficient sleep syndrome.

PubMed

Marti, Isabelle; Valko, Philipp O; Khatami, Ramin; Bassetti, Claudio L; Baumann, Christian R

2009-12-01

Short mean latencies to the first epoch of non-rapid eye movement sleep stage 1 (NREM1) and the presence of >or= 2 sleep onset REM (SOREM) periods on multiple sleep latency test (MSLT) occur in both narcolepsy-cataplexy (NC) and behaviourally induced insufficient sleep syndrome (BIISS). It is not known whether specific MSLT findings help differentiate the two disorders. We analyzed MSLT data including sleep latencies to and between different sleep stages of 60 age-, gender- and body mass index (BMI)-matched subjects (hypocretin-deficient NC, actigraphy-confirmed BIISS, healthy controls: each 20). Mean latency (in minutes) to NREM1 sleep was significantly shorter in NC (1.8+/-1.5) than in BIISS (4.7+/-2.1, p<0.001) and controls (11.4+/-3.3, p<0.001). Mean latency to NREM2 sleep was similar in NC (8.6+/-4.7) and BIISS (8.1+/-2.7, p=0.64); latency to either NREM2 or rapid eye movement (REM) sleep (i.e., the sum of the sleep latency to NREM1 and the duration of the first NREM1 sleep sequence), however, was shorter in NC (4.4+/-2.9) than in BIISS (7.9+/-3.5, p<0.001). Referring to all naps with SOREM periods, the sequence NREM1-REM-NREM2 was more common (71%) in NC than in BIISS (15%, p<0.001), reflecting the shorter latency from NREM1 to NREM2 in BIISS (3.7+/-2.5) than in NC (6.1+/-5.9, p<0.001). Our findings show that both sleepiness (as measured by NREM1 sleep latency) and REM sleep propensity are higher in NC than in BIISS. Furthermore, our finding of frequent REM sleep prior to NREM2 sleep in NC is in line with the recent assumption of an insufficient NREM sleep intensity in NC. Together with detailed clinical interviews, sleep logs, actigraphy, and nocturnal polysomnography, mean sleep latencies to NREM1 1-REM-NREM2 may be the best MSLT measures to discriminate NC from BIISS.

Factors influencing the latency of simple reaction time

PubMed Central

Woods, David L.; Wyma, John M.; Yund, E. William; Herron, Timothy J.; Reed, Bruce

2015-01-01

Simple reaction time (SRT), the minimal time needed to respond to a stimulus, is a basic measure of processing speed. SRTs were first measured by Francis Galton in the 19th century, who reported visual SRT latencies below 190 ms in young subjects. However, recent large-scale studies have reported substantially increased SRT latencies that differ markedly in different laboratories, in part due to timing delays introduced by the computer hardware and software used for SRT measurement. We developed a calibrated and temporally precise SRT test to analyze the factors that influence SRT latencies in a paradigm where visual stimuli were presented to the left or right hemifield at varying stimulus onset asynchronies (SOAs). Experiment 1 examined a community sample of 1469 subjects ranging in age from 18 to 65. Mean SRT latencies were short (231, 213 ms when corrected for hardware delays) and increased significantly with age (0.55 ms/year), but were unaffected by sex or education. As in previous studies, SRTs were prolonged at shorter SOAs and were slightly faster for stimuli presented in the visual field contralateral to the responding hand. Stimulus detection time (SDT) was estimated by subtracting movement initiation time, measured in a speeded finger tapping test, from SRTs. SDT latencies averaged 131 ms and were unaffected by age. Experiment 2 tested 189 subjects ranging in age from 18 to 82 years in a different laboratory using a larger range of SOAs. Both SRTs and SDTs were slightly prolonged (by 7 ms). SRT latencies increased with age while SDT latencies remained stable. Precise computer-based measurements of SRT latencies show that processing speed is as fast in contemporary populations as in the Victorian era, and that age-related increases in SRT latencies are due primarily to slowed motor output. PMID:25859198

Low Latency Messages on Distributed Memory Multiprocessors

DOE PAGES

Rosing, Matt; Saltz, Joel

1995-01-01

This article describes many of the issues in developing an efficient interface for communication on distributed memory machines. Although the hardware component of message latency is less than 1 ws on many distributed memory machines, the software latency associated with sending and receiving typed messages is on the order of 50 μs. The reason for this imbalance is that the software interface does not match the hardware. By changing the interface to match the hardware more closely, applications with fine grained communication can be put on these machines. This article describes several tests performed and many of the issues involvedmore » in supporting low latency messages on distributed memory machines.« less

DART: A Microcomputer Program for Response Latency Analysis.

ERIC Educational Resources Information Center

Greene, John O.; Greene, Barry F.

1987-01-01

Discusses how chronometric measures such as the DART (Display And Response Timing) computer program, have become virtually indispensable in testing cognitive theories of human social behavior. Describes how the DART (1) provides a way to collect response latency data; and (2) allows measurement of response latencies to a set of user-specified,…

Coexistence of enhanced mobile broadband communications and ultra-reliable low-latency communications in mobile front-haul

NASA Astrophysics Data System (ADS)

Ying, Kai; Kowalski, John M.; Nogami, Toshizo; Yin, Zhanping; Sheng, Jia

2018-01-01

5G systems are supposed to support coexistence of multiple services such as ultra reliable low latency communications (URLLC) and enhanced mobile broadband (eMBB) communications. The target of eMBB communications is to meet the high-throughput requirement while URLLC are used for some high priority services. Due to the sporadic nature and low latency requirement, URLLC transmission may pre-empt the resource of eMBB transmission. Our work is to analyze the URLLC impact on eMBB transmission in mobile front-haul. Then, some solutions are proposed to guarantee the reliability/latency requirements for URLLC services and minimize the impact to eMBB services at the same time.

The Human Immunodeficiency Virus 1 ASP RNA promotes viral latency by recruiting the Polycomb Repressor Complex 2 and promoting nucleosome assembly.

PubMed

Zapata, Juan C; Campilongo, Federica; Barclay, Robert A; DeMarino, Catherine; Iglesias-Ussel, Maria D; Kashanchi, Fatah; Romerio, Fabio

2017-06-01

Various epigenetic marks at the HIV-1 5'LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), thus promoting nucleosome assembly and suppressing gene expression. We found that an HIV-1 antisense transcript expressed from the 3'LTR and encoding the antisense protein ASP promotes proviral latency. Expression of ASP RNA reduced HIV-1 replication in Jurkat cells. Moreover, ASP RNA expression promoted the establishment and maintenance of HIV-1 latency in Jurkat E4 cells. We show that this transcript interacts with and recruits PRC2 to the HIV-1 5'LTR, increasing accumulation of the suppressive epigenetic mark H3K27me3, while reducing RNA Polymerase II and thus proviral transcription. Altogether, our results suggest that the HIV-1 ASP transcript promotes epigenetic silencing of the HIV-1 5'LTR and proviral latency through the PRC2 pathway. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Low-Latency Lunar Surface Telerobotics from Earth-Moon Libration Points

NASA Technical Reports Server (NTRS)

Lester, Daniel; Thronson, Harley

2011-01-01

Concepts for a long-duration habitat at Earth-Moon LI or L2 have been advanced for a number of purposes. We propose here that such a facility could also have an important role for low-latency telerobotic control of lunar surface equipment, both for lunar science and development. With distances of about 60,000 km from the lunar surface, such sites offer light-time limited two-way control latencies of order 400 ms, making telerobotic control for those sites close to real time as perceived by a human operator. We point out that even for transcontinental teleoperated surgical procedures, which require operational precision and highly dexterous manipulation, control latencies of this order are considered adequate. Terrestrial telerobots that are used routinely for mining and manufacturing also involve control latencies of order several hundred milliseconds. For this reason, an Earth-Moon LI or L2 control node could build on the technology and experience base of commercially proven terrestrial ventures. A lunar libration-point telerobotic node could demonstrate exploration strategies that would eventually be used on Mars, and many other less hospitable destinations in the solar system. Libration-point telepresence for the Moon contrasts with lunar telerobotic control from the Earth, for which two-way control latencies are at least six times longer. For control latencies that long, telerobotic control efforts are of the "move-and-wait" variety, which is cognitively inferior to near real-time control.

Time Counts! Some Comments on System Latency in Head-Referenced Displays

NASA Technical Reports Server (NTRS)

Ellis, Stephen R.; Adelstein, Bernard D.

2013-01-01

System response latency is a prominent characteristic of human-computer interaction. Laggy systems are; however, not simply annoying but substantially reduce user productivity. The impact of latency on head referenced display systems, particularly head-mounted systems, is especially disturbing since not only can it interfere with dynamic registration in augmented reality displays but it also can in some cases indirectly contribute to motion sickness. We will summarize several experiments using standard psychophysical discrimination techniques that suggest what system latencies will be required to achieve perceptual stability for spatially referenced computer-generated imagery. In conclusion I will speculate about other system performance characteristics that I would hope to have for a dream augmented reality system.

In vivo expression of human cytomegalovirus (HCMV) microRNAs during latency.

PubMed

Meshesha, Mesfin K; Bentwich, Zvi; Solomon, Semaria A; Avni, Yonat Shemer

2016-01-01

Viral encoded microRNAs play key roles in regulating gene expression and the life cycle of human herpes viruses. Latency is one of the hallmarks of the human cytomegalovirus (HCMV or HHV5) life cycle, and its control may have immense practical applications. The present study aims to identify HCMV encoded microRNAs during the latency phase of the virus. We used a highly sensitive real time PCR (RTPCR) assay that involves a pre-amplification step before RTPCR. It can detect HCMV encoded microRNAs (miRNAs) during latency in purified monocytes and PBMCs from HCMV IgG positive donors and in latently infected monocytic THP-1 cell lines. During the latency phase, only eight HCMV encoded microRNAs were detected in PBMCs, monocytes and in the THP-1 cells. Five originated from the UL region of the virus genome and three from the US region. Reactivation of the virus from latency, in monocytes obtained from the same donor, using dexamethasone restored the expression of all known HCMV encoded miRNAs including those that were absent during latency. We observed a shift in the abundance of the two arms of mir-US29 between the productive and latency stages of the viral life cycle, suggesting that the star "passenger" form of this microRNA is preferentially expressed during latency. As a whole, our study demonstrates that HCMV expresses during the latency phase, both in vivo and in vitro, only a subset of its microRNAs, which may indicate that they play an important role in maintenance and reactivation of latency. Copyright © 2015 Elsevier B.V. All rights reserved.

Latency in Distributed Acquisition and Rendering for Telepresence Systems.

PubMed

Ohl, Stephan; Willert, Malte; Staadt, Oliver

2015-12-01

Telepresence systems use 3D techniques to create a more natural human-centered communication over long distances. This work concentrates on the analysis of latency in telepresence systems where acquisition and rendering are distributed. Keeping latency low is important to immerse users in the virtual environment. To better understand latency problems and to identify the source of such latency, we focus on the decomposition of system latency into sub-latencies. We contribute a model of latency and show how it can be used to estimate latencies in a complex telepresence dataflow network. To compare the estimates with real latencies in our prototype, we modify two common latency measurement methods. This presented methodology enables the developer to optimize the design, find implementation issues and gain deeper knowledge about specific sources of latency.

Long Noncoding RNA uc002yug.2 Activates HIV-1 Latency through Regulation of mRNA Levels of Various RUNX1 Isoforms and Increased Tat Expression.

PubMed

Huan, Chen; Li, Zhaolong; Ning, Shanshan; Wang, Hong; Yu, Xiao-Fang; Zhang, Wenyan

2018-05-01

The HIV-1 reservoir is a major obstacle to complete eradication of the virus. Although many proteins and RNAs have been characterized as regulators in HIV-1/AIDS pathogenesis and latency, only a few long noncoding RNAs (lncRNAs) have been shown to be closely associated with HIV-1 replication and latency. In this study, we demonstrated that lncRNA uc002yug.2 plays a key role in HIV-1 replication and latency. uc002yug.2 potentially enhances HIV-1 replication, long terminal repeat (LTR) activity, and the activation of latent HIV-1 in both cell lines and CD4 + T cells from patients. Further investigation revealed that uc002yug.2 activates latent HIV-1 through downregulating RUNX1b and -1c and upregulating Tat protein expression. The accumulated evidence supports our model that the Tat protein has the key role in the uc002yug.2-mediated regulatory effect on HIV-1 reactivation. Moreover, uc002yug.2 showed an ability to activate HIV-1 similar to that of suberoylanilide hydroxamic acid or phorbol 12-myristate 13-acetate using latently infected cell models. These findings improve our understanding of lncRNA regulation of HIV-1 replication and latency, providing new insights into potential targeted therapeutic interventions. IMPORTANCE The latent viral reservoir is the primary obstacle to curing HIV-1 disease. To date, only a few lncRNAs, which play major roles in various biological processes, including viral infection, have been identified as regulators in HIV-1 latency. In this study, we demonstrated that lncRNA uc002yug.2 is important for both HIV-1 replication and activation of latent viruses. Moreover, uc002yug.2 was shown to activate latent HIV-1 through regulating alternative splicing of RUNX1 and increasing the expression of Tat protein. These findings highlight the potential merit of targeting lncRNA uc002yug.2 as an activating agent for latent HIV-1. Copyright © 2018 American Society for Microbiology.

Prolonged P300 latency in children with the D[sub 2] dopamine receptor A1 allele

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

Noble, E.P.; Berman, S.M.; Ozkaragoz, T.Z.

1994-04-01

Previous studies have indicated the presence of a hereditary component in the generation of the P300, or P3, a late positive component of the event-related potential. Moreover, the dopaminergic system has been implicated in the P3. In the present study, 98 healthy Caucasian boys, mean age of 12.5 years and of above-average intelligence, were studied. The sample was composed of 32 sons of active alcoholic (SAA) fathers, 36 sons of recovering alcoholic (SRA) fathers, and 30 sons of social drinker (SSD) fathers, with none of them having yet begun to consume alcohol or other drugs. TaqI A D[sub 2] dopaminemore » receptor alleles (A1 and A2) were determined. A significant difference in the frequency of the A1 allele was found among these three groups of boys, with the SAA group having the highest A1 allele frequency (.313), followed by the SRA (.139) and the SSD (.133) groups. The relationship of the A1 and A2 alleles to P3 amplitude and latency was also determined. The results showed no significant difference in P3 amplitude between boys with the A1 and A2 allele. However, P3 latency was significantly longer in the total sample of boys with the A1 allele compared with those carrying the A2 allele. These findings suggest that polymorphism of the D[sub 2] dopamine receptor gene is an important determinant of P3 latency. 84 refs., 2 figs., 3 tabs.« less

JPEG XS, a new standard for visually lossless low-latency lightweight image compression

NASA Astrophysics Data System (ADS)

Descampe, Antonin; Keinert, Joachim; Richter, Thomas; Fößel, Siegfried; Rouvroy, Gaël.

2017-09-01

JPEG XS is an upcoming standard from the JPEG Committee (formally known as ISO/IEC SC29 WG1). It aims to provide an interoperable visually lossless low-latency lightweight codec for a wide range of applications including mezzanine compression in broadcast and Pro-AV markets. This requires optimal support of a wide range of implementation technologies such as FPGAs, CPUs and GPUs. Targeted use cases are professional video links, IP transport, Ethernet transport, real-time video storage, video memory buffers, and omnidirectional video capture and rendering. In addition to the evaluation of the visual transparency of the selected technologies, a detailed analysis of the hardware and software complexity as well as the latency has been done to make sure that the new codec meets the requirements of the above-mentioned use cases. In particular, the end-to-end latency has been constrained to a maximum of 32 lines. Concerning the hardware complexity, neither encoder nor decoder should require more than 50% of an FPGA similar to Xilinx Artix 7 or 25% of an FPGA similar to Altera Cyclon 5. This process resulted in a coding scheme made of an optional color transform, a wavelet transform, the entropy coding of the highest magnitude level of groups of coefficients, and the raw inclusion of the truncated wavelet coefficients. This paper presents the details and status of the standardization process, a technical description of the future standard, and the latest performance evaluation results.

Transcriptomic Analysis Implicates the p53 Signaling Pathway in the Establishment of HIV-1 Latency in Central Memory CD4 T Cells in an In Vitro Model.

PubMed

White, Cory H; Moesker, Bastiaan; Beliakova-Bethell, Nadejda; Martins, Laura J; Spina, Celsa A; Margolis, David M; Richman, Douglas D; Planelles, Vicente; Bosque, Alberto; Woelk, Christopher H

2016-11-01

The search for an HIV-1 cure has been greatly hindered by the presence of a viral reservoir that persists despite antiretroviral therapy (ART). Studies of HIV-1 latency in vivo are also complicated by the low proportion of latently infected cells in HIV-1 infected individuals. A number of models of HIV-1 latency have been developed to examine the signaling pathways and viral determinants of latency and reactivation. A primary cell model of HIV-1 latency, which incorporates the generation of primary central memory CD4 T cells (TCM), full-length virus infection (HIVNL4-3) and ART to suppress virus replication, was used to investigate the establishment of HIV latency using RNA-Seq. Initially, an investigation of host and viral gene expression in the resting and activated states of this model indicated that the resting condition was reflective of a latent state. Then, a comparison of the host transcriptome between the uninfected and latently infected conditions of this model identified 826 differentially expressed genes, many of which were related to p53 signaling. Inhibition of the transcriptional activity of p53 by pifithrin-α during HIV-1 infection reduced the ability of HIV-1 to be reactivated from its latent state by an unknown mechanism. In conclusion, this model may be used to screen latency reversing agents utilized in shock and kill approaches to cure HIV, to search for cellular markers of latency, and to understand the mechanisms by which HIV-1 establishes latency.

Positioning In Macular hole Surgery (PIMS): statistical analysis plan for a randomised controlled trial.

PubMed

Bell, Lauren; Hooper, Richard; Bunce, Catey; Pasu, Saruban; Bainbridge, James

2017-06-13

The treatment of idiopathic full-thickness macular holes involves surgery to close the hole. Some surgeons advise patients to adopt a face-down position to increase the likelihood of successful macular hole closure. However, patients often find the face-down positioning arduous. There is a lack of conclusive evidence that face-down positioning improves the outcome. The 'Positioning In Macular hole Surgery' (PIMS) trial will assess whether advice to position face-down after surgery improves the surgical success rate for the closure of large (≥400 μm) macular holes. The PIMS trial is a multicentre, parallel-group, superiority clinical trial with 1:1 randomisation. Patients (n = 192) with macular holes (≥400 μm) will be randomised after surgery to either face-down positioning or face-forward positioning for at least 8 h (which can be either consecutive or nonconsecutive) a day, for 5 days following surgery. Inclusion criteria are: presence of an idiopathic full-thickness macular hole ≥400 μm in diameter, as measured by optical coherence tomography (OCT) scans, on either or both eyes; patients electing to have surgery for a macular hole, with or without simultaneous phacoemulsification and intraocular lens implant; ability and willingness to position face-down or in an inactive face-forward position; a history of visual loss suggesting a macular hole of 12 months' or less duration. The primary outcome is successful macular hole closure at 3 months post surgery. The treatment effect will be reported as an odds ratio with 95% confidence interval, adjusted for size of macular hole and phakic lens status at baseline. Secondary outcome measures at 3 months are: further surgery for macular holes performed or planned (of those with unsuccessful closure); patient-reported experience of positioning; whether patients report they would still have elected to have the operation given what they know at follow-up; best-corrected visual acuity (BCVA) measured

Construction and Evaluation of an Ultra Low Latency Frameless Renderer for VR.

PubMed

Friston, Sebastian; Steed, Anthony; Tilbury, Simon; Gaydadjiev, Georgi

2016-04-01

Latency - the delay between a user's action and the response to this action - is known to be detrimental to virtual reality. Latency is typically considered to be a discrete value characterising a delay, constant in time and space - but this characterisation is incomplete. Latency changes across the display during scan-out, and how it does so is dependent on the rendering approach used. In this study, we present an ultra-low latency real-time ray-casting renderer for virtual reality, implemented on an FPGA. Our renderer has a latency of ~1 ms from 'tracker to pixel'. Its frameless nature means that the region of the display with the lowest latency immediately follows the scan-beam. This is in contrast to frame-based systems such as those using typical GPUs, for which the latency increases as scan-out proceeds. Using a series of high and low speed videos of our system in use, we confirm its latency of ~1 ms. We examine how the renderer performs when driving a traditional sequential scan-out display on a readily available HMO, the Oculus Rift OK2. We contrast this with an equivalent apparatus built using a GPU. Using captured human head motion and a set of image quality measures, we assess the ability of these systems to faithfully recreate the stimuli of an ideal virtual reality system - one with a zero latency tracker, renderer and display running at 1 kHz. Finally, we examine the results of these quality measures, and how each rendering approach is affected by velocity of movement and display persistence. We find that our system, with a lower average latency, can more faithfully draw what the ideal virtual reality system would. Further, we find that with low display persistence, the sensitivity to velocity of both systems is lowered, but that it is much lower for ours.

Fault latency in the memory - An experimental study on VAX 11/780

NASA Technical Reports Server (NTRS)

Chillarege, Ram; Iyer, Ravishankar K.

1986-01-01

Fault latency is the time between the physical occurrence of a fault and its corruption of data, causing an error. The measure of this time is difficult to obtain because the time of occurrence of a fault and the exact moment of generation of an error are not known. This paper describes an experiment to accurately study the fault latency in the memory subsystem. The experiment employs real memory data from a VAX 11/780 at the University of Illinois. Fault latency distributions are generated for s-a-0 and s-a-1 permanent fault models. Results show that the mean fault latency of a s-a-0 fault is nearly 5 times that of the s-a-1 fault. Large variations in fault latency are found for different regions in memory. An analysis of a variance model to quantify the relative influence of various workload measures on the evaluated latency is also given.

Advanced LIGO low-latency searches

NASA Astrophysics Data System (ADS)

Kanner, Jonah; LIGO Scientific Collaboration, Virgo Collaboration

2016-06-01

Advanced LIGO recently made the first detection of gravitational waves from merging binary black holes. The signal was first identified by a low-latency analysis, which identifies gravitational-wave transients within a few minutes of data collection. More generally, Advanced LIGO transients are sought with a suite of automated tools, which collectively identify events, evaluate statistical significance, estimate source position, and attempt to characterize source properties. This low-latency effort is enabling a broad multi-messenger approach to the science of compact object mergers and other transients. This talk will give an overview of the low-latency methodology and recent results.

Perceived ejaculatory latency and pleasure in different outlets.

PubMed

Corty, Eric W

2008-11-01

Ejaculatory latencies have been studied in coitus and with masturbation, but not with oral or manual stimulation by a partner. The present study extended research on ejaculatory latency to these outlets, and investigated the effect of perceived pleasure on self-reported ejaculatory latency. A convenience sample of male college students, not selected for sexual dysfunction, completed questionnaires assessing the outcome measures. Self-report measures of latency to ejaculation in, and perceived pleasure associated with, four different outlets (vaginal intercourse, oral intercourse, manual stimulation by a partner, and masturbation). Ejaculatory latencies in partnered activities were predictive of each other. Masturbatory latencies were predictive of coital latencies but not oral or manual stimulation latencies; all the partnered activities were predictive of each other. There was no difference in time to ejaculation among any of the partnered outlets, although ejaculation occurred more quickly with masturbation than with coitus or manual stimulation. In terms of pleasure associated with the outlets, vaginal and oral intercourse were perceived as equally pleasurable, and both were rated as more pleasurable than manual stimulation or masturbation, which did not differ from each other. These results suggest that rapidity of ejaculation is consistent across outlets for the partnered sexual activities, and that there is little unique-in terms of ejaculatory latency--about vaginal intercourse compared with oral or manual stimulation by a partner. Masturbation, however, does differ from the partnered activities. Although the average correlation, for individuals, between latency and pleasure for the different outlets is near zero, there are subgroups of men who have (i) a negative relation, (ii) a positive relation, or (iii) no relation. Results show that men, for whom greater pleasure is associated with shorter latency, are more likely to be dissatisfied with their

Decreased reactivation of a herpes simplex virus type 1 (HSV-1) latency associated transcript (LAT) mutant using the in vivo mouse UV-B model of induced reactivation

PubMed Central

BenMohamed, Lbachir; Osorio, Nelson; Srivastava, Ruchi; Khan, Arif A.; Simpson, Jennifer L.; Wechsler, Steven L.

2015-01-01

Blinding ocular herpetic disease in humans is due to herpes simplex virus type 1 (HSV-1) reactivations from latency, rather than to primary acute infection. The cellular and molecular mechanisms that control the HSV-1 latency-reactivation cycle remain to be fully elucidated. The aim of this study was to determine if reactivation of the HSV-1 latency associated transcript (LAT) deletion mutant (dLAT2903) was impaired in this model, as it is in the rabbit model of induced and spontaneous reactivation and in the explant TG induced reactivation model in mice. The eyes of mice latently infected with wild type HSV-1 strain McKrae (LAT(+) virus) or dLAT2903 (LAT(−) virus) were irradiated with UV-B and reactivation was determined. We found that compared to LAT(−) virus, LAT(+) virus reactivated at a higher rate as determined by shedding of virus in tears on days 3 to 7 after UV-B treatment. Thus, the UV-B induced reactivation model of HSV-1 appears to be a useful small animal model for studying the mechanisms involved in how LAT enhances the HSV-1 reactivation phenotype. The utility of the model for investigating the immune evasion mechanisms regulating the HSV-1 latency/reactivation cycle and for testing the protective efficacy of candidate therapeutic vaccines and drugs are discussed. PMID:26002839

Transcriptomic Analysis Implicates the p53 Signaling Pathway in the Establishment of HIV-1 Latency in Central Memory CD4 T Cells in an In Vitro Model

PubMed Central

White, Cory H.; Moesker, Bastiaan; Beliakova-Bethell, Nadejda; Martins, Laura J.; Richman, Douglas D.; Planelles, Vicente; Woelk, Christopher H.

2016-01-01

The search for an HIV-1 cure has been greatly hindered by the presence of a viral reservoir that persists despite antiretroviral therapy (ART). Studies of HIV-1 latency in vivo are also complicated by the low proportion of latently infected cells in HIV-1 infected individuals. A number of models of HIV-1 latency have been developed to examine the signaling pathways and viral determinants of latency and reactivation. A primary cell model of HIV-1 latency, which incorporates the generation of primary central memory CD4 T cells (TCM), full-length virus infection (HIVNL4-3) and ART to suppress virus replication, was used to investigate the establishment of HIV latency using RNA-Seq. Initially, an investigation of host and viral gene expression in the resting and activated states of this model indicated that the resting condition was reflective of a latent state. Then, a comparison of the host transcriptome between the uninfected and latently infected conditions of this model identified 826 differentially expressed genes, many of which were related to p53 signaling. Inhibition of the transcriptional activity of p53 by pifithrin-α during HIV-1 infection reduced the ability of HIV-1 to be reactivated from its latent state by an unknown mechanism. In conclusion, this model may be used to screen latency reversing agents utilized in shock and kill approaches to cure HIV, to search for cellular markers of latency, and to understand the mechanisms by which HIV-1 establishes latency. PMID:27898737

Communication latencies of Apple push notification messages relevant for delivery of time-critical information to anesthesia providers.

PubMed

Rothman, Brian S; Dexter, Franklin; Epstein, Richard H

2013-08-01

Tablet computers and smart phones have gained popularity in anesthesia departments for educational and patient care purposes. VigiVU(™) is an iOS application developed at Vanderbilt University for remote viewing of perioperative information, including text message notifications delivered via the Apple Push Notification (APN) service. In this study, we assessed the reliability of the APN service. Custom software was written to send a message every minute to iOS devices (iPad(®), iPod Touch(®), and iPhone(®)) via wireless local area network (WLAN) and cellular pathways 24 hours a day over a 4-month period. Transmission and receipt times were recorded and batched by days, with latencies calculated as their differences. The mean, SEM, and the exact 95% upper confidence limits for the percent of days with ≥1 prolonged (>100 seconds) latency were calculated. Acceptable performance was defined as mean latency <30 seconds and ≤0.5% of latencies >100 seconds. Testing conditions included fixed locations of devices in high signal strength locations. Mean latencies were <1 second for iPad and iPod devices (WLAN), and <4 seconds for iPhone (cellular). Among >173,000 iPad and iPod latencies, none were >100 seconds. For iPhone latencies, 0.03% ± 0.01% were >100 seconds. The 95% upper confidence limits of days with ≥1 prolonged latency were 42% (iPhone) and 5% to 8% (iPad, iPod). The APN service was reliable for all studied devices over WLAN and cellular pathways, and performance was better than third party paging systems using Internet connections previously investigated using the same criteria. However, since our study was a best-case assessment, testing is required at individual sites considering use of this technology for critical messaging. Furthermore, since the APN service may fail due to Internet or service provider disruptions, a backup paging system is recommended if the APN service were to be used for critical messaging.

Antibody purification-independent microarrays (PIM) by direct bacteria spotting on TiO2-treated slides.

PubMed

De Marni, Marzia L; Monegal, Ana; Venturini, Samuele; Vinati, Simone; Carbone, Roberta; de Marco, Ario

2012-02-01

The preparation of effective conventional antibody microarrays depends on the availability of high quality material and on the correct accessibility of the antibody active moieties following their immobilization on the support slide. We show that spotting bacteria that expose recombinant antibodies on their external surface directly on nanostructured-TiO(2) or epoxy slides (purification-independent microarray - PIM) is a simple and reliable alternative for preparing sensitive and specific microarrays for antigen detection. Variable domains of single heavy-chain antibodies (VHHs) against fibroblast growth factor receptor 1 (FGFR1) were used to capture the antigen diluted in serum or BSA solution. The FGFR1 detection was performed by either direct antigen labeling or using a sandwich system in which FGFR1 was first bound to its antibody and successively identified using a labeled FGF. In both cases the signal distribution within each spot was uniform and spot morphology regular. The signal-to-noise ratio of the signal was extremely elevated and the specificity of the system was proved statistically. The LOD of the system for the antigen was calculated being 0.4ng/mL and the dynamic range between 0.4ng/mL and 10μg/mL. The microarrays prepared with bacteria exposing antibodies remain fully functional for at least 31 days after spotting. We finally demonstrated that the method is suitable for other antigen-antibody pairs and expect that it could be easily adapted to further applications such as the display of scFv and IgG antibodies or the autoantibody detection using protein PIMs. Copyright © 2011. Published by Elsevier Inc.

In Silico Determination of Gas Permeabilities by Non-Equilibrium Molecular Dynamics: CO2 and He through PIM-1

PubMed Central

Frentrup, Hendrik; Hart, Kyle E.; Colina, Coray M.; Müller, Erich A.

2015-01-01

We study the permeation dynamics of helium and carbon dioxide through an atomistically detailed model of a polymer of intrinsic microporosity, PIM-1, via non-equilibrium molecular dynamics (NEMD) simulations. This work presents the first explicit molecular modeling of gas permeation through a high free-volume polymer sample, and it demonstrates how permeability and solubility can be obtained coherently from a single simulation. Solubilities in particular can be obtained to a very high degree of confidence and within experimental inaccuracies. Furthermore, the simulations make it possible to obtain very specific information on the diffusion dynamics of penetrant molecules and yield detailed maps of gas occupancy, which are akin to a digital tomographic scan of the polymer network. In addition to determining permeability and solubility directly from NEMD simulations, the results shed light on the permeation mechanism of the penetrant gases, suggesting that the relative openness of the microporous topology promotes the anomalous diffusion of penetrant gases, which entails a deviation from the pore hopping mechanism usually observed in gas diffusion in polymers. PMID:25764366

A HiPIMS plasma source with a magnetic nozzle that accelerates ions: application in a thruster

NASA Astrophysics Data System (ADS)

Bathgate, Stephen N.; Ganesan, Rajesh; Bilek, Marcela M. M.; McKenzie, David R.

2017-01-01

We demonstrate a solid fuel electrodeless ion thruster that uses a magnetic nozzle to collimate and accelerate copper ions produced by a high power impulse magnetron sputtering discharge (HiPIMS). The discharge is initiated using argon gas but in a practical device the consumption of argon could be minimised by exploiting the self-sputtering of copper. The ion fluence produced by the HiPIMS discharge was measured with a retarding field energy analyzer (RFEA) as a function of the magnetic field strength of the nozzle. The ion fraction of the copper was determined from the deposition rate of copper as a function of substrate bias and was found to exceed 87%. The ion fluence and ion energy increased in proportion with the magnetic field of the nozzle and the energy of the ions was found to follow a Maxwell-Boltzmann distribution with a directed velocity. The effectiveness of the magnetic nozzle in converting the randomized thermal motion of the ions into a jet was demonstrated from the energy distribution of the ions. The maximum ion exhaust velocity of at least 15.1 km/s, equivalent to a specific impulse of 1543 s was measured which is comparable to existing Hall thrusters and exceeds that of Teflon pulsed plasma thrusters.

Evaluation of the relation between triceps surae H-reflex, M-response latencies and thigh length in normal population.

PubMed

Khosrawi, Saeid; Fallah, Salman

2013-03-01

The H-reflex is a useful electrophysiological procedure for evaluating the status of the peripheral nervous system, especially at the proximal segment of the peripheral nerve. The purpose of this study is to investigate the relation between triceps surae H-reflex and M- response latencies and thigh length in normal population, in order to determine if there is any regression equation between them. After screening 75 volunteers by considering inclusion and exclusion criteria, 72 of them were selected to enroll into our study (34 men and 38 women with the mean age of 36.04 ± 7.7 years). In all of the subjects H-reflex and M-response latencies were recorded by standard electrophysiological techniques and thigh length was measured. Finally, our data was analyzed for its relations with respect to ages in both sexes by appropriate statistical and mathematical methods. Mean ± SD for H-reflex latency was 27.94 ± 1.6 ms. We found a significant correlation between H-reflex latency and M-latency (r = 0.28), no significant correlation was found between H-reflex latency and thigh length (r = -0.051). Finally based on our findings we introduce a new formula in this paper. We found a significant correlation among of M-response latency and other variables (H-reflex latency and thigh length). Despite this it was eliminated from our formula. The relationship between H-reflex latency and age was significant. Further studies are required to delineate the clinical usage and interpretation of the formula, which we found in this study.

The effect of monitor raster latency on VEPs, ERPs and Brain-Computer Interface performance.

PubMed

Nagel, Sebastian; Dreher, Werner; Rosenstiel, Wolfgang; Spüler, Martin

2018-02-01

Visual neuroscience experiments and Brain-Computer Interface (BCI) control often require strict timings in a millisecond scale. As most experiments are performed using a personal computer (PC), the latencies that are introduced by the setup should be taken into account and be corrected. As a standard computer monitor uses a rastering to update each line of the image sequentially, this causes a monitor raster latency which depends on the position, on the monitor and the refresh rate. We technically measured the raster latencies of different monitors and present the effects on visual evoked potentials (VEPs) and event-related potentials (ERPs). Additionally we present a method for correcting the monitor raster latency and analyzed the performance difference of a code-modulated VEP BCI speller by correcting the latency. There are currently no other methods validating the effects of monitor raster latency on VEPs and ERPs. The timings of VEPs and ERPs are directly affected by the raster latency. Furthermore, correcting the raster latency resulted in a significant reduction of the target prediction error from 7.98% to 4.61% and also in a more reliable classification of targets by significantly increasing the distance between the most probable and the second most probable target by 18.23%. The monitor raster latency affects the timings of VEPs and ERPs, and correcting resulted in a significant error reduction of 42.23%. It is recommend to correct the raster latency for an increased BCI performance and methodical correctness. Copyright © 2017 Elsevier B.V. All rights reserved.

Mitochondrial enzymes are protected from stress-induced aggregation by mitochondrial chaperones and the Pim1/LON protease

PubMed Central

Bender, Tom; Lewrenz, Ilka; Franken, Sebastian; Baitzel, Catherina; Voos, Wolfgang

2011-01-01

Proteins in a natural environment are constantly challenged by stress conditions, causing their destabilization, unfolding, and, ultimately, aggregation. Protein aggregation has been associated with a wide variety of pathological conditions, especially neurodegenerative disorders, stressing the importance of adequate cellular protein quality control measures to counteract aggregate formation. To secure protein homeostasis, mitochondria contain an elaborate protein quality control system, consisting of chaperones and ATP-dependent proteases. To determine the effects of protein aggregation on the functional integrity of mitochondria, we set out to identify aggregation-prone endogenous mitochondrial proteins. We could show that major metabolic pathways in mitochondria were affected by the aggregation of key enzyme components, which were largely inactivated after heat stress. Furthermore, treatment with elevated levels of reactive oxygen species strongly influenced the aggregation behavior, in particular in combination with elevated temperatures. Using specific chaperone mutant strains, we showed a protective effect of the mitochondrial Hsp70 and Hsp60 chaperone systems. Moreover, accumulation of aggregated polypeptides was strongly decreased by the AAA-protease Pim1/LON. We therefore propose that the proteolytic breakdown of aggregation-prone polypeptides represents a major protective strategy to prevent the in vivo formation of aggregates in mitochondria. PMID:21209324

Dopamine Modulation of Avoidance Behavior in Caenorhabditis elegans Requires the NMDA Receptor NMR-1

PubMed Central

Baidya, Melvin; Genovez, Marx; Torres, Marissa; Chao, Michael Y.

2014-01-01

The nematode C. elegans utilizes a relatively simple neural circuit to mediate avoidance responses to noxious stimuli such as the volatile odorant octanol. This avoidance behavior is modulated by dopamine. cat-2 mutant animals that are deficient in dopamine biosynthesis have an increased response latency to octanol compared to wild type animals, and this defect can be fully restored with the application of exogenous dopamine. Because this avoidance behavior is mediated by glutamatergic signaling between sensory neurons and premotor interneurons, we investigated the genetic interactions between dopaminergic signaling and ionotropic glutamate receptors. cat-2 mutant animals lacking either the GLR-1 or GLR-2 AMPA/kainate receptors displayed an increased response latency to octanol, which could be restored via exogenous dopamine. However, whereas cat-2 mutant animals lacking the NMR-1 NMDA receptor had increased response latency to octanol they were insensitive to exogenous dopamine. Mutants that lacked both AMPA/kainate and NMDA receptors were also insensitive to exogenous dopamine. Our results indicate that dopamine modulation of octanol avoidance requires NMR-1, consistent with NMR-1 as a potential downstream signaling target for dopamine. PMID:25089710

Pursuit Latency for Chromatic Targets

NASA Technical Reports Server (NTRS)

Mulligan, Jeffrey B.; Ellis, Stephen R. (Technical Monitor)

1998-01-01

The temporal dynamics of eye movement response to a change in direction of stimulus motion has been used to compare the processing speeds of different types of stimuli (Mulligan, ARVO '97). In this study, the pursuit response to colored targets was measured to test the hypothesis that the slow response of the chromatic system (as measured using traditional temporal sensitivity measures such as contrast sensitivity) results in increased eye movement latencies. Subjects viewed a small (0.4 deg) Gaussian spot which moved downward at a speed of 6.6 deg/sec. At a variable time during the trajectory, the dot's direction of motion changed by 30 degrees, either to the right or left. Subjects were instructed to pursue the spot. Eye movements were measured using a video ophthalmoscope with an angular resolution of approximately 1 arc min and a temporal sampling rate of 60 Hz. Stimuli were modulated in chrominance for a variety of hue directions, combined with a range of small luminance increments and decrements, to insure that some of the stimuli fell in the subjects' equiluminance planes. The smooth portions of the resulting eye movement traces were fit by convolving the stimulus velocity with an exponential having variable onset latency, time constant and amplitude. Smooth eye movements with few saccades were observed for all stimuli. Pursuit responses to stimuli having a significant luminance component are well-fit by exponentials having latencies and time constants on the order of 100 msec. Increases in pursuit response latency on the order of 100-200 msec are observed in response to certain stimuli, which occur in pairs of complementary hues, corresponding to the intersection of the stimulus section with the subjects' equiluminant plane. Smooth eye movements can be made in response to purely chromatic stimuli, but are slower than responses to stimuli with a luminance component.

A primary cell model of HIV-1 latency that uses activation through the T cell receptor and return to quiescence to establish latent infection

PubMed Central

Kim, Michelle; Hosmane, Nina N.; Bullen, C. Korin; Capoferri, Adam; Yang, Hung-Chih; Siliciano, Janet D.; Siliciano, Robert F.

2015-01-01

A mechanistic understanding of HIV-1 latency depends upon a model system that recapitulates the in vivo condition of latently infected, resting CD4+ T lymphocytes. Latency appears to be established after activated CD4+ T cells, the principal targets of HIV-1 infection, become productively infected and survive long enough to return to a resting memory state in which viral expression is inhibited by changes in the cellular environment. This protocol describes an ex vivo primary cell system that is generated under conditions that reflect the in vivo establishment of latency. Creation of these latency model cells takes 12 weeks and, once established, the cells can be maintained and used for several months. The resulting cell population contains both uninfected and latently infected cells. This primary cell model can be used to perform drug screens, study CTL responses to HIV-1, compare viral alleles, or to expand the ex vivo lifespan of cells from HIV-1 infected individuals for extended study. PMID:25375990

Signal, noise, and variation in neural and sensory-motor latency

PubMed Central

Lee, Joonyeol; Joshua, Mati; Medina, Javier F.; Lisberger, Stephen G.

2016-01-01

Analysis of the neural code for sensory-motor latency in smooth pursuit eye movements reveals general principles of neural variation and the specific origin of motor latency. The trial-by-trial variation in neural latency in MT comprises: a shared component expressed as neuron-neuron latency correlations; and an independent component that is local to each neuron. The independent component arises heavily from fluctuations in the underlying probability of spiking with an unexpectedly small contribution from the stochastic nature of spiking itself. The shared component causes the latency of single neuron responses in MT to be weakly predictive of the behavioral latency of pursuit. Neural latency deeper in the motor system is more strongly predictive of behavioral latency. A model reproduces both the variance of behavioral latency and the neuron-behavior latency correlations in MT if it includes realistic neural latency variation, neuron-neuron latency correlations in MT, and noisy gain control downstream from MT. PMID:26971946

Optimizing latency in Xilinx FPGA implementations of the GBT

NASA Astrophysics Data System (ADS)

Muschter, S.; Baron, S.; Bohm, C.; Cachemiche, J.-P.; Soos, C.

2010-12-01

The GigaBit Transceiver (GBT) [1] system has been developed to replace the Timing, Trigger and Control (TTC) system [2], currently used by LHC, as well as to provide data transmission between on-detector and off-detector components in future sLHC detectors. A VHDL version of the GBT-SERDES, designed for FPGAs, was released in March 2010 as a GBT-FPGA Starter Kit for future GBT users and for off-detector GBT implementation [3]. This code was optimized for resource utilization [4], as the GBT protocol is very demanding. It was not, however, optimized for latency — which will be a critical parameter when used in the trigger path. The GBT-FPGA Starter Kit firmware was first analyzed in terms of latency by looking at the separate components of the VHDL version. Once the parts which contribute most to the latency were identified and modified, two possible optimizations were chosen, resulting in a latency reduced by a factor of three. The modifications were also analyzed in terms of logic utilization. The latency optimization results were compared with measurement results from a Virtex 6 ML605 development board [5] equipped with a XC6VLX240T with speedgrade-1 and the package FF1156. Bit error rate tests were also performed to ensure an error free operation. The two final optimizations were analyzed for utilization and compared with the original code, distributed in the Starter Kit.

Latency causes and reduction in optical metro networks

NASA Astrophysics Data System (ADS)

Bobrovs, Vjaceslavs; Spolitis, Sandis; Ivanovs, Girts

2013-12-01

The dramatic growth of transmitted information in fiber optical networks is leading to a concern about the network latency for high-speed reliable services like financial transactions, telemedicine, virtual and augmented reality, surveillance, and other applications. In order to ensure effective latency engineering, the delay variability needs to be accurately monitored and measured, in order to control it. This paper in brief describes causes of latency in fiber optical metro networks. Several available latency reduction techniques and solutions are also discussed, namely concerning usage of different chromatic dispersion compensation methods, low-latency amplifiers, optical fibers as well as other network elements.

The Influence of Non-Nociceptive Factors on Hot Plate Latency in Rats

PubMed Central

Gunn, Amanda; Bobeck, Erin N.; Weber, Ceri; Morgan, Michael M.

2010-01-01

The hot plate is a widely used test to assess nociception. The effect of non-nociceptive factors (weight, sex, activity, habituation, and repeated testing) on hot plate latency was examined. Comparison of body weight and hot plate latency revealed a small but significant inverse correlation (light rats had longer latencies). Habituating rats to the test room for 1 hr prior to testing did not decrease hot plate latency except for female rats tested on Days 2 - 4. Hot plate latency decreased with repeated daily testing, but this was not caused by a decrease in locomotor activity or learning to respond. Activity on the hot plate was consistent across all four trials, and prior exposure to a room temperature plate caused a similar decrease in latency as rats tested repeatedly on the hot plate. Despite this decrease in baseline hot plate latency, there was no difference in morphine antinociceptive potency. The present study shows that weight, habituation to the test room, and repeated testing can alter baseline hot plate latency, but these effects are small and have relatively little impact on morphine antinociception. PMID:20797920

Identification of a novel herpes simplex virus type 1 transcript and protein (AL3) expressed during latency.

PubMed

Jaber, Tareq; Henderson, Gail; Li, Sumin; Perng, Guey-Chuen; Carpenter, Dale; Wechsler, Steven L; Jones, Clinton

2009-10-01

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is abundantly expressed in latently infected sensory neurons. In small animal models of infection, expression of the first 1.5 kb of LAT coding sequences is necessary and sufficient for wild-type reactivation from latency. The ability of LAT to inhibit apoptosis is important for reactivation from latency. Within the first 1.5 kb of LAT coding sequences and LAT promoter sequences, additional transcripts have been identified. For example, the anti-sense to LAT transcript (AL) is expressed in the opposite direction to LAT from the 5' end of LAT and LAT promoter sequences. In addition, the upstream of LAT (UOL) transcript is expressed in the LAT direction from sequences in the LAT promoter. Further examination of the first 1.5 kb of LAT coding sequences revealed two small ORFs that are anti-sense with respect to LAT (AL2 and AL3). A transcript spanning AL3 was detected in productively infected cells, mouse neuroblastoma cells stably expressing LAT and trigeminal ganglia (TG) of latently infected mice. Peptide-specific IgG directed against AL3 specifically recognized a protein migrating near 15 kDa in cells stably transfected with LAT, mouse neuroblastoma cells transfected with a plasmid containing the AL3 ORF and TG of latently infected mice. The inability to detect the AL3 protein during productive infection may have been because the 5' terminus of the AL3 transcript was downstream of the first in-frame methionine of the AL3 ORF during productive infection.

PIMS Data Storage, Access, and Neural Network Processing

NASA Technical Reports Server (NTRS)

McPherson, Kevin M.; Moskowitz, Milton E.

1998-01-01

The Principal Investigator Microgravity Services (PIMS) project at NASA's Lewis Research Center has supported microgravity science Principal Investigator's (PIs) by processing, analyzing, and storing the acceleration environment data recorded on the NASA Space Shuttles and the Russian Mir space station. The acceleration data recorded in support of the microgravity science investigated on these platforms has been generated in discrete blocks totaling approximately 48 gigabytes for the Orbiter missions and 50 gigabytes for the Mir increments. Based on the anticipated volume of acceleration data resulting from continuous or nearly continuous operations, the International Space Station (ISS) presents a unique set of challenges regarding the storage of and access to microgravity acceleration environment data. This paper presents potential microgravity environment data storage, access, and analysis concepts for the ISS era.

Somatosensory spatial attention modulates amplitudes, latencies, and latency jitter of laser-evoked brain potentials.

PubMed

Franz, Marcel; Nickel, Moritz M; Ritter, Alexander; Miltner, Wolfgang H R; Weiss, Thomas

2015-04-01

Several studies provided evidence that the amplitudes of laser-evoked potentials (LEPs) are modulated by attention. However, previous reports were based on across-trial averaging of LEP responses at the expense of losing information about intertrial variability related to attentional modulation. The aim of this study was to investigate the effects of somatosensory spatial attention on single-trial parameters (i.e., amplitudes, latencies, and latency jitter) of LEP components (N2 and P2). Twelve subjects participated in a sustained spatial attention paradigm while noxious laser stimuli (left hand) and noxious electrical stimuli (right hand) were sequentially delivered to the dorsum of the respective hand with nonnoxious air puffs randomly interspersed within the sequence of noxious stimuli. Participants were instructed to mentally count all stimuli (i.e., noxious and nonnoxious) applied to the attended location. Laser stimuli, presented to the attended hand (ALS), elicited larger single-trial amplitudes of the N2 component compared with unattended laser stimuli (ULS). In contrast, single-trial amplitudes of the P2 component were not significantly affected by spatial attention. Single-trial latencies of the N2 and P2 were significantly smaller for ALS vs. ULS. Additionally, the across-trial latency jitter of the N2 component was reduced for ALS. Conversely, the latency jitter of the P2 component was smaller for ULS compared with ALS. With the use of single-trial analysis, the study provided new insights into brain dynamics of LEPs related to spatial attention. Our results indicate that single-trial parameters of LEP components are differentially modulated by spatial attention. Copyright © 2015 the American Physiological Society.

A speculated ribozyme site in the herpes simplex virus type 1 latency-associated transcript gene is not essential for a wild-type reactivation phenotype

PubMed Central

Carpenter, Dale; Singh, Sukhpreet; Osorio, Nelson; Hsiang, Chinhui; Jiang, Xianzhi; Jin, Ling; Jones, Clinton; Wechsler, Steven L

2010-01-01

During herpes simplex virus-1 (HSV-1) latency in sensory neurons, LAT (latency-associated transcript) is the only abundantly expressed viral gene. LAT plays an important role in the HSV-1 latency-reactivation cycle, because LAT deletion mutants have a significantly decreased reactivation phenotype. Based solely on sequence analysis, it was speculated that LAT encodes a ribozyme that plays an important role in how LAT enhances the virus’ reactivation phenotype. Because LAT ribozyme activity has never been reported, we decided to test the converse hypothesis, namely, that this region of LAT does not encode a ribozyme function important for LAT’s ability to enhance the reactivation phenotype. We constructed a viral mutant (LAT-Rz) in which the speculated ribozyme consensus sequence was altered such that no ribozyme was encoded. We report here that LAT-Rz had a wild-type reactivation phenotype in mice, confirming the hypothesis that the speculated LAT ribozyme is not a dominant factor in stimulating the latency-reactivation cycle in mice. PMID:18982533

Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated?

PubMed

Al-Dujaili, Lena J; Clerkin, Patrick P; Clement, Christian; McFerrin, Harris E; Bhattacharjee, Partha S; Varnell, Emily D; Kaufman, Herbert E; Hill, James M

2011-08-01

Most humans are infected with herpes simplex virus (HSV) type 1 in early childhood and remain latently infected throughout life. While most individuals have mild or no symptoms, some will develop destructive HSV keratitis. Ocular infection with HSV-1 and its associated sequelae account for the majority of corneal blindness in industrialized nations. Neuronal latency in the peripheral ganglia is established when transcription of the viral genome is repressed (silenced) except for the latency-associated transcripts and microRNAs. The functions of latency-associated transcripts have been investigated since 1987. Roles have been suggested relating to reactivation, establishment of latency, neuronal protection, antiapoptosis, apoptosis, virulence and asymptomatic shedding. Here, we review HSV-1 latent infections, reactivation, recurrent disease and antiviral therapies for the ocular HSV diseases.

Characterization and device applications of ZnO films deposited by high power impulse magnetron sputtering (HiPIMS)

NASA Astrophysics Data System (ADS)

Partridge, J. G.; Mayes, E. L. H.; McDougall, N. L.; Bilek, M. M. M.; McCulloch, D. G.

2013-04-01

ZnO films have been reactively deposited on sapphire substrates at 300 °C using a high impulse power magnetron sputtering deposition system and characterized structurally, optically and electronically. The unintentionally doped n-type ZnO films exhibit high transparency, moderate carrier concentration (˜5 × 1018 cm-3) and a Hall mobility of 8.0 cm2 V-1 s-1, making them suitable for electronic device applications. Pt/ZnO Schottky diodes formed on the HiPIMS deposited ZnO exhibited rectification ratios up to 104 at ±2 V and sensitivity to UV light.

Accommodation and vergence latencies in human infants

PubMed Central

Tondel, Grazyna M.; Candy, T. Rowan

2008-01-01

Purpose Achieving simultaneous single and clear visual experience during postnatal development depends on the temporal relationship between accommodation and vergence, in addition to their accuracies. This study was designed to examine one component of the dynamic relationship, the latencies of the responses. Methods Infants and adults were tested in three conditions i) Binocular viewing of a target moving in depth at 5cm/s (closed loop) ii) monocular viewing of the same target (vergence open loop) iii) binocular viewing of a low spatial frequency Difference of Gaussian target during a prism induced step change in retinal disparity (accommodation open loop). Results There was a significant correlation between accommodation and vergence latencies in binocular conditions for infants from 7 to 23 weeks of age. Some of the infants, as young as 7 or 8 weeks, generated adult-like latencies of less than 0.5 s. Latencies in the vergence open loop and accommodation open loop conditions tended to be shorter for the stimulated system than the open loop system in both cases, and all latencies were typically less than 2 seconds across the infant age range. Conclusions Many infants between 7 and 23 weeks of age were able to generate accommodation and vergence responses with latencies of less than a second in full binocular closed loop conditions. The correlation between the latencies in the two systems suggests that they are limited by related factors from the earliest ages tested. PMID:18199466

Accommodation and vergence latencies in human infants.

PubMed

Tondel, Grazyna M; Candy, T Rowan

2008-02-01

Achieving simultaneous single and clear visual experience during postnatal development depends on the temporal relationship between accommodation and vergence, in addition to their accuracies. This study was designed to examine one component of the dynamic relationship, the latencies of the responses. Infants and adults were tested in three conditions (i) binocular viewing of a target moving in depth at 5 cm/s (closed loop) (ii) monocular viewing of the same target (vergence open loop) (iii) binocular viewing of a low spatial frequency Difference of Gaussian target during a prism induced step change in retinal disparity (accommodation open loop). There was a significant correlation between accommodation and vergence latencies in binocular conditions for infants from 7 to 23 weeks of age. Some of the infants, as young as 7 or 8 weeks, generated adult-like latencies of less than 0.5 s. Latencies in the vergence open loop and accommodation open loop conditions tended to be shorter for the stimulated system than the open loop system in both cases, and all latencies were typically less than 2 s across the infant age range. Many infants between 7 and 23 weeks of age were able to generate accommodation and vergence responses with latencies of less than a second in full binocular closed loop conditions. The correlation between the latencies in the two systems suggests that they are limited by related factors from the earliest ages tested.

Latency Entry of Herpes Simplex Virus 1 Is Determined by the Interaction of Its Genome with the Nuclear Environment

PubMed Central

Cohen, Camille; Streichenberger, Nathalie; Texier, Pascale; Takissian, Julie; Rousseau, Antoine; Poccardi, Nolwenn; Welsch, Jérémy; Corpet, Armelle; Schaeffer, Laurent; Labetoulle, Marc; Lomonte, Patrick

2016-01-01

Herpes simplex virus 1 (HSV-1) establishes latency in trigeminal ganglia (TG) sensory neurons of infected individuals. The commitment of infected neurons toward the viral lytic or latent transcriptional program is likely to depend on both viral and cellular factors, and to differ among individual neurons. In this study, we used a mouse model of HSV-1 infection to investigate the relationship between viral genomes and the nuclear environment in terms of the establishment of latency. During acute infection, viral genomes show two major patterns: replication compartments or multiple spots distributed in the nucleoplasm (namely “multiple-acute”). Viral genomes in the “multiple-acute” pattern are systematically associated with the promyelocytic leukemia (PML) protein in structures designated viral DNA-containing PML nuclear bodies (vDCP-NBs). To investigate the viral and cellular features that favor the acquisition of the latency-associated viral genome patterns, we infected mouse primary TG neurons from wild type (wt) mice or knock-out mice for type 1 interferon (IFN) receptor with wt or a mutant HSV-1, which is unable to replicate due to the synthesis of a non-functional ICP4, the major virus transactivator. We found that the inability of the virus to initiate the lytic program combined to its inability to synthesize a functional ICP0, are the two viral features leading to the formation of vDCP-NBs. The formation of the “multiple-latency” pattern is favored by the type 1 IFN signaling pathway in the context of neurons infected by a virus able to replicate through the expression of a functional ICP4 but unable to express functional VP16 and ICP0. Analyses of TGs harvested from HSV-1 latently infected humans showed that viral genomes and PML occupy similar nuclear areas in infected neurons, eventually forming vDCP-NB-like structures. Overall our study designates PML protein and PML-NBs to be major cellular components involved in the control of HSV-1 latency

Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated?

PubMed Central

Al-Dujaili, Lena J; Clerkin, Patrick P; Clement, Christian; McFerrin, Harris E; Bhattacharjee, Partha S; Varnell, Emily D; Kaufman, Herbert E; Hill, James M

2012-01-01

Most humans are infected with herpes simplex virus (HSV) type 1 in early childhood and remain latently infected throughout life. While most individuals have mild or no symptoms, some will develop destructive HSV keratitis. Ocular infection with HSV-1 and its associated sequelae account for the majority of corneal blindness in industrialized nations. Neuronal latency in the peripheral ganglia is established when transcription of the viral genome is repressed (silenced) except for the latency-associated transcripts and microRNAs. The functions of latency-associated transcripts have been investigated since 1987. Roles have been suggested relating to reactivation, establishment of latency, neuronal protection, antiapoptosis, apoptosis, virulence and asymptomatic shedding. Here, we review HSV-1 latent infections, reactivation, recurrent disease and antiviral therapies for the ocular HSV diseases. PMID:21861620

An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression.

PubMed

Darcis, Gilles; Kula, Anna; Bouchat, Sophie; Fujinaga, Koh; Corazza, Francis; Ait-Ammar, Amina; Delacourt, Nadège; Melard, Adeline; Kabeya, Kabamba; Vanhulle, Caroline; Van Driessche, Benoit; Gatot, Jean-Stéphane; Cherrier, Thomas; Pianowski, Luiz F; Gama, Lucio; Schwartz, Christian; Vila, Jorge; Burny, Arsène; Clumeck, Nathan; Moutschen, Michel; De Wit, Stéphane; Peterlin, B Matija; Rouzioux, Christine; Rohr, Olivier; Van Lint, Carine

2015-07-01

The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations

An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression

PubMed Central

Bouchat, Sophie; Fujinaga, Koh; Corazza, Francis; Ait-Ammar, Amina; Delacourt, Nadège; Melard, Adeline; Kabeya, Kabamba; Vanhulle, Caroline; Van Driessche, Benoit; Gatot, Jean-Stéphane; Cherrier, Thomas; Pianowski, Luiz F.; Gama, Lucio; Schwartz, Christian; Vila, Jorge; Burny, Arsène; Clumeck, Nathan; Moutschen, Michel; De Wit, Stéphane; Peterlin, B. Matija; Rouzioux, Christine; Rohr, Olivier; Van Lint, Carine

2015-01-01

The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations

The influence of non-nociceptive factors on hot-plate latency in rats.

PubMed

Gunn, Amanda; Bobeck, Erin N; Weber, Ceri; Morgan, Michael M

2011-02-01

The hot plate is a widely used test to assess nociception. The effect of non-nociceptive factors (weight, sex, activity, habituation, and repeated testing) on hot-plate latency was examined. Comparison of body weight and hot-plate latency revealed a small but significant inverse correlation (light rats had longer latencies). Habituating rats to the test room for 1 hour prior to testing did not decrease hot-plate latency except for female rats tested on days 2 to 4. Hot-plate latency decreased with repeated daily testing, but this was not caused by a decrease in locomotor activity or learning to respond. Activity on the hot plate was consistent across all 4 trials, and prior exposure to a room-temperature plate caused a similar decrease in latency as rats tested repeatedly on the hot plate. Despite this decrease in baseline hot-plate latency, there was no difference in morphine antinociceptive potency. The present study shows that weight, habituation to the test room, and repeated testing can alter baseline hot-plate latency, but these effects are small and have relatively little impact on morphine antinociception. This manuscript shows that non-nociceptive factors such as body weight, habituation, and repeated testing can alter hot-plate latency, but these factors do not alter morphine potency. In sum, the hot-plate test is an easy to use and reliable method to assess supraspinally organized nociceptive responses. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

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

Kim, Kyung-Chang; School of Life Science and Biotechnology, Korea University, Seoul; Kim, Hyeon Guk

2011-01-14

Research highlights: {yields} CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. {yields} CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. {yields} HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. {yields} H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. {yields} HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also asmore » the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56{sup Lck}, ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56{sup Lck}, ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new

Latency of Epstein-Barr virus is stabilized by antisense-mediated control of the viral immediate-early gene BZLF-1.

PubMed

Prang, N; Wolf, H; Schwarzmann, F

1999-12-01

The ability of the Epstein-Barr virus (EBV) to avoid lytic replication and to establish a latent infection in B-lymphocytes is fundamental for its lifelong persistence and the pathogenesis of various EBV-associated diseases. The viral immediate-early gene BZLF-1 plays a key role for the induction of lytic replication and its activity is strictly regulated on different levels of gene expression. Recently, it was demonstrated that BZLF-1 is also controlled by a posttranscriptional mechanism. Transient synthesis of a mutated competitor RNA saturated this mechanism and caused both expression of the BZLF-1 protein and the induction of lytic viral replication. Using short overlapping fragments of the competitor, it is shown that this control acts on the unspliced primary transcript. RT-PCR demonstrated unspliced BZLF-1 RNA in latently infected B-lymphocytes in the absence of BZLF-1 protein. Due to the complementarity of the gene BZLF-1 and the latency-associated gene EBNA-1 on the opposite strand of the genome, we propose an antisense-mediated mechanism. RNase protection assays demonstrated transcripts in antisense orientation to the BZLF-1 transcript during latency, which comprise a comparable constellation to other herpesviruses. A combined RNAse protection/RT-PCR assay detected the double-stranded hybrid RNA, consisting of the unspliced BZLF-1 transcript and a noncoding intron of the EBNA-1 gene. Binding of BZLF-1 transcripts is suggested to be an important backup control mechanism in addition to transcriptional regulation, stabilizing latency and preventing inappropriate lytic viral replication in vivo. Copyright 1999 Wiley-Liss, Inc.

PA28γ is a novel corepressor of HTLV-1 replication and controls viral latency

PubMed Central

Ko, Nga Ling; Taylor, John M.; Bellon, Marcia; Bai, Xue Tao; Shevtsov, Sergey P.; Dundr, Miroslav

2013-01-01

The establishment of a latent reservoir by human tumor viruses is a vital step in initiating cellular transformation and represents a major shortcoming to current therapeutic strategies and the ability to eradicate virus-infected cells. Human T-cell leukemia virus type 1 (HTLV-1) establishes a lifelong infection and is linked to adult T-cell leukemia lymphoma (ATLL). Here, we demonstrate that HTLV-1 p30 recruits the cellular proteasome activator PA28γ onto the viral tax/rex mRNA to prevent its nuclear export and suppress virus replication. Interaction of p30 with a PA28γ retaining fully functional proteasome activity is required for p30's ability to repress HTLV-1. Consistently, HTLV-1 molecular clones replicate better and produce more virus particles in PA28γ-deficient cells. These results define a unique and novel role for the cellular factor PA28γ in the control of nuclear RNA trafficking and HTLV-1–induced latency. Importantly, knockdown of PA28γ expression in ATLL cells latently infected with HTLV-1 reactivates expression of viral tax/rex RNA and the Tax protein. Because Tax is the most immunogenic viral antigen and triggers strong CTL responses, our results suggest that PA28γ-targeted therapy may reactivate virus expression from latently infected cells and allow their eradication from the host. PMID:23104922

Factors influencing the response latencies of subnormal children in naming pictures.

PubMed

Elliott, C

1978-08-01

The times taken to name 56 drawings of objects on five separate occasions were analysed for 21 ESN(M) and 21 ESN(S) children, matched for picture-naming vocabulary. The ESN(S) group not only had a higher mean response latency but also showed greater inter- and intra-subject variance. Nine objects were selected whose names have a Thorndike-Lorge language frequency of 50 words per million or greater, and nine others were selected with a frequency of less than 50 words per million. Each object was drawn in two ways, one giving a two-dimensional outline with the addition of important detail, the other drawing also incorporating cues indicating the depth of the object. An analysis of variance of the children's latencies in naming the selected 36 pictures of 18 objects over five trials indicated that the method of drawing had no effect upon naming latencies. Pictures with high-frequency names were named faster than those with lower frequency names, the ESN(S) group showing a greater rate of increase in naming latency for the lower frequency words than the ESN(M) children. Results were discussed in terms of the Oldfield and Lachman models of lexical memory storage and of the search processes required for the retrieval of names.

Energy latency tradeoffs for medium access and sleep scheduling in wireless sensor networks

NASA Astrophysics Data System (ADS)

Gang, Lu

Wireless sensor networks are expected to be used in a wide range of applications from environment monitoring to event detection. The key challenge is to provide energy efficient communication; however, latency remains an important concern for many applications that require fast response. The central thesis of this work is that energy efficient medium access and sleep scheduling mechanisms can be designed without necessarily sacrificing application-specific latency performance. We validate this thesis through results from four case studies that cover various aspects of medium access and sleep scheduling design in wireless sensor networks. Our first effort, DMAC, is to design an adaptive low latency and energy efficient MAC for data gathering to reduce the sleep latency. We propose staggered schedule, duty cycle adaptation, data prediction and the use of more-to-send packets to enable seamless packet forwarding under varying traffic load and channel contentions. Simulation and experimental results show significant energy savings and latency reduction while ensuring high data reliability. The second research effort, DESS, investigates the problem of designing sleep schedules in arbitrary network communication topologies to minimize the worst case end-to-end latency (referred to as delay diameter). We develop a novel graph-theoretical formulation, derive and analyze optimal solutions for the tree and ring topologies and heuristics for arbitrary topologies. The third study addresses the problem of minimum latency joint scheduling and routing (MLSR). By constructing a novel delay graph, the optimal joint scheduling and routing can be solved by M node-disjoint paths algorithm under multiple channel model. We further extended the algorithm to handle dynamic traffic changes and topology changes. A heuristic solution is proposed for MLSR under single channel interference. In the fourth study, EEJSPC, we first formulate a fundamental optimization problem that provides tunable

[The significance of the interaural latency difference of VEMP].

PubMed

Wu, Ziming; Zhang, Suzhen; Ji, Fei; Zhou, Na; Guo, Weiwei; Yang, Weiyan; Han, Dongyi

2005-05-01

To investigate the significance of the interaural latency (IAL) difference of the latency of VEMP and to raise the sensitivity of the test. Vestibular evoked myogenic potentials (VEMP) were tested in 20 healthy subjects; 13 patients with acoustic neuromaor cerebellopontile angle occupying lesions and 1 patient with multiple sclerosis. IAL differences of the wave p13,n23 and p13-n23 (abbreviatd as /delta p13/, /delta n23/ and /delta p13-n23/, respectively) were analysed to determine the normal range and the upper limit of the norm data. Four illustrative cases with the abnormality of the IAL difference were given as examples. The upper limit of the IAL of /delta p13/ was 1.13 ms; that of the /delta n23/ was 1.38 ms and that of /delta p13-n23/ was 1.54 ms. The /p13-n23/ latency between the right and left side had no significant difference (P > 0.05). /delta p13/, /delta n23/ and /delta p13-n23/, especially /delta p13/ of VEMP can suggest abnormality in the neural pathway and it may be applicable in practice.

Reducing audio stimulus presentation latencies across studies, laboratories, and hardware and operating system configurations.

PubMed

Babjack, Destiny L; Cernicky, Brandon; Sobotka, Andrew J; Basler, Lee; Struthers, Devon; Kisic, Richard; Barone, Kimberly; Zuccolotto, Anthony P

2015-09-01

Using differing computer platforms and audio output devices to deliver audio stimuli often introduces (1) substantial variability across labs and (2) variable time between the intended and actual sound delivery (the sound onset latency). Fast, accurate audio onset latencies are particularly important when audio stimuli need to be delivered precisely as part of studies that depend on accurate timing (e.g., electroencephalographic, event-related potential, or multimodal studies), or in multisite studies in which standardization and strict control over the computer platforms used is not feasible. This research describes the variability introduced by using differing configurations and introduces a novel approach to minimizing audio sound latency and variability. A stimulus presentation and latency assessment approach is presented using E-Prime and Chronos (a new multifunction, USB-based data presentation and collection device). The present approach reliably delivers audio stimuli with low latencies that vary by ≤1 ms, independent of hardware and Windows operating system (OS)/driver combinations. The Chronos audio subsystem adopts a buffering, aborting, querying, and remixing approach to the delivery of audio, to achieve a consistent 1-ms sound onset latency for single-sound delivery, and precise delivery of multiple sounds that achieves standard deviations of 1/10th of a millisecond without the use of advanced scripting. Chronos's sound onset latencies are small, reliable, and consistent across systems. Testing of standard audio delivery devices and configurations highlights the need for careful attention to consistency between labs, experiments, and multiple study sites in their hardware choices, OS selections, and adoption of audio delivery systems designed to sidestep the audio latency variability issue.

Manufacturing and characterization of PIM-W materials as plasma facing materials

NASA Astrophysics Data System (ADS)

Pintsuk, G.; Antusch, S.; Rieth, M.; Wirtz, M.

2016-02-01

Powder injection molding (PIM) was used to produce pure and particle reinforced W materials to be qualified for the use as plasma facing material. As alloying elements La2O3, Y2O3, TiC, and TaC were chosen with a particle size between 50 nm and 2.5 μm, depending on the alloying element. The fabrication of alloyed materials was done for different compositions using powder mixtures. Final sintering was performed in H2 atmosphere at 2400 °C resulting in plates of 55 × 22 × 4 mm3 with ˜98% theoretical density. The qualification of the materials was done via high heat flux testing in the electron beam facility JUDITH-1. Thereby, ELM-like 1000 thermal shock loads of 0.38 GW m-2 for 1 ms and 100 disruption like loads of 1.13 GW m-2 for 1 ms at a base temperature of 1000 °C were applied. The obtained damage characteristics, i.e. surface roughening and crack formation, were qualified versus an industrially manufactured pure reference tungsten material and linked to the material’s microstructure and mechanical properties.

Gum chewing improves swallow frequency and latency in Parkinson patients: a preliminary study.

PubMed

South, Angela R; Somers, Stephanie M; Jog, Mandar S

2010-04-13

Reduced swallowing frequency affects secretion management in Parkinson disease (PD). Gum chewing increases saliva flow and swallow frequency. This study uses chewing gum to modify swallow frequency and latency between swallows in patients with PD. 1) Assess the frequency and latency of swallow at baseline (BL), during gum chewing (GC), and post gum chewing (PGC) for participants with PD (stage 2-4) nonsymptomatic for prandial dysphagia; and 2) assess carryover after gum is expectorated. Twenty participants were studied across 3 tasks, each of 5 minutes in duration: BL, GC, and PGC. Respiratory and laryngeal signals were continuously recorded using PowerLab (version 5.5.5; ADI Instruments, Castle Hill, Australia). Frequency and latency of swallow events were calculated. Differences (analysis of variance) are reported for frequency (p < 0.000001) and latency (p < 0.000001). Swallow frequency (mean +/- SD) increased during GC (14.95 +/- 3.02) compared with BL (3.1 +/- 2.85) and PGC (7.0 +/- 2.57). Latency in seconds (mean +/- SD) decreased during GC (24.1 +/- 4.174) and increased with BL (131.8 +/- 59.52) and PGC (mean = 60.74 +/- 25.25). Intertask comparisons (t test) found differences in swallow frequency and latency between tasks: BL vs GC (p < 0.0001, p < 0.0001), BL vs PGC (p < 0.0011, p < 0.0009), and GC vs PGC (p < 0.0001, p < 0.0002), respectively. Post hoc analysis showed carryover to 5.317 minutes. Modifying sensorimotor input by chewing gum alters frequency and latency of swallowing and may be an effective strategy for secretion management in Parkinson disease. This study provides Class III evidence that chewing gum increases swallow frequency and decreases latency of swallowing in an experiment in patients with stage 2 to 4 Parkinson disease who are nonsymptomatic for significant prandial dysphagia.

Latency study of the High Performance Time to Digital Converter for the ATLAS Muon Spectrometer trigger upgrade

NASA Astrophysics Data System (ADS)

Meng, X. T.; Levin, D. S.; Chapman, J. W.; Li, D. C.; Yao, Z. E.; Zhou, B.

2017-02-01

The High Performance Time to Digital Converter (HPTDC), a multi-channel ASIC designed by the CERN Microelectronics group, has been proposed for the digitization of the thin-Resistive Plate Chambers (tRPC) in the ATLAS Muon Spectrometer Phase-1 upgrade project. These chambers, to be staged for higher luminosity LHC operation, will increase trigger acceptance and reduce or eliminate the fake muon trigger rates in the barrel-endcap transition region, corresponding to pseudo-rapidity range 1<|η|<1.3. Low level trigger candidates must be flagged within a maximum latency of 1075 ns, thus imposing stringent signal processing time performance requirements on the readout system in general, and on the digitization electronics in particular. This paper investigates the HPTDC signal latency performance based on a specially designed evaluation board coupled with an external FPGA evaluation board, when operated in triggerless mode, and under hit rate conditions expected in Phase-I. This hardware based study confirms previous simulations and demonstrates that the HPTDC in triggerless operation satisfies the digitization timing requirements in both leading edge and pair modes.

Powder Injection Molding (PIM) for Low Cost Manufacturing of Intricate Parts to Net-Shape

DTIC Science & Technology

2006-05-01

tungsten - or molybdenum-pseudoalloys, which can be net-shape manufactured only by PIM because of the tight dimension tolerances needed for the final...materials. Rhenium metal, for instance, which costs about US$ 800 /lb, offers the advantage of a high melting point. It can maintain reasonable...tubes, valves and thrusters of solid fluid propeller systems. Production of these components is however both expensive and difficult, as rhenium cannot

The Inhibition of Aluminum Corrosion in Sulfuric Acid by Poly(1-vinyl-3-alkyl-imidazolium Hexafluorophosphate).

PubMed

Arellanes-Lozada, Paulina; Olivares-Xometl, Octavio; Guzmán-Lucero, Diego; Likhanova, Natalya V; Domínguez-Aguilar, Marco A; Lijanova, Irina V; Arce-Estrada, Elsa

2014-08-07

Compounds of poly(ionic liquid)s (PILs), derived from imidazole with different alkylic chain lengths located in the third position of the imidazolium ring (poly(1-vinyl-3-dodecyl-imidazolium) (PImC 12 ), poly(1-vinyl-3-octylimidazolium) (PImC₈) and poly(1-vinyl-3-butylimidazolium) (PImC₄) hexafluorophosphate) were synthesized. These compounds were tested as corrosion inhibitors on aluminum alloy AA6061 in diluted sulfuric acid (0.1-1 M H₂SO₄) by weight loss tests, polarization resistance measurements and inductively coupled plasma optical emission spectroscopy. Langmuir's isotherms suggested film formation on bare alloy while standard free energy indicated inhibition by a physisorption process. However, compound efficiencies as inhibitors ranked low (PImC 12 > PImC₈ > PImC₄) to reach 61% for PImC 12 in highly diluted acidic solution. Apparently, the high mobility of sulfates favored their adsorption in comparison to PILs. The surface film displayed general corrosion, and pitting occurred as a consequence of PILs' partial inhibition along with a continuous dissolution of defective patchy film on formation. A slight improvement in efficiency was displayed by compounds having high molecular weight and a long alkyl chain, as a consequence of steric hindrance and PIL interactions.

Low-Latency Embedded Vision Processor (LLEVS)

DTIC Science & Technology

2016-03-01

26 3.2.3 Task 3 Projected Performance Analysis of FPGA- based Vision Processor ........... 31 3.2.3.1 Algorithms Latency Analysis ...Programmable Gate Array Custom Hardware for Real- Time Multiresolution Analysis . ............................................... 35...conduct data analysis for performance projections. The data acquired through measurements , simulation and estimation provide the requisite platform for

Reducing the latency of the Fractal Iterative Method to half an iteration

NASA Astrophysics Data System (ADS)

Béchet, Clémentine; Tallon, Michel

2013-12-01

The fractal iterative method for atmospheric tomography (FRiM-3D) has been introduced to solve the wavefront reconstruction at the dimensions of an ELT with a low-computational cost. Previous studies reported the requirement of only 3 iterations of the algorithm in order to provide the best adaptive optics (AO) performance. Nevertheless, any iterative method in adaptive optics suffer from the intrinsic latency induced by the fact that one iteration can start only once the previous one is completed. Iterations hardly match the low-latency requirement of the AO real-time computer. We present here a new approach to avoid iterations in the computation of the commands with FRiM-3D, thus allowing low-latency AO response even at the scale of the European ELT (E-ELT). The method highlights the importance of "warm-start" strategy in adaptive optics. To our knowledge, this particular way to use the "warm-start" has not been reported before. Futhermore, removing the requirement of iterating to compute the commands, the computational cost of the reconstruction with FRiM-3D can be simplified and at least reduced to half the computational cost of a classical iteration. Thanks to simulations of both single-conjugate and multi-conjugate AO for the E-ELT,with FRiM-3D on Octopus ESO simulator, we demonstrate the benefit of this approach. We finally enhance the robustness of this new implementation with respect to increasing measurement noise, wind speed and even modeling errors.

HSV-1 Genome Subnuclear Positioning and Associations with Host-Cell PML-NBs and Centromeres Regulate LAT Locus Transcription during Latency in Neurons

PubMed Central

Catez, Frédéric; Picard, Christel; Held, Kathrin; Gross, Sylvain; Rousseau, Antoine; Theil, Diethilde; Sawtell, Nancy; Labetoulle, Marc; Lomonte, Patrick

2012-01-01

Major human pathologies are caused by nuclear replicative viruses establishing life-long latent infection in their host. During latency the genomes of these viruses are intimately interacting with the cell nucleus environment. A hallmark of herpes simplex virus type 1 (HSV-1) latency establishment is the shutdown of lytic genes expression and the concomitant induction of the latency associated (LAT) transcripts. Although the setting up and the maintenance of the latent genetic program is most likely dependent on a subtle interplay between viral and nuclear factors, this remains uninvestigated. Combining the use of in situ fluorescent-based approaches and high-resolution microscopic analysis, we show that HSV-1 genomes adopt specific nuclear patterns in sensory neurons of latently infected mice (28 days post-inoculation, d.p.i.). Latent HSV-1 genomes display two major patterns, called “Single” and “Multiple”, which associate with centromeres, and with promyelocytic leukemia nuclear bodies (PML-NBs) as viral DNA-containing PML-NBs (DCP-NBs). 3D-image reconstruction of DCP-NBs shows that PML forms a shell around viral genomes and associated Daxx and ATRX, two PML partners within PML-NBs. During latency establishment (6 d.p.i.), infected mouse TGs display, at the level of the whole TG and in individual cells, a substantial increase of PML amount consistent with the interferon-mediated antiviral role of PML. “Single” and “Multiple” patterns are reminiscent of low and high-viral genome copy-containing neurons. We show that LAT expression is significantly favored within the “Multiple” pattern, which underlines a heterogeneity of LAT expression dependent on the viral genome copy number, pattern acquisition, and association with nuclear domains. Infection of PML-knockout mice demonstrates that PML/PML-NBs are involved in virus nuclear pattern acquisition, and negatively regulate the expression of the LAT. This study demonstrates that nuclear domains

Health Outcomes Associated With Potentially Inappropriate Medication Use in Older Adults

PubMed Central

Fick, Donna M.; Mion, Lorraine C.; Beers, Mark H.; Waller, Jennifer L.

2008-01-01

The purpose of this study was to examine the prevalence of potentially inappropriate medication use (PIMs) among community-dwelling older adults and the association between PIMs and health care outcomes. Participants were 17,971 individuals age 65 years and older. PIM use was defined by the Beers criteria. Drug-related problems (DRPs) were defined using ICD-9 codes. Forty percent of the 17,971 individuals filled at least 1 PIM prescription, and 13% filled 2 or more PIM prescriptions. Overall DRP prevalence among those with at least 1 PIM prescription was 14.3% compared to 4.7% in the non-PIM group (p < .001). In conclusion, preventing PIM use may be important for decreasing medication-related problems, which are increasingly being recognized as requiring an integrated interdisciplinary approach. PMID:18163447

Reducing the PAPR in FBMC-OQAM systems with low-latency trellis-based SLM technique

NASA Astrophysics Data System (ADS)

Bulusu, S. S. Krishna Chaitanya; Shaiek, Hmaied; Roviras, Daniel

2016-12-01

Filter-bank multi-carrier (FBMC) modulations, and more specifically FBMC-offset quadrature amplitude modulation (OQAM), are seen as an interesting alternative to orthogonal frequency division multiplexing (OFDM) for the 5th generation radio access technology. In this paper, we investigate the problem of peak-to-average power ratio (PAPR) reduction for FBMC-OQAM signals. Recently, it has been shown that FBMC-OQAM with trellis-based selected mapping (TSLM) scheme not only is superior to any scheme based on symbol-by-symbol approach but also outperforms that of the OFDM with classical SLM scheme. This paper is an extension of that work, where we analyze the TSLM in terms of computational complexity, required hardware memory, and latency issues. We have proposed an improvement to the TSLM, which requires very less hardware memory, compared to the originally proposed TSLM, and also have low latency. Additionally, the impact of the time duration of partial PAPR on the performance of TSLM is studied, and its lower bound has been identified by proposing a suitable time duration. Also, a thorough and fair comparison of performance has been done with an existing trellis-based scheme proposed in literature. The simulation results show that the proposed low-latency TSLM yields better PAPR reduction performance with relatively less hardware memory requirements.

The B-Cell Specific Transcription Factor, Oct-2, Promotes Epstein-Barr Virus Latency by Inhibiting the Viral Immediate-Early Protein, BZLF1

PubMed Central

Robinson, Amanda R.; Kwek, Swee Sen; Kenney, Shannon C.

2012-01-01

The Epstein-Barr virus (EBV) latent-lytic switch is mediated by the BZLF1 immediate-early protein. EBV is normally latent in memory B cells, but cellular factors which promote viral latency specifically in B cells have not been identified. In this report, we demonstrate that the B-cell specific transcription factor, Oct-2, inhibits the function of the viral immediate-early protein, BZLF1, and prevents lytic viral reactivation. Co-transfected Oct-2 reduces the ability of BZLF1 to activate lytic gene expression in two different latently infected nasopharyngeal carcinoma cell lines. Furthermore, Oct-2 inhibits BZLF1 activation of lytic EBV promoters in reporter gene assays, and attenuates BZLF1 binding to lytic viral promoters in vivo. Oct-2 interacts directly with BZLF1, and this interaction requires the DNA-binding/dimerization domain of BZLF1 and the POU domain of Oct-2. An Oct-2 mutant (Δ262–302) deficient for interaction with BZLF1 is unable to inhibit BZLF1-mediated lytic reactivation. However, an Oct-2 mutant defective for DNA-binding (Q221A) retains the ability to inhibit BZLF1 transcriptional effects and DNA-binding. Importantly, shRNA-mediated knockdown of endogenous Oct-2 expression in several EBV-positive Burkitt lymphoma and lymphoblastoid cell lines increases the level of lytic EBV gene expression, while decreasing EBNA1 expression. Moreover, treatments which induce EBV lytic reactivation, such as anti-IgG cross-linking and chemical inducers, also decrease the level of Oct-2 protein expression at the transcriptional level. We conclude that Oct-2 potentiates establishment of EBV latency in B cells. PMID:22346751

Herpes simplex virus 1 microRNAs expressed abundantly during latent infection are not essential for latency in mouse trigeminal ganglia

PubMed Central

Kramer, Martha F.; Jurak, Igor; Pesola, Jean M.; Boissel, Sandrine; Knipe, David M.; Coen, Donald M.

2013-01-01

Several herpes simplex virus 1 microRNAs are encoded within or near the latency associated transcript (LAT) locus, and are expressed abundantly during latency. Some of these microRNAs can repress the expression of important viral proteins and are hypothesized to play important roles in establishing and/or maintaining latent infections. We found that in lytically infected cells and in acutely infected mouse ganglia, expression of LAT-encoded microRNAs was weak and unaffected by a deletion that includes the LAT promoter. In mouse ganglia latently infected with wild type virus, the microRNAs accumulated to high levels, but deletions of the LAT promoter markedly reduced expression of LAT-encoded microRNAs and also miR-H6, which is encoded upstream of LAT and can repress expression of ICP4. Because these LAT deletion mutants establish and maintain latent infections, these microRNAs are not essential for latency, at least in mouse trigeminal ganglia, but may help promote it. PMID:21782205

The Inhibition of Aluminum Corrosion in Sulfuric Acid by Poly(1-vinyl-3-alkyl-imidazolium Hexafluorophosphate)

PubMed Central

Arellanes-Lozada, Paulina; Olivares-Xometl, Octavio; Guzmán-Lucero, Diego; Likhanova, Natalya V.; Domínguez-Aguilar, Marco A.; Lijanova, Irina V.; Arce-Estrada, Elsa

2014-01-01

Compounds of poly(ionic liquid)s (PILs), derived from imidazole with different alkylic chain lengths located in the third position of the imidazolium ring (poly(1-vinyl-3-dodecyl-imidazolium) (PImC12), poly(1-vinyl-3-octylimidazolium) (PImC8) and poly(1-vinyl-3-butylimidazolium) (PImC4) hexafluorophosphate) were synthesized. These compounds were tested as corrosion inhibitors on aluminum alloy AA6061 in diluted sulfuric acid (0.1–1 M H2SO4) by weight loss tests, polarization resistance measurements and inductively coupled plasma optical emission spectroscopy. Langmuir’s isotherms suggested film formation on bare alloy while standard free energy indicated inhibition by a physisorption process. However, compound efficiencies as inhibitors ranked low (PImC12 > PImC8 > PImC4) to reach 61% for PImC12 in highly diluted acidic solution. Apparently, the high mobility of sulfates favored their adsorption in comparison to PILs. The surface film displayed general corrosion, and pitting occurred as a consequence of PILs’ partial inhibition along with a continuous dissolution of defective patchy film on formation. A slight improvement in efficiency was displayed by compounds having high molecular weight and a long alkyl chain, as a consequence of steric hindrance and PIL interactions. PMID:28788156

Ego Functioning During Latency

PubMed Central

Adams, Milton S.

1979-01-01

The latency period is an extremely important transition between the preschool years and adolescence. Normal ego functioning is described, especially cognition, socialization, motor development, and defensive functions. PMID:529320

Mid-latency evoked potentials in self-reported impulsive aggression.

PubMed

Houston, R J; Stanford, M S

2001-02-01

The present study was conducted to examine psychophysiological differences in arousability among individuals who display impulsive aggressive outbursts. Amplitude and latency for the mid-latency evoked potentials (P1, N1 and P2) were obtained at scalp electrode sites. The evoking stimuli were three intensities (low, medium, high) of photic stimulation. Compared to non-aggressive controls, impulsive aggressive subjects showed significantly reduced P1 amplitude, which is indicative of an inefficient sensory gating mechanism. In addition, these subjects exhibited significantly larger N1 amplitude implying an enhanced orienting of attention to stimuli. Impulsive aggressive subjects also exhibited shorter P1, N1 and P2 peak latency. These results suggest that impulsive aggressive individuals may display quicker orienting and processing of stimuli in an attempt to compensate for low resting arousal levels. Finally, impulsive aggressive subjects augmented the P1-N1 component more frequently than controls, which is consistent with previous studies examining impulsivity and sensation seeking. Together, these findings extend previous work concerning the underlying physiology of impulsive aggression. It has been suggested that impulsive aggressive individuals may attempt to compensate for low resting arousal levels by engaging in stimulus seeking behaviors. Accordingly, the present findings imply similar physiological compensatory responses as demonstrated by heightened orienting of attention, processing and arousability. In addition, a compromised sensory gating system in impulsive aggressors may exacerbate such circumstances, and lead to later cognitive processing deficits.

Investigation of koi herpesvirus latency in koi.

PubMed

Eide, Kathleen E; Miller-Morgan, Tim; Heidel, Jerry R; Kent, Michael L; Bildfell, Rob J; Lapatra, Scott; Watson, Gregory; Jin, Ling

2011-05-01

Koi herpesvirus (KHV) has recently been classified as a member of the family of Alloherpesviridae within the order of Herpesvirales. One of the unique features of Herpesviridae is latent infection following a primary infection. However, KHV latency has not been recognized. To determine if latency occurs in clinically normal fish from facilities with a history of KHV infection or exposure, the presence of the KHV genome was investigated in healthy koi by PCR and Southern blotting. KHV DNA, but not infectious virus or mRNAs from lytic infection, was detected in white blood cells from investigated koi. Virus shedding was examined via tissue culture and reverse transcription-PCR (RT-PCR) testing of gill mucus and feces from six koi every other day for 1 month. No infectious virus or KHV DNA was detected in fecal secretion or gill swabs, suggesting that neither acute nor persistent infection was present. To determine if KHV latent infections can be reactivated, six koi were subjected to a temperature stress regime. KHV DNA and infectious virus were detected in both gill and fecal swabs by day 8 following temperature stress. KHV DNA was also detectable in brain, spleen, gills, heart, eye, intestine, kidney, liver, and pancreas in euthanized koi 1 month post-temperature stress. Our study suggests that KHV may become latent in leukocytes and other tissues, that it can be reactivated from latency by temperature stress, and that it may be more widespread in the koi population than previously suspected.

Methodology for Calculating Latency of GPS Probe Data

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

Wang, Zhongxiang; Hamedi, Masoud; Young, Stanley

Crowdsourced GPS probe data, such as travel time on changeable-message signs and incident detection, have been gaining popularity in recent years as a source for real-time traffic information to driver operations and transportation systems management and operations. Efforts have been made to evaluate the quality of such data from different perspectives. Although such crowdsourced data are already in widespread use in many states, particularly the high traffic areas on the Eastern seaboard, concerns about latency - the time between traffic being perturbed as a result of an incident and reflection of the disturbance in the outsourced data feed - havemore » escalated in importance. Latency is critical for the accuracy of real-time operations, emergency response, and traveler information systems. This paper offers a methodology for measuring probe data latency regarding a selected reference source. Although Bluetooth reidentification data are used as the reference source, the methodology can be applied to any other ground truth data source of choice. The core of the methodology is an algorithm for maximum pattern matching that works with three fitness objectives. To test the methodology, sample field reference data were collected on multiple freeway segments for a 2-week period by using portable Bluetooth sensors as ground truth. Equivalent GPS probe data were obtained from a private vendor, and their latency was evaluated. Latency at different times of the day, impact of road segmentation scheme on latency, and sensitivity of the latency to both speed-slowdown and recovery-from-slowdown episodes are also discussed.« less

Low-Latency Telerobotics from Mars Orbit: The Case for Synergy Between Science and Human Exploration

NASA Technical Reports Server (NTRS)

Valinia, A.; Garvin, J. B.; Vondrak, R.; Thronson, H.; Lester, D.; Schmidt, G.; Fong, T.; Wilcox, B.; Sellers, P.; White, N.

2012-01-01

Initial, science-directed human exploration of Mars will benefit from capabilities in which human explorers remain in orbit to control telerobotic systems on the surface (Figure 1). Low-latency, high-bandwidth telerobotics (LLT) from Mars orbit offers opportunities for what the terrestrial robotics community considers to be high-quality telepresence. Such telepresence would provide high quality sensory perception and situation awareness, and even capabilities for dexterous manipulation as required for adaptive, informed selection of scientific samples [1]. Astronauts on orbit in close communication proximity to a surface exploration site (in order to minimize communication latency) represent a capability that would extend human cognition to Mars (and potentially for other bodies such as asteroids, Venus, the Moon, etc.) without the challenges, expense, and risk of putting those humans on hazardous surfaces or within deep gravity wells. Such a strategy may be consistent with goals for a human space flight program that, are currently being developed within NASA.

Design And Commissioning Status Of New Cylindrical HiPIMS Nb Coating System for SRF Cavities

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

Phillips, H. Lawrence; Macha, Kurt M.; Valente-Feliciano, Anne-Marie

2014-02-01

For the past 19 years Jefferson Lab has sustained a program studying niobium films deposited on small samples in order to develop an understanding of the correlation between deposition parameters, film micro-structure, and RF performance. A new cavity deposition system employing a cylindrical cathode using the HiPIMS technique has been developed to apply this work to cylindrical cavities. The status of this system will be presented.

Short latency vestibular evoked potentials in the Japanese quail (Coturnix coturnix japonica)

NASA Technical Reports Server (NTRS)

Jones, S. M.; Jones, T. A.; Shukla, R.

1997-01-01

Short-latency vestibular-evoked potentials to pulsed linear acceleration were characterized in the quail. Responses occurred within 8 ms following the onset of stimuli and were composed of a series of positive and negative peaks. The latencies and amplitudes of the first four peaks were quantitatively characterized. Mean latencies at 1.0 g ms-1 ranged from 1265 +/- 208 microseconds (P1, N = 18) to 4802 +/- 441 microseconds (N4, N = 13). Amplitudes ranged from 3.72 +/- 1.51 microV (P1/N1, N = 18) to 1.49 +/- 0.77 microV (P3/N3, N = 16). Latency-intensity (LI) slopes ranged from -38.7 +/- 7.3 microseconds dB-1 (P1, N = 18) to -71.6 +/- 21.9 microseconds dB-1 (N3, N = 15) and amplitude-intensity (AI) slopes ranged from 0.20 +/- 0.08 microV dB-1 (P1/N1, N = 18) to 0.07 +/- 0.04 microV dB-1 (P3/N3, N = 11). The mean response threshold across all animals was -21.83 +/- 3.34 dB re: 1.0 g ms-1 (N = 18). Responses remained after cochlear extirpation showing that they could not depend critically on cochlear activity. Responses were eliminated by destruction of the vestibular end organs, thus showing that responses depended critically and specifically on the vestibular system. The results demonstrate that the responses are vestibular and the findings provide a scientific basis for using vestibular responses to evaluate vestibular function through ontogeny and senescence in the quail.

Latency as a region contrast: Measuring ERP latency differences with Dynamic Time Warping.

PubMed

Zoumpoulaki, A; Alsufyani, A; Filetti, M; Brammer, M; Bowman, H

2015-12-01

Methods for measuring onset latency contrasts are evaluated against a new method utilizing the dynamic time warping (DTW) algorithm. This new method allows latency to be measured across a region instead of single point. We use computer simulations to compare the methods' power and Type I error rates under different scenarios. We perform per-participant analysis for different signal-to-noise ratios and two sizes of window (broad vs. narrow). In addition, the methods are tested in combination with single-participant and jackknife average waveforms for different effect sizes, at the group level. DTW performs better than the other methods, being less sensitive to noise as well as to placement and width of the window selected. © 2015 Society for Psychophysiological Research.

Short latency vestibular evoked potentials in the chicken embryo

NASA Technical Reports Server (NTRS)

Jones, S. M.; Jones, T. A.

1996-01-01

Electrophysiological responses to pulsed linear acceleration stimuli were recorded in chicken embryos incubated for 19 or 20 days (E19/E20). Responses occurred within the first 16 ms following the stimulus onset. The evoked potentials disappeared following bilateral labyrinthectomy, but persisted following cochlear destruction alone, thus demonstrating that the responses were vestibular. Approximately 8 to 10 response peaks could be identified. The first 4 positive and corresponding negative components (early peaks with latencies < 6.0 ms) were scored and latencies and amplitudes quantified. Vestibular response latencies were significantly longer (P < 0.01) and amplitudes significantly smaller (P < 0.001) than those observed in 2-week-old birds. Mean response threshold for anesthetized embryos was -15.9dBre 1.0 g/ms, which was significantly higher (P < 0.03) than those observed in 2-week-old birds (-23.0dBre 1.0 g/ms). Latency/intensity functions (that is, slopes) were not significantly different between embryos and 2-week-old animals, but amplitude/intensity functions for embryos were significantly shallower than those for 2-week-old birds (P < 0.001). We presume that these differences reflect the refinement of sensory function that occurs following 19 to 20 days of incubation. The recording of vestibular evoked potentials provides an objective, direct and noninvasive measure of peripheral vestibular function in the embryo and, as such, the method shows promise as an investigative tool. The results of the present study form the definitive basis for using vestibular evoked potentials in the detailed study of avian vestibular ontogeny and factors that may influence it.

Predictive Displays for High Latency Teleoperation

DTIC Science & Technology

2016-08-04

PREDICTIVE DISPLAYS FOR HIGH LATENCY TELEOPERATION” Analysis of existing approach 3 C om m s. C hannel Vehicle OCU D Throttle, Steer, Brake D Video ...presents opportunity mitigate outgoing latency. • Video is not governed by physics, however, video is dependent on the state of the vehicle, which...Commands, estimates UDP: H.264 Video UDP: Vehicle state • C++ implementation • 2 threads • OpenCV for image manipulation • FFMPEG for video decoding

Histone deacetylase inhibitors containing a benzamide functional group and a pyridyl cap are preferentially effective human immunodeficiency virus-1 latency-reversing agents in primary resting CD4+ T cells

PubMed Central

Gélinas, Céline

2017-01-01

Antiretroviral therapy (ART) can control human immunodeficiency virus-1 (HIV-1) replication in infected individuals. Unfortunately, patients remain persistently infected owing to the establishment of latent infection requiring that ART be maintained indefinitely. One strategy being pursued involves the development of latency-reversing agents (LRAs) to eliminate the latent arm of the infection. One class of molecules that has been tested for LRA activity is the epigenetic modulating compounds histone deacetylases inhibitors (HDACis). Previously, initial screening of these molecules typically commenced using established cell models of viral latency, and although certain drugs such as the HDACi suberoylanilide hydroxamic acid demonstrated strong activity in these models, it did not translate to comparable activity with patient samples. Here we developed a primary cell model of viral latency using primary resting CD4+ T cells infected with Vpx-complemented HIV-1 and found that the activation profile using previously described LRAs mimicked that obtained with patient samples. This primary cell model was used to evaluate 94 epigenetic compounds. Not surprisingly, HDACis were found to be the strongest activators. However, within the HDACi class, the most active LRAs with the least pronounced toxicity contained a benzamide functional moiety with a pyridyl cap group, as exemplified by the HDACi chidamide. The results indicate that HDACis with a benzamide moiety and pyridyl cap group should be considered for further drug development in the pursuit of a successful viral clearance strategy. PMID:28113052

Recovery cycle times of inferior colliculus neurons in the awake bat measured with spike counts and latencies

PubMed Central

Sayegh, Riziq; Aubie, Brandon; Fazel-Pour, Siavosh; Faure, Paul A.

2012-01-01

Neural responses in the mammalian auditory midbrain (inferior colliculus; IC) arise from complex interactions of synaptic excitation, inhibition, and intrinsic properties of the cell. Temporally selective duration-tuned neurons (DTNs) in the IC are hypothesized to arise through the convergence of excitatory and inhibitory synaptic inputs offset in time. Synaptic inhibition can be inferred from extracellular recordings by presenting pairs of pulses (paired tone stimulation) and comparing the evoked responses of the cell to each pulse. We obtained single unit recordings from the IC of the awake big brown bat (Eptesicus fuscus) and used paired tone stimulation to measure the recovery cycle times of DTNs and non-temporally selective auditory neurons. By systematically varying the interpulse interval (IPI) of the paired tone stimulus, we determined the minimum IPI required for a neuron's spike count or its spike latency (first- or last-spike latency) in response to the second tone to recover to within ≥50% of the cell's baseline count or to within 1 SD of it's baseline latency in response to the first tone. Recovery times of shortpass DTNs were significantly shorter than those of bandpass DTNs, and recovery times of bandpass DTNs were longer than allpass neurons not selective for stimulus duration. Recovery times measured with spike counts were positively correlated with those measured with spike latencies. Recovery times were also correlated with first-spike latency (FSL). These findings, combined with previous studies on duration tuning in the IC, suggest that persistent inhibition is a defining characteristic of DTNs. Herein, we discuss measuring recovery times of neurons with spike counts and latencies. We also highlight how persistent inhibition could determine neural recovery times and serve as a potential mechanism underlying the precedence effect in humans. Finally, we explore implications of recovery times for DTNs in the context of bat hearing and

Simulation Based Studies of Low Latency Teleoperations for NASA Exploration Missions

NASA Technical Reports Server (NTRS)

Gernhardt, Michael L.; Crues, Edwin Z.; Bielski, Paul; Dexter, Dan; Litaker, Harry L.; Chappell, Steven P.; Beaton, Kara H.; Bekdash, Omar S.

2017-01-01

distance ranging from beyond 10m in Zone 1, through 1 cm to contact in Zone 5 with a step size factor of 10. Collected data consists of both objective simulation data (time, distance, hand controller inputs, velocity) and subjective questionnaire data. The second simulation provides a simple real-time operator interface with displays and control of a simulated surface rover. The rover traverses a synthetic Mars-like terrain and must be maneuvered to avoid obstacles while progressing to its destination. Like the manipulator simulation, subjects are tested using five operating latencies that represent teleoperation conditions from local surface operations to orbital operations at Phobos, Deimos and ultimately high Martian orbit. The rover is also operated at three different traverse speeds to assess the correlation between latency and speed. Collected data consisted of both objective simulation data (time, distance, hand controller inputs, braking) and subjective questionnaire data. These studies are exploring relationships between task complexity, operating speeds, operator efficiencies, and communications latencies for low latency teleoperations in support of human planetary exploration. This paper presents early results from these studies along with the current observations and conclusions. These and planned future studies will help to inform NASA on the potential for low latency teleoperations to support human exploration of Mars and inform the design of robotic systems and exploration missions.

Investigation of Koi Herpesvirus Latency in Koi▿

PubMed Central

Eide, Kathleen E.; Miller-Morgan, Tim; Heidel, Jerry R.; Kent, Michael L.; Bildfell, Rob J.; LaPatra, Scott; Watson, Gregory; Jin, Ling

2011-01-01

Koi herpesvirus (KHV) has recently been classified as a member of the family of Alloherpesviridae within the order of Herpesvirales. One of the unique features of Herpesviridae is latent infection following a primary infection. However, KHV latency has not been recognized. To determine if latency occurs in clinically normal fish from facilities with a history of KHV infection or exposure, the presence of the KHV genome was investigated in healthy koi by PCR and Southern blotting. KHV DNA, but not infectious virus or mRNAs from lytic infection, was detected in white blood cells from investigated koi. Virus shedding was examined via tissue culture and reverse transcription-PCR (RT-PCR) testing of gill mucus and feces from six koi every other day for 1 month. No infectious virus or KHV DNA was detected in fecal secretion or gill swabs, suggesting that neither acute nor persistent infection was present. To determine if KHV latent infections can be reactivated, six koi were subjected to a temperature stress regime. KHV DNA and infectious virus were detected in both gill and fecal swabs by day 8 following temperature stress. KHV DNA was also detectable in brain, spleen, gills, heart, eye, intestine, kidney, liver, and pancreas in euthanized koi 1 month post-temperature stress. Our study suggests that KHV may become latent in leukocytes and other tissues, that it can be reactivated from latency by temperature stress, and that it may be more widespread in the koi population than previously suspected. PMID:21389134

Latency and User Performance in Virtual Environments and Augmented Reality

NASA Technical Reports Server (NTRS)

Ellis, Stephen R.

2009-01-01

System rendering latency has been recognized by senior researchers, such as Professor Fredrick Brooks of UNC (Turing Award 1999), as a major factor limiting the realism and utility of head-referenced displays systems. Latency has been shown to reduce the user's sense of immersion within a virtual environment, disturb user interaction with virtual objects, and to contribute to motion sickness during some simulation tasks. Latency, however, is not just an issue for external display systems since finite nerve conduction rates and variation in transduction times in the human body's sensors also pose problems for latency management within the nervous system. Some of the phenomena arising from the brain's handling of sensory asynchrony due to latency will be discussed as a prelude to consideration of the effects of latency in interactive displays. The causes and consequences of the erroneous movement that appears in displays due to latency will be illustrated with examples of the user performance impact provided by several experiments. These experiments will review the generality of user sensitivity to latency when users judge either object or environment stability. Hardware and signal processing countermeasures will also be discussed. In particular the tuning of a simple extrapolative predictive filter not using a dynamic movement model will be presented. Results show that it is possible to adjust this filter so that the appearance of some latencies may be hidden without the introduction of perceptual artifacts such as overshoot. Several examples of the effects of user performance will be illustrated by three-dimensional tracking and tracing tasks executed in virtual environments. These experiments demonstrate classic phenomena known from work on manual control and show the need for very responsive systems if they are indented to support precise manipulation. The practical benefits of removing interfering latencies from interactive systems will be emphasized with some

Using Arduino microcontroller boards to measure response latencies.

PubMed

Schubert, Thomas W; D'Ausilio, Alessandro; Canto, Rosario

2013-12-01

Latencies of buttonpresses are a staple of cognitive science paradigms. Often keyboards are employed to collect buttonpresses, but their imprecision and variability decreases test power and increases the risk of false positives. Response boxes and data acquisition cards are precise, but expensive and inflexible, alternatives. We propose using open-source Arduino microcontroller boards as an inexpensive and flexible alternative. These boards connect to standard experimental software using a USB connection and a virtual serial port, or by emulating a keyboard. In our solution, an Arduino measures response latencies after being signaled the start of a trial, and communicates the latency and response back to the PC over a USB connection. We demonstrated the reliability, robustness, and precision of this communication in six studies. Test measures confirmed that the error added to the measurement had an SD of less than 1 ms. Alternatively, emulation of a keyboard results in similarly precise measurement. The Arduino performs as well as a serial response box, and better than a keyboard. In addition, our setup allows for the flexible integration of other sensors, and even actuators, to extend the cognitive science toolbox.

Saccade latency reveals episodic representation of object color.

PubMed

Gordon, Robert D

2014-08-01

While previous studies suggest that identity, but not color, plays a role in episodic object representation, such studies have typically used tasks in which only identity is relevant, raising the possibility that the results reflect task demands, rather than the general principles that underlie object representation. In the present study, participants viewed a preview display containing one (Experiments 1 and 2) or two (Experiment 3) letters, then viewed a target display containing a single letter, in either the same or a different location. Participants executed an immediate saccade to fixate the target; saccade latency served as the dependent variable. In all experiments, saccade latencies were longer to fixate a target appearing in its previewed location, consistent with a bias to attend to new objects rather than to objects for which episodic representations are being maintained in visual working memory. The results of Experiment 3 further demonstrate, however, that changing target color eliminates these latency differences. The results suggest that color and identity are part of episodic representation even when not task relevant and that examining biases in saccade execution may be a useful approach to studying episodic representation.

On the frequency dependence of the otoacoustic emission latency in hypoacoustic and normal ears

NASA Astrophysics Data System (ADS)

Sisto, R.; Moleti, A.

2002-01-01

Experimental measurements of the otoacoustic emission (OAE) latency of adult subjects have been obtained, as a function of frequency, by means of wavelet time-frequency analysis based on the iterative application of filter banks. The results are in agreement with previous OAE latency measurements by Tognola et al. [Hear. Res. 106, 112-122 (1997)], as regards both the latency values and the frequency dependence, and seem to be incompatible with the steep 1/f law that is predicted by scale-invariant full cochlear models. The latency-frequency relationship has been best fitted to a linear function of the cochlear physical distance, using the Greenwood map, and to an exponential function of the cochlear distance, for comparison with derived band ABR latency measurements. Two sets of ears [94 audiometrically normal and 42 impaired with high-frequency (f>3 kHz) hearing loss] have been separately analyzed. Significantly larger average latencies were found in the impaired ears in the mid-frequency range. Theoretical implications of these findings on the transmission of the traveling wave are discussed.

An M2 Rather than a TH2 Response Contributes to Better Protection against Latency Reactivation following Ocular Infection of Naive Mice with a Recombinant Herpes Simplex Virus 1 Expressing Murine Interleukin-4.

PubMed

Lee, Dhong Hyun; Ghiasi, Homayon

2018-05-15

We found previously that altering macrophage polarization toward M2 responses by injection of colony-stimulating factor 1 (CSF-1) was more effective in reducing both primary and latent infections in mice ocularly infected with herpes simplex virus 1 (HSV-1) than M1 polarization by gamma interferon (IFN-γ) injection. Cytokines can coordinately regulate macrophage and T helper (T H ) responses, with interleukin-4 (IL-4) inducing type 2 T H (T H 2) as well as M2 responses and IFN-γ inducing T H 1 as well as M1 responses. We have now differentiated the contributions of these immune compartments to protection against latency reactivation and corneal scarring by comparing the effects of infection with recombinant HSV-1 in which the latency-associated transcript (LAT) gene was replaced with either the IL-4 (HSV-IL-4) or IFN-γ (HSV-IFN-γ) gene using infection with the parental (LAT-negative) virus as a control. Analysis of peritoneal macrophages in vitro established that the replacement of LAT with the IL-4 or IFN-γ gene did not affect virus infectivity and promoted polarization appropriately. Protection against corneal scarring was significantly higher in mice ocularly infected with HSV-IL-4 than in those infected with HSV-IFN-γ or parental virus. Levels of primary virus replication in the eyes and trigeminal ganglia (TG) were similar in the three groups of mice, but the numbers of gC + cells were lower on day 5 postinfection in the eyes of HSV-IL-4-infected mice than in those infected with HSV-IFN-γ or parental virus. Latency and explant reactivation were lower in both HSV-IL-4- and HSV-IFN-γ-infected mice than in those infected with parental virus, with the lowest level of latency being associated with HSV-IL-4 infection. Higher latency correlated with higher levels of CD8, PD-1, and IFN-γ mRNA, while reduced latency and T-cell exhaustion correlated with lower gC + expression in the TG. Depletion of macrophages increased the levels of latency in all ocularly

Time-resolved multi-mass ion imaging: Femtosecond UV-VUV pump-probe spectroscopy with the PImMS camera.

PubMed

Forbes, Ruaridh; Makhija, Varun; Veyrinas, Kévin; Stolow, Albert; Lee, Jason W L; Burt, Michael; Brouard, Mark; Vallance, Claire; Wilkinson, Iain; Lausten, Rune; Hockett, Paul

2017-07-07

The Pixel-Imaging Mass Spectrometry (PImMS) camera allows for 3D charged particle imaging measurements, in which the particle time-of-flight is recorded along with (x, y) position. Coupling the PImMS camera to an ultrafast pump-probe velocity-map imaging spectroscopy apparatus therefore provides a route to time-resolved multi-mass ion imaging, with both high count rates and large dynamic range, thus allowing for rapid measurements of complex photofragmentation dynamics. Furthermore, the use of vacuum ultraviolet wavelengths for the probe pulse allows for an enhanced observation window for the study of excited state molecular dynamics in small polyatomic molecules having relatively high ionization potentials. Herein, preliminary time-resolved multi-mass imaging results from C 2 F 3 I photolysis are presented. The experiments utilized femtosecond VUV and UV (160.8 nm and 267 nm) pump and probe laser pulses in order to demonstrate and explore this new time-resolved experimental ion imaging configuration. The data indicate the depth and power of this measurement modality, with a range of photofragments readily observed, and many indications of complex underlying wavepacket dynamics on the excited state(s) prepared.

Cellular Transcription Factors Induced in Trigeminal Ganglia during Dexamethasone-Induced Reactivation from Latency Stimulate Bovine Herpesvirus 1 Productive Infection and Certain Viral Promoters

PubMed Central

Workman, Aspen; Eudy, James; Smith, Lynette; Frizzo da Silva, Leticia; Sinani, Devis; Bricker, Halie; Cook, Emily; Doster, Alan

2012-01-01

Bovine herpesvirus 1 (BHV-1), an alphaherpesvirinae subfamily member, establishes latency in sensory neurons. Elevated corticosteroid levels, due to stress, reproducibly triggers reactivation from latency in the field. A single intravenous injection of the synthetic corticosteroid dexamethasone (DEX) to latently infected calves consistently induces reactivation from latency. Lytic cycle viral gene expression is detected in sensory neurons within 6 h after DEX treatment of latently infected calves. These observations suggested that DEX stimulated expression of cellular genes leads to lytic cycle viral gene expression and productive infection. In this study, a commercially available assay—Bovine Gene Chip—was used to compare cellular gene expression in the trigeminal ganglia (TG) of calves latently infected with BHV-1 versus DEX-treated animals. Relative to TG prepared from latently infected calves, 11 cellular genes were induced more than 10-fold 3 h after DEX treatment. Pentraxin three, a regulator of innate immunity and neurodegeneration, was stimulated 35- to 63-fold after 3 or 6 h of DEX treatment. Two transcription factors, promyelocytic leukemia zinc finger (PLZF) and Slug were induced more than 15-fold 3 h after DEX treatment. PLZF or Slug stimulated productive infection 20- or 5-fold, respectively, and Slug stimulated the late glycoprotein C promoter more than 10-fold. Additional DEX-induced transcription factors also stimulated productive infection and certain viral promoters. These studies suggest that DEX-inducible cellular transcription factors and/or signaling pathways stimulate lytic cycle viral gene expression, which subsequently leads to successful reactivation from latency in a small subset of latently infected neurons. PMID:22190728

Comparison of Sleep Latency and Number of SOREMPs in the Home and Hospital With a Modified Multiple Sleep Latency Test: A Randomized Crossover Study.

PubMed

Beiske, Kornelia K; Sand, Trond; Rugland, Eyvind; Stavem, Knut

2017-05-01

Comparison of mean sleep latencies and number of sleep-onset rapid eye movement periods (SOREMPs) between modified multiple sleep latency test (MSLT) performed in the unattended home and in-hospital laboratory setting. A randomized crossover single-blinded design. Thirty-four subjects referred to MSLT for suspected hypersomnia or narcolepsy were included. Participants were randomized to perform modified MSLT in the unattended home or in the hospital first. Scores in the two settings were compared using Wilcoxon signed-rank test or exact McNemar test. Agreement between home and hospital categorized mean sleep latency and number of SOREMPs was assessed using simple kappa (κ) and proportion agreement. Agreement between home and hospital mean sleep latency was assessed using a Bland-Altman plot and an intraclass correlation coefficient. There was no difference between home and hospital assessment of mean sleep latency (P = 0.86). Two or more SOREMPs were found more frequently on modified MSLTs performed at home compared with those at the hospital (7 and 2, respectively; P = 0.025). Agreement was moderate for categorized sleep latency (κ = 0.53) and fair for categorized SOREMPs (κ = 0.39) in the 2 settings. Analysis of mean sleep latency using intraclass correlation coefficient showed a very good agreement between the two settings. Group mean sleep latency for home modified MSLTs seems to be reliable compared with that for the attended sleep-laboratory setting. Higher rate of SOREMP in the unattended home suggests that napping in a familiar environment facilitates the transition into REM sleep. Further studies are needed to assess the normal limit, sensitivity, and specificity for SOREMP at home before the clinical utility of home-based napping can be determined.

Temporal processing and long-latency auditory evoked potential in stutterers.

PubMed

Prestes, Raquel; de Andrade, Adriana Neves; Santos, Renata Beatriz Fernandes; Marangoni, Andrea Tortosa; Schiefer, Ana Maria; Gil, Daniela

Stuttering is a speech fluency disorder, and may be associated with neuroaudiological factors linked to central auditory processing, including changes in auditory processing skills and temporal resolution. To characterize the temporal processing and long-latency auditory evoked potential in stutterers and to compare them with non-stutterers. The study included 41 right-handed subjects, aged 18-46 years, divided into two groups: stutterers (n=20) and non-stutters (n=21), compared according to age, education, and sex. All subjects were submitted to the duration pattern tests, random gap detection test, and long-latency auditory evoked potential. Individuals who stutter showed poorer performance on Duration Pattern and Random Gap Detection tests when compared with fluent individuals. In the long-latency auditory evoked potential, there was a difference in the latency of N2 and P3 components; stutterers had higher latency values. Stutterers have poor performance in temporal processing and higher latency values for N2 and P3 components. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

ScriptingRT: A Software Library for Collecting Response Latencies in Online Studies of Cognition

PubMed Central

Schubert, Thomas W.; Murteira, Carla; Collins, Elizabeth C.; Lopes, Diniz

2013-01-01

ScriptingRT is a new open source tool to collect response latencies in online studies of human cognition. ScriptingRT studies run as Flash applets in enabled browsers. ScriptingRT provides the building blocks of response latency studies, which are then combined with generic Apache Flex programming. Six studies evaluate the performance of ScriptingRT empirically. Studies 1–3 use specialized hardware to measure variance of response time measurement and stimulus presentation timing. Studies 4–6 implement a Stroop paradigm and run it both online and in the laboratory, comparing ScriptingRT to other response latency software. Altogether, the studies show that Flash programs developed in ScriptingRT show a small lag and an increased variance in response latencies. However, this did not significantly influence measured effects: The Stroop effect was reliably replicated in all studies, and the found effects did not depend on the software used. We conclude that ScriptingRT can be used to test response latency effects online. PMID:23805326

Latency Determination and Compensation in Real-Time Gnss/ins Integrated Navigation Systems

NASA Astrophysics Data System (ADS)

Solomon, P. D.; Wang, J.; Rizos, C.

2011-09-01

Unmanned Aerial Vehicle (UAV) technology is now commonplace in many defence and civilian environments. However, the high cost of owning and operating a sophisticated UAV has slowed their adoption in many commercial markets. Universities and research groups are actively experimenting with UAVs to further develop the technology, particularly for automated flying operations. The two main UAV platforms used are fixed-wing and helicopter. Helicopter-based UAVs offer many attractive features over fixed-wing UAVs, including vertical take-off, the ability to loiter, and highly dynamic flight. However the control and navigation of helicopters are significantly more demanding than those of fixed-wing UAVs and as such require a high bandwidth real-time Position, Velocity, Attitude (PVA) navigation system. In practical Real-Time Navigation Systems (RTNS) there are delays in the processing of the GNSS data prior to the fusion of the GNSS data with the INS measurements. This latency must be compensated for otherwise it degrades the solution of the navigation filter. This paper investigates the effect of latency in the arrival time of the GNSS data in a RTNS. Several test drives and flights were conducted with a low-cost RTNS, and compared with a high quality GNSS/INS solution. A technique for the real-time, automated and accurate estimation of the GNSS latency in low-cost systems was developed and tested. The latency estimates were then verified through cross-correlation with the time-stamped measurements from the reference system. A delayed measurement Extended Kalman Filter was then used to allow for the real-time fusing of the delayed measurements, and then a final system developed for on-the-fly measurement and compensation of GNSS latency in a RTNS.

RESPONSE LATENCIES OF NORMAL AND FOCAL-HEAD IRRADIATED MONKEYS

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

McDowell, A.A.; Brown, W.L.

1963-12-01

This study was designed to determine whether focal-head irradiated rhesus monkeys differ from normal monkeys in a manner analogous to that previously found in whole-body irradiated monkeys with respect to response latencies under both familiar and novel stimulus conditions. Five control and four focal-head irradiated rhesus monkeys with nearly identical training histories were used; the latter were survivors of a focal-head irradiation study conducted four years earlier. They had received 3000 r x radiation to the inferior parietal lobule and posterior aspect of the temporal lobe of the brain, and 30 days later the same dosage to the same areamore » of the brain. The testing was conducted in a modified version of the Wisconsin General Test Apparatus, with 24 trials per day for two days, on response latency to a single food-rewarded wooden block placed randomly over either of the two extreme food-well positions. Then, 24 trials were conducted per day for two days on response latency to either the same food-rewarded wooden block or to a novel nonrewarded wooden block presented simultaneously. On the single-block condition, median response latencies of the two groups were comparable and the groups improved in a similar manner with practice. Optimal performance latencies were also comparable for the two groups. When the novel nonrewarded stimulus block was introduced, both groups manifested comparable disruption of median response latencies, but disruption of optimal response latencies was shown only by the focalhead irradiated group. The findings show that monkeys with previous focal-head irradiation of the posterior association areas, unlike relatively high-dose whole-body irradiated monkeys, manifest median response latencies comparable to those of controls. These data indicate the lasting effects of focal-head irradiation with x rays, and suggest that the sites of permanent damage for monkeys given sublethal whole-body radiation exposure differ from the sites

Temporal parameters and time course of perceptual latency priming.

PubMed

Scharlau, Ingrid; Neumann, Odmar

2003-06-01

Visual stimuli (primes) reduce the perceptual latency of a target appearing at the same location (perceptual latency priming, PLP). Three experiments assessed the time course of PLP by masked and, in Experiment 3, unmasked primes. Experiments 1 and 2 investigated the temporal parameters that determine the size of priming. Stimulus onset asynchrony was found to exert the main influence accompanied by a small effect of prime duration. Experiment 3 used a large range of priming onset asynchronies. We suggest to explain PLP by the Asynchronous Updating Model which relates it to the asynchrony of 2 central coding processes, preattentive coding of basic visual features and attentional orienting as a prerequisite for perceptual judgments and conscious perception.

Response Latency as a Function of Hypothesis-Testing Strategies in Concept Identification

ERIC Educational Resources Information Center

Fink, Richard T.

1972-01-01

The ability of M. Levine's subset-sampling assumptions to account for the decrease in response latency following the trial of the last error was investigated by employing a distributed stimulus set composed of four binary dimensions and a procedure which required Ss to make an overt response in order to sample each dimension. (Author)

Group II muscle afferents probably contribute to the medium latency soleus stretch reflex during walking in humans

PubMed Central

Grey, Michael J; Ladouceur, Michel; Andersen, Jacob B; Nielsen, Jens Bo; Sinkjær, Thomas

2001-01-01

The objective of this study was to determine which afferents contribute to the medium latency response of the soleus stretch reflex resulting from an unexpected perturbation during human walking. Fourteen healthy subjects walked on a treadmill at approximately 3.5 km h−1 with the left ankle attached to a portable stretching device. The soleus stretch reflex was elicited by applying small amplitude (∼8 deg) dorsiflexion perturbations 200 ms after heel contact. Short and medium latency responses were observed with latencies of 55 ± 5 and 78 ± 6 ms, respectively. The short latency response was velocity sensitive (P < 0.001), while the medium latency response was not (P = 0.725). Nerve cooling increased the delay of the medium latency component to a greater extent than that of the short latency component (P < 0.005). Ischaemia strongly decreased the short latency component (P = 0.004), whereas the medium latency component was unchanged (P = 0.437). Two hours after the ingestion of tizanidine, an α2-adrenergic receptor agonist known to selectively depress the transmission in the group II afferent pathway, the medium latency reflex was strongly depressed (P = 0.007), whereas the short latency component was unchanged (P = 0.653). An ankle block with lidocaine hydrochloride was performed to suppress the cutaneous afferents of the foot and ankle. Neither the short (P = 0.453) nor medium (P = 0.310) latency reflexes were changed. Our results support the hypothesis that, during walking the medium latency component of the stretch reflex resulting from an unexpected perturbation is contributed to by group II muscle afferents. PMID:11483721

Are chirps better than clicks and tonebursts for evoking middle latency responses?

PubMed

Atcherson, Samuel R; Moore, Page C

2014-06-01

The middle latency response (MLR) is considered a valid clinical tool for assessing the integrity of cortical and subcortical structures. Several investigators have demonstrated that a rising frequency chirp stimulus is capable of eliciting not only larger wave V amplitudes but larger MLR components as well. However, the chirp has never been specifically examined in a hemispheric electrode montage setup that is typical for neurodiagnostic application and site-of-lesion testing. The purpose of this study was to examine the effect of chirp, click, and toneburst stimuli on MLR waveform peak latency and peak-to-peak amplitude in a hemispheric electrode montage setup. This study used a repeated-measures design. A total of 10 young adult participants (3 males, 7 females) with normal hearing were recruited and had negative histories of audiologic, otologic, and neurologic involvement, and no reported language or learning difficulties. MLR latencies (Na, Pa, Nb, and Pb) and peak-to-peak amplitudes (Na-Pa, Pa-Nb, and Nb-Pb) were measured for all conditions and were statistically evaluated for left hemisphere-right ear (C3-A2) and right hemisphere-left ear (C4-A1) recordings. Statistical analyses revealed no significant difference between C3-A2 and C4-A1 peak-to-peak amplitudes; therefore, data were collapsed. Stimulus comparisons revealed that Na evoked by tonebursts were statistically prolonged compared with both chirp and click, and that both Na-Pa and Pa-Nb peak-to-peak amplitudes were statistically larger for chirps compared with both clicks and tonebursts, and for clicks compared with tonebursts. The results of this study support the hypothesis that a chirp would offer a clinical advantage to the click and toneburst in overall peak-to-peak amplitude. As expected, normal-hearing participants did not exhibit hemispheric differences when comparing C3-A2 and C4-A1 peak-to-peak amplitudes demonstrating symmetric auditory brain function. However, chirp-evoked MLRs will

A gene capable of blocking apoptosis can substitute for the herpes simplex virus type 1 latency-associated transcript gene and restore wild-type reactivation levels.

PubMed

Perng, Guey-Chuen; Maguen, Barak; Jin, Ling; Mott, Kevin R; Osorio, Nelson; Slanina, Susan M; Yukht, Ada; Ghiasi, Homayon; Nesburn, Anthony B; Inman, Melissa; Henderson, Gail; Jones, Clinton; Wechsler, Steven L

2002-02-01

After ocular herpes simplex virus type 1 (HSV-1) infection, the virus travels up axons and establishes a lifelong latent infection in neurons of the trigeminal ganglia. LAT (latency-associated transcript), the only known viral gene abundantly transcribed during HSV-1 neuronal latency, is required for high levels of reactivation. The LAT function responsible for this reactivation phenotype is not known. Recently, we showed that LAT can block programmed cell death (apoptosis) in neurons of the trigeminal ganglion in vivo and in tissue culture cells in vitro (G.-C. Perng et al., Science 287:1500-1503, 2000; M. Inman et al., J. Virol. 75:3636-3646, 2001). Consequently, we proposed that this antiapoptosis function may be a key to the mechanism by which LAT enhances reactivation. To study this further, we constructed a recombinant HSV-1 virus in which the HSV-1 LAT gene was replaced by an alternate antiapoptosis gene. We used the bovine herpes virus 1 (BHV-1) latency-related (LR) gene, which was previously shown to have antiapoptosis activity, for this purpose. The resulting chimeric virus, designated CJLAT, contains two complete copies of the BHV-1 LR gene (one in each viral long repeat) in place of the normal two copies of the HSV-1 LAT, on an otherwise wild-type HSV-1 strain McKrae genomic background. We report here that in both rabbits and mice reactivation of CJLAT was significantly greater than the LAT null mutant dLAT2903 (P < 0.0004 and P = 0.001, respectively) and was at least as efficient as wild-type McKrae. This strongly suggests that a BHV-1 LR gene function was able to efficiently substitute for an HSV-1 LAT gene function involved in reactivation. Although replication of CJLAT in rabbits and mice was similar to that of wild-type McKrae, CJLAT killed more mice during acute infection and caused more corneal scarring in latently infected rabbits. This suggested that the BHV-1 LR gene and the HSV-1 LAT gene are not functionally identical. However, LR and LAT

Automatic latency equalization in VHDL-implemented complex pipelined systems

NASA Astrophysics Data System (ADS)

Zabołotny, Wojciech M.

2016-09-01

In the pipelined data processing systems it is very important to ensure that parallel paths delay data by the same number of clock cycles. If that condition is not met, the processing blocks receive data not properly aligned in time and produce incorrect results. Manual equalization of latencies is a tedious and error-prone work. This paper presents an automatic method of latency equalization in systems described in VHDL. The proposed method uses simulation to measure latencies and verify introduced correction. The solution is portable between different simulation and synthesis tools. The method does not increase the complexity of the synthesized design comparing to the solution based on manual latency adjustment. The example implementation of the proposed methodology together with a simple design demonstrating its use is available as an open source project under BSD license.

High-frequency tone burst-evoked ABR latency-intensity functions.

PubMed

Fausti, S A; Olson, D J; Frey, R H; Henry, J A; Schaffer, H I

1993-01-01

High-frequency tone burst stimuli (8, 10, 12, and 14 kHz) have been developed and demonstrated to provide reliable and valid auditory brainstem responses (ABRs) in normal-hearing subjects. In this study, latency-intensity functions (LIFs) were determined using these stimuli in 14 normal-hearing individuals. Significant shifts in response latency occurred as a function of stimulus intensity for all tone burst frequencies. For each 10 dB shift in intensity, latency shifts for waves I and V were statistically significant except for one isolated instance. LIF slopes were comparable between frequencies, ranging from 0.020 to 0.030 msec/dB. These normal LIFs for high-frequency tone burst-evoked ABRs suggest the degree of response latency change that might be expected from, for example, progressive hearing loss due to ototoxic insult, although these phenomena may not be directly related.

Role of microRNAs in herpesvirus latency and persistence.

PubMed

Grey, Finn

2015-04-01

The identification of virally encoded microRNAs (miRNAs) has had a major impact on the field of herpes virology. Given their ability to target cellular and viral transcripts, and the lack of immune response to small RNAs, miRNAs represent an ideal mechanism of gene regulation during viral latency and persistence. In this review, we discuss the role of miRNAs in virus latency and persistence, specifically focusing on herpesviruses. We cover the current knowledge on miRNAs in establishing and maintaining virus latency and promoting survival of infected cells through targeting of both viral and cellular transcripts, highlighting key publications in the field. We also discuss potential areas of future research and how novel technologies may aid in determining how miRNAs shape virus latency in the context of herpesvirus infections. © 2015 The Author.

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique.

PubMed

Martrus, G; Niehrs, A; Cornelis, R; Rechtien, A; García-Beltran, W; Lütgehetmann, M; Hoffmann, C; Altfeld, M

2016-10-15

HIV-1 establishes a pool of latently infected cells early following infection. New therapeutic approaches aiming at diminishing this persisting reservoir by reactivation of latently infected cells are currently being developed and tested. However, the reactivation kinetics of viral mRNA and viral protein production, and their respective consequences for phenotypical changes in infected cells that might enable immune recognition, remain poorly understood. We adapted a novel approach to assess the dynamics of HIV-1 mRNA and protein expression in latently and newly infected cells on the single-cell level by flow cytometry. This technique allowed the simultaneous detection of gagpol mRNA, intracellular p24 Gag protein, and cell surface markers. Following stimulation of latently HIV-1-infected J89 cells with human tumor necrosis factor alpha (hTNF-α)/romidepsin (RMD) or HIV-1 infection of primary CD4(+) T cells, four cell populations were detected according to their expression levels of viral mRNA and protein. gagpol mRNA in J89 cells was quantifiable for the first time 3 h after stimulation with hTNF-α and 12 h after stimulation with RMD, while p24 Gag protein was detected for the first time after 18 h poststimulation. HIV-1-infected primary CD4(+) T cells downregulated CD4, BST-2, and HLA class I expression at early stages of infection, proceeding Gag protein detection. In conclusion, here we describe a novel approach allowing quantification of the kinetics of HIV-1 mRNA and protein synthesis on the single-cell level and phenotypic characterization of HIV-1-infected cells at different stages of the viral life cycle. Early after infection, HIV-1 establishes a pool of latently infected cells, which hide from the immune system. Latency reversal and immune-mediated elimination of these latently infected cells are some of the goals of current HIV-1 cure approaches; however, little is known about the HIV-1 reactivation kinetics following stimulation with latency

HyspIRI Low Latency Concept and Benchmarks

NASA Technical Reports Server (NTRS)

Mandl, Dan

2010-01-01

Topics include HyspIRI low latency data ops concept, HyspIRI data flow, ongoing efforts, experiment with Web Coverage Processing Service (WCPS) approach to injecting new algorithms into SensorWeb, low fidelity HyspIRI IPM testbed, compute cloud testbed, open cloud testbed environment, Global Lambda Integrated Facility (GLIF) and OCC collaboration with Starlight, delay tolerant network (DTN) protocol benchmarking, and EO-1 configuration for preliminary DTN prototype.

12-bit 32 channel 500 MS/s low-latency ADC for particle accelerators real-time control

NASA Astrophysics Data System (ADS)

Karnitski, Anton; Baranauskas, Dalius; Zelenin, Denis; Baranauskas, Gytis; Zhankevich, Alexander; Gill, Chris

2017-09-01

Particle beam control systems require real-time low latency digital feedback with high linearity and dynamic range. Densely packed electronic systems employ high performance multichannel digitizers causing excessive heat dissipation. Therefore, low power dissipation is another critical requirement for these digitizers. A described 12-bit 500 MS/s ADC employs a sub-ranging architecture based on a merged sample & hold circuit, a residue C-DAC and a shared 6-bit flash core ADC. The core ADC provides a sequential coarse and fine digitization featuring a latency of two clock cycles. The ADC is implemented in a 28 nm CMOS process and consumes 4 mW of power per channel from a 0.9 V supply (interfacing and peripheral circuits are excluded). Reduced power consumption and small on-chip area permits the implementation of 32 ADC channels on a 10.7 mm2 chip. The ADC includes a JESD204B standard compliant output data interface operated at the 7.5 Gbps/ch rate. To minimize the data interface related time latency, a special feature permitting to bypass the JESD204B interface is built in. DoE Phase I Award Number: DE-SC0017213.

A low-latency high-port count optical switch with optical delay line buffering for disaggregated data centers

NASA Astrophysics Data System (ADS)

Moralis-Pegios, M.; Terzenidis, N.; Mourgias-Alexandris, G.; Vyrsokinos, K.; Pleros, N.

2018-02-01

Disaggregated Data Centers (DCs) have emerged as a powerful architectural framework towards increasing resource utilization and system power efficiency, requiring, however, a networking infrastructure that can ensure low-latency and high-bandwidth connectivity between a high-number of interconnected nodes. This reality has been the driving force towards high-port count and low-latency optical switching platforms, with recent efforts concluding that the use of distributed control architectures as offered by Broadcast-and-Select (BS) layouts can lead to sub-μsec latencies. However, almost all high-port count optical switch designs proposed so far rely either on electronic buffering and associated SerDes circuitry for resolving contention or on buffer-less designs with packet drop and re-transmit procedures, unavoidably increasing latency or limiting throughput. In this article, we demonstrate a 256x256 optical switch architecture for disaggregated DCs that employs small-size optical delay line buffering in a distributed control scheme, exploiting FPGA-based header processing over a hybrid BS/Wavelength routing topology that is implemented by a 16x16 BS design and a 16x16 AWGR. Simulation-based performance analysis reveals that even the use of a 2- packet optical buffer can yield <620nsec latency with >85% throughput for up to 100% loads. The switch has been experimentally validated with 10Gb/s optical data packets using 1:16 optical splitting and a SOA-MZI wavelength converter (WC) along with fiber delay lines for the 2-packet buffer implementation at every BS outgoing port, followed by an additional SOA-MZI tunable WC and the 16x16 AWGR. Error-free performance in all different switch input/output combinations has been obtained with a power penalty of <2.5dB.

Attention Influences Single Unit and Local Field Potential Response Latencies in Visual Cortical Area V4

PubMed Central

Sundberg, Kristy A.; Mitchell, Jude F.; Gawne, Timothy J.

2012-01-01

Many previous studies have demonstrated that changes in selective attention can alter the response magnitude of visual cortical neurons, but there has been little evidence for attention affecting response latency. Small latency differences, though hard to detect, can potentially be of functional importance, and may also give insight into the mechanisms of neuronal computation. We therefore reexamined the effect of attention on the response latency of both single units and the local field potential (LFP) in primate visual cortical area V4. We find that attention does produce small (1–2 ms) but significant reductions in the latency of both the spiking and LFP responses. Though attention, like contrast elevation, reduces response latencies, we find that the two have different effects on the magnitude of the LFP. Contrast elevations increase and attention decreases the magnitude of the initial deflection of the stimulus-evoked LFP. Both contrast elevation and attention increase the magnitude of the spiking response. We speculate that latencies may be reduced at higher contrast because stronger stimulus inputs drive neurons more rapidly to spiking threshold, while attention may reduce latencies by placing neurons in a more depolarized state closer to threshold before stimulus onset. PMID:23136440

Characterization of herpes simplex virus type 2 latency-associated transcription in human sacral ganglia and in cell culture.

PubMed

Croen, K D; Ostrove, J M; Dragovic, L; Straus, S E

1991-01-01

The ability of herpes simplex virus type 2 (HSV-2) to establish latency in and reactivate from sacral dorsal root sensory ganglia is the basis for recurrent genital herpes. The expression of HSV-2 genes in latently infected human sacral ganglia was investigated by in situ hybridization. Hybridizations with a probe from the long repeat region of HSV-2 revealed strong nuclear signals overlying neurons in sacral ganglia from five of nine individuals. The RNA detected overlaps with the transcript for infected cell protein O but in the opposite, or "anti-sense," orientation. These observations mimic those made previously with HSV-1 in human trigeminal ganglia and confirm the recent findings during latency in HSV-2-infected mice and guinea pigs. Northern hybridization of RNA from infected Vero cells showed that an HSV-2 latency-associated transcript was similar in size to the larger (1.85 kb) latency transcript of HSV-1. Thus, HSV-1 and HSV-2 latency in human sensory ganglia are similar, if not identical, in terms of their cellular localization and pattern of transcription.

Application of artificial neural networks to establish a predictive mortality risk model in children admitted to a paediatric intensive care unit.

PubMed

Chan, C H; Chan, E Y; Ng, D K; Chow, P Y; Kwok, K L

2006-11-01

Paediatric risk of mortality and paediatric index of mortality (PIM) are the commonly-used mortality prediction models (MPM) in children admitted to paediatric intensive care unit (PICU). The current study was undertaken to develop a better MPM using artificial neural network, a domain of artificial intelligence. The purpose of this retrospective case series was to compare an artificial neural network (ANN) model and PIM with the observed mortality in a cohort of patients admitted to a five-bed PICU in a Hong Kong non-teaching general hospital. The patients were under the age of 17 years and admitted to our PICU from April 2001 to December 2004. Data were collected from each patient admitted to our PICU. All data were randomly allocated to either the training or validation set. The data from the training set were used to construct a series of ANN models. The data from the validation set were used to validate the ANN and PIM models. The accuracy of ANN models and PIM was assessed by area under the receiver operator characteristics (ROC) curve and calibration. All data were randomly allocated to either the training (n=274) or validation set (n=273). Three ANN models were developed using the data from the training set, namely ANN8 (trained with variables required for PIM), ANN9 (trained with variables required for PIM and pre-ICU intubation) and ANN23 (trained with variables required for ANN9 and 14 principal ICU diagnoses). Three ANN models and PIM were used to predict mortality in the validation set. We found that PIM and ANN9 had a high ROC curve (PIM: 0.808, 95 percent confidence interval 0.552 to 1.000, ANN9: 0.957, 95 percent confidence interval 0.915 to 1.000), whereas ANN8 and ANN23 gave a suboptimal area under the ROC curve. ANN8 required only five variables for the calculation of risk, compared with eight for PIM. The current study demonstrated the process of predictive mortality risk model development using ANN. Further multicentre studies are required to

Human embryonic stem cell lines model experimental human cytomegalovirus latency.

PubMed

Penkert, Rhiannon R; Kalejta, Robert F

2013-05-28

Herpesviruses are highly successful pathogens that persist for the lifetime of their hosts primarily because of their ability to establish and maintain latent infections from which the virus is capable of productively reactivating. Human cytomegalovirus (HCMV), a betaherpesvirus, establishes latency in CD34(+) hematopoietic progenitor cells during natural infections in the body. Experimental infection of CD34(+) cells ex vivo has demonstrated that expression of the viral gene products that drive productive infection is silenced by an intrinsic immune defense mediated by Daxx and histone deacetylases through heterochromatinization of the viral genome during the establishment of latency. Additional mechanistic details about the establishment, let alone maintenance and reactivation, of HCMV latency remain scarce. This is partly due to the technical challenges of CD34(+) cell culture, most notably, the difficulty in preventing spontaneous differentiation that drives reactivation and renders them permissive for productive infection. Here we demonstrate that HCMV can establish, maintain, and reactivate in vitro from experimental latency in cultures of human embryonic stem cells (ESCs), for which spurious differentiation can be prevented or controlled. Furthermore, we show that known molecular aspects of HCMV latency are faithfully recapitulated in these cells. In total, we present ESCs as a novel, tractable model for studies of HCMV latency.

Gilgamesh: A Multithreaded Processor-In-Memory Architecture for Petaflops Computing

NASA Technical Reports Server (NTRS)

Sterling, T. L.; Zima, H. P.

2002-01-01

Processor-in-Memory (PIM) architectures avoid the von Neumann bottleneck in conventional machines by integrating high-density DRAM and CMOS logic on the same chip. Parallel systems based on this new technology are expected to provide higher scalability, adaptability, robustness, fault tolerance and lower power consumption than current MPPs or commodity clusters. In this paper we describe the design of Gilgamesh, a PIM-based massively parallel architecture, and elements of its execution model. Gilgamesh extends existing PIM capabilities by incorporating advanced mechanisms for virtualizing tasks and data and providing adaptive resource management for load balancing and latency tolerance. The Gilgamesh execution model is based on macroservers, a middleware layer which supports object-based runtime management of data and threads allowing explicit and dynamic control of locality and load balancing. The paper concludes with a discussion of related research activities and an outlook to future work.

Impact of wave propagation delay on latency in optical communication systems

NASA Astrophysics Data System (ADS)

Kawanishi, Tetsuya; Kanno, Atsushi; Yoshida, Yuki; Kitayama, Ken-ichi

2012-12-01

Latency is an important figure to describe performance of transmission systems for particular applications, such as data transfer for earthquake early warning, transaction for financial businesses, interactive services such as online games, etc. Latency consists of delay due to signal processing at nodes and transmitters, and of signal propagation delay due to propagation of electromagnetic waves. The lower limit of the latency in transmission systems using conventional single mode fibers (SMFs) depends on wave propagation speed in the SMFs which is slower than c. Photonic crystal fibers, holly fibers and large core fibers can have low effective refractive indices, and can transfer light faster than in SMFs. In free-space optical systems, signals propagate with the speed c, so that the latency could be smaller than in optical fibers. For example, LEO satellites would transmit data faster than optical submarine cables, when the transmission distance is longer than a few thousand kilometers. This paper will discuss combination of various transmission media to reduce negative impact of the latency, as well as applications of low-latency systems.

Effects of structured nontarget stimuli on saccadic latency.

PubMed

White, Brian J; Gegenfurtner, Karl R; Kerzel, Dirk

2005-06-01

It has been suggested that the remote distractor effect is the result of nontarget stimulation of a central region representing a collicular fixation zone near the time of target onset. The distributed network of the cells responsible for this effect is believed to extend over a large area, responding to distractors < or =10 deg in the periphery. Several studies also implicate the superior colliculus as the substrate behind an inhibited saccadic response arising from a display change. We investigated this further by using a patch of pink noise of various sizes as a nontarget stimulus. We show that the onset of a small patch (2.3 x 2.3 deg) of centrally displayed pink noise can produce a significant increase in saccadic latency to a simultaneously presented peripheral Gabor target. In contrast, a large patch (36 x 36 deg) of pink noise did not increase latency despite the fact that it also stimulated the region representing the fixation zone. Furthermore, only the large patch of noise facilitated latency when presented before target onset. We also examined the effect of patch sizes between these two extremes and found a steady decrease in latency as patch size increased. This confirms that nontarget stimulation of the region representing the fixation zone near the time of target onset is not in itself sufficient to produce the increase in latency typically found with remote distractors. The results are consistent with the idea that only a spatially confined object leads to a discharge of collicular fixation neurons.

Perceptual latency priming by masked and unmasked stimuli: evidence for an attentional interpretation.

PubMed

Scharlau, Ingrid; Neumann, Odmar

2003-08-01

Four experiments investigated the influence of a metacontrast-masked prime on temporal order judgments. The main results were (1) that a masked prime reduced the latency of the mask's conscious perception (perceptual latency priming), (2) that this effect was independent of whether the prime suffered strong or weak masking, (3) that it was unaffected by the degree of visual similarity between the prime and the mask, and that (4) there was no difference between congruent and incongruent primes. Finding (1) suggests that location cueing affects not only response times but also the latency of conscious perception. (2) The finding that priming was unaffected by the prime's detectability argues against a response bias interpretation of this effect. (3) Since visual similarity had no effect on the prime's efficiency, it is unlikely that sensory priming was involved. (4) The lack of a divergence between the effects of congruent and incongruent primes implies a functional difference between the judgments in the temporal order judgment task and speeded responses that have demonstrated differential effects of congruent and incongruent primes (e.g., Klotz & Neumann, 1999). These results can best be interpreted by assuming that the prime affects perceptual latency by initiating a shift of attention, as suggested by the Asynchronous Updating Model (AUM; Neumann 1978, 1982).

An operations-partnered evaluation of care redesign for high-risk patients in the Veterans Health Administration (VHA): Study protocol for the PACT Intensive Management (PIM) randomized quality improvement evaluation.

PubMed

Chang, Evelyn T; Zulman, Donna M; Asch, Steven M; Stockdale, Susan E; Yoon, Jean; Ong, Michael K; Lee, Martin; Simon, Alissa; Atkins, David; Schectman, Gordon; Kirsh, Susan R; Rubenstein, Lisa V

2018-06-01

Patient-centered medical homes have made great strides providing comprehensive care for patients with chronic conditions, but may not provide sufficient support for patients at highest risk for acute care use. To address this, the Veterans Health Administration (VHA) initiated a five-site demonstration project to evaluate the effectiveness of augmenting the VA's Patient Aligned Care Team (PACT) medical home with PACT Intensive Management (PIM) teams for Veterans at highest risk for hospitalization. Researchers partnered with VHA leadership to design a mixed-methods prospective multi-site evaluation that met leadership's desire for a rigorous evaluation conducted as quality improvement rather than research. We conducted a randomized QI evaluation and assigned high-risk patients to participate in PIM and compared them with high-risk Veterans receiving usual care through PACT. The summative evaluation examines whether PIM: 1) decreases VHA emergency department and hospital use; 2) increases satisfaction with VHA care; 3) decreases provider burnout; and 4) generates positive returns on investment. The formative evaluation aims to support improved care for high-risk patients at demonstration sites and to inform future initiatives for high-risk patients. The evaluation was reviewed by representatives from the VHA Office of Research and Development and the Office of Research Oversight and met criteria for quality improvement. VHA aims to function as a learning organization by rapidly implementing and rigorously testing QI innovations prior to final program or policy development. We observed challenges and opportunities in designing an evaluation consistent with QI standards and operations priorities, while also maintaining scientific rigor. This trial was retrospectively registered at ClinicalTrials.gov on April 3, 2017: NCT03100526. Protocol v1, FY14-17. Copyright © 2018 Elsevier Inc. All rights reserved.

Latency versus persistence or intermittent recurrences: evidence for a latent state of murine cytomegalovirus in the lungs.

PubMed

Kurz, S; Steffens, H P; Mayer, A; Harris, J R; Reddehase, M J

1997-04-01

The state of cytomegalovirus (CMV) after the resolution of acute infection is an unsolved problem in CMV research. While the term "latency" is in general use to indicate the maintenance of the viral genome, a formal exclusion of low-level persistent productive infection depends on the sensitivity of the assay for detecting infectious virus. We have improved the method for detecting infectivity by combining centrifugal infection of permissive indicator cells in culture, expansion to an infectious focus, and sensitive detection of immediate-early RNA in the infected cells by reverse transcriptase PCR. A limiting-dilution approach defined the sensitivity of this assay. Infectivity was thereby found to require as few as 2 to 9 virion DNA molecules of murine CMV, whereas the standard measure of infectivity, the PFU, is the equivalent of ca. 500 viral genomes. Since murine CMV forms multicapsid virions in most infected tissues, the genome-to-infectivity ratio is necessarily >1. This assay thus sets a new standard for investigating CMV latency. In mice in which acute infection was resolved, the viral DNA load in the lungs, a known organ site of CMV latency and recurrence, was found to be 1 genome per 40 lung cells, or a total of ca. 1 million genomes. Despite this high load of CMV DNA, infectious virus was not detected with the improved assay, but recurrence was inducible. These data provide evidence against a low-level persistent productive infection and also imply that intermittent spontaneous recurrence is not a frequent event in latently infected lungs.

Defining the Transcriptional Landscape during Cytomegalovirus Latency with Single-Cell RNA Sequencing

PubMed Central

2018-01-01

ABSTRACT Primary infection with human cytomegalovirus (HCMV) results in a lifelong infection due to its ability to establish latent infection, with one characterized viral reservoir being hematopoietic cells. Although reactivation from latency causes serious disease in immunocompromised individuals, our molecular understanding of latency is limited. Here, we delineate viral gene expression during natural HCMV persistent infection by analyzing the massive transcriptome RNA sequencing (RNA-seq) atlas generated by the Genotype-Tissue Expression (GTEx) project. This systematic analysis reveals that HCMV persistence in vivo is prevalent in diverse tissues. Notably, we find only viral transcripts that resemble gene expression during various stages of lytic infection with no evidence of any highly restricted latency-associated viral gene expression program. To further define the transcriptional landscape during HCMV latent infection, we also used single-cell RNA-seq and a tractable experimental latency model. In contrast to some current views on latency, we also find no evidence for any highly restricted latency-associated viral gene expression program. Instead, we reveal that latency-associated gene expression largely mirrors a late lytic viral program, albeit at much lower levels of expression. Overall, our work has the potential to revolutionize our understanding of HCMV persistence and suggests that latency is governed mainly by quantitative changes, with a limited number of qualitative changes, in viral gene expression. PMID:29535194

Protein kinase G confers survival advantage to Mycobacterium tuberculosis during latency-like conditions.

PubMed

Khan, Mehak Zahoor; Bhaskar, Ashima; Upadhyay, Sandeep; Kumari, Pooja; Rajmani, Raju S; Jain, Preeti; Singh, Amit; Kumar, Dhiraj; Bhavesh, Neel Sarovar; Nandicoori, Vinay Kumar

2017-09-29

Protein kinase G (PknG), a thioredoxin-fold-containing eukaryotic-like serine/threonine protein kinase, is a virulence factor in Mycobacterium tuberculosis , required for inhibition of phagolysosomal fusion. Here, we unraveled novel functional facets of PknG during latency-like conditions. We found that PknG mediates persistence under stressful conditions like hypoxia and abets drug tolerance. PknG mutant displayed minimal growth in nutrient-limited conditions, suggesting its role in modulating cellular metabolism. Intracellular metabolic profiling revealed that PknG is necessary for efficient metabolic adaptation during hypoxia. Notably, the PknG mutant exhibited a reductive shift in mycothiol redox potential and compromised stress response. Exposure to antibiotics and hypoxic environment resulted in higher oxidative shift in mycothiol redox potential of PknG mutant compared with the wild type. Persistence during latency-like conditions required kinase activity and thioredoxin motifs of PknG and is mediated through phosphorylation of a central metabolic regulator GarA. Finally, using a guinea pig model of infection, we assessed the in vivo role of PknG in manifestation of disease pathology and established a role for PknG in the formation of stable granuloma, hallmark structures of latent tuberculosis. Taken together, PknG-mediated GarA phosphorylation is important for maintenance of both mycobacterial physiology and redox poise, an axis that is dispensable for survival under normoxic conditions but is critical for non-replicating persistence of mycobacteria. In conclusion, we propose that PknG probably acts as a modulator of latency-associated signals. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Glomerular latency coding in artificial olfaction.

PubMed

Yamani, Jaber Al; Boussaid, Farid; Bermak, Amine; Martinez, Dominique

2011-01-01

Sensory perception results from the way sensory information is subsequently transformed in the brain. Olfaction is a typical example in which odor representations undergo considerable changes as they pass from olfactory receptor neurons (ORNs) to second-order neurons. First, many ORNs expressing the same receptor protein yet presenting heterogeneous dose-response properties converge onto individually identifiable glomeruli. Second, onset latency of glomerular activation is believed to play a role in encoding odor quality and quantity in the context of fast information processing. Taking inspiration from the olfactory pathway, we designed a simple yet robust glomerular latency coding scheme for processing gas sensor data. The proposed bio-inspired approach was evaluated using an in-house SnO(2) sensor array. Glomerular convergence was achieved by noting the possible analogy between receptor protein expressed in ORNs and metal catalyst used across the fabricated gas sensor array. Ion implantation was another technique used to account both for sensor heterogeneity and enhanced sensitivity. The response of the gas sensor array was mapped into glomerular latency patterns, whose rank order is concentration-invariant. Gas recognition was achieved by simply looking for a "match" within a library of spatio-temporal spike fingerprints. Because of its simplicity, this approach enables the integration of sensing and processing onto a single-chip.

In vitro effects of the small-molecule protein kinase C agonists on HIV latency reactivation.

PubMed

Brogdon, Jessica; Ziani, Widade; Wang, Xiaolei; Veazey, Ronald S; Xu, Huanbin

2016-12-12

The persistence of latently HIV-infected cellular reservoirs represents the major obstacle to virus eradication in patients under antiretroviral therapy (ART). Cure strategies to eliminate these reservoirs are thus needed to reactivate proviral gene expression in latently infected cells. In this study, we tested optimal concentrations of PKC agonist candidates (PEP005/Ingenol-3-angelate, prostratin, bryostatin-1, and JQ1) to reactivate HIV latency in vitro, and examined their effects on cell survival, activation and epigenetic histone methylation after treatment alone or in combination in cell line and isolated CD4 T cells from SIV-infected macaques. The results showed that PKC agonists increased cell activation with different degrees of latency reactivation, concomitant with reduced levels of histone methylation. With increasing concentrations, prostratin and byrostain-1 treatment rapidly reduced cell survival and cell activation. The PKC agonist combinations, or in combination with JQ1, led to modest levels of synergistic reactivation of HIV. Remarkably, PEP005 treatment alone caused marked reactivation of HIV latency, similar to PMA stimulation. These findings suggested that PEP005 alone, as indicated its lower cytotoxicity and lower effective dose inducing maximal reactivation, might be a candidate for effectively reactivating HIV latency as part of a therapeutic strategy for HIV infection.

M109 Family of Vehicles, Paladin Integrated Management (PIM): Operational Assessment of the Initial Operational Test and Evaluation (IOT and E)

DTIC Science & Technology

2017-01-01

procedures and Army doctrine. During pre -IOT&E training and developmental testing , the combat developer discovered that when projectiles were fired using...Director, Operational Test and Evaluation M109 Family of Vehicles, Paladin Integrated Management (PIM) Operational Assessment of the...Initial Operational Test and Evaluation October 2011 January 2017 J. Michael Gilmore Director

GBU-X bounding requirements for highly flexible munitions

NASA Astrophysics Data System (ADS)

Bagby, Patrick T.; Shaver, Jonathan; White, Reed; Cafarelli, Sergio; Hébert, Anthony J.

2017-04-01

This paper will present the results of an investigation into requirements for existing software and hardware solutions for open digital communication architectures that support weapon subsystem integration. The underlying requirements of such a communication architecture would be to achieve the lowest latency possible at a reasonable cost point with respect to the mission objective of the weapon. The determination of the latency requirements of the open architecture software and hardware were derived through the use of control system and stability margins analyses. Studies were performed on the throughput and latency of different existing communication transport methods. The two architectures that were tested in this study include Data Distribution Service (DDS) and Modular Open Network Architecture (MONARCH). This paper defines what levels of latency can be achieved with current technology and how this capability may translate to future weapons. The requirements moving forward within communications solutions are discussed.

Polymorphism of alpha-1-antitrypsin in hematological malignancies

PubMed Central

2009-01-01

Alpha-1-antitrypsin (AAT) or serine protease inhibitor A1 (SERPINA1) is an important serine protease inhibitor in humans. The main physiological role of AAT is to inhibit neutrophil elastase (NE) released from triggered neutrophils, with an additional lesser role in the defense against damage inflicted by other serine proteases, such as cathepsin G and proteinase 3. Although there is a reported association between AAT polymorphism and different types of cancer, this association with hematological malignancies (HM) is, as yet, unknown. We identified AAT phenotypes by isoelectric focusing (in the pH 4.2-4.9 range) in 151 serum samples from patients with HM (Hodgkins lymphomas, non-Hodgkins lymphomas and malignant monoclonal gammopathies). Healthy blood-donors constituted the control group (n = 272). The evaluated population of patients as well as the control group, were at Hardy-Weinberg equilibrium for the AAT gene (χ2 = 4.42, d.f.11, p = 0.96 and χ2 = 4.71, d.f.11, p = 0.97, respectively). There was no difference in the frequency of deficient AAT alleles (Pi Z and Pi S) between patients and control. However, we found a significantly higher frequency of PiM1M1 homozygote and PiM1 allele in HM patients than in control (for phenotype: f = 0.5166 and 0.4118 respectively, p = 0.037; for allele: f = 0.7020 and 0.6360 respectively, p = 0.05). In addition, PiM homozygotes in HM-patients were more numerous than in controls (59% and 48%, respectively, p = 0.044). PiM1 alleles and PiM1 homozygotes are both associated with hematological malignancies, although this is considered a functionally normal AAT variant. PMID:21637443

Increased latencies to respond in a judgment bias test are not associated with pessimistic biases in rats.

PubMed

Barker, Timothy Hugh; Howarth, Gordon Stanley; Whittaker, Alexandra Louise

2018-01-01

Extinction of learning is a common, yet under-reported limitation of judgment bias testing methods Repeated exposure to the ambiguous probe of a judgment bias paradigm encourages the animal to cease display of the required behaviours. However, there remains a need to repeatedly test animals to achieve statistical power. A delicate balance therefore needs to be struck between over- and under-exposure of the animals to the test conditions. This study presents the data of rats, a common animal subject of judgment bias testing. Rats were exposed to the ambiguous probe of a common, active-choice judgment bias test for 11 consecutive days. There was a significant increase in the latency to respond to the ambiguous probe following day 8, with no significant increase experienced for either the positive or less-positive probes. Following day 8 there was a significant increase in both optimistic and pessimistic latencies in response to the ambiguous probe. Therefore, repeated exposure to the ambiguous probe caused an increased latency in response even though optimistic interpretations were recorded. This implies that the use of response latency alone as a measure in judgment bias testing can falsely identify pessimism. Researchers should modify experimental design to include both choice and latency measures. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Global EOS: exploring the 300-ms-latency region

NASA Astrophysics Data System (ADS)

Mascetti, L.; Jericho, D.; Hsu, C.-Y.

2017-10-01

EOS, the CERN open-source distributed disk storage system, provides the highperformance storage solution for HEP analysis and the back-end for various work-flows. Recently EOS became the back-end of CERNBox, the cloud synchronisation service for CERN users. EOS can be used to take advantage of wide-area distributed installations: for the last few years CERN EOS uses a common deployment across two computer centres (Geneva-Meyrin and Budapest-Wigner) about 1,000 km apart (∼20-ms latency) with about 200 PB of disk (JBOD). In late 2015, the CERN-IT Storage group and AARNET (Australia) set-up a challenging R&D project: a single EOS instance between CERN and AARNET with more than 300ms latency (16,500 km apart). This paper will report about the success in deploy and run a distributed storage system between Europe (Geneva, Budapest), Australia (Melbourne) and later in Asia (ASGC Taipei), allowing different type of data placement and data access across these four sites.

Measurement-based analysis of error latency. [in computer operating system

NASA Technical Reports Server (NTRS)

Chillarege, Ram; Iyer, Ravishankar K.

1987-01-01

This paper demonstrates a practical methodology for the study of error latency under a real workload. The method is illustrated with sampled data on the physical memory activity, gathered by hardware instrumentation on a VAX 11/780 during the normal workload cycle of the installation. These data are used to simulate fault occurrence and to reconstruct the error discovery process in the system. The technique provides a means to study the system under different workloads and for multiple days. An approach to determine the percentage of undiscovered errors is also developed and a verification of the entire methodology is performed. This study finds that the mean error latency, in the memory containing the operating system, varies by a factor of 10 to 1 (in hours) between the low and high workloads. It is found that of all errors occurring within a day, 70 percent are detected in the same day, 82 percent within the following day, and 91 percent within the third day. The increase in failure rate due to latency is not so much a function of remaining errors but is dependent on whether or not there is a latent error.

Aging and wave-component latency delays in oVEMP and cVEMP: a systematic review with meta-analysis.

PubMed

Macambira, Ysa Karen Dos Santos; Carnaúba, Aline Tenório Lins; Fernandes, Luciana Castelo Branco Camurça; Bueno, Nassib Bezerra; Menezes, Pedro de Lemos

The natural aging process may result in morphological changes in the vestibular system and in the afferent neural pathway, including loss of hair cells, decreased numbers of vestibular nerve cells, and loss of neurons in the vestibular nucleus. Thus, with advancing age, there should be a decrease in amplitudes and an increase in latencies of the vestibular evoked myogenic potentials, especially the prolongation of p13 latency. Moreover, many investigations have found no significant differences in latencies with advancing age. To determine if there are significant differences in the latencies of cervical and ocular evoked myogenic potentials between elderly and adult patients. This is a systematic review with meta-analysis of observational studies, comparing the differences of these parameters between elderly and young adults, without language or date restrictions, in the following databases: Pubmed, ScienceDirect, SCOPUS, Web of Science, SciELO and LILACS, in addition to the gray literature databases: OpenGrey.eu and DissOnline, as well as Research Gate. The n1 oVEMP latencies had a mean delay in the elderly of 2.32ms with 95% CI of 0.55-4.10ms. The overall effect test showed p=0.01, disclosing that such difference was significant. The heterogeneity found was I 2 =96% (p<0.001). Evaluation of p1 latency was not possible due to the low number of articles selected for this condition. cVEMP analysis was performed in 13 articles. For the p13 component, the mean latency delay in the elderly was 1.34ms with 95% CI of 0.56-2.11ms. The overall effect test showed a p<0.001, with heterogeneity value I 2 =92% (p<0.001). For the n23 component, the mean latency delay for the elderly was 2.82ms with 95% CI of 0.33-5.30ms. The overall effect test showed p=0.03. The heterogeneity found was I 2 =99% (p<0.001). The latency of oVEMP n1 wave component and latencies of cVEMP p13 and n23 wave components are longer in the elderly aged >60 years than in young adults. Copyright © 2017

Maturation of long latency auditory evoked potentials in hearing children: systematic review.

PubMed

Silva, Liliane Aparecida Fagundes; Magliaro, Fernanda Cristina Leite; Carvalho, Ana Claudia Martinho de; Matas, Carla Gentile

2017-05-15

To analyze how Auditory Long Latency Evoked Potentials (LLAEP) change according to age in children population through a systematic literature review. After formulation of the research question, a bibliographic survey was done in five data bases with the following descriptors: Electrophysiology (Eletrofisiologia), Auditory Evoked Potentials (Potenciais Evocados Auditivos), Child (Criança), Neuronal Plasticity (Plasticidade Neuronal) and Audiology (Audiologia). Level 1 evidence articles, published between 1995 and 2015 in Brazilian Portuguese or English language. Aspects related to emergence, morphology and latency of P1, N1, P2 and N2 components were analyzed. A total of 388 studies were found; however, only 21 studies contemplated the established criteria. P1 component is characterized as the most frequent component in young children, being observed around 100-150 ms, which tends to decrease as chronological age increases. The N2 component was shown to be the second most commonly observed component in children, being observed around 200-250 ms.. The other N1 and P2 components are less frequent and begin to be seen and recorded throughout the maturational process. The maturation of LLAEP occurs gradually, and the emergence of P1, N1, P2 and N2 components as well as their latency values are variable in childhood. P1 and N2 components are the most observed and described in pediatric population. The diversity of protocols makes the comparison between studies difficult.

Memory-dependent adjustment of vocal response latencies in a territorial songbird.

PubMed

Geberzahn, Nicole; Hultsch, Henrike; Todt, Dietmar

2013-06-01

Vocal interactions in songbirds can be used as a model system to investigate the interplay of intrinsic singing programmes (e.g. influences from vocal memories) and external variables (e.g. social factors). When characterizing vocal interactions between territorial rivals two aspects are important: (1) the timing of songs in relation to the conspecific's singing and (2) the use of a song pattern that matches the rival's song. Responses in both domains can be used to address a territorial rival. This study is the first to investigate the relation of the timing of vocal responses to (1) the vocal memory of a responding subject and (2) the selection of the song pattern that the subject uses as a response. To this end, we conducted interactive playback experiments with adult nightingales (Luscinia megarhynchos) that had been hand-reared and tutored in the laboratory. We analysed the subjects' vocal response latencies towards broadcast playback stimuli that they either had in their own vocal repertoire (songs shared with playback) or that they had not heard before (unknown songs). Likewise, we compared vocal response latencies between responses that matched the stimulus song and those that did not. Our findings showed that the latency of singing in response to the playback was shorter for shared versus unknown song stimuli when subjects overlapped the playback stimuli with their own song. Moreover birds tended to overlap faster when vocally matching the stimulus song rather than when replying with a non-matching song type. We conclude that memory of song patterns influenced response latencies and discuss possible mechanisms. Copyright © 2012 Elsevier Ltd. All rights reserved.

The influence of target angular velocity on visual latency difference determined using the rotating Pulfrich effect.

PubMed

Nickalls, R W

1996-09-01

Visual latency difference was determined directly in normal volunteers, using the rotating Pulfrich technique described by Nickalls [Vision Research, 26, 367-372 (1986)]. Subjects fixated a black vertical rod rotating clockwise on a horizontal turntable turning with constant angular velocity (16.6,33.3 or 44.7 revs/min) with a neutral density filter (OD 0.7 or 1.5) in front of the right eye. For all subjects the latency difference associated with the 1.5 OD filter was significantly greater (P < 0.001) with the rod rotating at 16.6 rev/min than at 33.3 revs/min. The existence of an inverse relationship between latency difference and angular velocity is hypothesized.

Stochastic Game Analysis and Latency Awareness for Self-Adaptation

DTIC Science & Technology

2014-01-01

this paper, we introduce a formal analysis technique based on model checking of stochastic multiplayer games (SMGs) that enables us to quantify the...Additional Key Words and Phrases: Proactive adaptation, Stochastic multiplayer games , Latency 1. INTRODUCTION When planning how to adapt, self-adaptive...contribution of this paper is twofold: (1) A novel analysis technique based on model checking of stochastic multiplayer games (SMGs) that enables us to

Discrete Serotonin Systems Mediate Memory Enhancement and Escape Latencies after Unpredicted Aversive Experience in Drosophila Place Memory

PubMed Central

Sitaraman, Divya; Kramer, Elizabeth F.; Kahsai, Lily; Ostrowski, Daniela; Zars, Troy

2017-01-01

Feedback mechanisms in operant learning are critical for animals to increase reward or reduce punishment. However, not all conditions have a behavior that can readily resolve an event. Animals must then try out different behaviors to better their situation through outcome learning. This form of learning allows for novel solutions and with positive experience can lead to unexpected behavioral routines. Learned helplessness, as a type of outcome learning, manifests in part as increases in escape latency in the face of repeated unpredicted shocks. Little is known about the mechanisms of outcome learning. When fruit fly Drosophila melanogaster are exposed to unpredicted high temperatures in a place learning paradigm, flies both increase escape latencies and have a higher memory when given control of a place/temperature contingency. Here we describe discrete serotonin neuronal circuits that mediate aversive reinforcement, escape latencies, and memory levels after place learning in the presence and absence of unexpected aversive events. The results show that two features of learned helplessness depend on the same modulatory system as aversive reinforcement. Moreover, changes in aversive reinforcement and escape latency depend on local neural circuit modulation, while memory enhancement requires larger modulation of multiple behavioral control circuits. PMID:29321732

Low-Latency Science Exploration of Planetary Bodies: How ISS Might Be Used as Part of a Low-Latency Analog Campaign for Human Exploration

NASA Technical Reports Server (NTRS)

Thronson, Harley; Valinia, Azita; Bleacher, Jacob; Eigenbrode, Jennifer; Garvin, Jim; Petro, Noah

2014-01-01

We suggest that the International Space Station be used to examine the application and validation of low-latency telepresence for surface exploration from space as an alternative, precursor, or potentially as an adjunct to astronaut "boots on the ground." To this end, controlled experiments that build upon and complement ground-based analog field studies will be critical for assessing the effects of different latencies (0 to 500 milliseconds), task complexity, and alternate forms of feedback to the operator. These experiments serve as an example of a pathfinder for NASA's roadmap of missions to Mars with low-latency telerobotic exploration as a precursor to astronaut's landing on the surface to conduct geological tasks.

[Upper-limb work-related musculoskeletal disorders (UL-WMSDs) and latency of effect].

PubMed

Nicoletti, S; Battevi, N

2008-01-01

Trends in work-related upper limb musculoskeletal disorders appear to be in constant increase in industrialized countries. In Europe claims and compensation for these disorders have significantly increased. The aim of this study was to investigate the temporal relationship between the beginning of occupational exposure to repetitive movements and exertions of upper limbs, assessed through the OCRA index, and the manifestation of the disorders. Clinical and questionnaire information about 557 cases of UL-WMSDs in the upholstered furniture industry were analyzed in order to investigate the mean latency period of the disorders and to verify to what extent different levels of exposure influence the latency time. The latency of UL-WMSDs is influenced by the level of exposure to risk, measured by means of the OCRA index. Shorter latency times were found for wrist/hand tendonitis, with a mean latency time of 5.4 years and with a greater sensitivity to the level of exposure assessed with the OCRA index value. This might support a sort of predictive value with reference to other UL-WMSDs with longer latency. Probably a latency period of 12 years may be suggested as the cut-off limit to assess a causal relationship between tendon or canalicular WMISDs and occupational exposure to repetitive movements and exertions of upper limbs.

Prolongation of latencies for passive avoidance responses in rats treated with aniracetam or piracetam.

PubMed

Yamada, K; Inoue, T; Tanaka, M; Furukawa, T

1985-04-01

Effects of aniracetam (1-anysoyl-2-pyrrolodone) and piracetam (1-acetamido-2-pyrrolidone) on passive avoidance behavior were studied in 2 and 18 months old rats using a step-down passive avoidance task. Repeated administration of aniracetam (30 and 50 mg/kg, IP X 5 days) or piracetam (100 mg/kg, IP X 5 days) significantly prolonged step-down latencies for a passive avoidance task in 2 months old rats. Administration of aniracetam (50 mg/kg, IP) or piracetam (100 mg/kg, IP), however, did not affect locomotor activity. This prolongation of latencies was also seen with oral administration of aniracetam (50 mg/kg X 5 days). Similar prolongation of latencies also occurred in 18 months old rat treated with aniracetam (50 mg/kg, IP X 5 days). The results imply that aniracetam may improve learning and/or memory in 2 and 18 months old rats.

A new, ultra-low latency data transmission protocol for Earthquake Early Warning Systems

NASA Astrophysics Data System (ADS)

Hill, P.; Hicks, S. P.; McGowan, M.

2016-12-01

One measure used to assess the performance of Earthquake Early Warning Systems (EEWS) is the delay time between earthquake origin and issued alert. EEWS latency is dependent on a number of sources (e.g. P-wave propagation, digitisation, transmission, receiver processing, triggering, event declaration). Many regional seismic networks use the SEEDlink protocol; however, packet size is fixed to 512-byte miniSEED records, resulting in transmission latencies of >0.5 s. Data packetisation is seen as one of the main sources of delays in EEWS (Brown et al., 2011). Optimising data-logger and telemetry configurations is a cost-effective strategy to improve EEWS alert times (Behr et al., 2015). Digitisers with smaller, selectable packets can result in faster alerts (Sokos et al., 2016). We propose a new seismic protocol for regional seismic networks benefiting low-latency applications such as EEWS. The protocol, based on Güralp's existing GDI-link format is an efficient and flexible method to exchange data between seismic stations and data centers for a range of network configurations. The main principle is to stream data sample-by-sample instead of fixed-length packets to minimise transmission latency. Self-adaptive packetisation with compression maximises available telemetry bandwidth. Highly flexible metadata fields within GDI-link are compatible with existing miniSEED definitions. Data is sent as integers or floats, supporting a wide range of data formats, including discrete parameters such as Pd & τC for on-site earthquake early warning. Other advantages include: streaming station state-of-health information, instrument control, support of backfilling and fail-over strategies during telemetry outages. Based on tests carried out on the Güralp Minimus data-logger, we show our new protocol can reduce transmission latency to as low as 1 ms. The low-latency protocol is currently being implemented with common processing packages. The results of these tests will help to

First low-latency LIGO+Virgo search for binary inspirals and their electromagnetic counterparts

NASA Astrophysics Data System (ADS)

Abadie, J.; Abbott, B. P.; Abbott, R.; Abbott, T. D.; Abernathy, M.; Accadia, T.; Acernese, F.; Adams, C.; Adhikari, R.; Affeldt, C.; Agathos, M.; Agatsuma, K.; Ajith, P.; Allen, B.; Amador Ceron, E.; Amariutei, D.; Anderson, S. B.; Anderson, W. G.; Arai, K.; Arain, M. A.; Araya, M. C.; Aston, S. M.; Astone, P.; Atkinson, D.; Aufmuth, P.; Aulbert, C.; Aylott, B. E.; Babak, S.; Baker, P.; Ballardin, G.; Ballmer, S.; Barayoga, J. C. B.; Barker, D.; Barone, F.; Barr, B.; Barsotti, L.; Barsuglia, M.; Barton, M. A.; Bartos, I.; Bassiri, R.; Bastarrika, M.; Basti, A.; Batch, J.; Bauchrowitz, J.; Bauer, Th. S.; Bebronne, M.; Beck, D.; Behnke, B.; Bejger, M.; Beker, M. G.; Bell, A. S.; Belletoile, A.; Belopolski, I.; Benacquista, M.; Berliner, J. M.; Bertolini, A.; Betzwieser, J.; Beveridge, N.; Beyersdorf, P. T.; Bilenko, I. A.; Billingsley, G.; Birch, J.; Biswas, R.; Bitossi, M.; Bizouard, M. A.; Black, E.; Blackburn, J. K.; Blackburn, L.; Blair, D.; Bland, B.; Blom, M.; Bock, O.; Bodiya, T. P.; Bogan, C.; Bondarescu, R.; Bondu, F.; Bonelli, L.; Bonnand, R.; Bork, R.; Born, M.; Boschi, V.; Bose, S.; Bosi, L.; Bouhou, B.; Braccini, S.; Bradaschia, C.; Brady, P. R.; Braginsky, V. B.; Branchesi, M.; Brau, J. E.; Breyer, J.; Briant, T.; Bridges, D. O.; Brillet, A.; Brinkmann, M.; Brisson, V.; Britzger, M.; Brooks, A. F.; Brown, D. A.; Bulik, T.; Bulten, H. J.; Buonanno, A.; Burguet-Castell, J.; Buskulic, D.; Buy, C.; Byer, R. L.; Cadonati, L.; Cagnoli, G.; Calloni, E.; Camp, J. B.; Campsie, P.; Cannizzo, J.; Cannon, K.; Canuel, B.; Cao, J.; Capano, C. D.; Carbognani, F.; Carbone, L.; Caride, S.; Caudill, S.; Cavaglià, M.; Cavalier, F.; Cavalieri, R.; Cella, G.; Cepeda, C.; Cesarini, E.; Chaibi, O.; Chalermsongsak, T.; Charlton, P.; Chassande-Mottin, E.; Chelkowski, S.; Chen, W.; Chen, X.; Chen, Y.; Chincarini, A.; Chiummo, A.; Cho, H. S.; Chow, J.; Christensen, N.; Chua, S. S. Y.; Chung, C. T. Y.; Chung, S.; Ciani, G.; Clara, F.; Clark, D. E.; Clark, J.; Clayton, J. H.; Cleva, F.; Coccia, E.; Cohadon, P.-F.; Colacino, C. N.; Colas, J.; Colla, A.; Colombini, M.; Conte, A.; Conte, R.; Cook, D.; Corbitt, T. R.; Cordier, M.; Cornish, N.; Corsi, A.; Costa, C. A.; Coughlin, M.; Coulon, J.-P.; Couvares, P.; Coward, D. M.; Cowart, M.; Coyne, D. C.; Creighton, J. D. E.; Creighton, T. D.; Cruise, A. M.; Cumming, A.; Cunningham, L.; Cuoco, E.; Cutler, R. M.; Dahl, K.; Danilishin, S. L.; Dannenberg, R.; D'Antonio, S.; Danzmann, K.; Dattilo, V.; Daudert, B.; Daveloza, H.; Davier, M.; Daw, E. J.; Day, R.; Dayanga, T.; De Rosa, R.; DeBra, D.; Debreczeni, G.; Del Pozzo, W.; del Prete, M.; Dent, T.; Dergachev, V.; DeRosa, R.; DeSalvo, R.; Dhurandhar, S.; Di Fiore, L.; Di Lieto, A.; Di Palma, I.; Emilio, M. Di Paolo; Di Virgilio, A.; Díaz, M.; Dietz, A.; Donovan, F.; Dooley, K. L.; Drago, M.; Drever, R. W. P.; Driggers, J. C.; Du, Z.; Dumas, J.-C.; Dwyer, S.; Eberle, T.; Edgar, M.; Edwards, M.; Effler, A.; Ehrens, P.; Endrőczi, G.; Engel, R.; Etzel, T.; Evans, K.; Evans, M.; Evans, T.; Factourovich, M.; Fafone, V.; Fairhurst, S.; Fan, Y.; Farr, B. F.; Fazi, D.; Fehrmann, H.; Feldbaum, D.; Feroz, F.; Ferrante, I.; Fidecaro, F.; Finn, L. S.; Fiori, I.; Fisher, R. P.; Flaminio, R.; Flanigan, M.; Foley, S.; Forsi, E.; Forte, L. A.; Fotopoulos, N.; Fournier, J.-D.; Franc, J.; Frasca, S.; Frasconi, F.; Frede, M.; Frei, M.; Frei, Z.; Freise, A.; Frey, R.; Fricke, T. T.; Friedrich, D.; Fritschel, P.; Frolov, V. V.; Fujimoto, M.-K.; Fulda, P. J.; Fyffe, M.; Gair, J.; Galimberti, M.; Gammaitoni, L.; Garcia, J.; Garufi, F.; Gáspár, M. E.; Gemme, G.; Geng, R.; Genin, E.; Gennai, A.; Gergely, L. Á.; Ghosh, S.; Giaime, J. A.; Giampanis, S.; Giardina, K. D.; Giazotto, A.; Gil-Casanova, S.; Gill, C.; Gleason, J.; Goetz, E.; Goggin, L. M.; González, G.; Gorodetsky, M. L.; Goßler, S.; Gouaty, R.; Graef, C.; Graff, P. B.; Granata, M.; Grant, A.; Gras, S.; Gray, C.; Gray, N.; Greenhalgh, R. J. S.; Gretarsson, A. M.; Greverie, C.; Grosso, R.; Grote, H.; Grunewald, S.; Guidi, G. M.; Guido, C.; Gupta, R.; Gustafson, E. K.; Gustafson, R.; Ha, T.; Hallam, J. M.; Hammer, D.; Hammond, G.; Hanks, J.; Hanna, C.; Hanson, J.; Harms, J.; Harry, G. M.; Harry, I. W.; Harstad, E. D.; Hartman, M. T.; Haughian, K.; Hayama, K.; Hayau, J.-F.; Heefner, J.; Heidmann, A.; Heintze, M. C.; Heitmann, H.; Hello, P.; Hendry, M. A.; Heng, I. S.; Heptonstall, A. W.; Herrera, V.; Hewitson, M.; Hild, S.; Hoak, D.; Hodge, K. A.; Holt, K.; Holtrop, M.; Hong, T.; Hooper, S.; Hosken, D. J.; Hough, J.; Howell, E. J.; Hughey, B.; Husa, S.; Huttner, S. H.; Huynh-Dinh, T.; Ingram, D. R.; Inta, R.; Isogai, T.; Ivanov, A.; Izumi, K.; Jacobson, M.; James, E.; Jang, Y. J.; Jaranowski, P.; Jesse, E.; Johnson, W. W.; Jones, D. I.; Jones, G.; Jones, R.; Ju, L.; Kalmus, P.; Kalogera, V.; Kandhasamy, S.; Kang, G.; Kanner, J. B.; Kasturi, R.; Katsavounidis, E.; Katzman, W.; Kaufer, H.; Kawabe, K.; Kawamura, S.; Kawazoe, F.; Kelley, D.; Kells, W.; Keppel, D. G.; Keresztes, Z.; Khalaidovski, A.; Khalili, F. Y.; Khazanov, E. A.; Kim, B. K.; Kim, C.; Kim, H.; Kim, K.; Kim, N.; Kim, Y. M.; King, P. J.; Kinzel, D. L.; Kissel, J. S.; Klimenko, S.; Kokeyama, K.; Kondrashov, V.; Koranda, S.; Korth, W. Z.; Kowalska, I.; Kozak, D.; Kranz, O.; Kringel, V.; Krishnamurthy, S.; Krishnan, B.; Królak, A.; Kuehn, G.; Kumar, R.; Kwee, P.; Lam, P. K.; Landry, M.; Lantz, B.; Lastzka, N.; Lawrie, C.; Lazzarini, A.; Leaci, P.; Lee, C. H.; Lee, H. K.; Lee, H. M.; Leong, J. R.; Leonor, I.; Leroy, N.; Letendre, N.; Li, J.; Li, T. G. F.; Liguori, N.; Lindquist, P. E.; Liu, Y.; Liu, Z.; Lockerbie, N. A.; Lodhia, D.; Lorenzini, M.; Loriette, V.; Lormand, M.; Losurdo, G.; Lough, J.; Luan, J.; Lubinski, M.; Lück, H.; Lundgren, A. P.; Macdonald, E.; Machenschalk, B.; MacInnis, M.; Macleod, D. M.; Mageswaran, M.; Mailand, K.; Majorana, E.; Maksimovic, I.; Man, N.; Mandel, I.; Mandic, V.; Mantovani, M.; Marandi, A.; Marchesoni, F.; Marion, F.; Márka, S.; Márka, Z.; Markosyan, A.; Maros, E.; Marque, J.; Martelli, F.; Martin, I. W.; Martin, R. M.; Marx, J. N.; Mason, K.; Masserot, A.; Matichard, F.; Matone, L.; Matzner, R. A.; Mavalvala, N.; Mazzolo, G.; McCarthy, R.; McClelland, D. E.; McGuire, S. C.; McIntyre, G.; McIver, J.; McKechan, D. J. A.; McWilliams, S.; Meadors, G. D.; Mehmet, M.; Meier, T.; Melatos, A.; Melissinos, A. C.; Mendell, G.; Mercer, R. A.; Meshkov, S.; Messenger, C.; Meyer, M. S.; Miao, H.; Michel, C.; Milano, L.; Miller, J.; Minenkov, Y.; Mitrofanov, V. P.; Mitselmakher, G.; Mittleman, R.; Miyakawa, O.; Moe, B.; Mohan, M.; Mohanty, S. D.; Mohapatra, S. R. P.; Moraru, D.; Moreno, G.; Morgado, N.; Morgia, A.; Mori, T.; Morriss, S. R.; Mosca, S.; Mossavi, K.; Mours, B.; Mow-Lowry, C. M.; Mueller, C. L.; Mueller, G.; Mukherjee, S.; Mullavey, A.; Müller-Ebhardt, H.; Munch, J.; Murphy, D.; Murray, P. G.; Mytidis, A.; Nash, T.; Naticchioni, L.; Necula, V.; Nelson, J.; Neri, I.; Newton, G.; Nguyen, T.; Nishizawa, A.; Nitz, A.; Nocera, F.; Nolting, D.; Normandin, M. E.; Nuttall, L.; Ochsner, E.; O'Dell, J.; Oelker, E.; Ogin, G. H.; Oh, J. J.; Oh, S. H.; O'Reilly, B.; O'Shaughnessy, R.; Osthelder, C.; Ott, C. D.; Ottaway, D. J.; Ottens, R. S.; Overmier, H.; Owen, B. J.; Page, A.; Pagliaroli, G.; Palladino, L.; Palomba, C.; Pan, Y.; Pankow, C.; Paoletti, F.; Papa, M. A.; Parisi, M.; Pasqualetti, A.; Passaquieti, R.; Passuello, D.; Patel, P.; Pedraza, M.; Peiris, P.; Pekowsky, L.; Penn, S.; Perreca, A.; Persichetti, G.; Phelps, M.; Pichot, M.; Pickenpack, M.; Piergiovanni, F.; Pietka, M.; Pinard, L.; Pinto, I. M.; Pitkin, M.; Pletsch, H. J.; Plissi, M. V.; Poggiani, R.; Pöld, J.; Postiglione, F.; Prato, M.; Predoi, V.; Prestegard, T.; Price, L. R.; Prijatelj, M.; Principe, M.; Privitera, S.; Prix, R.; Prodi, G. A.; Prokhorov, L. G.; Puncken, O.; Punturo, M.; Puppo, P.; Quetschke, V.; Quitzow-James, R.; Raab, F. J.; Rabeling, D. S.; Rácz, I.; Radkins, H.; Raffai, P.; Rakhmanov, M.; Rankins, B.; Rapagnani, P.; Raymond, V.; Re, V.; Redwine, K.; Reed, C. M.; Reed, T.; Regimbau, T.; Reid, S.; Reitze, D. H.; Ricci, F.; Riesen, R.; Riles, K.; Robertson, N. A.; Robinet, F.; Robinson, C.; Robinson, E. L.; Rocchi, A.; Roddy, S.; Rodriguez, C.; Rodruck, M.; Rolland, L.; Rollins, J. G.; Romano, J. D.; Romano, R.; Romie, J. H.; Rosińska, D.; Röver, C.; Rowan, S.; Rüdiger, A.; Ruggi, P.; Ryan, K.; Sainathan, P.; Salemi, F.; Sammut, L.; Sandberg, V.; Sannibale, V.; Santamaría, L.; Santiago-Prieto, I.; Santostasi, G.; Sassolas, B.; Sathyaprakash, B. S.; Sato, S.; Saulson, P. R.; Savage, R. L.; Schilling, R.; Schnabel, R.; Schofield, R. M. S.; Schreiber, E.; Schulz, B.; Schutz, B. F.; Schwinberg, P.; Scott, J.; Scott, S. M.; Seifert, F.; Sellers, D.; Sentenac, D.; Sergeev, A.; Shaddock, D. A.; Shaltev, M.; Shapiro, B.; Shawhan, P.; Shoemaker, D. H.; Sibley, A.; Siemens, X.; Sigg, D.; Singer, A.; Singer, L.; Sintes, A. M.; Skelton, G. R.; Slagmolen, B. J. J.; Slutsky, J.; Smith, J. R.; Smith, M. R.; Smith, R. J. E.; Smith-Lefebvre, N. D.; Somiya, K.; Sorazu, B.; Soto, J.; Speirits, F. C.; Sperandio, L.; Stefszky, M.; Stein, A. J.; Stein, L. C.; Steinert, E.; Steinlechner, J.; Steinlechner, S.; Steplewski, S.; Stochino, A.; Stone, R.; Strain, K. A.; Strigin, S. E.; Stroeer, A. S.; Sturani, R.; Stuver, A. L.; Summerscales, T. Z.; Sung, M.; Susmithan, S.; Sutton, P. J.; Swinkels, B.; Tacca, M.; Taffarello, L.; Talukder, D.; Tanner, D. B.; Tarabrin, S. P.; Taylor, J. R.; Taylor, R.; Thomas, P.; Thorne, K. A.; Thorne, K. S.; Thrane, E.; Thüring, A.; Tokmakov, K. V.; Tomlinson, C.; Toncelli, A.; Tonelli, M.; Torre, O.; Torres, C.; Torrie, C. I.; Tournefier, E.; Travasso, F.; Traylor, G.; Tseng, K.; Ugolini, D.; Vahlbruch, H.; Vajente, G.; van den Brand, J. F. J.; Van Den Broeck, C.; van der Putten, S.; van Veggel, A. A.; Vass, S.; Vasuth, M.; Vaulin, R.; Vavoulidis, M.; Vecchio, A.; Vedovato, G.; Veitch, J.; Veitch, P. J.; Veltkamp, C.; Verkindt, D.; Vetrano, F.; Viceré, A.; Villar, A. E.; Vinet, J.-Y.; Vitale, S.; Vocca, H.; Vorvick, C.; Vyatchanin, S. P.; Wade, A.; Wade, L.; Wade, M.; Waldman, S. J.; Wallace, L.; Wan, Y.; Wang, M.; Wang, X.; Wang, Z.; Wanner, A.; Ward, R. L.; Was, M.; Weinert, M.; Weinstein, A. J.; Weiss, R.; Wen, L.; Wessels, P.; West, M.; Westphal, T.; Wette, K.; Whelan, J. T.; Whitcomb, S. E.; White, D. J.; Whiting, B. F.; Wilkinson, C.; Willems, P. A.; Williams, L.; Williams, R.; Willke, B.; Winkelmann, L.; Winkler, W.; Wipf, C. C.; Wiseman, A. G.; Wittel, H.; Woan, G.; Wooley, R.; Worden, J.; Yakushin, I.; Yamamoto, H.; Yamamoto, K.; Yancey, C. C.; Yang, H.; Yeaton-Massey, D.; Yoshida, S.; Yu, P.; Yvert, M.; Zadrożny, A.; Zanolin, M.; Zendri, J.-P.; Zhang, F.; Zhang, L.; Zhang, W.; Zhao, C.; Zotov, N.; Zucker, M. E.; Zweizig, J.

2012-05-01

Aims: The detection and measurement of gravitational-waves from coalescing neutron-star binary systems is an important science goal for ground-based gravitational-wave detectors. In addition to emitting gravitational-waves at frequencies that span the most sensitive bands of the LIGO and Virgo detectors, these sources are also amongst the most likely to produce an electromagnetic counterpart to the gravitational-wave emission. A joint detection of the gravitational-wave and electromagnetic signals would provide a powerful new probe for astronomy. Methods: During the period between September 19 and October 20, 2010, the first low-latency search for gravitational-waves from binary inspirals in LIGO and Virgo data was conducted. The resulting triggers were sent to electromagnetic observatories for followup. We describe the generation and processing of the low-latency gravitational-wave triggers. The results of the electromagnetic image analysis will be described elsewhere. Results: Over the course of the science run, three gravitational-wave triggers passed all of the low-latency selection cuts. Of these, one was followed up by several of our observational partners. Analysis of the gravitational-wave data leads to an estimated false alarm rate of once every 6.4 days, falling far short of the requirement for a detection based solely on gravitational-wave data.

Vestibular short latency responses to pulsed linear acceleration in unanesthetized animals

NASA Technical Reports Server (NTRS)

Jones, T. A.

1992-01-01

Linear acceleration transients were used to elicit vestibular compound action potentials in non-invasively prepared, unanesthetized animals for the first time (chicks, Gallus domesticus, n = 33). Responses were composed of a series of up to 8 dominant peaks occurring within 8 msec of the stimulus. Response amplitudes for 1.0 g stimulus ranged from 1 to 10 microV. A late, slow, triphasic, anesthesia-labile component was identified as a dominant response feature in unanesthetized animals. Amplitudes increased and latencies decreased as stimulus intensity was increased (MANOVA P less than 0.05). Linear regression slope ranges were: amplitudes = 1.0-5.0 microV/g; latencies = -300 to -1100 microseconds/g. Thresholds for single polarity stimuli (0.035 +/- 0.022 g, n = 11) were significantly lower than those of alternating polarity (0.074 +/- 0.028 g, n = 18, P less than 0.001). Bilateral labyrinthectomy eliminated responses whereas bilateral extirpation of cochleae did not significantly change response thresholds. Intense acoustic masking (100/104 dB SL) produced no effect in 2 animals, but did produce small to moderate effects on response amplitudes in 7 others. Changes were attributed to effects on vestibular end organs. Results of unilateral labyrinth blockade (tetrodotoxin) suggest that P1 and N1 preferentially reflect ipsilateral eighth nerve compound action potentials whereas components beyond approximately 2 msec reflect activity from vestibular neurons that depend on both labyrinths. The results demonstrate that short latency vestibular compound action potentials can be measured in unanesthetized, non-invasively prepared animals.

Fault and Error Latency Under Real Workload: an Experimental Study. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Chillarege, Ram

1986-01-01

A practical methodology for the study of fault and error latency is demonstrated under a real workload. This is the first study that measures and quantifies the latency under real workload and fills a major gap in the current understanding of workload-failure relationships. The methodology is based on low level data gathered on a VAX 11/780 during the normal workload conditions of the installation. Fault occurrence is simulated on the data, and the error generation and discovery process is reconstructed to determine latency. The analysis proceeds to combine the low level activity data with high level machine performance data to yield a better understanding of the phenomena. A strong relationship exists between latency and workload and that relationship is quantified. The sampling and reconstruction techniques used are also validated. Error latency in the memory where the operating system resides was studied using data on the physical memory access. Fault latency in the paged section of memory was determined using data from physical memory scans. Error latency in the microcontrol store was studied using data on the microcode access and usage.

The Herpes Simplex Virus 1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8+ T Cells in Latently Infected Trigeminal Ganglia: a Novel Immune Evasion Mechanism▿

PubMed Central

Chentoufi, Aziz A.; Kritzer, Elizabeth; Tran, Michael V.; Dasgupta, Gargi; Lim, Chang Hyun; Yu, David C.; Afifi, Rasha E.; Jiang, Xianzhi; Carpenter, Dale; Osorio, Nelson; Hsiang, Chinhui; Nesburn, Anthony B.; Wechsler, Steven L.; BenMohamed, Lbachir

2011-01-01

Following ocular herpes simplex virus 1 (HSV-1) infection of C57BL/6 mice, HSV-specific (HSV-gB498–505 tetramer+) CD8+ T cells are induced, selectively retained in latently infected trigeminal ganglia (TG), and appear to decrease HSV-1 reactivation. The HSV-1 latency-associated transcript (LAT) gene, the only viral gene that is abundantly transcribed during latency, increases reactivation. Previously we found that during latency with HSV-1 strain McKrae-derived viruses, more of the total TG resident CD8 T cells expressed markers of exhaustion with LAT+ virus compared to LAT− virus. Here we extend these findings to HSV-1 strain 17syn+-derived LAT+ and LAT− viruses and to a virus expressing just the first 20% of LAT. Thus, the previous findings were not an artifact of HSV-1 strain McKrae, and the LAT function involved mapped to the first 1.5 kb of LAT. Importantly, to our knowledge, we show here for the first time that during LAT+ virus latency, most of the HSV-1-specific TG resident CD8 T cells were functionally exhausted, as judged by low cytotoxic function and decreased gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. This resulted in LAT− TG having more functional HSV-gB498–505 tetramer+ CD8+ T cells compared to LAT+ TG. In addition, LAT expression, in the absence of other HSV-1 gene products, appeared to be able to directly or indirectly upregulate both PD-L1 and major histocompatibility complex class I (MHC-I) on mouse neuroblastoma cells (Neuro2A). These findings may constitute a novel immune evasion mechanism whereby the HSV-1 LAT directly or indirectly promotes functional exhaustion (i.e., dysfunction) of HSV-specific CD8+ T cells in latently infected TG, resulting in increased virus reactivation. PMID:21715478

Research on low-latency MAC protocols for wireless sensor networks

NASA Astrophysics Data System (ADS)

He, Chenguang; Sha, Xuejun; Lee, Chankil

2007-11-01

Energy-efficient should not be the only design goal in MAC protocols for wireless sensor networks, which involve the use of battery-operated computing and sensing devices. Low-latency operation becomes the same important as energy-efficient in the case that the traffic load is very heavy or the real-time constrain is used in applications like tracking or locating. This paper introduces some causes of traditional time delays which are inherent in a multi-hops network using existing WSN MAC protocols, illuminates the importance of low-latency MAC design for wireless sensor networks, and presents three MACs as examples of low-latency protocols designed specially for sleep delay, wait delay and wakeup delay in wireless sensor networks, respectively. The paper also discusses design trade-offs with emphasis on low-latency and points out their advantages and disadvantages, together with some design considerations and suggestions for MAC protocols for future applications and researches.

Epstein-Barr virus latency switch in human B-cells: a physico-chemical model.

PubMed

Werner, Maria; Ernberg, Ingemar; Zou, Jiezhi; Almqvist, Jenny; Aurell, Erik

2007-08-31

The Epstein-Barr virus is widespread in all human populations and is strongly associated with human disease, ranging from infectious mononucleosis to cancer. In infected cells the virus can adopt several different latency programs, affecting the cells' behaviour. Experimental results indicate that a specific genetic switch between viral latency programs, reprograms human B-cells between proliferative and resting states. Each of these two latency programs makes use of a different viral promoter, Cp and Qp, respectively. The hypothesis tested in this study is that this genetic switch is controlled by both human and viral transcription factors; Oct-2 and EBNA-1. We build a physico-chemical model to investigate quantitatively the dynamical properties of the promoter regulation and experimentally examine protein level variations between the two latency programs. Our experimental results display significant differences in EBNA-1 and Oct-2 levels between resting and proliferating programs. With the model we identify two stable latency programs, corresponding to a resting and proliferating cell. The two programs differ in robustness and transcriptional activity. The proliferating state is markedly more stable, with a very high transcriptional activity from its viral promoter. We predict the promoter activities to be mutually exclusive in the two different programs, and our relative promoter activities correlate well with experimental data. Transitions between programs can be induced, by affecting the protein levels of our transcription factors. Simulated time scales are in line with experimental results. We show that fundamental properties of the Epstein-Barr virus involvement in latent infection, with implications for tumor biology, can be modelled and understood mathematically. We conclude that EBNA-1 and Oct-2 regulation of Cp and Qp is sufficient to establish mutually exclusive expression patterns. Moreover, the modelled genetic control predict both mono- and bistable

Throughput and latency programmable optical transceiver by using DSP and FEC control.

PubMed

Tanimura, Takahito; Hoshida, Takeshi; Kato, Tomoyuki; Watanabe, Shigeki; Suzuki, Makoto; Morikawa, Hiroyuki

2017-05-15

We propose and experimentally demonstrate a proof-of-concept of a programmable optical transceiver that enables simultaneous optimization of multiple programmable parameters (modulation format, symbol rate, power allocation, and FEC) for satisfying throughput, signal quality, and latency requirements. The proposed optical transceiver also accommodates multiple sub-channels that can transport different optical signals with different requirements. Multi-degree-of-freedom of the parameters often leads to difficulty in finding the optimum combination among the parameters due to an explosion of the number of combinations. The proposed optical transceiver reduces the number of combinations and finds feasible sets of programmable parameters by using constraints of the parameters combined with a precise analytical model. For precise BER prediction with the specified set of parameters, we model the sub-channel BER as a function of OSNR, modulation formats, symbol rates, and power difference between sub-channels. Next, we formulate simple constraints of the parameters and combine the constraints with the analytical model to seek feasible sets of programmable parameters. Finally, we experimentally demonstrate the end-to-end operation of the proposed optical transceiver with offline manner including low-density parity-check (LDPC) FEC encoding and decoding under a specific use case with latency-sensitive application and 40-km transmission.

Identification of B Cells as a Major Site for Cyprinid Herpesvirus 3 Latency

PubMed Central

Reed, Aimee N.; Izume, Satoko; Dolan, Brian P.; LaPatra, Scott; Kent, Michael; Dong, Jing

2014-01-01

ABSTRACT Cyprinid herpesvirus 3 (CyHV-3), commonly known as koi herpesvirus (KHV), is a member of the Alloherpesviridae, and is a recently discovered emerging herpesvirus that is highly pathogenic for koi and common carp. Our previous study demonstrated that CyHV-3 becomes latent in peripheral white blood cells (WBC). In this study, CyHV-3 latency was further investigated in IgM+ WBC. The presence of the CyHV-3 genome in IgM+ WBC was about 20-fold greater than in IgM− WBC. To determine whether CyHV-3 expressed genes during latency, transcription from all eight open reading frames (ORFs) in the terminal repeat was investigated in IgM+ WBC from koi with latent CyHV-3 infection. Only a spliced ORF6 transcript was found to be abundantly expressed in IgM+ WBC from CyHV-3 latently infected koi. The spliced ORF6 transcript was also detected in vitro during productive infection as early as 1 day postinfection. The ORF6 transcript from in vitro infection begins at −127 bp upstream of the ATG codon and ends +188 bp downstream of the stop codon, +20 bp downstream of the polyadenylation signal. The hypothetical protein of ORF6 contains a consensus sequence with homology to a conserved domain of EBNA-3B and ICP4 from Epstein-Barr virus and herpes simplex virus 1, respectively, both members of the Herpesviridae. This is the first report of latent CyHV-3 in B cells and identification of gene transcription during latency for a member of the Alloherpesviridae. IMPORTANCE This is the first demonstration that a member of the Alloherpesviridae, cyprinid herpesvirus 3 (CyHV-3), establishes a latent infection in the B cells of its host, Cyprinus carpio. In addition, this is the first report of identification of gene transcription during latency for a member of Herpesvirales outside Herpesviridae. This is also the first report that the hypothetical protein of latent transcript of CyHV-3 contains a consensus sequence with homology to a conserved domain of EBNA-3B from Epstein

Identification of B cells as a major site for cyprinid herpesvirus 3 latency.

PubMed

Reed, Aimee N; Izume, Satoko; Dolan, Brian P; LaPatra, Scott; Kent, Michael; Dong, Jing; Jin, Ling

2014-08-01

Cyprinid herpesvirus 3 (CyHV-3), commonly known as koi herpesvirus (KHV), is a member of the Alloherpesviridae, and is a recently discovered emerging herpesvirus that is highly pathogenic for koi and common carp. Our previous study demonstrated that CyHV-3 becomes latent in peripheral white blood cells (WBC). In this study, CyHV-3 latency was further investigated in IgM(+) WBC. The presence of the CyHV-3 genome in IgM(+) WBC was about 20-fold greater than in IgM(-) WBC. To determine whether CyHV-3 expressed genes during latency, transcription from all eight open reading frames (ORFs) in the terminal repeat was investigated in IgM(+) WBC from koi with latent CyHV-3 infection. Only a spliced ORF6 transcript was found to be abundantly expressed in IgM(+) WBC from CyHV-3 latently infected koi. The spliced ORF6 transcript was also detected in vitro during productive infection as early as 1 day postinfection. The ORF6 transcript from in vitro infection begins at -127 bp upstream of the ATG codon and ends +188 bp downstream of the stop codon, +20 bp downstream of the polyadenylation signal. The hypothetical protein of ORF6 contains a consensus sequence with homology to a conserved domain of EBNA-3B and ICP4 from Epstein-Barr virus and herpes simplex virus 1, respectively, both members of the Herpesviridae. This is the first report of latent CyHV-3 in B cells and identification of gene transcription during latency for a member of the Alloherpesviridae. This is the first demonstration that a member of the Alloherpesviridae, cyprinid herpesvirus 3 (CyHV-3), establishes a latent infection in the B cells of its host, Cyprinus carpio. In addition, this is the first report of identification of gene transcription during latency for a member of Herpesvirales outside Herpesviridae. This is also the first report that the hypothetical protein of latent transcript of CyHV-3 contains a consensus sequence with homology to a conserved domain of EBNA-3B from Epstein-Barr virus and ICP4

Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis

PubMed Central

Jones, Clinton

2013-01-01

α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which will restore wild type levels of reactivation from latency to a LAT null mutant virus. Two small non-coding RNAs encoded by LAT possess anti-apoptosis functions in transfected cells. The BHV-1 latency related RNA (LR-RNA), like LAT, is abundantly expressed during latency. The LR-RNA encodes a protein (ORF2) and two microRNAs that are expressed in certain latently infected neurons. Wild-type expression of LR gene products is required for stress-induced reactivation from latency in cattle. ORF2 has anti-apoptosis functions and interacts with certain cellular transcription factors that stimulate viral transcription and productive infection. ORF2 is predicted to promote survival of infected neurons by inhibiting apoptosis and sequestering cellular transcription factors which stimulate productive infection. In addition, the LR encoded microRNAs inhibit viral transcription and apoptosis. In summary, the ability of BHV-1 and HSV-1 to interfere with apoptosis and productive infection in sensory neurons is crucial for the life-long latency-reactivation cycle in their respective hosts. PMID:25278776

Modelling Transposition Latencies: Constraints for Theories of Serial Order Memory

ERIC Educational Resources Information Center

Farrell, Simon; Lewandowsky, Stephan

2004-01-01

Several competing theories of short-term memory can explain serial recall performance at a quantitative level. However, most theories to date have not been applied to the accompanying pattern of response latencies, thus ignoring a rich and highly diagnostic aspect of performance. This article explores and tests the error latency predictions of…

Arbitration in crossbar interconnect for low latency

DOEpatents

Ohmacht, Martin; Sugavanam, Krishnan

2013-02-05

A system and method and computer program product for reducing the latency of signals communicated through a crossbar switch, the method including using at slave arbitration logic devices associated with Slave devices for which access is requested from one or more Master devices, two or more priority vector signals cycled among their use every clock cycle for selecting one of the requesting Master devices and updates the respective priority vector signal used every clock cycle. Similarly, each Master for which access is requested from one or more Slave devices, can have two or more priority vectors and can cycle among their use every clock cycle to further reduce latency and increase throughput performance via the crossbar.

Synthesis of Pyridine and Spiropyridine Derivatives Derived from 2-aminoprop- 1-ene-1,1,3-tricarbonitrile Together with their c-Met Kinase and Antiproliferative Evaluations.

PubMed

Mohareb, Rafat M; Abouzied, Amr S; Abbas, Nermeen S

2018-02-07

Among a wide range of pyridines, 3-cyanopyridines acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the pyridine nucleus were known in the market. The aim of this work was to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of 3-cyanopyridine derivatives using 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1) as the key starting material for many heterocyclization reactions. Muticoponent reactions were adopted using compound 1 to get different pyridine derivatives that were capable for different heterocyclization reactions. Antiproliferative evaluations and c-Met kinase, Pim-1 kinse inhibitions were perform where some compounds gave high activities. Compounds that showed high antiprolifeative activity were tested gor c-Met-independent and the results showed that compounds 5c, 5e, 5f, 7c, 7f and 16d were more active than foretinib. The Pim-1 kinase inhibition activity of some selected compounds showed that compounds 5e and 16c were high potent to inhibit Pim-1 activity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Contribution of the Major ND10 Proteins PML, hDaxx and Sp100 to the Regulation of Human Cytomegalovirus Latency and Lytic Replication in the Monocytic Cell Line THP-1

PubMed Central

Wagenknecht, Nadine; Reuter, Nina; Scherer, Myriam; Reichel, Anna; Müller, Regina; Stamminger, Thomas

2015-01-01

Promyelocytic leukemia nuclear bodies, also termed nuclear domain 10 (ND10), have emerged as nuclear protein accumulations mediating an intrinsic cellular defense against viral infections via chromatin-based mechanisms, however, their contribution to the control of herpesviral latency is still controversial. In this study, we utilized the monocytic cell line THP-1 as an in vitro latency model for human cytomegalovirus infection (HCMV). Characterization of THP-1 cells by immunofluorescence and Western blot analysis confirmed the expression of all major ND10 components. THP-1 cells with a stable, individual knockdown of PML, hDaxx or Sp100 were generated. Importantly, depletion of the major ND10 proteins did not prevent the terminal cellular differentiation of THP-1 monocytes. After construction of a recombinant, endotheliotropic human cytomegalovirus expressing IE2-EYFP, we investigated whether the depletion of ND10 proteins affects the onset of viral IE gene expression. While after infection of differentiated, THP-1-derived macrophages as well as during differentiation-induced reactivation from latency an increase in the number of IE-expressing cells was readily detectable in the absence of the major ND10 proteins, no effect was observed in non-differentiated monocytes. We conclude that PML, hDaxx and Sp100 primarily act as cellular restriction factors during lytic HCMV replication and during the dynamic process of reactivation but do not serve as key determinants for the establishment of HCMV latency. PMID:26057166

Importance of latency and amplitude values of recurrent laryngeal nerve during thyroidectomy in diabetic patients.

PubMed

Ozemir, Ibrahim Ali; Ozyalvac, Ferman; Yildiz, Gorkem; Eren, Tunc; Aydin-Ozemir, Zeynep; Alimoglu, Orhan

2016-11-01

Diabetes mellitus may cause degeneration in the myelin and/or axonal structures of peripheral nerves. The aim of this study was to investigate the effects of diabetic neuropathy on intraoperative neuromonitoring findings such as latency and amplitude values of the recurrent laryngeal nerves during thyroidectomy. To our knowledge this is the first study to report comparison of the electrophysiologic features of diabetic and non-diabetic patients. One-hundred-and-eleven consecutive patients who received neuromonitoring during thyroidectomy between 2013 and 2015 were included to study. The patients were divided into two groups according to the presence of diabetes mellitus. Pre-thyroidectomy and post thyroidectomy motor response latency and amplitude values of recurrent laryngeal nerves were compared between groups. Neuromonitoring findings, demographic data and postoperative complications were evaluated. The diabetic group consisted of 29 (26.1%) patients while 82 (73.9%) patients were in non-diabetic group. The mean post-thyroidectomy amplitude values (millivolts-mV) of the recurrent laryngeal nerve were significantly lower in diabetic group (0.51 ± 0.26 mV vs. 0,70 ± 0,46 mV, p < 0.05), whereas the latency values were significantly higher (2.50 ± 0.86 ms vs. 1.85 ± 0.59 ms, p < 0.01) compared to non-diabetic group. Additionally, post-thyroidectomy latency values were significantly increased compared to the pre-thyroidectomy latency values (2.50 ± 0.86 ms vs. 2.02 ± 0.43 ms) in diabetic group patients (p < 0.05). Although postoperative complication rates were higher in diabetic group (10.3% vs. 5.9%), there were no statistical significance differences. Prolonged latency and decreased amplitude values in recurrent laryngeal nerves of diabetic patients show that diabetic neuropathy of the recurrent laryngeal nerves develop similarly to the peripheral nerves. Increased post-thyroidectomy latency values reveal that the recurrent laryngeal

Optimization on fixed low latency implementation of the GBT core in FPGA

NASA Astrophysics Data System (ADS)

Chen, K.; Chen, H.; Wu, W.; Xu, H.; Yao, L.

2017-07-01

In the upgrade of ATLAS experiment [1], the front-end electronics components are subjected to a large radiation background. Meanwhile high speed optical links are required for the data transmission between the on-detector and off-detector electronics. The GBT architecture and the Versatile Link (VL) project are designed by CERN to support the 4.8 Gbps line rate bidirectional high-speed data transmission which is called GBT link [2]. In the ATLAS upgrade, besides the link with on-detector, the GBT link is also used between different off-detector systems. The GBTX ASIC is designed for the on-detector front-end, correspondingly for the off-detector electronics, the GBT architecture is implemented in Field Programmable Gate Arrays (FPGA). CERN launches the GBT-FPGA project to provide examples in different types of FPGA [3]. In the ATLAS upgrade framework, the Front-End LInk eXchange (FELIX) system [4, 5] is used to interface the front-end electronics of several ATLAS subsystems. The GBT link is used between them, to transfer the detector data and the timing, trigger, control and monitoring information. The trigger signal distributed in the down-link from FELIX to the front-end requires a fixed and low latency. In this paper, several optimizations on the GBT-FPGA IP core are introduced, to achieve a lower fixed latency. For FELIX, a common firmware will be used to interface different front-ends with support of both GBT modes: the forward error correction mode and the wide mode. The modified GBT-FPGA core has the ability to switch between the GBT modes without FPGA reprogramming. The system clock distribution of the multi-channel FELIX firmware is also discussed in this paper.

Multiple sleep latency test in narcolepsy type 1 and narcolepsy type 2: A 5-year follow-up study.

PubMed

Huang, Yu-Shu; Guilleminault, Christian; Lin, Cheng-Hui; Chen, Chia-Hsiang; Chin, Wei-Chih; Chen, Tzu-Shuang

2018-05-29

Excessively sleepy teenagers and young adults without sleep-disordered breathing are diagnosed with either narcolepsy type 1 or narcolepsy type 2, or hypersomnia, based on the presence/absence of cataplexy and the results of a multiple sleep latency test. However, there is controversy surrounding this nomenclature. We will try to find the differences between different diagnoses of hypersomnia from the results of the long-term follow-up evaluation of a sleep study. We diagnosed teenagers who had developed excessive daytime sleepiness based on the criteria of the International Classification of Sleep Disorders, 3rd edition. Each individual received the same clinical neurophysiologic testing every year for 5 years after the initial diagnosis of narcolepsy type 1 (n = 111) or type 2 (n = 46). The follow-up evaluation demonstrated that narcolepsy type 1 (narcolepsy-cataplexy) is a well-defined clinical entity, with very reproducible clinical neurophysiologic findings over time, whereas patients with narcolepsy type 2 presented clear clinical and test variability. By the fifth year of the follow-up evaluation, 17.6% of subjects did not meet the diagnostic criteria of narcolepsy type 2, and 23.9% didn't show any two sleep-onset rapid eye movement periods in multiple sleep latency during the 5-year follow-up. Therefore narcolepsy type 1 (narcolepsy-cataplexy) is a well-defined syndrome, with the presentation clearly related to the known consequences of destruction of hypocretin/orexin neurons. Narcolepsy type 2 covers patients with clinical and test variability over time, thus bringing into question the usage of the term "narcolepsy" to label these patients. © 2018 European Sleep Research Society.

Region of Herpes Simplex Virus Type 1 Latency-Associated Transcript Sufficient for Wild-Type Spontaneous Reactivation Promotes Cell Survival in Tissue Culture

PubMed Central

Inman, Melissa; Perng, Guey-Chuen; Henderson, Gail; Ghiasi, Homayon; Nesburn, Anthony B.; Wechsler, Steven L.; Jones, Clinton

2001-01-01

The latency-associated transcript (LAT) is the only abundant herpes simplex virus type 1 (HSV-1) transcript expressed during latency. In the rabbit eye model, LAT null mutants do not reactivate efficiently from latency. We recently demonstrated that the LAT null mutant dLAT2903 induces increased levels of apoptosis in trigeminal ganglia of infected rabbits compared to LAT+ strains (G.-C. Perng, C. Jones, J. Ciacci-Zarella, M. Stone, G. Henderson, A. Yokht, S. M. Slanina, F. M. Hoffman, H. Ghiasi, A. B. Nesburn, and C. S. Wechsler, Science 287:1500–1503, 2000).The same study also demonstrated that a plasmid expressing LAT nucleotides 301 to 2659 enhanced cell survival of transfected cells after induction of apoptosis. Consequently, we hypothesized that LAT enhances spontaneous reactivation in part, because it promotes survival of infected neurons. Here we report on the ability of plasmids expressing different portions of the 5′ end of LAT to promote cell survival after induction of apoptosis. A plasmid expressing the first 1.5 kb of LAT (LAT nucleotides 1 to 1499) promoted cell survival in neuro-2A (mouse neuronal) and CV-1 (monkey fibroblast) cells. A plasmid expressing just the first 811 nucleotides of LAT promoted cell survival less efficiently. Plasmids expressing the first 661 nucleotides or less of LAT did not promote cell survival. We previously showed that a mutant expressing just the first 1.5 kb of LAT has wild-type spontaneous reactivation in rabbits, and a mutant expressing just the first 811 nucleotides of LAT has a reactivation frequency higher than that of dLAT2903 but lower than that of wild-type virus. In addition, mutants reported here for the first time, expressing just the first 661 or 76 nucleotides of LAT, had spontaneous reactivation indistinguishable from that of the LAT null mutant dLAT2903. In summary, these studies provide evidence that there is a functional relationship between the ability of LAT to promote cell survival and its

Thermal Shock and Oxidation Behavior of HiPIMS TiAlN Coatings Grown on Ti-48Al-2Cr-2Nb Intermetallic Alloy

PubMed Central

Badini, Claudio; Deambrosis, Silvia M.; Padovano, Elisa; Fabrizio, Monica; Ostrovskaya, Oxana; Miorin, Enrico; D’Amico, Giuseppe C.; Montagner, Francesco; Biamino, Sara; Zin, Valentina

2016-01-01

A High Power Impulse Magnetron Sputtering (HiPIMS) method for depositing TiAlN environmental barrier coatings on the surface of Ti-48Al-2Cr-2Nb alloy was developed in view of their exploitation in turbine engines. Three differently engineered TiAlN films were processed and their performance compared. Bare intermetallic alloy coupons and coated specimens were submitted to thermal cycling under oxidizing atmosphere up to 850 °C or 950 °C, at high heating and cooling rates. For this purpose, a burner rig able to simulate the operating conditions of the different stages of turbine engines was used. Microstructures of the samples were compared before and after each test using several techniques (microscopy, XRD, and XPS). Coating-intermetallic substrate adhesion and tribological properties were investigated too. All the TiAlN films provided a remarkable increase in oxidation resistance. Good adhesion properties were observed even after repeated thermal shocks. HiPIMS pretreatments of the substrate surfaces performed before the coating deposition significantly affected the oxidation rate, the oxide layer composition and the coating/substrate adhesion. PMID:28774082

Low-Latency Teleoperations for Human Exploration and Evolvable Mars Campaign

NASA Technical Reports Server (NTRS)

Lupisella, Mark; Wright, Michael; Arney, Dale; Gershman, Bob; Stillwagen, Fred; Bobskill, Marianne; Johnson, James; Shyface, Hilary; Larman, Kevin; Lewis, Ruthan;