Functional Knowledge of Pre-Exposure Prophylaxis for HIV Prevention Among Participants in a Web-Based Survey of Sexually Active Gay, Bisexual, and Other Men Who Have Sex With Men: Cross-Sectional Study

PubMed Central

2018-01-01

Background Awareness of pre-exposure prophylaxis (PrEP) for HIV prevention is increasing, but little is known about the functional knowledge of PrEP and its impact on willingness to use PrEP. Objective The objective of this study was to assess the functional knowledge of PrEP among a sample of gay, bisexual, and other men who have sex with men (MSM) participating in a Web-based survey of sexually active MSM. Methods Men at least 18 years old, residing in the United States, and reporting sex with a man in the previous 6 months were recruited through social networking websites. PrEP functional knowledge included the following 4 questions (1) efficacy of consistent PrEP use, (2) inconsistent PrEP use and effectiveness, (3) PrEP and condom use, and (4) effectiveness at reducing sexually transmitted infections (STIs). Ordinal logistic regression was used to identify respondent characteristics associated with PrEP functional knowledge. In a subsample of participants responding to HIV prevention questions, we compared willingness to use PrEP by response to PrEP functional knowledge using logistic regression analysis adjusted for age, race and ethnicity, and education level. Results Among 573 respondents, PrEP knowledge was high regarding adherence (488/573, 85.2%), condom use (532/573, 92.8%), and STIs (480/573, 83.8%), but only 252/573 (44.0%) identified the correct efficacy. Lower functional PrEP knowledge was associated with minority race/ethnicity (P=.005), lower education (P=.01), and not having an HIV test in the past year (P=.02). Higher PrEP knowledge was associated with willingness to use PrEP (P=.009). Younger age was not associated with higher PrEP functional knowledge or willingness to use PrEP. Conclusions PrEP knowledge was generally high in our study, including condom use and consistent use but may be lacking in higher risk MSM. The majority of respondents did not correctly identify PrEP efficacy with consistent use, which could impact motivation to seek out PrEP for HIV prevention. Targeted messaging to increase PrEP knowledge may increase PrEP use. PMID:29362213

Application of SR Methods for the Study of Nanocomposite Materials for Hydrogen Energy

NASA Astrophysics Data System (ADS)

Sadykov, V. A.; Pavlova, S. N.; Vinokurov, Z. S.; Shmakov, A. N.; Eremeev, N. F.; Fedorova, Yu. E.; Yakimchuk, E. P.; Kriventsov, V. V.; Bolotov, V. A.; Tanashev, Yu. Yu.; Sadovskaya, E. M.; Cherepanova, S. V.; Zolotarev, K. V.

This work summarizes results of synchrotron radiation (SR) studies of the real/defect structure of nanocrystalline/nanocomposite oxide materials, which determines their functional properties in hydrogen energy field as catalysts and mixed ionic electronic conductors (cathodes and anodes of solid oxide fuel cells, oxygen separation membranes). For nanocrystalline ceria-zirconia mixed oxide prepared via modified Pechini route using ethanol solution of reagents, a high spatial uniformity of cations distribution between domains along with the oxygen sublattice deficiency revealed by full-profile Rietveld refinement of SR diffraction data provide structure disordering enhancing oxygen mobility. For PrNi0.5Co0.5O3-δ - Ce0.9Y0.1O2-δ nanocomposite extensive transfer of Pr cations into fluorite domains generates a new path of fast oxygen diffusion along chains of Pr3+ - Pr4+ cations as directly proved by analysis of the unit cell relaxation after changing pO2 in perfect agreement with data obtained by oxygen isotope heteroexchange.

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Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2.

PubMed

Liu, Xiaoni; Kerov, Vasily; Haeseleer, Françoise; Majumder, Anurima; Artemyev, Nikolai; Baker, Sheila A; Lee, Amy

2013-01-01

Mutations in the gene encoding Cav 1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Cav 1.4 channels, there are defects in the development of "ribbon" synapses formed between photoreceptors (PRs) and second-order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Cav 1.4 channels. Whether defects in PR synapse development due to altered Cav 1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Cav 1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Cav 1.4 activation is either enhanced (Cav 1.4I756T) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Cav 1.4I756T and CaBP4 KO mice. Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences.

Signaling induced by hop/STI-1 depends on endocytosis

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

Americo, Tatiana A.; Chiarini, Luciana B.; Linden, Rafael

The co-chaperone hop/STI-1 is a ligand of the cell surface prion protein (PrP{sup C}), and their interaction leads to signaling and biological effects. Among these, hop/STI-1 induces proliferation of A172 glioblastoma cells, dependent on both PrP{sup C} and activation of the Erk pathway. We tested whether clathrin-mediated endocytosis affects signaling induced by hop/STI-1. Both hyperosmolarity induced by sucrose and monodansyl-cadaverine blocked Erk activity induced by hop/STI-1, without affecting the high basal Akt activity typical of A172. The endocytosis inhibitors also affected the sub-cellular distribution of phosphorylated Erk, consistent with blockade of the latter's activity. The data indicate that signaling inducedmore » by hop/STI-1 depends on endocytosis. These findings are consistent with a role of sub-cellular trafficking in signal transduction following engagement by PrP{sup C} by ligands such as hop/STI-1, and may help help unravel both the functions of the prion protein, as well as possible loss-of-function components of prion diseases.« less

Role of nuclear progesterone receptor isoforms in uterine pathophysiology

PubMed Central

Patel, Bansari; Elguero, Sonia; Thakore, Suruchi; Dahoud, Wissam; Bedaiwy, Mohamed; Mesiano, Sam

2015-01-01

BACKGROUND Progesterone is a key hormonal regulator of the female reproductive system. It plays a major role to prepare the uterus for implantation and in the establishment and maintenance of pregnancy. Actions of progesterone on the uterine tissues (endometrium, myometrium and cervix) are mediated by the combined effects of two progesterone receptor (PR) isoforms, designated PR-A and PR-B. Both receptors function primarily as ligand-activated transcription factors. Progesterone action on the uterine tissues is qualitatively and quantitatively determined by the relative levels and transcriptional activities of PR-A and PR-B. The transcriptional activity of the PR isoforms is affected by specific transcriptional coregulators and by PR post-translational modifications that affect gene promoter targeting. In this context, appropriate temporal and cell-specific expression and function of PR-A and PR-B are critical for normal uterine function. METHODS Relevant studies describing the role of PRs in uterine physiology and pathology (endometriosis, uterine leiomyoma, endometrial cancer, cervical cancer and recurrent pregnancy loss) were comprehensively searched using PubMed, Cochrane Library, Web of Science, and Google Scholar and critically reviewed. RESULTS Progesterone, acting through PR-A and PR-B, regulates the development and function of the endometrium and induces changes in cells essential for implantation and the establishment and maintenance of pregnancy. During pregnancy, progesterone via the PRs promotes myometrial relaxation and cervical closure. Withdrawal of PR-mediated progesterone signaling triggers menstruation and parturition. PR-mediated progesterone signaling is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen on eutopic normal endometrium, and on ectopic implants in endometriosis. Similarly, ligand-activated PRs function as tumor suppressors in endometrial cancer cells through inhibition of key cellular signaling pathways required for growth. In contrast, progesterone via PR activation appears to increase leiomyoma growth. The exact role of PRs in cervical cancer is unclear. PRs regulate implantation and therefore aberrant PR function may be implicated in recurrent pregnancy loss (RPL). PRs likely regulate key immunogenic factors involved in RPL. However, the exact role of PRs in the pathophysiology of RPL and the use of progesterone for therapeutic benefit remains uncertain. CONCLUSIONS PRs are key mediators of progesterone action in uterine tissues and are essential for normal uterine function. Aberrant PR function (due to abnormal expression and/or function) is a major cause of uterine pathophysiology. Further investigation of the underlying mechanisms of PR isoform action in the uterus is required, as this knowledge will afford the opportunity to create progestin/PR-based therapeutics to treat various uterine pathologies. PMID:25406186

Flap Conformations in HIV-1 Protease are Altered by Mutations

NASA Astrophysics Data System (ADS)

Fanucci, Gail; Blackburn, Mandy; Veloro, Angelo; Galiano, Luis; Fangu, Ding; Simmerling, Carlos

2009-03-01

HIV-1 protease (PR) is an enzyme that is a major drug target in the treatment of AIDS. Although the structure and function of HIV-1 PR have been studied for over 20 years, questions remain regarding the conformations and dynamics of the β-hairpin turns (flaps) that cover the active site cavity. Distance measurements with pulsed EPR spectroscopy of spin labeled constructs of HIV-1 PR have been used to characterize the flap conformations in the apo and inhibitor bound states. From the most probably distances and the breadth of the distance distribution profiles from analysis of the EPR data, insights regarding the flap conformations and flexibility are gained. The EPR results clearly show how drug pressure selected mutations alter the average conformation of the flaps and the degree of opening of the flaps. Molecular dynamics simulations successfully regenerate the experimentally determined distance distribution profiles, and more importantly, provide structural models for full interpretation of the EPR results. By combining experiment and theory to understand the role that altered flap flexibility/conformations play in the mechanism of drug resistance, key insights are gained toward the rational development of new inhibitors of this important enzyme.

Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes

PubMed Central

Lee, Yun; Sooranna, Suren R; Terzidou, Vasso; Christian, Mark; Brosens, Jan; Huhtinen, Kaisa; Poutanen, Matti; Barton, Geraint; Johnson, Mark R; Bennett, Phillip R

2012-01-01

The absence of a fall in circulating progesterone levels has led to the concept that human labour is associated with ‘functional progesterone withdrawal’ caused through changes in the expression or function of progesterone receptor (PR). At the time of labour, the human uterus is heavily infiltrated with inflammatory cells, which release cytokines to create a ‘myometrial inflammation’ via NF-κB activation. The negative interaction between NF-κB and PR, may represent a mechanism to account for ‘functional progesterone withdrawal’ at term. Conversely, PR may act to inhibit NF-κB function and so play a role in inhibition of myometrial inflammation during pregnancy. To model this inter-relationship, we have used small interfering (si) RNA-mediated knock-down of PR in human pregnant myocytes and whole genome microarray analysis to identify genes regulated through PR. We then activated myometrial inflammation using IL-1β stimulation to determine the role of PR in myometrial inflammation regulation. Through PR-knock-down, we found that PR regulates gene networks involved in myometrial quiescence and extracellular matrix integrity. Activation of myometrial inflammation was found to antagonize PR-induced gene expression, of genes normally upregulated via PR. We found that PR does not play a role in repression of pro-inflammatory gene networks induced by IL-1β and that only MMP10 was significantly regulated in opposite directions by IL-1β and PR. We conclude that progesterone acting through PR does not generally inhibit myometrial inflammation. Activation of myometrial inflammation does cause ‘functional progesterone withdrawal’ but only in the context of genes normally upregulated via PR. PMID:22435466

Dynamics of Preferential Substrate Recognition in HIV-1 Protease: Redefining the Substrate Envelope

PubMed Central

Özen, Ayşegül; Haliloğlu, Türkan; Schiffer, Celia A.

2011-01-01

HIV-1 protease (PR) permits viral maturation by processing the Gag and Gag-Pro-Pol polyproteins. Though HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy, the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates the consideration of drug resistance in novel drug-design strategies. Drug-resistant HIV-1 PR variants, while no longer efficiently inhibited, continue to efficiently hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we defined as the “substrate envelope”. We previously showed that resistance mutations arise where PIs protrude beyond the substrate envelope, as these regions are crucial for drug binding but not for substrate recognition. Here, we extend this model by considering the role of protein dynamics in the interaction of HIV-1 PR with its substrates. Seven molecular dynamics simulations of PR-substrate complexes were performed to estimate the conformational flexibility of substrates in their complexes. Interdependency of the substrate-protease interactions may compensate for the variations in cleavage-site sequences, and explain how a diverse set of sequences can be recognized as substrates by the same enzyme. This diversity may be essential for regulating sequential processing of substrates. We also define a dynamic substrate envelope as a more accurate representation of PR-substrate interactions. This dynamic substrate envelope, described by a probability distribution function, is a powerful tool for drug design efforts targeting ensembles of resistant HIV-1 PR variants with the aim of developing drugs that are less susceptible to resistance. PMID:21762811

Executive Function Variation in Children with Conduct Problems: Influences of Coexisting Reading Difficulties

ERIC Educational Resources Information Center

Kallitsoglou, Angeliki

2018-01-01

It is unknown whether children with conduct problems (CP) and poor reading (PR) skills exhibit more profound executive function impairments than children with CP only and whether such impairments are explained by coexisting PR. Executive functions were compared in four groups of 7- to 8-year-old children: 26 CP only, 35 PR only, 27 CP-PR, and 31…

Density functional theory calculations for the band gap and formation energy of Pr4-xCaxSi12O3+xN18-x; a highly disordered compound with low symmetry and a large cell size.

PubMed

Hong, Sung Un; Singh, Satendra Pal; Pyo, Myoungho; Park, Woon Bae; Sohn, Kee-Sun

2017-06-28

A novel oxynitride compound, Pr 4-x Ca x Si 12 O 3+x N 18-x , synthesized using a solid-state route has been characterized as a monoclinic structure in the C2 space group using Rietveld refinement on synchrotron powder X-ray diffraction data. The crystal structure of this compound was disordered due to the random distribution of Ca/Pr and N/O ions at various Wyckoff sites. A pragmatic approach for an ab initio calculation based on density function theory (DFT) for this disordered compound has been implemented to calculate an acceptable value of the band gap and formation energy. In general, for the DFT calculation of a disordered compound, a sufficiently large super cell and infinite variety of ensemble configurations is adopted to simulate the random distribution of ions; however, such an approach is time consuming and cost ineffective. Even a single unit cell model gave rise to 43 008 independent configurations as an input model for the DFT calculations. Since it was nearly impossible to calculate the formation energy and the band gap energy for all 43 008 configurations, an elitist non-dominated sorting genetic algorithm (NSGA-II) was employed to find the plausible configurations. In the NSGA-II, all 43 008 configurations were mathematically treated as genomes and the calculated band gap and the formation energy as the objective (fitness) function. Generalized gradient approximation (GGA) was first employed in the preliminary screening using NSGA-II, and thereafter a hybrid functional calculation (HSE06) was executed only for the most plausible GGA-relaxed configurations with lower formation and higher band gap energies. The final band gap energy (3.62 eV) obtained after averaging over the selected configurations, resembles closely the experimental band gap value (4.11 eV).

Impact of pulmonary rehabilitation on postoperative complications in patients with lung cancer and chronic obstructive pulmonary disease.

PubMed

Saito, Hajime; Hatakeyama, Kazutoshi; Konno, Hayato; Matsunaga, Toshiki; Shimada, Yoichi; Minamiya, Yoshihiro

2017-09-01

Given the extent of the surgical indications for pulmonary lobectomy in breathless patients, preoperative care and evaluation of pulmonary function are increasingly necessary. The aim of this study was to assess the contribution of preoperative pulmonary rehabilitation (PR) for reducing the incidence of postoperative pulmonary complications in non-small cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD). The records of 116 patients with COPD, including 51 patients who received PR, were retrospectively analyzed. Pulmonary function testing, including slow vital capacity (VC) and forced expiratory volume in one second (FEV 1 ), was obtained preoperatively, after PR, and at one and six months postoperatively. The recovery rate of postoperative pulmonary function was standardized for functional loss associated with the different resected lung volumes. Propensity score analysis generated matched pairs of 31 patients divided into PR and non-PR groups. The PR period was 18.7 ± 12.7 days in COPD patients. Preoperative pulmonary function was significantly improved after PR (VC 5.3%, FEV 1 5.5%; P < 0.05). The FEV 1 recovery rate one month after surgery was significantly better in the PR (101.6%; P < 0.001) than in the non-PR group (93.9%). In logistic regression analysis, predicted postoperative FEV 1 , predicted postoperative %FEV 1 , and PR were independent factors related to postoperative pulmonary complications after pulmonary lobectomy (odds ratio 18.9, 16.1, and 13.9, respectively; P < 0.05). PR improved the recovery rate of pulmonary function after lobectomy in the early period, and may decrease postoperative pulmonary complications. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Spectral Characterization of the Wave Energy Resource for Puerto Rico (PR) and the United States Virgin Islands (USVI)

NASA Astrophysics Data System (ADS)

Garcia, C. G.; Canals, M.; Irizarry, A. A.

2016-02-01

Nowadays a significant amount of wave energy assessments have taken place due to the development of the ocean energy markets worldwide. Energy contained in surface gravity waves is scattered along frequency components that can be described using wave spectra. Correspondingly, characterization and quantification of harvestable wave energy is inherently dictated by the nature of the two-dimensional wave spectrum. The present study uses spectral wave data from the operational SWAN-based CariCOOS Nearshore Wave Model to evaluate the capture efficiency of multiple wave energy converters (WEC). This study revolves around accurately estimating available wave energy as a function of varying spectral distributions, effectively providing a detailed insight concerning local wave conditions for PR and USVI and the resulting available-energy to generated-power ratio. Results in particular, provide a comprehensive characterization of three years' worth of SWAN-based datasets by outlining where higher concentrations of wave energy are localized in the spectrum. Subsequently, the aforementioned datasets were processed to quantify the amount of energy incident on two proposed sites located in PR and USVI. Results were largely influenced by local trade wind activity, which drive predominant sea states, and the amount of North-Atlantic swells that propagate towards the region. Each wave event was numerically analyzed in the frequency domain to evaluate the capacity of a WEC to perform under different spectral distribution scenarios, allowing for a correlation between electrical power output and spectral energy distribution to be established.

Dimerization and protease resistance: new insight into the function of PR-1

USDA-ARS?s Scientific Manuscript database

The group 1 pathogenesis-related (PR-1) proteins have long been considered hallmarks of hypersensitive response/defense pathways in plants, but their biochemical functions are still obscure despite resolution of the NMR/X-ray structures of several PR-1-like proteins, including P14a (the prototype PR...

PrPC has nucleic acid chaperoning properties similar to the nucleocapsid protein of HIV-1.

PubMed

Derrington, Edmund; Gabus, Caroline; Leblanc, Pascal; Chnaidermann, Jonas; Grave, Linda; Dormont, Dominique; Swietnicki, Wieslaw; Morillas, Manuel; Marck, Daniel; Nandi, Pradip; Darlix, Jean-Luc

2002-01-01

The function of the cellular prion protein (PrPC) remains obscure. Studies suggest that PrPC functions in several processes including signal transduction and Cu2+ metabolism. PrPC has also been established to bind nucleic acids. Therefore we investigated the properties of PrPC as a putative nucleic acid chaperone. Surprisingly, PrPC possesses all the nucleic acid chaperoning properties previously specific to retroviral nucleocapsid proteins. PrPC appears to be a molecular mimic of NCP7, the nucleocapsid protein of HIV-1. Thus PrPC, like NCP7, chaperones the annealing of tRNA(Lys) to the HIV-1 primer binding site, the initial step of retrovirus replication. PrPC also chaperones the two DNA strand transfers required for production of a complete proviral DNA with LTRs. Concerning the functions of NCP7 during budding, PrPC also mimices NCP7 by dimerizing the HIV-1 genomic RNA. These data are unprecedented because, although many cellular proteins have been identified as nucleic acid chaperones, none have the properties of retroviral nucleocapsid proteins.

PRN 93-11: Supplemental Guidance for PR Notice 93-7 - Labeling Revisions Required by the WPS

EPA Pesticide Factsheets

This pesticide registration notice augments the guidance provided by PR notice 97-3 to provide options that you may choose to allow efficient production and distribution of products that comply with PR Notice 93-7.

Inflammatory Stimuli Increase Progesterone Receptor-A Stability and Transrepressive Activity in Myometrial Cells

PubMed Central

Peters, Gregory A.; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Patel, Bansari; Amini, Peyvand; Tan, Huiqing

2017-01-01

The steroid hormone progesterone acting via the nuclear progesterone receptor (PR) isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), is essential for the maintenance of uterine quiescence during pregnancy. Inhibition of PR signaling augments uterine contractility and induces labor. Human parturition is thought to be triggered by modulation of PR signaling in myometrial cells to induce a functional progesterone withdrawal. One mechanism for functional progesterone withdrawal is increased abundance of PR-A, which decreases progesterone responsiveness by inhibiting the transcriptional activity of PR-B. Human parturition also involves tissue-level inflammation within the myometrium. This study examined the control of PR-A abundance and transrepressive activity in myometrial cells and the role of the inflammatory stimuli in the form of interleukin-1β (IL-1β) and lipopolysaccharide (LPS) in these processes. We found that abundance of PR-A was markedly increased by progesterone and by exposure to IL-1β and LPS via posttranslational mechanisms involving increased PR-A protein stability. In contrast, progesterone decreased abundance of PR-B by increasing its rate of degradation. Together, progesterone and proinflammatory stimuli induced a PR-A–dominant state in myometrial cells similar to that observed in term laboring myometrium. IL-1β and LPS also increased the capacity for PR-A to inhibit the transcriptional activity of PR-B. Taken together, our data suggest that proinflammatory stimuli increase the steady-state levels of PR-A and its transrepressive activity in myometrial cells and support the hypothesis that tissue-level inflammation triggers parturition by inducing PR-A–mediated functional progesterone withdrawal. PMID:27886516

Structure factor and radial distribution function of some liquid lanthanides using charged hard sphere

NASA Astrophysics Data System (ADS)

Patel, H. P.; Sonvane, Y. A.; Thakor, P. B.

2017-05-01

The structure factor S(q) and radial distribution function g(r) play vital role to study the various structural properties like electronic, dynamic, magnetic etc. The present paper deals with the structural studies of foresaid properties using our newly constructed parameter free model potential with the Charged Hard Sphere (CHS) approximation. The local field correction due to Sarkar et al. is used to incorporate exchange and correlation among the conduction electrons in dielectric screening. Here we report the S(q) and g(r) for some liquid lanthanides viz: La, Ce, Pr, Nd and Eu. Present computed results are compared with the available experimental data. Lastly we found that our parameter free model potential successfully explains the structural propertiesof4fliquidlanthanides.

Stochastic Modeling Approach to the Incubation Time of Prionic Diseases

NASA Astrophysics Data System (ADS)

Ferreira, A. S.; da Silva, M. A.; Cressoni, J. C.

2003-05-01

Transmissible spongiform encephalopathies are neurodegenerative diseases for which prions are the attributed pathogenic agents. A widely accepted theory assumes that prion replication is due to a direct interaction between the pathologic (PrPSc) form and the host-encoded (PrPC) conformation, in a kind of autocatalytic process. Here we show that the overall features of the incubation time of prion diseases are readily obtained if the prion reaction is described by a simple mean-field model. An analytical expression for the incubation time distribution then follows by associating the rate constant to a stochastic variable log normally distributed. The incubation time distribution is then also shown to be log normal and fits the observed BSE (bovine spongiform encephalopathy) data very well. Computer simulation results also yield the correct BSE incubation time distribution at low PrPC densities.

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

Riss P. J.; Fowler J.; Riss, P.J.

N-(4-fluorobut-2-yn-1-yl)-2{beta}-carbomethoxy-3{beta}-(4{prime}-tolyl)nortropane (PR04.MZ, 1) is a PET radioligand for the non-invasive exploration of the function of the cerebral dopamine transporter (DAT). A reliable automated process for routine production of the carbon-11 labelled analogue [{sup 11}C]PR04.MZ ([{sup 11}C]-1) has been developed using GMP compliant equipment. An adult female Papioanubis baboon was studied using a test-retest protocol with [{sup 11}C]-1 in order to assess test-retest reliability, metabolism and CNS distribution profile of the tracer in non-human primates. Blood sampling was performed throughout the studies for determination of the free fraction in plasma (fP), plasma input functions and metabolic degradation of the radiotracer [{supmore » 11}C]-1. Time-activity curves were derived for the putamen, the caudate nucleus, the ventral striatum, the midbrain and the cerebellum. Distribution volumes (VT) and non-displaceable binding potentials (BPND) for various brain regions and the blood were obtained from kinetic modelling. [{sup 11}C]-1 shows promising results as aselective marker of the presynaptic dopamine transporter. With the reliable visualisation of the extra-striatal dopaminergic neurons and no indication on labelled metabolites, the tracer provides excellent potential for translation into man.« less

Domain-Specific Activation of Death-Associated Intracellular Signalling Cascades by the Cellular Prion Protein in Neuroblastoma Cells.

PubMed

Vilches, Silvia; Vergara, Cristina; Nicolás, Oriol; Mata, Ágata; Del Río, José A; Gavín, Rosalina

2016-09-01

The biological functions of the cellular prion protein remain poorly understood. In fact, numerous studies have aimed to determine specific functions for the different protein domains. Studies of cellular prion protein (PrP(C)) domains through in vivo expression of molecules carrying internal deletions in a mouse Prnp null background have provided helpful data on the implication of the protein in signalling cascades in affected neurons. Nevertheless, understanding of the mechanisms underlying the neurotoxicity induced by these PrP(C) deleted forms is far from complete. To better define the neurotoxic or neuroprotective potential of PrP(C) N-terminal domains, and to overcome the heterogeneity of results due to the lack of a standardized model, we used neuroblastoma cells to analyse the effects of overexpressing PrP(C) deleted forms. Results indicate that PrP(C) N-terminal deleted forms were properly processed through the secretory pathway. However, PrPΔF35 and PrPΔCD mutants led to death by different mechanisms sharing loss of alpha-cleavage and activation of caspase-3. Our data suggest that both gain-of-function and loss-of-function pathogenic mechanisms may be associated with N-terminal domains and may therefore contribute to neurotoxicity in prion disease. Dissecting the molecular response induced by PrPΔF35 may be the key to unravelling the physiological and pathological functions of the prion protein.

PrP(C) signalling in neurons: from basics to clinical challenges.

PubMed

Hirsch, Théo Z; Hernandez-Rapp, Julia; Martin-Lannerée, Séverine; Launay, Jean-Marie; Mouillet-Richard, Sophie

2014-09-01

The cellular prion protein PrP(C) was identified over twenty-five years ago as the normal counterpart of the scrapie prion protein PrP(Sc), itself the main if not the sole component of the infectious agent at the root of Transmissible Spongiform Encephalopathies (TSEs). PrP(C) is a ubiquitous cell surface protein, abundantly expressed in neurons, which constitute the targets of PrP(Sc)-mediated toxicity. Converging evidence have highlighted that neuronal, GPI-anchored PrP(C) is absolutely required for prion-induced neuropathogenesis, which warrants investigating into the normal function exerted by PrP(C) in a neuronal context. It is now well-established that PrP(C) can serve as a cell signalling molecule, able to mobilize transduction cascades in response to interactions with partners. This function endows PrP(C) with the capacity to participate in multiple neuronal processes, ranging from survival to synaptic plasticity. A diverse array of data have allowed to shed light on how this function is corrupted by PrP(Sc). Recently, amyloid Aβ oligomers, whose accumulation is associated with Alzheimer's disease (AD), were shown to similarly instigate toxic events by deviating PrP(C)-mediated signalling. Here, we provide an overview of the various signal transduction cascades ascribed to PrP(C) in neurons, summarize how their subversion by PrP(Sc) or Aβ oligomers contributes to TSE or AD neuropathogenesis and discuss the ensuing clinical implications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Application of Financial Risk-reward Theory to Link and Network Optimization

DTIC Science & Technology

2011-10-01

OFDM systems the matrices V k and U k are Fourier matrices which diagonalize a circulant or block-circulant matrix Hk [18]. In multi-antenna systems...probability α=Pr(η r <=t) Figure 13: Mean link spectral efficiency as a function of target link spectral efficiency ηt and outage probability ζ in a MIMO ...in a MIMO channel. Distribution A: Approved for public release; distribution is unlimited. 41 (75) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 2 4 6 8

Effects of naloxone distribution alone or in combination with addiction treatment with or without pre-exposure prophylaxis for HIV prevention in people who inject drugs: a cost-effectiveness modelling study.

PubMed

Uyei, Jennifer; Fiellin, David A; Buchelli, Marianne; Rodriguez-Santana, Ramon; Braithwaite, R Scott

2017-03-01

In the USA, an epidemic of opioid overdose deaths is occurring, many of which are from heroin. Combining naloxone distribution with linkage to addiction treatment or pre-exposure prophylaxis (PrEP) for HIV prevention through syringe service programmes has the potential to save lives and be cost-effective. We estimated the outcomes and cost-effectiveness of five alternative strategies: no additional intervention, naloxone distribution, naloxone distribution plus linkage to addiction treatment, naloxone distribution plus PrEP, and naloxone distribution plus linkage to addiction treatment and PrEP. We developed a decision analytical Markov model to simulate opioid overdose, HIV incidence, overdose-related deaths, and HIV-related deaths in people who inject drugs in Connecticut, USA. Model input parameters were derived from published sources. We compared each strategy with no intervention, as well as simultaneously considering all strategies. Sensitivity analysis was done for all variables. Linkage to addiction treatment was referral to an opioid treatment programme for methadone. Endpoints were survival, life expectancy, quality-adjusted life-years (QALYs), number and percentage of overdose deaths averted, number of HIV-related deaths averted, total costs (in 2015 US$) associated with each strategy, and incremental cost per QALY gained. In the base-case analysis, compared with no additional intervention, the naloxone distribution strategy yielded an incremental cost-effectiveness ratio (ICER) of $323 per QALY, and naloxone distribution plus linkage to addiction treatment was cost saving compared with no additional intervention (greater effectiveness and less expensive). The most efficient strategies (ie, those conferring the greatest health benefit for a particular budget) were naloxone distribution combined with linkage to addiction treatment (cost saving), and naloxone distribution combined with PrEP and linkage to addiction treatment (ICER $95 337 per QALY) at a willingness-to-pay threshold of $100 000. In probabilistic sensitivity analysis, the combination of naloxone distribution, PrEP, and linkage to addiction treatment was the optimal strategy in 37% of iterations and the combination of naloxone distribution and linkage to addiction treatment was the optimal strategy in 34% of iterations. Naloxone distribution through syringe service programmes is cost-effective compared with syringe distribution alone, but when combined with linkage to addiction treatment is cost saving compared with no additional services. A strategy that combines naloxone distribution, PrEP, and linkage to addiction treatment results in greater health benefits in people who inject drugs and is also cost-effective. State of Connecticut Department of Public Health and the National Institute of Mental Health. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.

Responsiveness and Minimally Important Difference of the 6-Minute Stepper Test in Patients with Chronic Obstructive Pulmonary Disease.

PubMed

Pichon, Romain; Couturaud, Francis; Mialon, Philippe; Le Ber-Moy, Catherine; Péran, Loïc; Lochon, Chantal; Nowak, Emmanuel; Beaumont, Marc

2016-01-01

The validity and reproducibility of the 6-minute stepper test (6MST) have already been demonstrated in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the responsiveness of the 6MST to pulmonary rehabilitation (PR) in patients with COPD, to determine a minimal important difference (MID) for the 6MST, and to compare the 6MST and the 6-minute walk test (6MWT). Sixty-two patients with COPD were included in a prospective experimental study. Participants underwent a 3-week inpatient PR program. The primary outcome was the change in the number of steps during the 6MST measured before and after PR. The secondary outcome included the change in the 6-minute walking distance (6MWD) pulse oximetry, heart rate, dyspnea, and leg discomfort during the tests measured before and after PR. MID was determined by anchor-based and distribution approaches. After PR, we observed a significant increase in the number of steps during the 6MST (22.5 steps; 95% CI 13.8-31.3; p < 0.0001) and in the 6MWD (26.6 m; 95% CI 17.6-35.5; p < 0.0001). The 6MST and 6MWT were improved by 10.1 and 6.5%, respectively. The number of steps during the 6MST was significantly correlated with the 6MWD before (r = 0.72; p < 0.0001) and after PR (r = 0.66; p < 0.0001). MID was estimated to be around 20 steps. The 6MST appears to be as responsive as the 6MWT in assessing functional improvement during PR in patients with COPD. The 6MST is a low-cost assessment and requires limited space. © 2016 S. Karger AG, Basel.

Log-Gamma Polymer Free Energy Fluctuations via a Fredholm Determinant Identity

NASA Astrophysics Data System (ADS)

Borodin, Alexei; Corwin, Ivan; Remenik, Daniel

2013-11-01

We prove that under n 1/3 scaling, the limiting distribution as n → ∞ of the free energy of Seppäläinen’s log-Gamma discrete directed polymer is GUE Tracy-Widom. The main technical innovation we provide is a general identity between a class of n-fold contour integrals and a class of Fredholm determinants. Applying this identity to the integral formula proved in Corwin et al. (Tropical combinatorics and Whittaker functions. http://arxiv.org/abs/1110.3489v3 [math.PR], 2012) for the Laplace transform of the log-Gamma polymer partition function, we arrive at a Fredholm determinant which lends itself to asymptotic analysis (and thus yields the free energy limit theorem). The Fredholm determinant was anticipated in Borodin and Corwin (Macdonald processes. http://arxiv.org/abs/1111.4408v3 [math.PR], 2012) via the formalism of Macdonald processes yet its rigorous proof was so far lacking because of the nontriviality of certain decay estimates required by that approach.

The prion-ZIP connection: From cousins to partners in iron uptake

PubMed Central

Singh, Neena; Asthana, Abhishek; Baksi, Shounak; Desai, Vilok; Haldar, Swati; Hari, Sahi; Tripathi, Ajai K

2015-01-01

ABSTRACT Converging observations from disparate lines of inquiry are beginning to clarify the cause of brain iron dyshomeostasis in sporadic Creutzfeldt-Jakob disease (sCJD), a neurodegenerative condition associated with the conversion of prion protein (PrPC), a plasma membrane glycoprotein, from α-helical to a β-sheet rich PrP-scrapie (PrPSc) isoform. Biochemical evidence indicates that PrPC facilitates cellular iron uptake by functioning as a membrane-bound ferrireductase (FR), an activity necessary for the transport of iron across biological membranes through metal transporters. An entirely different experimental approach reveals an evolutionary link between PrPC and the Zrt, Irt-like protein (ZIP) family, a group of proteins involved in the transport of zinc, iron, and manganese across the plasma membrane. Close physical proximity of PrPC with certain members of the ZIP family on the plasma membrane and increased uptake of extracellular iron by cells that co-express PrPC and ZIP14 suggest that PrPC functions as a FR partner for certain members of this family. The connection between PrPC and ZIP proteins therefore extends beyond common ancestry to that of functional cooperation. Here, we summarize evidence supporting the facilitative role of PrPC in cellular iron uptake, and implications of this activity on iron metabolism in sCJD brains. PMID:26689487

Multiple intermediates on the energy landscape of a 15-HEAT-repeat protein

PubMed Central

Tsytlonok, Maksym; Craig, Patricio O.; Sivertsson, Elin; Serquera, David; Perrett, Sarah; Best, Robert B.; Wolynes, Peter G.; Itzhaki, Laura S.

2014-01-01

Repeat proteins are a special class of modular, non-globular proteins composed of small structural motifs arrayed to form elongated architectures and stabilised solely by short-range contacts. We find a remarkable complexity in the unfolding of the large HEAT repeat protein PR65/A. In contrast to what has been seen for small repeat proteins in which unfolding propagates from one end, the HEAT array of PR65/A ruptures at multiple distant sites, leading to intermediate states with non-contiguous folded subdomains. Kinetic analysis allows us to define a network of intermediates and to delineate the pathways that connect them. There is a dominant sequence of unfolding, reflecting a non-uniform distribution of stability across the repeat array; however the unfolding of certain intermediates is competitive, leading to parallel pathways. Theoretical models accounting for the heterogeneous contact density in the folded structure are able to rationalize the variation in stability across the array. This variation in stability also suggests how folding may direct function in a large repeat protein: The stability distribution enables certain regions to present rigid motifs for molecular recognition while affording others flexibility to broaden the search area as in a fly-casting mechanism. Thus PR65/A uses the two ends of the repeat array to bind diverse partners and thereby coordinate the dephosphorylation of many different substrates and of multiple sites within hyperphosphorylated substrates. PMID:24120762

Prion Protein Regulates Iron Transport by Functioning as a Ferrireductase

PubMed Central

Singh, Ajay; Haldar, Swati; Horback, Katharine; Tom, Cynthia; Zhou, Lan; Meyerson, Howard; Singh, Neena

2017-01-01

Prion protein (PrPC) is implicated in the pathogenesis of prion disorders, but its normal function is unclear. We demonstrate that PrPC is a ferrireductase (FR), and its absence causes systemic iron deficiency in PrP knock-out mice (PrP−/−). When exposed to non-transferrin-bound (NTB) radioactive-iron (59FeCl3) by gastric-gavage, PrP−/− mice absorb significantly more 59Fe from the intestinal lumen relative to controls, indicating appropriate systemic response to the iron deficiency. Chronic exposure to excess dietary iron corrects this deficiency, but unlike wild-type (PrP+/+) controls that remain iron over-loaded, PrP−/− mice revert back to the iron deficient phenotype after 5 months of chase on normal diet. Bone marrow (BM) preparations of PrP−/− mice on normal diet show relatively less stainable iron, and this phenotype is only partially corrected by intraperitoneal administration of excess iron-dextran. Cultured PrP−/− BM-macrophages incorporate significantly less NTB-59Fe in the absence or presence of excess extracellular iron, indicating reduced uptake and/or storage of available iron in the absence of PrPC. When expressed in neuroblastoma cells, PrPC exhibits NAD(P)H-dependent cell-surface and intracellular FR activity that requires the copper-binding octa-peptide-repeat region and linkage to the plasma membrane for optimal function. Incorporation of NTB-59Fe by neuroblastoma cells correlates with FR activity of PrPC, implicating PrPC in cellular iron uptake and metabolism. These observations explain the correlation between PrPC expression and cellular iron levels, and the cause of iron imbalance in sporadic-Creutzfeldt-Jakob-disease brains where PrPC accumulates as insoluble aggregates. PMID:23478311

Proteomic Analysis of Sauvignon Blanc Grape Skin, Pulp and Seed and Relative Quantification of Pathogenesis-Related Proteins.

PubMed

Tian, Bin; Harrison, Roland; Morton, James; Deb-Choudhury, Santanu

2015-01-01

Thaumatin-like proteins (TLPs) and chitinases are the main constituents of so-called protein hazes which can form in finished white wine and which is a great concern of winemakers. These soluble pathogenesis-related (PR) proteins are extracted from grape berries. However, their distribution in different grape tissues is not well documented. In this study, proteins were first separately extracted from the skin, pulp and seed of Sauvignon Blanc grapes, followed by trypsin digestion and analysis by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Proteins identified included 75 proteins from Sauvignon Blanc grape skin, 63 from grape pulp and 35 from grape seed, mostly functionally classified as associated with metabolism and energy. Some were present exclusively in specific grape tissues; for example, proteins involved in photosynthesis were only detected in grape skin and proteins found in alcoholic fermentation were only detected in grape pulp. Moreover, proteins identified in grape seed were less diverse than those identified in grape skin and pulp. TLPs and chitinases were identified in both Sauvignon Blanc grape skin and pulp, but not in the seed. To relatively quantify the PR proteins, the protein extracts of grape tissues were seperated by HPLC first and then analysed by SDS-PAGE. The results showed that the protein fractions eluted at 9.3 min and 19.2 min under the chromatographic conditions of this study confirmed that these corresponded to TLPs and chitinases seperately. Thus, the relative quantification of TLPs and chitinases in protein extracts was carried out by comparing the area of corresponding peaks against the area of a thamautin standard. The results presented in this study clearly demonstrated the distribution of haze-forming PR proteins in grape berries, and the relative quantification of TLPs and chitinases could be applied in fast tracking of changes in PR proteins during grape growth and determination of PR proteins in berries at harvest.

Proteomic Analysis of Sauvignon Blanc Grape Skin, Pulp and Seed and Relative Quantification of Pathogenesis-Related Proteins

PubMed Central

Tian, Bin; Harrison, Roland; Morton, James; Deb-Choudhury, Santanu

2015-01-01

Thaumatin-like proteins (TLPs) and chitinases are the main constituents of so-called protein hazes which can form in finished white wine and which is a great concern of winemakers. These soluble pathogenesis-related (PR) proteins are extracted from grape berries. However, their distribution in different grape tissues is not well documented. In this study, proteins were first separately extracted from the skin, pulp and seed of Sauvignon Blanc grapes, followed by trypsin digestion and analysis by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Proteins identified included 75 proteins from Sauvignon Blanc grape skin, 63 from grape pulp and 35 from grape seed, mostly functionally classified as associated with metabolism and energy. Some were present exclusively in specific grape tissues; for example, proteins involved in photosynthesis were only detected in grape skin and proteins found in alcoholic fermentation were only detected in grape pulp. Moreover, proteins identified in grape seed were less diverse than those identified in grape skin and pulp. TLPs and chitinases were identified in both Sauvignon Blanc grape skin and pulp, but not in the seed. To relatively quantify the PR proteins, the protein extracts of grape tissues were seperated by HPLC first and then analysed by SDS-PAGE. The results showed that the protein fractions eluted at 9.3 min and 19.2 min under the chromatographic conditions of this study confirmed that these corresponded to TLPs and chitinases seperately. Thus, the relative quantification of TLPs and chitinases in protein extracts was carried out by comparing the area of corresponding peaks against the area of a thamautin standard. The results presented in this study clearly demonstrated the distribution of haze-forming PR proteins in grape berries, and the relative quantification of TLPs and chitinases could be applied in fast tracking of changes in PR proteins during grape growth and determination of PR proteins in berries at harvest. PMID:26076362

The concordance index C and the Mann-Whitney parameter Pr(X>Y) with randomly censored data.

PubMed

Koziol, James A; Jia, Zhenyu

2009-06-01

Harrell's c-index or concordance C has been widely used as a measure of separation of two survival distributions. In the absence of censored data, the c-index estimates the Mann-Whitney parameter Pr(X>Y), which has been repeatedly utilized in various statistical contexts. In the presence of randomly censored data, the c-index no longer estimates Pr(X>Y); rather, a parameter that involves the underlying censoring distributions. This is in contrast to Efron's maximum likelihood estimator of the Mann-Whitney parameter, which is recommended in the setting of random censorship.

PrP(C) regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells.

PubMed

Llorens, Franc; Carulla, Patricia; Villa, Ana; Torres, Juan M; Fortes, Puri; Ferrer, Isidre; del Río, José A

2013-10-01

The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (PrP(SC)) has been studied in depth, the physiological role of PrP(C) remains elusive and controversial. PrP(C) is a cell-surface glycoprotein involved in multiple cellular functions at the plasma membrane, where it interacts with a myriad of partners and regulates several intracellular signal transduction cascades. However, little is known about the gene expression changes modulated by PrP(C) in animals and in cellular models. In this article, we present PrP(C)-dependent gene expression signature in N2a cells and its implication in the most overrepresented functions: cell cycle, cell growth and proliferation, and maintenance of cell shape. PrP(C) over-expression enhances cell proliferation and cell cycle re-entrance after serum stimulation, while PrP(C) silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B (AKT) pathway activation are under the regulation of PrP(C) in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor (EGFR) by PrP(C) in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how PrP(C) over-expression modulates filopodia formation by Rho GTPase regulation mainly in an AKT-Cdc42-N-WASP-dependent pathway. © 2013 International Society for Neurochemistry.

Copper and the Prion Protein: Methods, Structures, Function, and Disease

NASA Astrophysics Data System (ADS)

Millhauser, Glenn L.

2007-05-01

The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrPC to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrPC in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat domain. This review describes recent connections between copper and PrPC, with an emphasis on the electron paramagnetic resonance elucidation of the specific copper-binding sites, insights into PrPC function, and emerging connections between copper and prion disease.

The importance of exercise self-efficacy for clinical outcomes in pulmonary rehabilitation.

PubMed

Selzler, Anne-Marie; Rodgers, Wendy M; Berry, Tanya R; Stickland, Michael K

2016-11-01

Pulmonary rehabilitation (PR) improves functional exercise capacity and health status in people with chronic obstructive pulmonary disease (COPD), although these outcomes are often not maintained following PR. Self-efficacy is a precursor to outcomes achievement, yet few studies have examined the importance of self-efficacy to outcome improvement during PR, or how it develops over time. Further, the contribution of exercise-specific self-efficacy to outcomes in PR is unknown. The aims of this study were to determine (a) whether baseline exercise self-efficacy predicts PR attendance and change in functional exercise capacity and health status over PR, and (b) if exercise self-efficacy changes with PR. Fifty-eight out of 64 patients with COPD completed PR and assessments of exercise self-efficacy (task, coping, scheduling), the 6-minute walk test (6MWT), and St. George's Respiratory Questionnaire (SGRQ) at the beginning and end of PR. Analyses were conducted to predict attendance, and change in 6MWT and SGRQ, while controlling for baseline demographic and clinical indicators. Change in 6MWT, SGRQ, and self-efficacy with PR was also examined. Clinically significant increases in the 6MWT and SGRQ were achieved with PR. Stronger task self-efficacy predicted better attendance, while stronger coping self-efficacy predicted greater 6MWT improvement. No variables predicted SGRQ change. Scheduling self-efficacy significantly improved with PR, whereas task and coping self-efficacy did not. Baseline exercise self-efficacy appears to be a determinant of rehabilitation attendance and functional exercise improvement with PR. Clinicians should evaluate and target exercise self-efficacy to maximize adherence and health outcome improvement with PR. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Physician's sociodemographic profile and distribution across public and private health care: an insight into physicians' dual practice in Brazil.

PubMed

Miotto, Bruno Alonso; Guilloux, Aline Gil Alves; Cassenote, Alex Jones Flores; Mainardi, Giulia Marcelino; Russo, Giuliano; Scheffer, Mário César

2018-04-23

The intertwined relation between public and private care in Brazil is reshaping the medical profession, possibly affecting the distribution and profile of the country's medical workforce. Physicians' simultaneous engagement in public and private services is a common and unregulated practice in Brazil, but the influence played by contextual factors and personal characteristics over dual practice engagement are still poorly understood. This study aimed at exploring the sociodemographic profile of Brazilian physicians to shed light on the links between their personal characteristics and their distribution across public and private services. A nation-wide cross-sectional study using primary data was conducted in 2014. A representative sample size of 2400 physicians was calculated based  on the National Council of Medicine database registries; telephone interviews were conducted to explore physicians' sociodemographic characteristics and their engagement with public and private services. From the 2400 physicians included, 51.45% were currently working in both the public and private services, while 26.95% and 21.58% were working exclusively in the private and public sectors, respectively. Public sector physicians were found to be younger (PR 0.84 [0.68-0.89]; PR 0.47 [0.38-0.56]), less experienced (PR 0.78 [0.73-0.94]; PR 0.44 [0.36-0.53]) and predominantly female (PR 0.79 [0.71-0.88]; PR 0.68 [0.6-0.78]) when compared to dual and private practitioners; their income was substantially lower than those working exclusively for the private (PR 0.58 [0.48-0.69]) and mixed sectors (PR 0.31 [0.25-0.37]). Conversely, physicians from the private sector were found to be typically senior (PR 1.96 [1.58-2.43]), specialized (PR 1.29 [1.17-1.42]) and male (PR 1.35 [1.21-1.51]), often working less than 20 h per week (PR 2.04 [1.4-2.96]). Dual practitioners were mostly middle-aged (PR 1.3 [1.16-1.45]), male specialists with 10 to 30 years of medical practice (PR 1.23 [1.11-1.37]). The study shows that more than half of Brazilian physicians currently engage with dual practice, while only one fifth dedicate exclusively to public services, highlighting also substantial differences in socio-demographic and work-related characteristics between public, private and dual-practitioners. These results are consistent with the international literature suggesting that physicians' sociodemographic characteristics can help predict dual practice forms and prevalence in a country.

Heat Transfer Through Turbulent Friction Layers

NASA Technical Reports Server (NTRS)

Reichardt, H.

1943-01-01

The "general Prandtl number" Pr(exp 1) - A(sub q)/A Pr, aside from the Reynolds number determines the ratio of turbulent to molecular heat transfer, and the temperature distribution in turbulent friction layers. A(sub q) = exchange coefficient for heat; A = exchange coefficient for momentum transfer. A formula is derived from the equation defining the general Prandtl number which describes the temperature as a function of the velocity. For fully developed thermal boundary layers all questions relating to heat transfer to and from incompressible fluids can be treated in a simple manner if the ratio of the turbulent shear stress to the total stress T(sub t)/T in the layers near the wall is known, and if the A(sub q)/A can be regarded as independent of the distance from the wall. The velocity distribution across a flat smooth channel and deep into the laminar sublayer was measured for isothermal flow to establish the shear stress ratio T(sub t)/T and to extend the universal wall friction law. The values of T(sub t)/T which resulted from these measurements can be approximately represented by a linear function of the velocity in the laminar-turbulent transition zone. The effect of the temperature relationship of the material values on the flow near the wall is briefly analyzed. It was found that the velocity at the laminar boundary (in contrast to the thickness of the laminar layer) is approximately independent of the temperature distribution. The temperature gradient at the wall and the distribution of temperature and heat flow in the turbulent friction layers were calculated on the basis of the data under two equations. The derived formulas and the figures reveal the effects of the Prandtl number, the Reynolds number, the exchange quantities and the temperature relationship of the material values.

Translating PrEP effectiveness into public health impact: key considerations for decision-makers on cost-effectiveness, price, regulatory issues, distributive justice and advocacy for access.

PubMed

Hankins, Catherine; Macklin, Ruth; Warren, Mitchell

2015-01-01

The extraordinary feat of proving the effectiveness of oral pre-exposure prophylaxis (PrEP) in clinical trials in different populations in a variety of settings may prove to have been easier than ensuring it is used well. Decision-makers must make difficult choices to realize the promise of antiretroviral prophylaxis for their countries. This paper outlines key economic, regulatory and distributive justice issues that must be addressed for effective and acceptable PrEP implementation. In considering the role that PrEP can play in combination prevention programmes, decision-makers must determine who can benefit most from PrEP, how PrEP can be provided safely and efficiently, and what kind of health system support will ensure successful implementation. To do this, they need contextualized information on disease burden by population, analyses of how PrEP services might best be delivered, and projections of the human resource and infrastructure requirements for each potential delivery model. There are cost considerations, varying cost-effectiveness results and regulatory challenges. The principles of ethics can inform thorny discussions about who should be prioritized for oral PrEP and how best to introduce it fairly. We describe the cost-effectiveness of PrEP in different populations at higher risk of HIV exposure, its price in low- and middle-income countries, and the current regulatory situation. We explore the principles of ethics that can inform resource allocation decision-making about PrEP anchored in distributive justice, at a time when universal access to antiretroviral treatment remains to be assured. We then highlight the role of advocacy in moving the PrEP agenda forward. The time is ripe now for decisions about whether, how and for whom PrEP should be introduced into a country's HIV response. It has the potential to contribute significantly to high impact HIV prevention if it is tailored to those who can most benefit from it and if current regulatory and pricing barriers can be overcome. Advocacy at all levels can help inform decision-making and push the access agenda to avert HIV infections among those at highest risk of HIV exposure. The benefits will accrue beyond the individual level to slow HIV transmission at the population level.

Effects of proprioceptive exercises on pain and function in chronic neck- and low back pain rehabilitation: a systematic literature review.

PubMed

McCaskey, Michael A; Schuster-Amft, Corina; Wirth, Brigitte; Suica, Zorica; de Bruin, Eling D

2014-11-19

Proprioceptive training (PrT) is popularly applied as preventive or rehabilitative exercise method in various sports and rehabilitation settings. Its effect on pain and function is only poorly evaluated. The aim of this systematic review was to summarise and analyse the existing data on the effects of PrT on pain alleviation and functional restoration in patients with chronic (≥ 3 months) neck- or back pain. Relevant electronic databases were searched from their respective inception to February 2014. Randomised controlled trials comparing PrT with conventional therapies or inactive controls in patients with neck- or low back pain were included. Two review authors independently screened articles and assessed risk of bias (RoB). Data extraction was performed by the first author and crosschecked by a second author. Quality of findings was assessed and rated according to GRADE guidelines. Pain and functional status outcomes were extracted and synthesised qualitatively and quantitatively. In total, 18 studies involving 1380 subjects described interventions related to PrT (years 1994-2013). 6 studies focussed on neck-, 12 on low back pain. Three main directions of PrT were identified: Discriminatory perceptive exercises with somatosensory stimuli to the back (pPrT, n=2), multimodal exercises on labile surfaces (mPrT, n=13), or joint repositioning exercise with head-eye coordination (rPrT, n=3). Comparators entailed usual care, home based training, educational therapy, strengthening, stretching and endurance training, or inactive controls. Quality of studies was low and RoB was deemed moderate to high with a high prevalence of unclear sequence generation and group allocation (>60%). Low quality evidence suggests PrT may be more effective than not intervening at all. Low quality evidence suggests that PrT is no more effective than conventional physiotherapy. Low quality evidence suggests PrT is inferior to educational and behavioural approaches. There are few relevant good quality studies on proprioceptive exercises. A descriptive summary of the evidence suggests that there is no consistent benefit in adding PrT to neck- and low back pain rehabilitation and functional restoration.

A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers

PubMed Central

Noble, Geoffrey P.; Wang, Daphne W.; Walsh, Daniel J.; Barone, Justin R.; Miller, Michael B.; Nishina, Koren A.; Li, Sheng; Supattapone, Surachai

2015-01-01

Infectious prions contain a self-propagating, misfolded conformer of the prion protein termed PrPSc. A critical prediction of the protein-only hypothesis is that autocatalytic PrPSc molecules should be infectious. However, some autocatalytic recombinant PrPSc molecules have low or undetectable levels of specific infectivity in bioassays, and the essential determinants of recombinant prion infectivity remain obscure. To identify structural and functional features specifically associated with infectivity, we compared the properties of two autocatalytic recombinant PrP conformers derived from the same original template, which differ by >105-fold in specific infectivity for wild-type mice. Structurally, hydrogen/deuterium exchange mass spectrometry (DXMS) studies revealed that solvent accessibility profiles of infectious and non-infectious autocatalytic recombinant PrP conformers are remarkably similar throughout their protease-resistant cores, except for two domains encompassing residues 91-115 and 144-163. Raman spectroscopy and immunoprecipitation studies confirm that these domains adopt distinct conformations within infectious versus non-infectious autocatalytic recombinant PrP conformers. Functionally, in vitro prion propagation experiments show that the non-infectious conformer is unable to seed mouse PrPC substrates containing a glycosylphosphatidylinositol (GPI) anchor, including native PrPC. Taken together, these results indicate that having a conformation that can be specifically adopted by post-translationally modified PrPC molecules is an essential determinant of biological infectivity for recombinant prions, and suggest that this ability is associated with discrete features of PrPSc structure. PMID:26125623

Long-Term Outcome and Predictors of Noninstitutionalized Survival Subsequent to Prolonged Intensive Care Unit Stay After Cardiac Surgical Procedures.

PubMed

Manji, Rizwan A; Arora, Rakesh C; Singal, Rohit K; Hiebert, Brett; Moon, Michael C; Freed, Darren H; Menkis, Alan H

2016-01-01

There are minimal data on long-term functional survival (alive and not institutionalized) in patients undergoing cardiac operations who require a prolonged intensive care unit length of stay (prICULOS). We sought to describe 1- and 5-year functional survival in patients who had a prICULOS (ICULOS ≥ 5 days) and determine predictors of functional survival at 1 year. Data were obtained from linked clinical and administrative databases from January 1, 2000 to December 31, 2011 to conduct this retrospective single-region analysis. Logistic regression was used to develop a model predicting functional survival at 1 year for patients who had a prICULOS after cardiac operations. There were 9,545 admissions to the ICU after cardiac operations; of these patients, 728 (7.6%) experienced a prICULOS. There was an increasing trend in patients who had a prICULOS over this study period. The functional survival at 1 and 5 years from the surgical procedure for the non-prICULOS versus the prICULOS cohort was 1 year (94.9% versus 73.9%) and 5 years (84.9% versus 53.8%) (p < 0.001). Factors associated with lower rates of functional survival at 1 year were age 80 years or older, female sex, peripheral vascular disease, preoperative renal dysfunction, cerebrovascular disease, preoperative infection, need for extracorporeal membrane oxygenation/ventricular assist device (ECMO/VAD) after cardiotomy, number of days on mechanical ventilation, and number of days in the ICU beyond 5 days (area under the receiver operating characteristic [ROC] curve = 0.766). The majority of patients who had a prICULOS experienced successful functional survival up to 5 years after cardiac operations. Identification of risk factors for poor functional survival may be of assistance to clinicians, patients, and families for prognostication and decision making. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Molecular cloning and developmental expression of the catalytic and 65-kDa regulatory subunits of protein phosphatase 2A in Drosophila.

PubMed Central

Mayer-Jaekel, R E; Baumgartner, S; Bilbe, G; Ohkura, H; Glover, D M; Hemmings, B A

1992-01-01

cDNA clones encoding the catalytic subunit and the 65-kDa regulatory subunit of protein phosphatase 2A (PR65) from Drosophila melanogaster have been isolated by homology screening with the corresponding human cDNAs. The Drosophila clones were used to analyze the spatial and temporal expression of the transcripts encoding these two proteins. The Drosophila PR65 cDNA clones contained an open reading frame of 1773 nucleotides encoding a protein of 65.5 kDa. The predicted amino acid sequence showed 75 and 71% identity to the human PR65 alpha and beta isoforms, respectively. As previously reported for the mammalian PR65 isoforms, Drosophila PR65 is composed of 15 imperfect repeating units of approximately 39 amino acids. The residues contributing to this repeat structure show also the highest sequence conservation between species, indicating a functional importance for these repeats. The gene encoding Drosophila PR65 was located at 29B1,2 on the second chromosome. A major transcript of 2.8 kilobase (kb) encoding the PR65 subunit and two transcripts of 1.6 and 2.5 kb encoding the catalytic subunit could be detected throughout Drosophila development. All of these mRNAs were most abundant during early embryogenesis and were expressed at lower levels in larvae and adult flies. In situ hybridization of different developmental stages showed a colocalization of the PR65 and catalytic subunit transcripts. The mRNA expression is high in the nurse cells and oocytes, consistent with a high equally distributed expression in early embryos. In later embryonal development, the expression remains high in the nervous system and the gonads but the overall transcript levels decrease. In third instar larvae, high levels of mRNA could be observed in brain, imaginal discs, and in salivary glands. These results indicate that protein phosphatase 2A transcript levels change during development in a tissue and in a time-specific manner. Images PMID:1320961

Negative Effects of SRD5A1 on Nuclear Activity of Progesterone Receptor Isoform B in JEG3 Cells.

PubMed

Miao, Zhuo; Sun, Min; Jiang, Feng; Yao, Yuanqing; Li, Yi

2016-02-01

Progesterone withdrawal signals labor in mammals. Elevated intracellular metabolism contributes to progesterone functional withdrawal through unknown mechanism, which is thought to act via progesterone receptor (PR). This study aims to investigate molecular mechanisms underlying progesterone withdrawal during pregnancy and labor. We investigated the role of 5α-reductase type I (SRD5A1) in enzymatic catalysis of progesterone and loss of PR function in a human trophoblast choriocarcinoma cell line JEG3. The PR isoform B (PR-B) was robustly expressed in JEG3 cells. The SRD5A1 small-interfering RNA knockdown led to significant increase in PR-B nuclear import, ectopic, whereas SRD5A1 overexpression resulted in remarkable inhibition of nuclear PR-B in P4-treated cells. Repression of SRD5A1 activated PR-B responsive gene, whereas overexpression of SRD5A1 possessed an inhibitory effect. JEG3 cell line is a valuable tool to study mechanisms responsible for loss of PR function and screening of drugs for preterm birth treatment. Our study aims to investigate the molecular mechanisms underlying progesterone withdrawal during pregnancy and labor. © The Author(s) 2015.

Disordered Route to the Coulomb Quantum Spin Liquid: Random Transverse Fields on Spin Ice in Pr 2 Zr 2 O 7

DOE PAGES

Wen, J. -J.; Koohpayeh, S. M.; Ross, K. A.; ...

2017-03-08

Inelastic neutron scattering reveals a broad continuum of excitations in Pr 2 Zr 2 O 7 , the temperature and magnetic field dependence of which indicate a continuous distribution of quenched transverse fields ( Δ ) acting on the non-Kramers Pr 3 + crystal field ground state doublets. Spin-ice correlations are apparent within 0.2 meV of the Zeeman energy. In a random phase approximation an excellent account of the data is provided and contains a transverse field distribution ρ ( Δ ) ∝ ( Δ 2 + Γ 2 ) - 1 , where Γ = 0.27 ( 1 )more » meV . Established during high temperature synthesis due to an underlying structural instability, it appears disorder in Pr 2 Zr 2 O 7 actually induces a quantum spin liquid.« less

Multiple Instance Fuzzy Inference

DTIC Science & Technology

2015-12-02

very small probabilities. To compute Pr(t | Bi) for a given bag Bi, a conjunction measure of all its instances Bij , j = 1, . . . ,M is computed using...the noisy-or operator Pr(t | Bi) = 1− ∏ 1≤ j ≤M (1− Pr(Bij ∈ t)), (2.5) where Pr(Bij ∈ t) is computed from a Gaussian distribution centred at the concept...Xnk to target concept Ci, and its computed using Pr(Xnk ∈ Ci) = e−( ∑D j =1 sij(xnkj−cij)2) (2.9) In (4.5), sij is a scaling parameter that weights the

Electrophysiological Mapping of Novel Prefrontal – Cerebellar Pathways

PubMed Central

Watson, Thomas C.; Jones, Matthew W.; Apps, Richard

2009-01-01

Whilst the cerebellum is predominantly considered a sensorimotor control structure, accumulating evidence suggests that it may also subserve non-motor functions during cognition. However, this possibility is not universally accepted, not least because the nature and pattern of links between higher cortical structures and the cerebellum are poorly characterized. We have therefore used in vivo electrophysiological methods in anaesthetized rats to directly investigate connectivity between the medial prefrontal cortex (prelimbic subdivision, PrL) and the cerebellum. Stimulation of deep layers of PrL evoked distinct field potentials in the cerebellar cortex with a mean latency to peak of approximately 35 ms. These responses showed a well-defined topography, and were maximal in lobule VII of the contralateral vermis (a known oculomotor centre); they were not attenuated by local anaesthesia of the overlying M2 motor cortex, though M2 stimulation did evoke field potentials in lobule VII with a shorter latency (approximately 30 ms). Single unit recordings showed that prelimbic cortical stimulation elicits complex spikes in lobule VII Purkinje cells, indicating transmission via a previously undescribed cerebro-olivocerebellar pathway. Our results therefore establish a physiological basis for communication between PrL and the cerebellum. The role(s) of this pathway remain to be resolved, but presumably relate to control of eye movements and/or distributed networks associated with integrated prefrontal cortical functions. PMID:19738932

A PR-1-like Protein of Fusarium oxysporum Functions in Virulence on Mammalian Hosts*

PubMed Central

Prados-Rosales, Rafael C.; Roldán-Rodríguez, Raquel; Serena, Carolina; López-Berges, Manuel S.; Guarro, Josep; Martínez-del-Pozo, Álvaro; Di Pietro, Antonio

2012-01-01

The pathogenesis-related PR-1-like protein family comprises secreted proteins from the animal, plant, and fungal kingdoms whose biological function remains poorly understood. Here we have characterized a PR-1-like protein, Fpr1, from Fusarium oxysporum, an ubiquitous fungal pathogen that causes vascular wilt disease on a wide range of plant species and can produce life-threatening infections in immunocompromised humans. Fpr1 is secreted and proteolytically processed by the fungus. The fpr1 gene is required for virulence in a disseminated immunodepressed mouse model, and its function depends on the integrity of the proposed active site of PR-1-like proteins. Fpr1 belongs to a gene family that has expanded in plant pathogenic Sordariomycetes. These results suggest that secreted PR-1-like proteins play important roles in fungal pathogenicity. PMID:22553200

Expression and Functional Characterization of two Pathogenesis-Related Protein 10 Genes from Zea mays

USDA-ARS?s Scientific Manuscript database

Pathogenesis-related protein 10 (PR10) is one of seventeen PR protein families and plays important roles in plant response to biotic and abiotic stresses. A novel PR10 gene (ZmPR10.1), which shares 89.8% and 85.7% identity to the previous ZmPR10 at the nucleotide and amino acid sequence level, respe...

Binding of the fibronectin-mimetic peptide, PR_b, to α5β1 on pig islet cells increases fibronectin production and facilitates internalization of PR_b functionalized liposomes

PubMed Central

Atchison, Nicole A.; Fan, Wei; Papas, Klearchos K.; Hering, Bernhard J.; Tsapatsis, Michael; Kokkoli, Efrosini

2010-01-01

Islet transplantation is a promising treatment for type 1 diabetes. Recent studies have demonstrated that human islet allografts can restore insulin independence to patients with this disease. As islet isolation and immunotherapeutic techniques improve, the demand for this cell-based therapy will dictate the need for other sources of islets. Pig islets could provide an unlimited supply for xenotransplantation and have shown promise as an alternative to human islet allografts. However, stresses imposed during islet isolation and transplantation decrease islet viability, leading to loss of graft function. In this study, we investigated the ability of a fibronectin-mimetic peptide, PR_b, which specifically binds to the α5β1 integrin, to reestablish lost extracellular matrix (ECM) around isolated pig islets and increase internalization of liposomes. Confocal microscopy and western blotting were used to show the presence of the integrin α5β1 on the pig islets on day 0 (day of isolation), as well as different days of islet culture. Islets cultured in medium supplemented with free PR_b for 48 hours were found to have increased levels of ECM fibronectin secretion compared to islets in normal culture conditions. Using confocal microscopy and flow cytometry we found that PR_b peptide-amphiphile functionalized liposomes delivered to the pig islets internalized into the cells in a PR_b concentration dependent manner, and non-functionalized liposomes showed minimal internalization. These studies proved that the fibronectin-mimetic peptide, PR_b, is an appropriate peptide bullet for applications involving α5β1 expressing pig islet cells. Fibronectin production stimulated through α5β1 PR_b binding may decrease apoptosis and therefore increase islet viability in culture. In addition, PR_b peptide-amphiphile functionalized liposomes may be used for targeted delivery of different agents to pig islet cells. PMID:20704278

Some New Approaches to Multivariate Probability Distributions.

DTIC Science & Technology

1986-12-01

Krishnaiah (1977). The following example may serve as an illustration of this point. EXAMPLE 2. (Fre^*chet’s bivariate continuous distribution...the error in the theorem of "" Prakasa Rao (1974) and to Dr. P.R. Krishnaiah for his valuable comments on the initial draft, his monumental patience and...M. and Proschan, F. (1984). Nonparametric Concepts and Methods in Reliability, Handbook of Statistics, 4, 613-655, (eds. P.R. Krishnaiah and P.K

Linear Dichroism in Angle-Resolved Core-Level Photoemission Spectra Reflecting 4f Ground-State Symmetry of Strongly Correlated Cubic Pr Compounds

NASA Astrophysics Data System (ADS)

Hamamoto, Satoru; Fujioka, Shuhei; Kanai, Yuina; Yamagami, Kohei; Nakatani, Yasuhiro; Nakagawa, Koya; Fujiwara, Hidenori; Kiss, Takayuki; Higashiya, Atsushi; Yamasaki, Atsushi; Kadono, Toshiharu; Imada, Shin; Tanaka, Arata; Tamasaku, Kenji; Yabashi, Makina; Ishikawa, Tetsuya; Matsumoto, Keisuke T.; Onimaru, Takahiro; Takabatake, Toshiro; Sekiyama, Akira

2017-12-01

We report experimentally observed linear dichroism in angle-resolved core-level photoemission spectra of PrIr2Zn20 and PrB6 with cubic symmetry. The different anisotropic 4f charge distributions between the compounds due to the crystalline-electric-field splitting are responsible for the difference in the linear dichroism, which has been verified by spectral simulations with the full multiplet theory for a single-site Pr3+ ion with cubic symmetry. The observed linear dichroism and polarization-dependent spectra in two different photoelectron directions for PrIr2Zn20 are reproduced by theoretical analysis for the Γ3 ground state, whereas those of the Pr 3d and 4d core levels indicate the Γ5 ground state for PrB6.

Identification of novel putative-binding proteins for cellular prion protein and a specific interaction with the STIP1 homology and U-Box-containing protein 1

PubMed Central

Gimenez, Ana Paula Lappas; Richter, Larissa Morato Luciani; Atherino, Mariana Campos; Beirão, Breno Castello Branco; Fávaro, Celso; Costa, Michele Dietrich Moura; Zanata, Silvio Marques; Malnic, Bettina; Mercadante, Adriana Frohlich

2015-01-01

ABSTRACT Prion diseases involve the conversion of the endogenous cellular prion protein, PrPC, into a misfolded infectious isoform, PrPSc. Several functions have been attributed to PrPC, and its role has also been investigated in the olfactory system. PrPC is expressed in both the olfactory bulb (OB) and olfactory epithelium (OE) and the nasal cavity is an important route of transmission of diseases caused by prions. Moreover, Prnp−/− mice showed impaired behavior in olfactory tests. Given the high PrPC expression in OE and its putative role in olfaction, we screened a mouse OE cDNA library to identify novel PrPC-binding partners. Ten different putative PrPC ligands were identified, which were involved in functions such as cellular proliferation and apoptosis, cytoskeleton and vesicle transport, ubiquitination of proteins, stress response, and other physiological processes. In vitro binding assays confirmed the interaction of PrPC with STIP1 homology and U-Box containing protein 1 (Stub1) and are reported here for the first time. Stub1 is a co-chaperone with ubiquitin E3-ligase activity, which is associated with neurodegenerative diseases characterized by protein misfolding and aggregation. Physiological and pathological implications of PrPC-Stub1 interaction are under investigation. The PrPC-binding proteins identified here are not exclusive to the OE, suggesting that these interactions may occur in other tissues and play general biological roles. These data corroborate the proposal that PrPC is part of a multiprotein complex that modulates several cellular functions and provide a platform for further studies on the physiological and pathological roles of prion protein. PMID:26237451

Prion protein functions as a ferrireductase partner for ZIP14 and DMT1

PubMed Central

Qian, Juan; Beserra, Amber; Suda, Srinivas; Singh, Ajay; Hopfer, Ulrich; Chen, Shu G.; Garrick, Michael D.; Turner, Jerrold R.; Knutson, Mitchell D.; Singh, Neena

2015-01-01

Excess circulating iron is stored in the liver, and requires reduction of non-Tf-bound-iron (NTBI) and transferrin (Tf)-iron at the plasma membrane and endosomes respectively by ferrireductase (FR) proteins for transport across biological membranes through divalent metal transporters. Here, we report that prion-protein (PrPC), a ubiquitously expressed glycoprotein most abundant on neuronal cells, functions as a FR partner for divalent-metal transporter-1 (DMT1) and ZIP14. Thus, absence of PrPC in PrP-knock-out (PrP−/−) mice resulted in markedly reduced liver iron stores, a deficiency that was not corrected by chronic or acute administration of iron by the oral or intra-peritoneal routes. Likewise, preferential radiolabeling of circulating NTBI with 59Fe revealed significantly reduced uptake and storage of NTBI by the liver of PrP−/− mice relative to matched PrP+/+ controls. However, uptake, storage, and utilization of ferritin-bound iron that does not require reduction for uptake was increased in PrP−/− mice, indicating a compensatory response to the iron-deficiency. Expression of exogenous PrPC in HepG2-cells increased uptake and storage of ferric-iron (Fe3+), not ferrous-iron (Fe2+) from the medium, supporting the function of PrPC as a plasma membrane FR. Co-expression of PrPC with ZIP14 and DMT1 in HepG2 cells increased uptake of Fe3+ significantly, and surprisingly, increased the ratio of N-terminally truncated PrPC forms lacking the FR domain relative to full-length PrPC. Together, these observations indicate that PrPC promotes, and possibly regulates the uptake of NTBI through DMT1 and Zip14 via its FR activity. Implications of these observations for neuronal iron homeostasis under physiological and pathological conditions are discussed. PMID:25862412

Solar-panel and parasol strategies shape the proteorhodopsin distribution pattern in marine Flavobacteriia.

PubMed

Kumagai, Yohei; Yoshizawa, Susumu; Nakajima, Yu; Watanabe, Mai; Fukunaga, Tsukasa; Ogura, Yoshitoshi; Hayashi, Tetsuya; Oshima, Kenshiro; Hattori, Masahira; Ikeuchi, Masahiko; Kogure, Kazuhiro; DeLong, Edward F; Iwasaki, Wataru

2018-05-01

Proteorhodopsin (PR) is a light-driven proton pump that is found in diverse bacteria and archaea species, and is widespread in marine microbial ecosystems. To date, many studies have suggested the advantage of PR for microorganisms in sunlit environments. The ecophysiological significance of PR is still not fully understood however, including the drivers of PR gene gain, retention, and loss in different marine microbial species. To explore this question we sequenced 21 marine Flavobacteriia genomes of polyphyletic origin, which encompassed both PR-possessing as well as PR-lacking strains. Here, we show that the possession or alternatively the lack of PR genes reflects one of two fundamental adaptive strategies in marine bacteria. Specifically, while PR-possessing bacteria utilize light energy ("solar-panel strategy"), PR-lacking bacteria exclusively possess UV-screening pigment synthesis genes to avoid UV damage and would adapt to microaerobic environment ("parasol strategy"), which also helps explain why PR-possessing bacteria have smaller genomes than those of PR-lacking bacteria. Collectively, our results highlight the different strategies of dealing with light, DNA repair, and oxygen availability that relate to the presence or absence of PR phototrophy.

Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles.

PubMed

Martin, Katherine R; Kantari-Mimoun, Chahrazade; Yin, Min; Pederzoli-Ribeil, Magali; Angelot-Delettre, Fanny; Ceroi, Adam; Grauffel, Cédric; Benhamou, Marc; Reuter, Nathalie; Saas, Philippe; Frachet, Philippe; Boulanger, Chantal M; Witko-Sarsat, Véronique

2016-05-13

Proteinase 3 (PR3), the autoantigen in granulomatosis with polyangiitis, is expressed at the plasma membrane of resting neutrophils, and this membrane expression increases during both activation and apoptosis. Using surface plasmon resonance and protein-lipid overlay assays, this study demonstrates that PR3 is a phosphatidylserine-binding protein and this interaction is dependent on the hydrophobic patch responsible for membrane anchorage. Molecular simulations suggest that PR3 interacts with phosphatidylserine via a small number of amino acids, which engage in long lasting interactions with the lipid heads. As phosphatidylserine is a major component of microvesicles (MVs), this study also examined the consequences of this interaction on MV production and function. PR3-expressing cells produced significantly fewer MVs during both activation and apoptosis, and this reduction was dependent on the ability of PR3 to associate with the membrane as mutating the hydrophobic patch restored MV production. Functionally, activation-evoked MVs from PR3-expressing cells induced a significantly larger respiratory burst in human neutrophils compared with control MVs. Conversely, MVs generated during apoptosis inhibited the basal respiratory burst in human neutrophils, and those generated from PR3-expressing cells hampered this inhibition. Given that membrane expression of PR3 is increased in patients with granulomatosis with polyangiitis, MVs generated from neutrophils expressing membrane PR3 may potentiate oxidative damage of endothelial cells and promote the systemic inflammation observed in this disease. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles*

PubMed Central

Martin, Katherine R.; Kantari-Mimoun, Chahrazade; Yin, Min; Pederzoli-Ribeil, Magali; Angelot-Delettre, Fanny; Ceroi, Adam; Grauffel, Cédric; Benhamou, Marc; Reuter, Nathalie; Saas, Philippe; Frachet, Philippe; Boulanger, Chantal M.; Witko-Sarsat, Véronique

2016-01-01

Proteinase 3 (PR3), the autoantigen in granulomatosis with polyangiitis, is expressed at the plasma membrane of resting neutrophils, and this membrane expression increases during both activation and apoptosis. Using surface plasmon resonance and protein-lipid overlay assays, this study demonstrates that PR3 is a phosphatidylserine-binding protein and this interaction is dependent on the hydrophobic patch responsible for membrane anchorage. Molecular simulations suggest that PR3 interacts with phosphatidylserine via a small number of amino acids, which engage in long lasting interactions with the lipid heads. As phosphatidylserine is a major component of microvesicles (MVs), this study also examined the consequences of this interaction on MV production and function. PR3-expressing cells produced significantly fewer MVs during both activation and apoptosis, and this reduction was dependent on the ability of PR3 to associate with the membrane as mutating the hydrophobic patch restored MV production. Functionally, activation-evoked MVs from PR3-expressing cells induced a significantly larger respiratory burst in human neutrophils compared with control MVs. Conversely, MVs generated during apoptosis inhibited the basal respiratory burst in human neutrophils, and those generated from PR3-expressing cells hampered this inhibition. Given that membrane expression of PR3 is increased in patients with granulomatosis with polyangiitis, MVs generated from neutrophils expressing membrane PR3 may potentiate oxidative damage of endothelial cells and promote the systemic inflammation observed in this disease. PMID:26961880

Functional genomics identifies regulators of the phototransduction machinery in the Drosophila larval eye and adult ocelli.

PubMed

Mishra, Abhishek Kumar; Bargmann, Bastiaan O R; Tsachaki, Maria; Fritsch, Cornelia; Sprecher, Simon G

2016-02-15

Sensory perception of light is mediated by specialized Photoreceptor neurons (PRs) in the eye. During development all PRs are genetically determined to express a specific Rhodopsin (Rh) gene and genes mediating a functional phototransduction pathway. While the genetic and molecular mechanisms of PR development is well described in the adult compound eye, it remains unclear how the expression of Rhodopsins and the phototransduction cascade is regulated in other visual organs in Drosophila, such as the larval eye and adult ocelli. Using transcriptome analysis of larval PR-subtypes and ocellar PRs we identify and study new regulators required during PR differentiation or necessary for the expression of specific signaling molecules of the functional phototransduction pathway. We found that the transcription factor Krüppel (Kr) is enriched in the larval eye and controls PR differentiation by promoting Rh5 and Rh6 expression. We also identified Camta, Lola, Dve and Hazy as key genes acting during ocellar PR differentiation. Further we show that these transcriptional regulators control gene expression of the phototransduction cascade in both larval eye and adult ocelli. Our results show that PR cell type-specific transcriptome profiling is a powerful tool to identify key transcriptional regulators involved during several aspects of PR development and differentiation. Our findings greatly contribute to the understanding of how combinatorial action of key transcriptional regulators control PR development and the regulation of a functional phototransduction pathway in both larval eye and adult ocelli. Copyright © 2015 Elsevier Inc. All rights reserved.

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

PubMed Central

Amin Al Olama, Ali; Benlloch, Sara; Antoniou, Antonis C.; Zeigler-Johnson, Charnita; Stephenson, Robert; Cox, Angela; Southey, Melissa C.; Spurdle, Amanda B.; FitzGerald, Liesel; Leongamornlert, Daniel; Saunders, Edward; Tymrakiewicz, Malgorzata; Guy, Michelle; Dadaev, Tokhir; Little, Sarah J.; Govindasami, Koveela; Sawyer, Emma; Wilkinson, Rosemary; Herkommer, Kathleen; Hopper, John L.; Lophatonanon, Aritaya; Rinckleb, Antje E.; Kote-Jarai, Zsofia; Eeles, Rosalind A.; Easton, Douglas F.

2015-01-01

Background Genome-wide association studies have identified multiple genetic variants associated with prostate cancer (PrCa) risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of PrCa. Methods We genotyped 25 PrCa susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical Odds Ratios for PrCa associated with different risk strata defined by PRS and derived age-specific absolute risks of developing PrCa by PRS stratum and family history. Results The PrCa risk for men in the top 1% of the PRS distribution was 30.6 (95% CI 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI 3.2-5.5) fold compared with the median risk. The absolute risk of PrCa by age 85 was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation=0.09). Conclusions Risk profiling can identify men at substantially increased or reduced risk of PrCa. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of PrCa. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. PMID:25837820

PRN 97-8: Time Extension of PR Notice 96-7 - Termiticide Labeling

EPA Pesticide Factsheets

EPA intends to grant a 90-day extension to permit the distribution or sale of products not bearing labeling consistent with PR Notice 96-7. View the reasons for this extension and what products are affected.

Regional Variability in Convection and Rain Retrievals from the TRMM Microwave Imager (TMI)

NASA Technical Reports Server (NTRS)

Prabhakara, C.; Iacovazzi, R., Jr.

2003-01-01

Precipitation Radar (PR) on board the TRMM satellite shows that the average height of 30 dBz in convective rain areas of the tropics varies significantly from one region to the other. When the convection is weak this height is shallow and when convection is strong this height extends deeper into the troposphere. The brightness temperature (Tb) measured by the microwave radiometer by itself does not reflect this nature of convection satisfactorily. Radiative transfer simulations of Tbs reveal that this could be due to the variations in the vertical distribution of optically active water and ice hydrometeors and their density, shape, and size. These variations are not coupled uniquely to the strength of the convective updrafts, and as a result the Tbs do not reflect properly the convective strength indicated by PR. Because of this deficiency in the Tbs the rain rate deduced from them differs from that of PR. For this reason, to improve the estimation of rain rate we have developed an empirical method. In this method a parameter based on the areal extent of the Tbs that exceed a certain magnitude is included along with the Tbs. Rain rate deduced with this approach is better correlated with that of PR when compared to the current Version 5 operational algorithm. The percentage of rain volume as a function of rain rate, for a given region of 5deg lat. X 5deg long. over a period of three months, deduced from this method, is also in better agreement with that of the PR.

Expression of flavonoid 3'-hydroxylase is controlled by P1, the regulator of 3-deoxyflavonoid biosynthesis in maize.

PubMed

Sharma, Mandeep; Chai, Chenglin; Morohashi, Kengo; Grotewold, Erich; Snook, Maurice E; Chopra, Surinder

2012-11-01

The maize (Zea mays) red aleurone1 (pr1) encodes a CYP450-dependent flavonoid 3'-hydroxylase (ZmF3'H1) required for the biosynthesis of purple and red anthocyanin pigments. We previously showed that Zmf3'h1 is regulated by C1 (Colorless1) and R1 (Red1) transcription factors. The current study demonstrates that, in addition to its role in anthocyanin biosynthesis, the Zmf3'h1 gene also participates in the biosynthesis of 3-deoxyflavonoids and phlobaphenes that accumulate in maize pericarps, cob glumes, and silks. Biosynthesis of 3-deoxyflavonoids is regulated by P1 (Pericarp color1) and is independent from the action of C1 and R1 transcription factors. In maize, apiforol and luteoforol are the precursors of condensed phlobaphenes. Maize lines with functional alleles of pr1 and p1 (Pr1;P1) accumulate luteoforol, while null pr1 lines with a functional or non-functional p1 allele (pr1;P1 or pr1;p1) accumulate apiforol. Apiforol lacks a hydroxyl group at the 3'-position of the flavylium B-ring, while luteoforol has this hydroxyl group. Our biochemical analysis of accumulated compounds in different pr1 genotypes showed that the pr1 encoded ZmF3'H1 has a role in the conversion of mono-hydroxylated to bi-hydroxylated compounds in the B-ring. Steady state RNA analyses demonstrated that Zmf3'h1 mRNA accumulation requires a functional p1 allele. Using a combination of EMSA and ChIP experiments, we established that the Zmf3'h1 gene is a direct target of P1. Highlighting the significance of the Zmf3'h1 gene for resistance against biotic stress, we also show here that the p1 controlled 3-deoxyanthocyanidin and C-glycosyl flavone (maysin) defence compounds accumulate at significantly higher levels in Pr1 silks as compared to pr1 silks. By virtue of increased maysin synthesis in Pr1 plants, corn ear worm larvae fed on Pr1; P1 silks showed slower growth as compared to pr1; P1 silks. Our results show that the Zmf3'h1 gene participates in the biosynthesis of phlobaphenes and agronomically important 3-deoxyflavonoid compounds under the regulatory control of P1.

Oestrogen and progesterone receptor assays in breast tumours. The Prince Henry's Hospital experience, 1983-1990.

PubMed

Pearce, P T; Myles, K M; Funder, J W

1993-08-16

To present and analyse the results of eight years of experience (1983-1990) in breast tumour receptor analysis. All female primary breast tumour samples received (4683) were analysed for seasonal variation, patient age, relative risk index, oestrogen receptor (ER) and progesterone receptor (PR) status, ER and PR status as a function of age, ER and PR levels as a function of age, and ER and PR levels as a function of month of analysis. The assays were done at the Medical Research Centre, Prince Henry's Hospital, Melbourne, as a non-profit service to surgeons, oncologists and pathologists. The numbers of samples referred for assay increased progressively each year, from 473 in 1983 to 1097 in 1990, but the receptor status (ER +/-, PR +/-) appeared not to vary from year to year. ER+PR+ tumours were the most common in all age groups, steadily increasing from between 50% and 60% in premenopausal women to 70% or more in those aged over 80. In postmenopausal women, levels of ER in ER+ tumours were three times those in premenopausal women; PR levels in PR+ tumours, however, were bimodal, with higher levels in the age groups 35-49 and 70-89 years than in women aged 50-69 years. No significant seasonal variation was seen, and the overall patterns of receptor status are similar to those seen in Northern hemisphere studies.

Functional analysis of a pathogenesis-related thaumatin-like protein gene TaLr35PR5 from wheat induced by leaf rust fungus.

PubMed

Zhang, Jiarui; Wang, Fei; Liang, Fang; Zhang, Yanjun; Ma, Lisong; Wang, Haiyan; Liu, Daqun

2018-05-04

Plants have evolved multifaceted defence mechanisms to resist pathogen infection. Production of the pathogenesis-related (PR) proteins in response to pathogen attack has been implicated in plant disease resistance specialized in systemic-acquired resistance (SAR). Our earlier studies have reported that a full length TaLr35PR5 gene, encoding a protein exhibiting amino acid and structural similarity to a sweet protein thaumatin, was isolated from wheat near-isogenic line TcLr35. The present study aims to understand the function of TaLr35PR5 gene in Lr35-mediated adult resistance to Puccinia triticina. We determined that the TaLr35PR5 protein contained a functional secretion peptide by utilizing the yeast signal sequence trap system. Using a heterologous expression assay on onion epidermal cells we found that TaLr35PR5 protein was secreted into the apoplast of onion cell. Expression of TaLr35PR5 was significantly reduced in BSMV-induced gene silenced wheat plants, and pathology test on these silenced plants revealed that Lr35-mediated resistance phenotype was obviously altered, indicating that Lr35-mediated resistance was compromised. All these findings strongly suggest that TaLr35PR5 is involved in Lr35-mediated adult wheat defense in response to leaf rust attack.

Spatial distribution and ecological risk assessment of phthalic acid esters and phenols in surface sediment from urban rivers in Northeast China.

PubMed

Li, Bin; Liu, Ruixia; Gao, Hongjie; Tan, Ruijie; Zeng, Ping; Song, Yonghui

2016-12-01

Concentration and spatial distribution of six phthalic acid esters (PAEs) and eight phenols in sediments of urban rivers, namely the Xi River (XR) and Pu River (PR) in Shenyang city, Northeast China were investigated and the ecological risk of these target pollutants was assessed based on the risk quotient (RQ) approach. Target PAEs and phenols were detected in most of sediment samples collected from the XR and PR. The concentrations of total PAEs in sediments varied from 22.4 to 369 μg/g dw in the XR and 3.71-46.9 μg/g dw in the PR. The levels of phenols ranged from 2.72 to 106 μg/g dw in the XR and 0.811-25.0 μg/g dw in the PR, respectively. The dominant pollutants in both XR and PR were DEHP, phenol and 4-methylphnol. The sampling locations XR1-3 in the XR suffered severe contamination from PAEs and phenols. The sites PR1 and PR6 were heavily polluted by phenols and PAEs, respectively. Almost all target PAEs and phenolic compounds in sediment of the XR exhibited medium or high ecological risk to organisms and the ecological risk in the PR mainly originated from PEAs, phenol and 4-methylphenol. These results would provide guidance for individual pollutant control and indicate that it is imperative to take some effective measures to reduce the pollution of those contaminants. Copyright © 2016 Elsevier Ltd. All rights reserved.

Targeted drug delivery and enhanced intracellular release using functionalized liposomes

NASA Astrophysics Data System (ADS)

Garg, Ashish

The ability to target cancer cells using an appropriate drug delivery system can significantly reduce the associated side effects from cancer therapies and can help in improving the overall quality of life, post cancer survival. Integrin alpha5beta1 is expressed on several types of cancer cells, including colon cancer and plays an important role in tumor growth and metastasis. Thus, the ability to target the integrin alpha 5beta1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth and reducing tumor metastasis. The work in this thesis focuses on designing and optimizing, functionalized stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that specifically target the integrin alpha5beta1. The PEG provides a steric barrier allowing the liposomes to circulate in the blood for longer duration and the functionalizing moiety, PR_b peptide specifically recognizes and binds to integrin alpha5beta1 expressing cells. The work demonstrates that by optimizing the amount of PEG and PR_b on the liposomal interface, nano-vectors can be engineered that bind to CT26.WT colon cancer cells in a specific manner and internalize through alpha 5beta1-mediated endocytosis. To further improve the efficacy of the system, PR_b functionalized pH-sensitive stealth liposomes that exhibit triggered release under mild acidic conditions present in endocytotic vesicles were designed. The study showed that PR_b functionalized pH-sensitive stealth liposomes, undergo destabilization under mildly acidic conditions and incorporation of the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b functionalized pH-sensitive stealth liposomes bind to CT26.WT colon carcinoma cells that express integrin alpha5beta 1, undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. PR_b-targeted pH-sensitive stealth liposomes encapsulating 5-fluorouracil (5-FU) show significantly higher cytotoxicity than the PR_b-targeted inert stealth liposomes and the non-targeted stealth liposomes (both pH-sensitive and inert). The studies demonstrated that optimized PR_b functionalized pH sensitive liposomes have the potential to deliver a payload, such as chemotherapeutic agents, directly to colon cancer cells in an efficient and specific manner.

Prevalence and correlates of physical disability and functional limitation among community dwelling older people in rural Malaysia, a middle income country

PubMed Central

2010-01-01

Background The prevalence and correlates of physical disability and functional limitation among older people have been studied in many developed countries but not in a middle income country such as Malaysia. The present study investigated the epidemiology of physical disability and functional limitation among older people in Malaysia and compares findings to other countries. Methods A population-based cross sectional study was conducted in Alor Gajah, Malacca. Seven hundred and sixty five older people aged 60 years and above underwent tests of functional limitation (Tinetti Performance Oriented Mobility Assessment Tool). Data were also collected for self reported activities of daily living (ADL) using the Barthel Index (ten items). To compare prevalence with other studies, ADL disability was also defined using six basic ADL's (eating, bathing, dressing, transferring, toileting and walking) and five basic ADL's (eating, bathing, dressing, transferring and toileting). Results Ten, six and five basic ADL disability was reported by 24.7% (95% CI 21.6-27.9), 14.4% (95% CI 11.9-17.2) and 10.6% (95% CI 8.5-13.1), respectively. Functional limitation was found in 19.5% (95% CI 16.8-22.5) of participants. Variables independently associated with 10 item ADL disability physical disability, were advanced age (≥ 75 years: prevalence ratio (PR) 7.9; 95% CI 4.8-12.9), presence of diabetes (PR 1.8; 95% CI 1.4-2.3), stroke (PR 1.5; 95% CI 1.1-2.2), depressive symptomology (PR 1.3; 95% CI 1.1-1.8) and visual impairment (blind: PR 2.0; 95% CI 1.1-3.6). Advancing age (≥ 75 years: PR 3.0; 95% CI 1.7-5.2) being female (PR 2.7; 95% CI 1.2-6.1), presence of arthritis (PR 1.6; 95% CI 1.2-2.1) and depressive symptomology (PR 2.0; 95% CI 1.5-2.7) were significantly associated with functional limitation. Conclusions The prevalence of physical disability and functional limitation among older Malaysians appears to be much higher than in developed countries but is comparable to developing countries. Associations with socio-demographic and other health related variables were consistent with other studies. PMID:20716377

Benefits of pulmonary rehabilitation in idiopathic pulmonary fibrosis.

PubMed

Swigris, Jeffrey J; Fairclough, Diane L; Morrison, Marianne; Make, Barry; Kozora, Elizabeth; Brown, Kevin K; Wamboldt, Frederick S

2011-06-01

Information on the benefits of pulmonary rehabilitation (PR) in patients with idiopathic pulmonary fibrosis (IPF) is growing, but PR's effects on certain important outcomes is lacking. We conducted a pilot study of PR in IPF and analyzed changes in functional capacity, fatigue, anxiety, depression, sleep, and health status from baseline to after completion of a standard, 6-week PR program. Six-min walk distance improved a mean ± standard error 202 ± 135 feet (P = .01) from baseline. Fatigue Severity Scale score also improved significantly, declining an average 1.5 ± 0.5 points from baseline. There were trends toward improvement in anxiety, depression, and health status. PR improves functional capacity and fatigue in patients with IPF. (Clinical Trials.gov registration NCT00692796.)

Effect of preoperative and postoperative incentive spirometry on lung functions after laparoscopic cholecystectomy.

PubMed

Kundra, Pankaj; Vitheeswaran, Madhurima; Nagappa, Mahesh; Sistla, Sarath

2010-06-01

This study was designed to compare the effects of preoperative and postoperative incentive spirometry on lung functions after laparoscopic cholecystectomy in 50 otherwise normal healthy adults. Patients were randomized into a control group (group PO, n=25) and a study group (group PR, n=25). Patients in group PR were instructed to carry out incentive spirometry before the surgery 15 times, every fourth hourly, for 1 week whereas in group PO, incentive spirometry was carried out during the postoperative period. Lung functions were recorded at the time of preanesthetic evaluation, on the day before the surgery, postoperatively at 6, 24, and 48 hours, and at discharge. Significant improvement in the lung functions was seen after preoperative incentive spirometry (group PR), P<0.05. The lung functions were significantly reduced till the time of discharge in both the groups. However, lung functions were better preserved in group PR at all times when compared with group PO; P<0.05. To conclude, lung functions are better preserved with preoperative than postoperative incentive spirometry.

The PR-Set7 binding domain of Riz1 is required for the H4K20me1-H3K9me1 trans-tail 'histone code' and Riz1 tumor suppressor function.

PubMed

Congdon, Lauren M; Sims, Jennifer K; Tuzon, Creighton T; Rice, Judd C

2014-04-01

PR-Set7/Set8/KMT5a is the sole histone H4 lysine 20 monomethyltransferase (H4K20me1) in metazoans and is essential for proper cell division and genomic stability. We unexpectedly discovered that normal cellular levels of monomethylated histone H3 lysine 9 (H3K9me1) were also dependent on PR-Set7, but independent of its catalytic activity. This observation suggested that PR-Set7 interacts with an H3K9 monomethyltransferase to establish the previously reported H4K20me1-H3K9me1 trans-tail 'histone code'. Here we show that PR-Set7 specifically and directly binds the C-terminus of the Riz1/PRDM2/KMT8 tumor suppressor and demonstrate that the N-terminal PR/SET domain of Riz1 preferentially monomethylates H3K9. The PR-Set7 binding domain was required for Riz1 nuclear localization and maintenance of the H4K20me1-H3K9me1 trans-tail 'histone code'. Although Riz1 can function as a repressor, Riz1/H3K9me1 was dispensable for the repression of genes regulated by PR-Set7/H4K20me1. Frameshift mutations resulting in a truncated Riz1 incapable of binding PR-Set7 occur frequently in various aggressive cancers. In these cancer cells, expression of wild-type Riz1 restored tumor suppression by decreasing proliferation and increasing apoptosis. These phenotypes were not observed in cells expressing either the Riz1 PR/SET domain or PR-Set7 binding domain indicating that Riz1 methyltransferase activity and PR-Set7 binding domain are both essential for Riz1 tumor suppressor function.

Functional properties of LRRK2 mutations in Taiwanese Parkinson disease.

PubMed

Chang, Kuo-Hsuan; Chen, Chiung-Mei; Lin, Chih-Hsin; Chang, Wen-Teng; Jiang, Pei-Ru; Hsiao, Ya-Chin; Wu, Yih-Ru; Lee-Chen, Guey-Jen

2017-03-01

Leucine-rich repeat kinase 2 (LRRK2) is a large protein encoding multiple functional domains. Mutations within different LRRK2 domains have been considered to be involved in the development of Parkinson disease by different mechanisms. Our previous study found three LRRK2 mutations-p.R767H, p.S885N, and p.R1441H-in Taiwanese patients with Parkinson disease. We evaluated the functional properties of LRRK2 p.R767H, p.S885N, and p.R1441H mutations by overexpressing them in human embryonic kidney 293 and neuroblastoma SK-N-SH cells. The common p.G2019S mutation in the kinase domain was included for comparison. In 293 cells, overexpressed p.R1441H-but not p.R767H, p.S885N, or p.G2019-increased GTP binding affinity to prolong the active state. Overexpressed p.R1441H and p.G2019S generated inclusions in 293 cells. In SK-N-SH cells, the α-synuclein was coexpressed with wild type as well as mutated p.R767H, p.S885N, p.R1441H, and p.G2019 LRRK2 proteins. Part of the perinuclear inclusions formed by p.R1441H and p.G2019S were colocalized with α-synuclein. Additionally, p.S885N and p.R1441H mutations caused reduced interaction between LRRK2 and ARHGEF7, a putative guanine nucleotide exchange factor for LRRK2, whereas this interaction was well preserved in p.R767H and p.G2019S mutations. Our study suggests that p.R1441H protein facilitates the formation of intracellular inclusions, compromises GTP hydrolysis by increasing its affinity for GTP, and reduces its interaction with ARHGEF7. Copyright © 2016. Published by Elsevier B.V.

S1PR3 Signaling Drives Bacterial Killing and Is Required for Survival in Bacterial Sepsis.

PubMed

Hou, JinChao; Chen, QiXing; Wu, XiaoLiang; Zhao, DongYan; Reuveni, Hadas; Licht, Tamar; Xu, MengLong; Hu, Hu; Hoeft, Andreas; Ben-Sasson, Shmuel A; Shu, Qiang; Fang, XiangMing

2017-12-15

Efficient elimination of pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. To investigate the role of S1PR3 in antibacterial immunity during sepsis. Loss- and gain-of-function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers. S1PR3 protein levels were up-regulated in macrophages upon bacterial stimulation. S1pr3 -/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3 -/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3 -/- macrophages due to impaired recruitment of vacuolar protein-sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes. S1PR3 signaling drives bacterial killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.

Physiological reactivity during autobiographical narratives in older adults: the roles of depression and anxiety.

PubMed

Robertson, Sarah M C; Swickert, Rhonda J; Connelly, Kathryn; Galizio, Ann

2015-01-01

Physiological reactivity (PR) describes the change in physiological functioning (e.g., heart rate, blood pressure, pulse pressure) that occurs after the induction of a stressful task. This study aims to understand the influence of mental health symptoms on patterns of PR during autobiographical narratives in an older adult sample. Eighty older adults completed self-report measures regarding their symptoms of depression and anxiety. Next, their blood pressure was recorded while they completed two verbal autobiographical narratives. During the positive narrative, anxiety was positively associated with increased PR while depression was negatively associated with PR. During the negative narrative, a significant interaction occurred whereby anxiety was significantly positively associated with PR for those participants low in depression. The above results are explained in the context of the Tripartite Model of Depression and Anxiety, which predicts different patterns of PR as a function of mental health symptoms. Limitations and future directions are also discussed.

Differing specificities and isotypes of anti-citrullinated peptide/protein antibodies in palindromic rheumatism and rheumatoid arthritis.

PubMed

Cabrera-Villalba, Sonia; Gomara, María José; Cañete, Juan D; Ramírez, Julio; Salvador, Georgina; Ruiz-Esquide, Virginia; Hernández, Maria Victoria; Inciarte-Mundo, José; Haro, Isabel; Sanmartí, Raimon

2017-06-15

To analyze differences in the recognition of anti-citrullinated peptide/protein antibody (ACPA) citrullinated epitopes and isotypes in patients with palindromic rheumatism (PR) and rheumatoid arthritis (RA). ACPA fine specificities (citrullinated peptides of enolase, fibrin, and vimentin) and isotypes (IgG, IgM, and IgA) were analyzed in 54 patients with longstanding PR and 54 patients with established RA. CCP2 tested positive in 66.7% of patients with PR and RA. The ACPA distribution of fine specificities and isotypes differed between PR and RA patients. PR patients had a lower frequency of fine ACPA specificities than RA patients, which was significant in the case of a peptide derived from vimentin (PR 24.1% vs. 59.3% RA; p < 0.001). The mean number of ACPA specificities was lower in PR than in RA patients, and only 25.9% of PR patients recognized ≥2 additional specificities compared with 46.3% of RA patients. Significantly less isotype usage, especially IgA, was observed in PR patients. The ACPA immune response differed in patients with PR and RA, with fewer fine specificities and isotype usage in patients with PR. Some patients with PR may have impaired maturation of the B-cell response against citrullinated peptides with no progression to RA.

Rare earth substitutional impurities in germanium: A hybrid density functional theory study

NASA Astrophysics Data System (ADS)

Igumbor, E.; Omotoso, E.; Tunhuma, S. M.; Danga, H. T.; Meyer, W. E.

2017-10-01

The Heyd, Scuseria, and Ernzerhof (HSE06) hybrid functional by means of density functional theory has been used to model the electronic and structural properties of rare earth (RE) substitutional impurities in germanium (REGe) . The formation and charge state transition energies for the REGe (RE = Ce, Pr, Er and Eu) were calculated. The energy of formation for the neutral charge state of the REGe lies between -0.14 and 3.13 eV. The formation energy result shows that the Pr dopant in Ge (PrGe) has the lowest formation energy of -0.14 eV, and is most energetically favourable under equilibrium conditions. The REGe induced charge state transition levels within the band gap of Ge. Shallow acceptor levels were induced by both the Eu (EuGe) and Pr (PrGe) dopants in Ge. The CeGe and ErGe exhibited properties of negative-U ordering with effective-U values of -0.85 and -1.07 eV, respectively.

Pathophysiology of preterm labor with intact membranes.

PubMed

Talati, Asha N; Hackney, David N; Mesiano, Sam

2017-11-01

Preterm labor with intact membranes is a major cause of spontaneous preterm birth (sPTB). To prevent sPTB a clear understanding is needed of the hormonal interactions that initiate labor. The steroid hormone progesterone acting via its nuclear progesterone receptors (PRs) in uterine cells is essential for the establishment and maintenance of pregnancy and disruption of PR signaling (i.e., functional progesterone/PR withdrawal) is key trigger for labor. The process of parturition is also associated with inflammation within the uterine tissues and it is now generally accepted that inflammatory stimuli from multiple extrinsic and intrinsic sources induce labor. Recent studies suggest inflammatory stimuli induce labor by affecting PR transcriptional activity in uterine cells to cause functional progesterone/PR withdrawal. Advances in understanding the functional interaction of inflammatory load on the pregnancy uterus and progesterone/PR signaling is opening novel areas of research and may lead to rational therapeutic strategies to effectively prevent sPTB. Copyright © 2017 Elsevier Inc. All rights reserved.

Pathogenic prion protein fragment (PrP106-126) promotes human immunodeficiency virus type-1 infection in peripheral blood monocyte-derived macrophages.

PubMed

Bacot, Silvia M; Feldman, Gerald M; Yamada, Kenneth M; Dhawan, Subhash

2015-02-01

Transfusion of blood and blood products contaminated with the pathogenic form of prion protein Prp(sc), thought to be the causative agent of variant a Creutzfeldt-Jakob disease (vCJD), may result in serious consequences in recipients with a compromised immune system, for example, as seen in HIV-1 infection. In the present study, we demonstrate that treatment of peripheral blood monocyte-derived macrophages (MDM) with PrP106-126, a synthetic domain of PrP(sc) that has intrinsic functional activities related to the full-length protein, markedly increased their susceptibility to HIV-1 infection, induced cytokine secretion, and enhanced their migratory behavior in response to N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP). Live-cell imaging of MDM cultured in the presence of PrP106-126 showed large cell clusters indicative of cellular activation. Tyrosine kinase inhibitor STI-571, protein kinase C inhibitor K252B, and cyclin-dependent kinase inhibitor olomoucine attenuated PrP106-126-induced altered MDM functions. These findings delineate a previously undefined functional role of PrP106-126-mediated host cell response in promoting HIV-1 pathogenesis. Published by Elsevier Inc.

Regulation of GABAA and Glutamate Receptor Expression, Synaptic Facilitation and Long-Term Potentiation in the Hippocampus of Prion Mutant Mice

PubMed Central

Rangel, Alejandra; Madroñal, Noelia; Massó, Agnès Gruart i.; Gavín, Rosalina; Llorens, Franc; Sumoy, Lauro; Torres, Juan María; Delgado-García, José María; Río, José Antonio Del

2009-01-01

Background Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrPsc) of the natural cellular prion protein (PrPc) encoded by the Prnp gene. Although several roles have been attributed to PrPc, its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrPc studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Methodology/Principal Findings Here we explore the role of PrPc expression in neurotransmission and neural excitability using wild-type, Prnp −/− and PrPc-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp −/− mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using Illumina™ microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp −/− and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABAA and AMPA-kainate receptors are co-regulated in both Prnp −/− and Tg20 mice. Conclusions/Significance Present results demonstrate that PrPc is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABAA and AMPA-Kainate neurotransmission. New PrPc functions have recently been described, which point to PrPc as a target for putative therapies in Alzheimer's disease. However, our results indicate that a “gain of function” strategy in Alzheimer's disease, or a “loss of function” in prionopathies, may impair PrPc function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies. PMID:19855845

Potential Link between the Sphingosine-1-Phosphate (S1P) System and Defective Alveolar Macrophage Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)

PubMed Central

Barnawi, Jameel; Tran, Hai; Jersmann, Hubertus; Pitson, Stuart; Roscioli, Eugene; Hodge, Greg; Meech, Robyn; Haberberger, Rainer; Hodge, Sandra

2015-01-01

Introduction We previously reported that alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) are defective in their ability to phagocytose apoptotic cells, with a similar defect in response to cigarette smoke. The exact mechanisms for this defect are unknown. Sphingolipids including ceramide, sphingosine and sphingosine-1-phosphate (S1P) are involved in diverse cellular processes and we hypothesised that a comprehensive analysis of this system in alveolar macrophages in COPD may help to delineate the reasons for defective phagocytic function. Methods We compared mRNA expression of sphingosine kinases (SPHK1/2), S1P receptors (S1PR1-5) and S1P-degrading enzymes (SGPP1, SGPP2, SGPL1) in bronchoalveolar lavage-derived alveolar macrophages from 10 healthy controls, 7 healthy smokers and 20 COPD patients (10 current- and 10 ex-smokers) using Real-Time PCR. Phagocytosis of apoptotic cells was investigated using flow cytometry. Functional associations were assessed between sphingosine signalling system components and alveolar macrophage phagocytic ability in COPD. To elucidate functional effects of increased S1PR5 on macrophage phagocytic ability, we performed the phagocytosis assay in the presence of varying concentrations of suramin, an antagonist of S1PR3 and S1PR5. The effects of cigarette smoking on the S1P system were investigated using a THP-1 macrophage cell line model. Results We found significant increases in SPHK1/2 (3.4- and 2.1-fold increases respectively), S1PR2 and 5 (4.3- and 14.6-fold increases respectively), and SGPL1 (4.5-fold increase) in COPD vs. controls. S1PR5 and SGPL1 expression was unaffected by smoking status, suggesting a COPD “disease effect” rather than smoke effect per se. Significant associations were noted between S1PR5 and both lung function and phagocytosis. Cigarette smoke extract significantly increased mRNA expression of SPHK1, SPHK2, S1PR2 and S1PR5 by THP-1 macrophages, confirming the results in patient-derived macrophages. Antagonising SIPR5 significantly improved phagocytosis. Conclusion Our results suggest a potential link between the S1P signalling system and defective macrophage phagocytic function in COPD and advise therapeutic targets. PMID:26485657

Factorial inferential grid grouping and representativeness analysis for a systematic selection of representative grids

NASA Astrophysics Data System (ADS)

Cheng, Guanhui; Huang, Guohe; Dong, Cong; Xu, Ye; Yao, Yao

2017-08-01

A factorial inferential grid grouping and representativeness analysis (FIGGRA) approach is developed to achieve a systematic selection of representative grids in large-scale climate change impact assessment and adaptation (LSCCIAA) studies and other fields of Earth and space sciences. FIGGRA is applied to representative-grid selection for temperature (Tas) and precipitation (Pr) over the Loess Plateau (LP) to verify methodological effectiveness. FIGGRA is effective at and outperforms existing grid-selection approaches (e.g., self-organizing maps) in multiple aspects such as clustering similar grids, differentiating dissimilar grids, and identifying representative grids for both Tas and Pr over LP. In comparison with Pr, the lower spatial heterogeneity and higher spatial discontinuity of Tas over LP lead to higher within-group similarity, lower between-group dissimilarity, lower grid grouping effectiveness, and higher grid representativeness; the lower interannual variability of the spatial distributions of Tas results in lower impacts of the interannual variability on the effectiveness of FIGGRA. For LP, the spatial climatic heterogeneity is the highest in January for Pr and in October for Tas; it decreases from spring, autumn, summer to winter for Tas and from summer, spring, autumn to winter for Pr. Two parameters, i.e., the statistical significance level (α) and the minimum number of grids in every climate zone (Nmin), and their joint effects are significant for the effectiveness of FIGGRA; normalization of a nonnormal climate-variable distribution is helpful for the effectiveness only for Pr. For FIGGRA-based LSCCIAA studies, a low value of Nmin is recommended for both Pr and Tas, and a high and medium value of α for Pr and Tas, respectively.

PrP0\\0 mice show behavioral abnormalities that suggest PrPC has a role in maintaining the cytoskeleton.

USDA-ARS?s Scientific Manuscript database

Background/Introduction. PrPC is highly conserved among mammals, but its natural function is unclear. Prnp ablated mice (PrP0/0) appear to develop normally and are able to reproduce. These observations seem to indicate that the gene is not essential for viability, in spite of it being highly conse...

Molecular characterization and functional analysis of PR-1-like proteins identified from the wheat head blight fungus Fusarium graminearum

USDA-ARS?s Scientific Manuscript database

The group 1 pathogenesis-related (PR-1) proteins originally identified from plants and their homologues are also found in other eukaryotic kingdoms. Studies on non-plant PR-1-like (PR-1L) proteins have been pursued widely in humans/animals but rarely in filamentous ascomycetes. Here we report the ch...

S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3

PubMed Central

Priceman, Saul J.; Shen, Shudan; Wang, Lin; Deng, Jiehui; Yue, Chanyu; Kujawski, Maciej; Yu, Hua

2014-01-01

Summary S1PR1 signaling has been shown to restrain the number and function of Tregs in the periphery under physiological conditions and in colitis models, but its role in regulating tumor-associated T cells is unknown. Here, we show that S1PR1 signaling in T cells drives Treg accumulation in tumors, limits CD8+ T cell recruitment and activation, and promotes tumor growth. S1PR1 intrinsic in T cells affects Tregs, but not CD8+ T cells, as demonstrated by adoptive transfer models and transient pharmacological S1PR1 modulation. We further investigated the molecular mechanism(s) underlying S1PR1-mediated Treg accumulation in tumors, showing that increasing S1PR1 in CD4+ T cells promotes STAT3 activation and JAK/STAT3-dependent Treg tumor migration. Furthermore functionally ablating STAT3 in T cells diminishes tumor-associated Treg accumulation and tumor growth. Our study demonstrates a stark contrast of the consequences by the same signaling receptor, namely S1PR1, in regulating Tregs in the periphery and in tumors. PMID:24630990

Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer.

PubMed

Paulo, Paula; Maia, Sofia; Pinto, Carla; Pinto, Pedro; Monteiro, Augusta; Peixoto, Ana; Teixeira, Manuel R

2018-04-01

Considering that mutations in known prostate cancer (PrCa) predisposition genes, including those responsible for hereditary breast/ovarian cancer and Lynch syndromes, explain less than 5% of early-onset/familial PrCa, we have sequenced 94 genes associated with cancer predisposition using next generation sequencing (NGS) in a series of 121 PrCa patients. We found monoallelic truncating/functionally deleterious mutations in seven genes, including ATM and CHEK2, which have previously been associated with PrCa predisposition, and five new candidate PrCa associated genes involved in cancer predisposing recessive disorders, namely RAD51C, FANCD2, FANCI, CEP57 and RECQL4. Furthermore, using in silico pathogenicity prediction of missense variants among 18 genes associated with breast/ovarian cancer and/or Lynch syndrome, followed by KASP genotyping in 710 healthy controls, we identified "likely pathogenic" missense variants in ATM, BRIP1, CHEK2 and TP53. In conclusion, this study has identified putative PrCa predisposing germline mutations in 14.9% of early-onset/familial PrCa patients. Further data will be necessary to confirm the genetic heterogeneity of inherited PrCa predisposition hinted in this study.

Praseodymium-142 glass seeds for the brachytherapy of prostate cancer

NASA Astrophysics Data System (ADS)

Jung, Jae Won

A beta-emitting glass seed was proposed for the brachytherapy treatment of prostate cancer. Criteria for seed design were derived and several beta-emitting nuclides were examined for suitability. 142Pr was selected as the isotope of choice. Seeds 0.08 cm in diameter and 0.9 cm long were manufactured for testing. The seeds were activated in the Texas A&M University research reactor. The activity produced was as expected when considering the meta-stable state and epi-thermal neutron flux. The MCNP5 Monte Carlo code was used to calculate the quantitative dosimetric parameters suggested in the American Association of Physicists in Medicine (AAPM) TG-43/60. The Monte Carlo calculation results were compared with those from a dose point kernel code. The dose profiles agree well with each other. The gamma dose of 142Pr was evaluated. The gamma dose is 0.3 Gy at 1.0 cm with initial activity of 5.95 mCi and is insignificant to other organs. Measurements were performed to assess the 2-dimensional axial dose distributions using Gafchromic radiochromic film. The radiochromic film was calibrated using an X-ray machine calibrated against a National Institute of Standards and Technology (NIST) traceable ion chamber. A calibration curve was derived using a least squares fit of a second order polynomial. The measured dose distribution agrees well with results from the Monte Carlo simulation. The dose was 130.8 Gy at 6 mm from the seed center with initial activity of 5.95 mCi. AAPM TG-43/60 parameters were determined. The reference dose rate for 2 mm and 6 mm were 0.67 and 0.02 cGy/s/mCi, respectively. The geometry function, radial dose function and anisotropy function were generated.

Expression of flavonoid 3’-hydroxylase is controlled by P1, the regulator of 3-deoxyflavonoid biosynthesis in maize

PubMed Central

2012-01-01

Background The maize (Zea mays) red aleurone1 (pr1) encodes a CYP450-dependent flavonoid 3’-hydroxylase (ZmF3’H1) required for the biosynthesis of purple and red anthocyanin pigments. We previously showed that Zmf3’h1 is regulated by C1 (Colorless1) and R1 (Red1) transcription factors. The current study demonstrates that, in addition to its role in anthocyanin biosynthesis, the Zmf3’h1 gene also participates in the biosynthesis of 3-deoxyflavonoids and phlobaphenes that accumulate in maize pericarps, cob glumes, and silks. Biosynthesis of 3-deoxyflavonoids is regulated by P1 (Pericarp color1) and is independent from the action of C1 and R1 transcription factors. Results In maize, apiforol and luteoforol are the precursors of condensed phlobaphenes. Maize lines with functional alleles of pr1 and p1 (Pr1;P1) accumulate luteoforol, while null pr1 lines with a functional or non-functional p1 allele (pr1;P1 or pr1;p1) accumulate apiforol. Apiforol lacks a hydroxyl group at the 3’-position of the flavylium B-ring, while luteoforol has this hydroxyl group. Our biochemical analysis of accumulated compounds in different pr1 genotypes showed that the pr1 encoded ZmF3’H1 has a role in the conversion of mono-hydroxylated to bi-hydroxylated compounds in the B-ring. Steady state RNA analyses demonstrated that Zmf3’h1 mRNA accumulation requires a functional p1 allele. Using a combination of EMSA and ChIP experiments, we established that the Zmf3’h1 gene is a direct target of P1. Highlighting the significance of the Zmf3’h1 gene for resistance against biotic stress, we also show here that the p1 controlled 3-deoxyanthocyanidin and C-glycosyl flavone (maysin) defence compounds accumulate at significantly higher levels in Pr1 silks as compared to pr1 silks. By virtue of increased maysin synthesis in Pr1 plants, corn ear worm larvae fed on Pr1; P1 silks showed slower growth as compared to pr1; P1 silks. Conclusions Our results show that the Zmf3’h1 gene participates in the biosynthesis of phlobaphenes and agronomically important 3-deoxyflavonoid compounds under the regulatory control of P1. PMID:23113982

Neutrophil proteinase 3 (PR3) acts on protease-activated receptor-2 (PAR-2) to enhance vascular endothelial cell barrier function

PubMed Central

Kuckleburg, Christopher J.; Newman, Peter J.

2013-01-01

The principle role of the vascular endothelium is to present a semi-impermeable barrier to soluble factors and circulating cells, while still permitting the passage of leukocytes from the bloodstream into the tissue. The process of diapedesis involves the selective disruption of endothelial cell junctions, an event that could in theory compromise vascular integrity. It is therefore somewhat surprising that neutrophil transmigration does not significantly impair endothelial barrier function. We examined whether neutrophils might secrete factors that promote vascular integrity during the latter stages of neutrophil transmigration, and found that neutrophil proteinase 3 (PR3) – a serine protease harbored in azurophilic granules – markedly enhanced barrier function in endothelial cells. PR3 functioned in this capacity both in its soluble form and in a complex with cell-surface NB1. PR3-mediated enhancement of endothelial cell junctional integrity required its proteolytic activity, as well as endothelial cell expression of the protease-activated receptor, PAR-2. Importantly, PR3 suppressed the vascular permeability changes and disruption of junctional proteins induced by the action of PAR-1 agonists. These findings establish the potential for neutrophil-derived PR3 to play a role in reestablishing vascular integrity following leukocyte transmigration, and in protecting endothelial cells from PAR-1-induced permeability changes that occur during thrombotic and inflammatory events. PMID:23202369

Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus.

PubMed

Mehta, Fabiola F; Son, Jieun; Hewitt, Sylvia C; Jang, Eunjung; Lydon, John P; Korach, Kenneth S; Chung, Sang-Hyuk

2016-04-05

While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock-in mouse models expressing ERα mutants, we determined that the DNA-binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus.

HIV-1 Protease in the Fission Yeast Schizosaccharomyces pombe.

PubMed

Benko, Zsigmond; Elder, Robert T; Li, Ge; Liang, Dong; Zhao, Richard Y

2016-01-01

HIV-1 protease (PR) is an essential viral enzyme. Its primary function is to proteolyze the viral Gag-Pol polyprotein for production of viral enzymes and structural proteins and for maturation of infectious viral particles. Increasing evidence suggests that PR cleaves host cellular proteins. However, the nature of PR-host cellular protein interactions is elusive. This study aimed to develop a fission yeast (Schizosaccharomyces pombe) model system and to examine the possible interaction of HIV-1 PR with cellular proteins and its potential impact on cell proliferation and viability. A fission yeast strain RE294 was created that carried a single integrated copy of the PR gene in its chromosome. The PR gene was expressed using an inducible nmt1 promoter so that PR-specific effects could be measured. HIV-1 PR from this system cleaved the same indigenous viral p6/MA protein substrate as it does in natural HIV-1 infections. HIV-1 PR expression in fission yeast cells prevented cell proliferation and induced cellular oxidative stress and changes in mitochondrial morphology that led to cell death. Both these PR activities can be prevented by a PR-specific enzymatic inhibitor, indinavir, suggesting that PR-mediated proteolytic activities and cytotoxic effects resulted from enzymatic activities of HIV-1 PR. Through genome-wide screening, a serine/threonine kinase, Hhp2, was identified that suppresses HIV-1 PR-induced protease cleavage and cell death in fission yeast and in mammalian cells, where it prevented PR-induced apoptosis and cleavage of caspase-3 and caspase-8. This is the first report to show that HIV-1 protease is functional as an enzyme in fission yeast, and that it behaves in a similar manner as it does in HIV-1 infection. HIV-1 PR-induced cell death in fission yeast could potentially be used as an endpoint for mechanistic studies, and this system could be used for developing a high-throughput system for drug screenings.

Cognitive Remediation in Middle-Aged or Older Inpatients with Chronic Schizophrenia: A Randomized Controlled Trial in Korea.

PubMed

Choi, Kee-Hong; Kang, Jinsook; Kim, Sun-Min; Lee, Seung-Hwan; Park, Seon-Cheol; Lee, Won-Hye; Choi, Sun; Park, Kiho; Hwang, Tae-Yeon

2017-01-01

Background: Accumulating evidence indicates that cognitive remediation (CR) is effective for improving various cognitive deficits in adult patients with schizophrenia. Although reports of brain plasticity in older adults and the service needs for chronic patients with schizophrenia are increasing, very few randomized controlled trials of CR have been conducted in middle-aged or older inpatients with chronic schizophrenia. We investigated the efficacy of individualized CR on the cognitive impairments of middle-aged or older inpatients with chronic schizophrenia within the context of comprehensive psychiatric rehabilitation (PR) by comparing the results obtained with PR only and treatment as usual (TAU). Method: Fifty-seven middle-aged and older individuals with chronic schizophrenia and mild to moderate cognitive deficits were enrolled. Thirty-eight who were undergoing PR were randomly assigned to CR + PR ( N = 19) or PR-only ( N = 19) groups. Nineteen participants who were undergoing TAU without CR or PR were evaluated pre- and post-treatment. Results: CR was easily provided and well received (drop-out rates = 5.3%) by middle-aged or older psychiatric inpatients. Compared to the PR-Only or TAU patients, patients in the CR + PR group showed greater improvement in executive functioning. Compared to TAU patients, CR + PR and PR-only patients showed greater improvement in logical memory. More patients in the CR + PR group improved clinically significantly in executive functioning and logical memory, compared with the PR-only and TAU patients. Conclusions: These results suggested that CR improved some cognitive deficits in middle-aged or older inpatients with chronic schizophrenia and that it was effective as an adjunctive treatment to the usual PR services provided in inpatient settings. Clinical Registration: KCT0002609.

Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells.

PubMed

Amini, Peyvand; Michniuk, Daniel; Kuo, Kelly; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Peters, Gregory A; Tan, Huiqing; Wang, Junye; Malemud, Charles J; Mesiano, Sam

2016-11-01

The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1β and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HM A/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC 50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition.

Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells

PubMed Central

Amini, Peyvand; Michniuk, Daniel; Kuo, Kelly; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Peters, Gregory A.; Tan, Huiqing; Wang, Junye; Malemud, Charles J.

2016-01-01

The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1β and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HMA/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition. PMID:27653036

Moving Average Models with Bivariate Exponential and Geometric Distributions.

DTIC Science & Technology

1985-03-01

ordinary time series and of point processes. Developments in Statistics, Vol. 1, P.R. Krishnaiah , ed. Academic Press, New York. [9] Esary, J.D. and...valued and discrete - valued time series with ARMA correlation structure. Multivariate Analysis V, P.R. Krishnaiah , ed. North-Holland. 151-166. [28

Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus

PubMed Central

Lee, Jae Hee; Kim, Tae Hoon; Oh, Seo Jin; Yoo, Jung-Yoon; Akira, Shizuo; Ku, Bon Jeong; Lydon, John P.; Jeong, Jae-Wook

2013-01-01

Recent studies have shown that activation of the signal transducer and activator of transcription-3 (Stat3) is required for decidualization, interacting with progesterone receptor (PR) in uterus. Based on previous reports, we hypothesized that crosstalk between STAT3 and PR signaling is required for successful implantation. To identify the interaction between STAT3 and PR isoforms, we performed immunoprecipitation following transient cotransfection and found that STAT3 physically interacted with PR-A, which is known to be important for uterine development and function, but not with PR-B. To further investigate the role of Stat3 in uterine function, Stat3 was conditionally ablated only in the PR-positive cells (PRcre/+ Stat3f/f; Stat3d/d). Our studies revealed that ovarian function and uterine development of Stat3d/d mice were normal. However, Stat3d/d female mice were infertile due to defective embryo implantation. Unlike Stat3f/f mice, Stat3d/d mice exhibited an unclosed uterine lumen. Furthermore, uteri of Stat3d/d mice were unable to undergo a well-characterized hormonally induced decidual reaction. The expression of stromal PR was decreased during decidualization and preimplantation period in Stat3d/d mice, and PR target genes were significantly down-regulated after progesterone induction. Our results suggest that STAT3 and PR crosstalk is required for successful implantation in the mouse uterus.—Lee, J. H., Kim, T. H., Oh, S. J., Yoo, J.-Y., Akira, S., Ku, B. J., Lydon, J. P., Jeong, J.-W. Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. PMID:23531596

Joint Multifractal Analysis of penetration resistance variability in an olive orchard.

NASA Astrophysics Data System (ADS)

Lopez-Herrera, Juan; Herrero-Tejedor, Tomas; Saa-Requejo, Antonio; Villeta, Maria; Tarquis, Ana M.

2016-04-01

Spatial variability of soil properties is relevant for identifying those zones with physical degradation. We used descriptive statistics and multifractal analysis for characterizing the spatial patterns of soil penetrometer resistance (PR) distributions and compare them at different soil depths and soil water content to investigate the tillage effect in soil compactation. The study was conducted on an Inceptisol dedicated to olive orchard for the last 70 years. Two parallel transects of 64 m were selected as different soil management plots, conventional tillage (CT) and no tillage (NT). Penetrometer resistance readings were carried out at 50 cm intervals within the first 20 cm of soil depth (López de Herrera et al., 2015a). Two way ANOVA highlighted that tillage system, soil depth and their interaction are statistically significant to explain the variance of PR data. The comparison of CT and NT results at different depths showed that there are significant differences deeper than 10 cm but not in the first two soil layers. The scaling properties of each PR profile was characterized by τ(q) function, calculated in the range of moment orders (q) between -5 and +5 taken at 0.5 lag increments. Several parameters were calculated from this to establish different comparisons (López de Herrera et al., 2015b). While the multifractal analysis characterizes the distribution of a single variable along its spatial support, the joint multifractal analysis can be used to characterize the joint distribution of two or more variables along a common spatial support (Kravchenko et al., 2000; Zeleke and Si, 2004). This type of analysis was performed to study the scaling properties of the joint distribution of PR at different depths. The results showed that this type of analysis added valuable information to describe the spatial arrangement of depth-dependent penetrometer data sets in all the soil layers. References Kravchenko AN, Bullock DG, Boast CW (2000) Joint multifractal analysis of crop yield and terrain slope. Agro. j. 92: 1279-1290. López de Herrera, J., Tomas Herrero Tejedor, Antonio Saa-Requejo and Ana M. Tarquis (2015a) Influence of tillage in soil penetration resistance variability in an olive orchard. Geophysical Research Abstracts, 17, EGU2015-15425. López de Herrera, J., Tomás Herrero Tejedor, Antonio Saa-Requejo, A.M. Tarquis. Influence of tillage in soil penetration resistance variability in an olive orchard. Soil Research, accepted, 2015b. doi: SR15046 Zeleke TB, Si BC (2004) Scaling properties of topographic indices and crop yield: Multifractal and joint multifractal approaches. Agro. j. 96: 1082-1090.

PrEP as a feature in the optimal landscape of combination HIV prevention in sub-Saharan Africa

PubMed Central

McGillen, Jessica B; Anderson, Sarah-Jane; Hallett, Timothy B

2016-01-01

Introduction The new WHO guidelines recommend offering pre-exposure prophylaxis (PrEP) to people who are at substantial risk of HIV infection. However, where PrEP should be prioritised, and for which population groups, remains an open question. The HIV landscape in sub-Saharan Africa features limited prevention resources, multiple options for achieving cost saving, and epidemic heterogeneity. This paper examines what role PrEP should play in optimal prevention in this complex and dynamic landscape. Methods We use a model that was previously developed to capture subnational HIV transmission in sub-Saharan Africa. With this model, we can consider how prevention funds could be distributed across and within countries throughout sub-Saharan Africa to enable optimal HIV prevention (that is, avert the greatest number of infections for the lowest cost). Here, we focus on PrEP to elucidate where, and to whom, it would optimally be offered in portfolios of interventions (alongside voluntary medical male circumcision, treatment as prevention, and behaviour change communication). Over a range of continental expenditure levels, we use our model to explore prevention patterns that incorporate PrEP, exclude PrEP, or implement PrEP according to a fixed incidence threshold. Results At low-to-moderate levels of total prevention expenditure, we find that the optimal intervention portfolios would include PrEP in only a few regions and primarily for female sex workers (FSW). Prioritisation of PrEP would expand with increasing total expenditure, such that the optimal prevention portfolios would offer PrEP in more subnational regions and increasingly for men who have sex with men (MSM) and the lower incidence general population. The marginal benefit of including PrEP among the available interventions increases with overall expenditure by up to 14% (relative to excluding PrEP). The minimum baseline incidence for the optimal offer of PrEP declines for all population groups as expenditure increases. We find that using a fixed incidence benchmark to guide PrEP decisions would incur considerable losses in impact (up to 7%) compared with an approach that uses PrEP more flexibly in light of prevailing budget conditions. Conclusions Our findings suggest that, for an optimal distribution of prevention resources, choices of whether to implement PrEP in subnational regions should depend on the scope for impact of other possible interventions, local incidence in population groups, and total resources available. If prevention funding were to become restricted in the future, it may be suboptimal to use PrEP according to a fixed incidence benchmark, and other prevention modalities may be more cost-effective. In contrast, expansions in funding could permit PrEP to be used to its full potential in epidemiologically driven prevention portfolios and thereby enable a more cost-effective HIV response across Africa. PMID:27760682

Ocatin. A Novel Tuber Storage Protein from the Andean Tuber Crop Oca with Antibacterial and Antifungal Activities1

PubMed Central

Flores, Teresita; Alape-Girón, Alberto; Flores-Díaz, Marietta; Flores, Hector E.

2002-01-01

The most abundant soluble tuber protein from the Andean crop oca (Oxalis tuberosa Mol.), named ocatin, has been purified and characterized. Ocatin accounts for 40% to 60% of the total soluble oca tuber proteins, has an apparent molecular mass of 18 kD and an isoelectric point of 4.8. This protein appears to be found only in tubers and is accumulated only within the cells of the pith and peridermis layers (peel) of the tuber as it develops. Ocatin inhibits the growth of several phytopathogenic bacteria (Agrobacterium tumefaciens, Agrobacterium radiobacter, Serratia marcescens, and Pseudomonas aureofaciens) and fungi (Phytophthora cinnamomi, Fusarium oxysporum, Rhizoctonia solani, and Nectria hematococcus). Ocatin displays substantial amino acid sequence similarity with a widely distributed group of intracellular pathogenesis-related proteins with a hitherto unknown biological function. Our results showed that ocatin serves as a storage protein, has antimicrobial properties, and belongs to the Betv 1/PR-10/MLP protein family. Our findings suggest that an ancient scaffolding protein was recruited in the oca tuber to serve a storage function and that proteins from the Betv 1/PR-10/MLP family might play a role in natural resistance to pathogens. PMID:11950978

Ocatin. A novel tuber storage protein from the andean tuber crop oca with antibacterial and antifungal activities.

PubMed

Flores, Teresita; Alape-Girón, Alberto; Flores-Díaz, Marietta; Flores, Hector E

2002-04-01

The most abundant soluble tuber protein from the Andean crop oca (Oxalis tuberosa Mol.), named ocatin, has been purified and characterized. Ocatin accounts for 40% to 60% of the total soluble oca tuber proteins, has an apparent molecular mass of 18 kD and an isoelectric point of 4.8. This protein appears to be found only in tubers and is accumulated only within the cells of the pith and peridermis layers (peel) of the tuber as it develops. Ocatin inhibits the growth of several phytopathogenic bacteria (Agrobacterium tumefaciens, Agrobacterium radiobacter, Serratia marcescens, and Pseudomonas aureofaciens) and fungi (Phytophthora cinnamomi, Fusarium oxysporum, Rhizoctonia solani, and Nectria hematococcus). Ocatin displays substantial amino acid sequence similarity with a widely distributed group of intracellular pathogenesis-related proteins with a hitherto unknown biological function. Our results showed that ocatin serves as a storage protein, has antimicrobial properties, and belongs to the Betv 1/PR-10/MLP protein family. Our findings suggest that an ancient scaffolding protein was recruited in the oca tuber to serve a storage function and that proteins from the Betv 1/PR-10/MLP family might play a role in natural resistance to pathogens.

Copper attachment to prion protein at a non-octarepeat site

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Bernholc, Jerry

2011-03-01

Prion protein (PrP) plays a causative role in a group of neurodegenerative diseases, which include ``mad cow disease'' or its human form variant Creutzfeld-Jacob disease. Normal function of PrP remains unknown, but it is now well established that PrP can efficiently bind copper ions and this ability has been linked to its function. The primary binding sites are located in the so-called octarepeat region located between residues 60-91. While these are by now well characterized, the sites located outside these region remain mostly undetermined. In this work, we investigate the properties of Cu binding site located at His 111 using recently developed hybrid Kohn-Sham/orbital-free density functional simulations. Experimental data indicate that copper is coordinated by either four nitrogens or three nitrogens and one oxygen. We investigate both possibilities, comparing their energetics and attachment geometries. Similarities and differences with other binding sites and implications for PrP function will also be discussed.

Production of a soluble recombinant prion protein fused to blue fluorescent protein without refolding or detergents in Escherichia coli cells.

PubMed

Arii, Yasuhiro; Yamaguchi, Hidenori; Fukuoka, Shin-Ichi

2007-10-01

The physiological function of prion proteins (PrP) remains unclear. To investigate the physiological relevance of PrP, we constructed a fusion protein of PrP with enhanced blue fluorescent protein (PrP-EBFP) to quantify the interaction of PrP with other molecules. Production of soluble PrP-EBFP was achieved by lowering the expression temperature in Escherichia coli (E. coli) cells to 15 degrees C. Soluble PrP-EBFP was purified on cation exchange and heparin-affinity columns to yield high purity protein. This is the first report of the preparation of soluble recombinant PrP without refolding following solubilization using denaturants or disruption using detergents. To confirm the integrity of PrP-EBFP, anisotropy was estimated under physiological conditions in the presence of heparin, which interacts with PrP. The dissociation constant was determined to be 0.88+/-0.07 microM. PrP-EBFP should be useful in the quantification of PrP interactions with other molecules.

Preliminary investigation of foot pressure distribution variation in men and women adults while standing.

PubMed

Periyasamy, R; Mishra, A; Anand, Sneh; Ammini, A C

2011-09-01

Women and men are anatomically and physiologically different in a number of ways. They differ in both shape and size. These differences could potentially mean foot pressure distribution variation in men and women. The purpose of this study was to analyze standing foot pressure image to obtain the foot pressure distribution parameter - power ratio variation between men and women using image processing in frequency domain. We examined 28 healthy adult subjects (14 men and 14 women) aged between 20 and 45 years was recruited for our study. Foot pressure distribution patterns while standing are obtained by using a PedoPowerGraph plantar pressure measurement system for foot image formation, a digital camera for image capturing, a TV tuner PC-add on card, a WinDvr software for still capture and Matlab software with dedicated image processing algorithms have been developed. Various PedoPowerGraphic parameters such as percentage medial impulse (PMI), fore foot to hind foot pressure distribution ratio (F/H), big toe to fore foot pressure distribution ratio (B/F) and power ratio (PR) were evaluated. In men, contact area was significantly larger in all regions of the foot compared with women. There were significant differences in plantar pressure distribution but there was no significant difference in F/H and B/F ratio. Mean PR value was significantly greater in men than women under the hind foot and fore foot. PMI value was greater in women than men. As compared to men, women have maximum PR variations in the mid foot. Hence there is significant difference at level p<0.05 in medial mid foot and mid foot PR of women as compared to men. There was variation in plantar pressure distribution because the contact area of the men foot was larger than that of women foot. Hence knowledge of pressure distributions variation of both feet can provide suitable guidelines to biomedical engineers and doctor for designing orthotic devices for reliving the area of excessively high pressure. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cocaine- and amphetamine-regulated transcript and calcium binding proteins immunoreactivity in the subicular complex of the guinea pig.

PubMed

Wasilewska, Barbara; Najdzion, Janusz; Równiak, Maciej; Bogus-Nowakowska, Krystyna; Hermanowicz, Beata; Kolenkiewicz, Małgorzata; Żakowski, Witold; Robak, Anna

2016-03-01

In this study we present the distribution and colocalization pattern of cocaine- and amphetamine-regulated transcript (CART) and three calcium-binding proteins: calbindin (CB), calretinin (CR) and parvalbumin (PV) in the subicular complex (SC) of the guinea pig. The subiculum (S) and presubiculum (PrS) showed higher CART-immunoreactivity (-IR) than the parasubiculum (PaS) as far as the perikarya and neuropil were concerned. CART- IR cells were mainly observed in the pyramidal layer and occasionally in the molecular layer of the S. In the PrS and PaS, single CART-IR perikarya were dispersed, however with a tendency to be found only in superficial layers. CART-IR fibers were observed throughout the entire guinea pig subicular neuropil. Double-labeling immunofluorescence showed that CART-IR perikarya, as well as fibers, did not stain positively for any of the three CaBPs. CART-IR fibers were only located near the CB-, CR-, PV-IR perikarya, whereas CART-IR fibers occasionally intersected fibers containing one of the three CaBPs. The distribution pattern of CART was more similar to that of CB and CR than to that of PV. In the PrS, the CART, CB and CR immunoreactivity showed a laminar distribution pattern. In the case of the PV, this distribution pattern in the PrS was much less prominent than that of CART, CB and CR. We conclude that a heterogeneous distribution of the CART and CaBPs in the guinea pig SC is in keeping with findings from other mammals, however species specific differences have been observed. Copyright © 2015 Elsevier GmbH. All rights reserved.

Plasminogen stimulates propagation of protease-resistant prion protein in vitro.

PubMed

Mays, Charles E; Ryou, Chongsuk

2010-12-01

To clarify the role of plasminogen as a cofactor for prion propagation, we conducted functional assays using a cell-free prion protein (PrP) conversion assay termed protein misfolding cyclic amplification (PMCA) and prion-infected cell lines. Here, we report that plasminogen stimulates propagation of the protease-resistant scrapie PrP (PrP(Sc)). Compared to control PMCA conducted without plasminogen, addition of plasminogen in PMCA using wild-type brain material significantly increased PrP conversion, with an EC(50) = ∼56 nM. PrP conversion in PMCA was substantially less efficient with plasminogen-deficient brain material than with wild-type material. The activity stimulating PrP conversion was specific for plasminogen and conserved in its kringle domains. Such activity was abrogated by modification of plasminogen structure and interference of PrP-plasminogen interaction. Kinetic analysis of PrP(Sc) generation demonstrated that the presence of plasminogen in PMCA enhanced the PrP(Sc) production rate to ∼0.97 U/μl/h and reduced turnover time to ∼1 h compared to those (∼0.4 U/μl/h and ∼2.5 h) obtained without supplementation. Furthermore, as observed in PMCA, plasminogen and kringles promoted PrP(Sc) propagation in ScN2a and Elk 21(+) cells. Our results demonstrate that plasminogen functions in stimulating conversion processes and represents the first cellular protein cofactor that enhances the hypothetical mechanism of prion propagation.

Formally exact integral equation theory of the exchange-only potential in density functional theory: Refined closure approximation

NASA Astrophysics Data System (ADS)

March, N. H.; Nagy, Á.

A fonnally exact integral equation theory for the exchange-only potential Vx(r) in density functional theory was recently set up by Howard and March [I.A. Howard, N.H. March, J. Chem. Phys. 119 (2003) 5789]. It involved a `closure' function P(r) satisfying the exact sum rule ∫ P(r) dr = 0. The simplest choice P(r) = 0 recovers then the approximation proposed by Della Sala and Görling [F. Della Sala, A. Görling, J. Chem. Phys. 115 (2001) 5718] and by Gritsenko and Baerends [O.V. Gritsenko, E.J. Baerends, Phys. Rev. A 64 (2001) 042506]. Here, refined choices of P(r) are proposed, the most direct being based on the KLI (Krieger-Li-Iafrate) approximation. A further choice given some attention is where P(r) involves frontier orbital properties. In particular, the introduction of the LUMO (lowest unoccupied molecular) orbital, along with the energy separation between HOMO (highest occupied molecular orbital) and LUMO levels, should prove a significant step beyond current approximations to the optimized potential method, all of which involve only single-particle occupied orbitals.

The α-Secretase-derived N-terminal Product of Cellular Prion, N1, Displays Neuroprotective Function in Vitro and in Vivo*

PubMed Central

Guillot-Sestier, Marie-Victoire; Sunyach, Claire; Druon, Charlotte; Scarzello, Sabine; Checler, Frédéric

2009-01-01

Cellular prion protein (PrPc) undergoes a disintegrin-mediated physiological cleavage, generating a soluble amino-terminal fragment (N1), the function of which remained unknown. Recombinant N1 inhibits staurosporine-induced caspase-3 activation by modulating p53 transcription and activity, whereas the PrPc-derived pathological fragment (N2) remains biologically inert. Furthermore, N1 protects retinal ganglion cells from hypoxia-induced apoptosis, reduces the number of terminal deoxynucleotidyltransferase-mediated biotinylated UTP nick end labeling-positive and p53-immunoreactive neurons in a pressure-induced ischemia model of the rat retina and triggers a partial recovery of b-waves but not a-waves of rat electroretinograms. Our work is the first demonstration that the α-secretase-derived PrPc fragment N1, but not N2, displays in vivo and in vitro neuroprotective function by modulating p53 pathway. It further demonstrates that distinct N-terminal cleavage products of PrPc harbor different biological activities underlying the various phenotypes linking PrPc to cell survival. PMID:19850936

Prion protein β2–α2 loop conformational landscape

PubMed Central

Caldarulo, Enrico; Wüthrich, Kurt; Parrinello, Michele

2017-01-01

In transmissible spongiform encephalopathies (TSEs), which are lethal neurodegenerative diseases that affect humans and a wide range of other mammalian species, the normal “cellular” prion protein (PrPC) is transformed into amyloid aggregates representing the “scrapie form” of the protein (PrPSc). Continued research on this system is of keen interest, since new information on the physiological function of PrPC in healthy organisms is emerging, as well as new data on the mechanism of the transformation of PrPC to PrPSc. In this paper we used two different approaches: a combination of the well-tempered ensemble (WTE) and parallel tempering (PT) schemes and metadynamics (MetaD) to characterize the conformational free-energy surface of PrPC. The focus of the data analysis was on an 11-residue polypeptide segment in mouse PrPC(121–231) that includes the β2–α2 loop of residues 167–170, for which a correlation between structure and susceptibility to prion disease has previously been described. This study includes wild-type mouse PrPC and a variant with the single-residue replacement Y169A. The resulting detailed conformational landscapes complement in an integrative manner the available experimental data on PrPC, providing quantitative insights into the nature of the structural transition-related function of the β2–α2 loop. PMID:28827331

Enhanced susceptibility of Prnp-deficient mice to kainate-induced seizures, neuronal apoptosis, and death: Role of AMPA/kainate receptors.

PubMed

Rangel, Alejandra; Burgaya, Ferran; Gavín, Rosalina; Soriano, Eduardo; Aguzzi, Adriano; Del Río, José A

2007-09-01

Normal physiologic functions of the cellular prion protein (PrPc) are still elusive. This GPI-anchored protein exerts many functions, including roles in neuron proliferation, neuroprotection or redox homeostasis. There are, however, conflicting data concerning its role in synaptic transmission. Although several studies report that PrPc participates in NMDA-mediated neurotransmission, parallel studies describe normal behavior of PrPc-mutant mice. Abnormal axon connections have been described in the dentate gyrus of the hippocampi of PrPc-deficient mice similar to those observed in epilepsy. A study indicates increased susceptibility to kainate (KA) in these mutant mice. We extend the observation of these studies by means of several histologic and biochemical analyses of KA-treated mice. PrPc-deficient mice showed increased sensitivity to KA-induced seizures in vivo and in vitro in organotypic slices. In addition, we show that this sensitivity is cell-specific because interference experiments to abolish PrPc expression increased susceptibility to KA in PrPc-expressing cells. We indicate a correlation of susceptibility to KA in cells lacking PrPc with the differential expression of GluR6 and GluR7 KA receptor subunits using real-time RT-PCR methods. These results indicate that PrPc exerts a neuroprotective role against KA-induced neurotoxicity, probably by regulating the expression of KA receptor subunits. (c) 2007 Wiley-Liss, Inc.

Moss Pathogenesis-Related-10 Protein Enhances Resistance to Pythium irregulare in Physcomitrella patens and Arabidopsis thaliana

PubMed Central

Castro, Alexandra; Vidal, Sabina; Ponce de León, Inés

2016-01-01

Plants respond to pathogen infection by activating signaling pathways leading to the accumulation of proteins with diverse roles in defense. Here, we addressed the functional role of PpPR-10, a pathogenesis-related (PR)-10 gene, of the moss Physcomitrella patens, in response to biotic stress. PpPR-10 belongs to a multigene family and encodes a protein twice the usual size of PR-10 proteins due to the presence of two Bet v1 domains. Moss PR-10 genes are differentially regulated during development and inoculation with the fungal pathogen Botrytis cinerea. Specifically, PpPR-10 transcript levels increase significantly by treatments with elicitors of Pectobacterium carotovorum subsp. carotovorum, spores of B. cinerea, and the defense hormone salicylic acid. To characterize the role of PpPR-10 in plant defense against pathogens, we conducted overexpression analysis in P. patens and in Arabidopsis thaliana. We demonstrate that constitutive expression of PpPR-10 in moss tissues increased resistance against the oomycete Pythium irregulare. PpPR-10 overexpressing moss plants developed less symptoms and decreased mycelium growth than wild type plants. In addition, PpPR-10 overexpressing plants constitutively produced cell wall depositions in protonemal tissue. Ectopic expression of PpPR-10 in Arabidopsis resulted in increased resistance against P. irregulare as well, evidenced by smaller lesions and less cellular damage compared to wild type plants. These results indicate that PpPR-10 is functionally active in the defense against the pathogen P. irregulare, in both P. patens and Arabidopsis, two evolutionary distant plants. Thus, P. patens can serve as an interesting source of genes to improve resistance against pathogen infection in flowering plants. PMID:27200053

Azole Functionalized Polyoxo-Titanium Clusters with Sunlight-Driven Dye Degradation Applications: Synthesis, Structure, and Photocatalytic Studies.

PubMed

Narayanam, Nagaraju; Chintakrinda, Kalpana; Fang, Wei-Hui; Kang, Yao; Zhang, Lei; Zhang, Jian

2016-10-06

Six polyoxo-titanium clusters (PTCs) with varying nuclearities containing Ti-N bonds and heteronuclearity, namely, [Ti 6 (μ 3 -O) 2 (μ 2 -O) 2 (O 3 P-Phen) 2 (OiPr) 10 (1-hbta) 2 ] (PTC-37), Ti 8 (μ 3 -O) 2 (μ 2 -O) 2 (O 3 P-Phen) 2 (OiPr) 16 (adn) 2 (NO 3 ) 2 ] (PTC-38), [Ti 4 (μ 3 -O)(μ 2 -O)(μ 2 -OiPr) 2 (OiPr) 4 (O 3 P-Phen) 3 (1,10-phn)](HOiPr) (PTC-39), [Ti 4 (μ 3 -O)(μ 2 -OiPr) 3 (OiPr) 5 (O 3 P-Phen) 3 (Im)] (PTC-40), [Ti 4 (μ 3 -O)(μ 2 -OiPr) 3 (OiPr) 5 (O 3 P-Phen) 3 (Im)][Ti 3 M(μ 3 -O)(μ 2 -OiPr) 3 (OiPr) 3 (O 3 P-Phen) 3 (Im)] (M = Co for PTC-41 and M = Zn for PTC-42; O 3 P-Phen = phenyl phosphonate, 1-hbta = 1-hydroxy benzotriazolate, adn = adenine, 1,10-phn = 1,10-phenanthroline, Im = imidazolate, and OiPr = isopropoxide) were prepared as crystalline samples and structurally characterized. Simultaneous doping of nitrogen and transition metal heteroatoms into the Ti-O clusters created complex chemical environments in the resulting hybrid materials. Thus, photocatalytic methylene blue degradation studies were performed to understand structure-property relationships in these Ti cluster-based materials. The complex chemical environment created in these novel molecular clusters had proved to exhibit ligand-dependent photocatalytic activities under normal sunlight. Adenine-functionalized PTC-38 presented moderate activities, while other PTCs all show rapid dye degradation.

Prolonged-Release Oxycodone/Naloxone Improves Anal Sphincter Relaxation Compared to Oxycodone Plus Macrogol 3350.

PubMed

Poulsen, Jakob Lykke; Brock, Christina; Grønlund, Debbie; Liao, Donghua; Gregersen, Hans; Krogh, Klaus; Drewes, Asbjørn Mohr

2017-11-01

Opioid analgesics inhibit anal sphincter function and contribute to opioid-induced bowel dysfunction (OIBD). However, it is unknown whether the inhibition can be reduced by opioid antagonism with prolonged-release (PR) naloxone and how this compares to laxative treatment. To compare the effects of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350 on anal sphincter function and gastrointestinal symptoms. A randomized, double-blind, crossover trial was conducted in 20 healthy men. Participants were treated for 5 days with combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Resting anal pressure, anal canal distensibility, and relaxation of the internal sphincter to rectal distension were evaluated before treatment (baseline) and on day 5. The Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire, stool frequency, and stool consistency were assessed daily. Both PR oxycodone/naloxone and PR oxycodone plus macrogol treatment decreased sphincter relaxation compared to baseline (- 27.5%; P < 0.001 and - 14.7%; P = 0.01). However, sphincter relaxation was increased after PR naloxone/oxycodone treatment compared to macrogol (difference = + 17.6%; P < 0.001). Resting anal pressure and anal canal distensibility did not differ between treatments. PAC-SYM abdominal symptoms score was lower during PR naloxone compared to macrogol (0.2 vs. 3.2; P = 0.002). The number of bowel movements was lower during PR naloxone versus macrogol (4.2 vs. 5.4; P = 0.035). Relaxation of the internal anal sphincter was significantly better after PR oxycodone/naloxone treatment compared to PR oxycodone plus macrogol 3350. These findings highlight that OIBD may require specific therapy against the complex, pan-intestinal effects of opioids.

Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions*

PubMed Central

Hu, Ping Ping; Morales, Rodrigo; Duran-Aniotz, Claudia; Moreno-Gonzalez, Ines; Khan, Uffaf; Soto, Claudio

2016-01-01

One intriguing feature of prion diseases is their strain variation. Prion strains are differentiated by the clinical consequences they generate in the host, their biochemical properties, and their potential to infect other animal species. The selective targeting of these agents to specific brain structures have been extensively used to characterize prion strains. However, the molecular basis dictating strain-specific neurotropism are still elusive. In this study, isolated brain structures from animals infected with four hamster prion strains (HY, DY, 139H, and SSLOW) were analyzed for their content of protease-resistant PrPSc. Our data show that these strains have different profiles of PrP deposition along the brain. These patterns of accumulation, which were independent of regional PrPC production, were not reproduced by in vitro replication when different brain regions were used as substrate for the misfolding-amplification reaction. On the contrary, our results show that in vitro replication efficiency depended exclusively on the amount of PrPC present in each part of the brain. Our results suggest that the variable regional distribution of PrPSc in distinct strains is not determined by differences on prion formation, but on other factors or cellular pathways. Our findings may contribute to understand the molecular mechanisms of prion pathogenesis and strain diversity. PMID:27056328

Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.

PubMed

Chen, RuiQi; Yu, Yue; Dong, Xuesen

2017-02-01

Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cryo-immunogold electron microscopy for prions: toward identification of a conversion site.

PubMed

Godsave, Susan F; Wille, Holger; Kujala, Pekka; Latawiec, Diane; DeArmond, Stephen J; Serban, Ana; Prusiner, Stanley B; Peters, Peter J

2008-11-19

Prion diseases are caused by accumulation of an abnormally folded isoform (PrP(Sc)) of the cellular prion protein (PrP(C)). The subcellular distribution of PrP(Sc) and the site of its formation in brain are still unclear. We performed quantitative cryo-immunogold electron microscopy on hippocampal sections from mice infected with the Rocky Mountain Laboratory strain of prions. Two antibodies were used: R2, which recognizes both PrP(C) and PrP(Sc); and F4-31, which only detects PrP(C) in undenatured sections. At a late subclinical stage of prion infection, both PrP(C) and PrP(Sc) were detected principally on neuronal plasma membranes and on vesicles resembling early endocytic or recycling vesicles in the neuropil. The R2 labeling was approximately six times higher in the infected than the uninfected hippocampus and gold clusters were only evident in infected tissue. The biggest increase in labeling density (24-fold) was found on the early/recycling endosome-like vesicles of small-diameter neurites, suggesting these as possible sites of conversion. Trypsin digestion of infected hippocampal sections resulted in a reduction in R2 labeling of >85%, which suggests that a high proportion of PrP(Sc) may be oligomeric, protease-sensitive PrP(Sc).

Survival Benefits of Small Anatomical Resection of the Liver for Patients with Hepatocellular Carcinoma and Impaired Liver Function, Based on New-Era Imaging Studies.

PubMed

Sakoda, Masahiko; Ueno, Shinichi; Iino, Satoshi; Hiwatashi, Kiyokazu; Minami, Koji; Kawasaki, Yota; Kurahara, Hiroshi; Mataki, Yuko; Maemura, Kosei; Shinchi, Hiroyuki; Natsugoe, Shoji

2016-01-01

It has been reported that anatomical resection of the liver may be preferred for primary hepatocellular carcinoma (HCC), and is at least recommended for systematic removal of a segment confined by tumor-bearing portal tributaries. However, nonanatomical resection (NAR) is often selected because of the patient's background, impairment of liver function, and tumor factors. The aims of the present study were to retrospectively compare the recurrence-free survival (RFS) rates for cases of partial resection (PR) and for small anatomical resection (SAR), which is regarded as NAR for primary HCC with impaired liver function. So-called NAR was performed for a primary and solitary (≤ 5cm) HCC in 47 patients; the patients were classified into PR (n=25) and SAR (n=22) groups. Clinicopathological factors, survival data, and recurrence patterns were compared between groups. There were no significant differences in the preoperative characteristics between the two groups. Operative time was significantly longer in the SAR group than in the PR group. There was no significant difference in the postoperative morbidity and tumor pathological characteristics between the two groups. The RFS of the SAR group was significantly better than those of the PR group. Although there was no significant difference in the pattern of recurrence between the two groups, the rate of intrahepatic recurrence in the same segment as the initial tumor tended to be higher in the PR group than in the SAR group. Multivariate analysis revealed that only the PR operative procedure was significant independent risk factor for poorer RFS. Compared with PR, SAR effectively improves the rate of RFS after surgery for a primary and solitary HCC with impaired liver function.

Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus

PubMed Central

Mehta, Fabiola F.; Son, Jieun; Hewitt, Sylvia C.; Jang, Eunjung; Lydon, John P.; Korach, Kenneth S.; Chung, Sang-Hyuk

2016-01-01

While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock−in mouse models expressing ERα mutants, we determined that the DNA−binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus. PMID:27007157

Effect of Bhrāmarī Prāṇāyāma Practice on Pulmonary Function in Healthy Adolescents: A Randomized Control Study.

PubMed

Kuppusamy, Maheshkumar; Dilara, K; Ravishankar, P; Julius, A

2017-01-01

Prāṇāyāma , the fourth limb of ancient aṣṭāṅga yoga consists of breathing techniques which produce various physiological and psychological effects. Though various types of prāṇāyāma and their effects have been scientifically established, Bhrāmarī prāṇāyāma (Bhr.P) is the one whose effects still remain understated. The present study was conducted to find the effects of Bhrāmarī prāṇāyāma practice on pulmonary function in healthy adolescents. Randomized control trial. 90 healthy adolescents including 32 females and 58 males participated in the study. They were randomly divided into Bhr.P group ( n = 45) and Control group ( n = 45) by a simple lottery method. Pulmonary function test was done at baseline and at end of 12 th week using RMS Helios spirometry. Prāṇāyāma group students were trained to do Bhr.P as 3 to 4 breaths/min for 5 min followed by 2 min rest. This was one cycle and in this way, they were instructed to do five cycles each time for 45 minutes five days in a week. Control group students were not allowed to practice any kind of exercise throughout the study period. Student paired and unpaired T tests were used to analyse the intra group and intergroup differences using R statistical software. A significant ( P < 0.05) improvement in all pulmonary function parameters; FVC, FEV1, FEV1/FVC ratio, FEF 25%-75% and PEFR was seen in the Bhr.P group than the control group adolescents. Slow vital capacity (SVC) and Maximum Voluntary Volume (MVV) also showed significant improvement in the prāṇāyāma group. Bhrāmarī Prāṇāyāma practice is effective in improving the pulmonary function among the adolescents which could be utilized for further clinical studies.

Disease-Associated Prion Protein in Neural and Lymphoid Tissues of Mink (Mustela vison) Inoculated with Transmissible Mink Encephalopathy

PubMed Central

Schneider, D. A.; Harrington, R. D.; Zhuang, D.; Yan, H.; Truscott, T. C.; Dassanayake, R. P.; O'Rourke, K. I.

2012-01-01

Summary Transmissible spongiform encephalopathies (TSEs) are diagnosed by immunodetection of disease-associated prion protein (PrPd). The distribution of PrPd within the body varies with the time-course of infection and between species, during interspecies transmission, as well as with prion strain. Mink are susceptible to a form of TSE known as transmissible mink encephalopathy (TME), presumed to arise due to consumption of feed contaminated with a single prion strain of ruminant origin. After extended passage of TME isolates in hamsters, two strains emerge, HY and DY, each of which is associated with unique structural isoforms of PrPTME and of which only the HY strain is associated with accumulation of PrPTME in lymphoid tissues. Information on the structural nature and lymphoid accumulation of PrPTME in mink is limited. In this study, 13 mink were challenged by intracerebral inoculation using late passage TME inoculum after which brain and lymphoid tissues were collected at preclinical and clinical time points. The distribution and molecular nature of PrPTME was investigated by techniques including blotting of paraffin wax-embedded tissue and epitope mapping by western blotting. PrPTME was detected readily in the brain and retropharyngeal lymph node during preclinical infection with delayed progression of accumulation within other lymphoid tissues. For comparison, three mink were inoculated by the oral route and examined during clinical disease. Accumulation of PrPTME in these mink was greater and more widespread, including follicles of rectoanal mucosa-associated lymphoid tissue. Western blot analyses revealed that PrPTME accumulating in the brain of mink is structurally most similar to that accumulating in the brain of hamsters infected with the DY strain. Collectively, the results of extended passage in mink are consistent with the presence of only a single strain of TME, the DY strain, capable of inducing accumulation of PrPTME in the lymphoid tissues of mink but not in hamsters. Thus mink are a relevant animal model for further study of this unique strain, which ultimately may have been introduced through consumption of a TSE of ruminant origin. PMID:22595634

Thermodynamics of reaction of praseodymium with gallium-indium eutectic alloy

NASA Astrophysics Data System (ADS)

Melchakov, S. Yu.; Ivanov, V. A.; Yamshchikov, L. F.; Volkovich, V. A.; Osipenko, A. G.; Kormilitsyn, M. V.

2013-06-01

Thermodynamic properties of Ga-In eutectic alloys saturated with praseodymium were determined for the first time employing the electromotive force method. The equilibrium potentials of the Pr-In alloys saturated with praseodymium (8.7-12.1 mol.% Pr) and Pr-Ga-In alloys (containing 0.0012-6.71 mol.% Pr) were measured between 573-1073 K. Pr-In alloy containing solid PrIn3 with known thermodynamic properties was used as the reference electrode when measuring the potentials of ternary Pr-In-Ga alloys. Activity, partial and excessive thermodynamic functions of praseodymium in alloys with indium and Ga-In eutectic were calculated. Activity (a), activity coefficients (γ) and solubility (X) of praseodymium in the studied temperature range can be expressed by the following equations: lgaα-Pr(In) = 4.425 - 11965/T ± 0.026. lgаα-Pr(Ga-In) = 5.866 - 14766/T ± 0.190. lgγα-Pr(Ga-In) = 2.351 - 9996/T ± 0.39. lgХPr(Ga-In) = 3.515 - 4770/T ± 0.20.

Novel orally available salvinorin A analog PR-38 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome.

PubMed

Sałaga, M; Polepally, P R; Sobczak, M; Grzywacz, D; Kamysz, W; Sibaev, A; Storr, M; Do Rego, J C; Zjawiony, J K; Fichna, J

2014-07-01

The opioid and cannabinoid systems play a crucial role in multiple physiological processes in the central nervous system and in the periphery. Selective opioid as well as cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain. In this study, we examined (in vitro and in vivo) whether PR-38 (2-O-cinnamoylsalvinorin B), a novel analog of salvinorin A, can interact with both systems and demonstrate therapeutic effects. We used mouse models of hypermotility, diarrhea, and abdominal pain. We also assessed the influence of PR-38 on the central nervous system by measurement of motoric parameters and exploratory behaviors in mice. Subsequently, we investigated the pharmacokinetics of PR-38 in mouse blood samples after intraperitoneal and oral administration. PR-38 significantly inhibited mouse colonic motility in vitro and in vivo. Administration of PR-38 significantly prolonged the whole GI transit time, and this effect was mediated by µ- and κ-opioid receptors and the CB1 receptor. PR-38 reversed hypermotility and reduced pain in mouse models mimicking functional GI disorders. These data expand our understanding of the interactions between opioid and cannabinoid systems and their functions in the GI tract. We also provide a novel framework for the development of future potential treatments of functional GI disorders. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Visualization of early events in acetic acid denaturation of HIV-1 protease: a molecular dynamics study.

PubMed

Borkar, Aditi Narendra; Rout, Manoj Kumar; Hosur, Ramakrishna V

2011-01-01

Protein denaturation plays a crucial role in cellular processes. In this study, denaturation of HIV-1 Protease (PR) was investigated by all-atom MD simulations in explicit solvent. The PR dimer and monomer were simulated separately in 9 M acetic acid (9 M AcOH) solution and water to study the denaturation process of PR in acetic acid environment. Direct visualization of the denaturation dynamics that is readily available from such simulations has been presented. Our simulations in 9 M AcOH reveal that the PR denaturation begins by separation of dimer into intact monomers and it is only after this separation that the monomer units start denaturing. The denaturation of the monomers is flagged off by the loss of crucial interactions between the α-helix at C-terminal and surrounding β-strands. This causes the structure to transit from the equilibrium dynamics to random non-equilibrating dynamics. Residence time calculations indicate that denaturation occurs via direct interaction of the acetic acid molecules with certain regions of the protein in 9 M AcOH. All these observations have helped to decipher a picture of the early events in acetic acid denaturation of PR and have illustrated that the α-helix and the β-sheet at the C-terminus of a native and functional PR dimer should maintain both the stability and the function of the enzyme and thus present newer targets for blocking PR function.

Modulation of Progesterone Receptor Isoform Expression in Pregnant Human Myometrium

PubMed Central

2017-01-01

Background. Regulation of myometrial progesterone receptor (PR) expression is an unresolved issue central to understanding the mechanism of functional progesterone withdrawal and initiation of labor in women. Objectives. To determine whether pregnant human myometrium undergoes culture-induced changes in PR isoform expression ex situ and, further, to determine if conditions approaching the in vivo environment stabilise PR isoform expression in culture. Methods. Term nonlaboring human myometrial tissues were cultured under specific conditions: serum supplementation, steroids, stretch, cAMP, PMA, PGF2α, NF-κB inhibitors, or TSA. Following 48 h culture, PR-T, PR-A, and PR-B mRNA levels were determined using qRT-PCR. PR-A/PR-B ratios were calculated. Results. PR-T and PR-A expression and the PR-A/PR-B ratio significantly increased in culture. Steroids prevented the culture-induced increase in PR-T and PR-A expression. Stretch blocked the effects of steroids on PR-T and PR-A expression. PMA further increased the PR-A/PR-B ratio, while TSA blocked culture-induced increases of PR-A expression and the PR-A/PR-B ratio. Conclusion. Human myometrial tissue in culture undergoes changes in PR gene expression consistent with transition toward a laboring phenotype. TSA maintained the nonlaboring PR isoform expression pattern. This suggests that preserving histone and/or nonhistone protein acetylation is critical for maintaining the progesterone dependent quiescent phenotype of human myometrium in culture. PMID:28540297

Purification, cloning, functional expression and characterization of perakine reductase: the first example from the AKR enzyme family, extending the alkaloidal network of the plant Rauvolfia.

PubMed

Sun, Lianli; Ruppert, Martin; Sheludko, Yuri; Warzecha, Heribert; Zhao, Yu; Stöckigt, Joachim

2008-07-01

Perakine reductase (PR) catalyzes an NADPH-dependent step in a side-branch of the 10-step biosynthetic pathway of the alkaloid ajmaline. The enzyme was cloned by a "reverse-genetic" approach from cell suspension cultures of the plant Rauvolfia serpentina (Apocynaceae) and functionally expressed in Escherichia coli as the N-terminal His(6)-tagged protein. PR displays a broad substrate acceptance, converting 16 out of 28 tested compounds with reducible carbonyl function which belong to three substrate groups: benzaldehyde, cinnamic aldehyde derivatives and monoterpenoid indole alkaloids. The enzyme has an extraordinary selectivity in the group of alkaloids. Sequence alignments define PR as a new member of the aldo-keto reductase (AKR) super family, exhibiting the conserved catalytic tetrad Asp52, Tyr57, Lys84, His126. Site-directed mutagenesis of each of these functional residues to an alanine residue results in >97.8% loss of enzyme activity, in compounds of each substrate group. PR represents the first example of the large AKR-family which is involved in the biosynthesis of plant monoterpenoid indole alkaloids. In addition to a new esterase, PR significantly extends the Rauvolfia alkaloid network to the novel group of peraksine alkaloids.

Geographic differences in the distribution of molecular subtypes of breast cancer in Brazil

PubMed Central

2014-01-01

Background To compare the distribution of the intrinsic molecular subtypes of breast cancer based on immunohistochemical profile in the five major geographic regions of Brazil, a country of continental dimension, with a wide racial variation of people. Methods The study was retrospective observational. We classified 5,687 invasive breast cancers by molecular subtype based on immunohistochemical expression of estrogen-receptor (ER), progesterone-receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 proliferation index. Cases were classified as luminal A (ER and/or PR positive and HER2 negative, Ki-67 < 14%), luminal B (ER and/or PR positive, HER2 negative, and Ki-67 > 14%), triple-positive (ER and/or PR positive and HER2 positive), HER2-enriched (ER and PR negative, and HER2- positive), and triple-negative (TN) (ER negative, PR negative, and HER2- negative). Comparisons of the ages of patients and molecular subtypes between different geographic regions were performed. Results South and Southeast regions with a higher percentage of European ancestry and higher socioeconomic status presented with the highest proportion of luminal tumors. The North region presented with more aggressive subtypes (HER2-enriched and triple-negative), while the Central-West region predominated triple-positive carcinomas. The Northeast—a region with a high African influence—presented intermediate frequency of the different molecular subtypes. The differences persisted in subgroups of patients under and over 50 years. Conclusions The geographic regions differ according to the distribution of molecular subtypes of breast cancer. However, other differences, beside those related to African ancestry, such as socioeconomic, climatic, nutritional, and geographic, have to be considered to explain our results. The knowledge of the differences in breast cancer characteristics among the geographic regions may help to organize healthcare programs in large countries like Brazil with diverse economic and race composition among different geographic regions. PMID:25174527

A Method to Retrieve Rainfall Rate over Land from TRMM Observations

NASA Technical Reports Server (NTRS)

Prabhakara, C.; Iacovazzi, R., Jr.; Yoo, J.-M.

2002-01-01

Tropical Rainfall Measuring Mission (TRMM) Precipitation Radar (PR) observations over mesoscale convective systems (MCSs) reveal that there are localized maxima in the rain rate with a scale of about 10 to 20 km that represent thunderstorms (Cbs). Some of these Cbs are developing or intense, while others are decaying or weak. These Cbs constitute only about 20 % of the rain area of a given MCS. Outside of Cbs, the average rain rate is much weaker than that within Cbs. From an analysis of the PR data, we find that the spatial distribution of rain and its character, convective or stratiform, is highly inhomogeneous. This complex nature of rain exists on a scale comparable to that of a Cb. The 85 GHz brightness temperature, T85, observations of the TRMM Microwave Imager (TMI) radiometer taken over an MCS reflect closely the PR rain rate pattern over land. Local maxima in rain rate shown by PR are observed as local minima in T85. Where there are no minima in T85, PR observations indicate there is light rain. However, the TMI brightness temperature measurements (Tbs) have poor ability to discriminate convective rain from stratiform rain. For this reason, a TMI rain retrieval procedure that depends primarily on the magnitude of Tbs performs poorly. In order to retrieve rain rate from TMI data on land one has to include the spatial distribution information deduced from the T85 data in the retrieval method. Then, quantitative estimation of rain rate can be accomplished. A TMI rain retrieval method developed along these lines can yield estimates of rain rate and its frequency distribution which agree closely with that given by PR. We find the current TRMM project TMI (Version 5) rain retrieval algorithm on land could be improved with the retrieval scheme developed here. To support the conceptual frame work of the rain retrieval method developed here, a theoretical analysis of the TMI brightness temperatures in convective and stratiform regions is presented.

Structural and electrochemical characterization of carbon supported Pt-Pr catalysts for direct ethanol fuel cells prepared using a modified formic acid method in a CO atmosphere.

PubMed

Corradini, Patricia Gon; Antolini, Ermete; Perez, Joelma

2013-07-28

Pt-Pr/C electrocatalysts were prepared using a modified formic acid method, and their activity for carbon monoxide and ethanol oxidation was compared to Pt/C. No appreciable alloy formation was detected by XRD analysis. By TEM measurements it was found that Pt particle size increases with an increasing Pr content in the catalysts and with decreasing metal precursor addition time. XPS measurements indicated Pt segregation on the catalyst surface and the presence of Pr2O3 and PrO2 oxides. The addition of Pr increased the electro-catalytic activity of Pt for both CO and CH3CH2OH oxidation. The enhanced activity of Pt-Pr/C catalysts was ascribed to both an electronic effect, caused by the presence of Pr2O3, and the bi-functional mechanism, caused by the presence of PrO2.

Proteasome inhibitors promote the sequestration of PrPSc into aggresomes within the cytosol of prion-infected CAD neuronal cells.

PubMed

Dron, Michel; Dandoy-Dron, Françoise; Farooq Salamat, Muhammad Khalid; Laude, Hubert

2009-08-01

Dysfunction of the endoplasmic reticulum associated protein degradation/proteasome system is believed to contribute to the initiation or aggravation of neurodegenerative disorders associated with protein misfolding, and there is some evidence to suggest that proteasome dysfunctions might be implicated in prion disease. This study investigated the effect of proteasome inhibitors on the biogenesis of both the cellular (PrP(C)) and abnormal (PrP(Sc)) forms of prion protein in CAD neuronal cells, a newly introduced prion cell system. In uninfected cells, proteasome impairment altered the intracellular distribution of PrP(C), leading to a strong accumulation in the Golgi apparatus. Moreover, a detergent-insoluble and weakly protease-resistant PrP species of 26 kDa, termed PrP(26K), accumulated in the cells, whether they were prion-infected or not. However, no evidence was found that, in infected cells, this PrP(26K) species converts into the highly proteinase K-resistant PrP(Sc). In the infected cultures, proteasome inhibition caused an increased intracellular aggregation of PrP(Sc) that was deposited into large aggresomes. These findings strengthen the view that, in neuronal cells expressing wild-type PrP(C) from the natural promoter, proteasomal impairment may affect both the process of PrP(C) biosynthesis and the subcellular sites of PrP(Sc) accumulation, despite the fact that these two effects could essentially be disconnected.

Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer

PubMed Central

Dai, Donghai; Meng, Xiangbing; Thiel, Kristina W.; Leslie, Kimberly K.; Yang, Shujie

2016-01-01

Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR). However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term “molecularly enhanced progestin therapy.” What remained unclear was the mechanism of action and if estrogen receptor α (ERα), the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi) was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA) database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data reveal a previously unanticipated inverse relationship between the tumor suppressor PR and the oncogene Myc in endometrial cancer. PMID:26859414

Low- and high-spin excited states in 139Pr

NASA Astrophysics Data System (ADS)

Aryaeinejad, R.; McHarris, Wm. C.

1988-05-01

The level structure of the N=80 nucleus 139Pr has been studied in-beam by the 140Ce(p,2nγ)139Pr reaction using a 25-MeV p beam and by the 139La(α,4nγ)139Pr reaction using a 47-MeV α beam. γ-ray singles, γ-γ coincidence (prompt and delayed), and γ-ray angular distribution experiments were performed. We have assigned 41 γ rays deexciting 24 states in 139Pr from the (p,2nγ) reaction and 43 γ rays deexciting 31 (generally higher-spin) states from the (α,4nγ) reaction, for a total of 43 different states. These in-beam experiments, taken together with results from 139Ndm+g decay and the 141Pr(p,t)139Pr reaction, allowed Jπ assignments to be made for most of the states and allowed us to deduce the intrinsic configurations for many of them. These are discussed in terms of single-quasiparticle shell-model states and triaxial weak-coupled collective states and are compared with systematics for this nuclear region.

Pulmonary rehabilitation for mild COPD: a systematic review.

PubMed

Jácome, Cristina; Marques, Alda

2014-04-01

Pulmonary rehabilitation (PR) is effective in improving exercise capacity and health-related quality of life (HRQOL) in patients with moderate-to-very-severe COPD. Quadriceps strength and HRQOL can be impaired in patients with mild COPD, therefore, patients at this grade may already benefit from PR. However, the impact of PR in patients with mild COPD remains unestablished. Thus, this systematic review assessed the impact of PR on exercise capacity, HRQOL, health-care resource use and lung function in patients with mild COPD. The Web of Knowledge, EBSCO, MEDLINE, and SCOPUS databases were searched up to April 2013. Reviewers independently selected studies according to the eligibility criteria. Three studies with different designs (retrospective, one group pretest-posttest, and randomized controlled trial) were included. Out-patient PR programs were implemented in two studies, which included mainly aerobic, strength, and respiratory muscle training. The randomized controlled trial compared a PR home-based program, consisting of 6 months of walking and participating in ball games, with standard medical treatment. Significant improvements in exercise capacity (effect size [ES] 0.87-1.82) and HRQOL (ES 0.24-0.86) were found when comparing pretest-posttest data and when comparing PR with standard medical treatment. In one study, a significant decrease in hospitalization days was found (ES 0.38). No significant effects were observed on the number of emergency department visits (ES 0.32), number of hospitalizations (ES 0.219), or lung function (ES 0.198). Most of the PR programs had significant positive effects on exercise capacity and HRQOL in patients with mild COPD; however, their effects on health-care resource use and lung function were inconclusive. This systematic review suggests that patients with mild COPD may benefit from PR; however, insufficient evidence is still available. Studies with robust designs and with longer follow-up times should be conducted.

Persistence length changes dramatically as RNA folds.

PubMed

Caliskan, G; Hyeon, C; Perez-Salas, U; Briber, R M; Woodson, S A; Thirumalai, D

2005-12-31

We determine the persistence length l(p) for a bacterial group I ribozyme as a function of concentration of monovalent and divalent cations by fitting the distance distribution functions P(r) obtained from small angle x-ray scattering intensity data to the asymptotic form of the calculated P(WLC)(r) for a wormlike chain. The l(p) values change dramatically over a narrow range of Mg(2+) concentration from approximately 21 Angstroms in the unfolded state (U) to approximately 10 Angstroms in the compact (I(C)) and native states. Variations in l(p) with increasing Na(+) concentration are more gradual. In accord with the predictions of polyelectrolyte theory we find l(p) alpha 1/kappa(2) where kappa is the inverse Debye-screening length.

PRROC: computing and visualizing precision-recall and receiver operating characteristic curves in R.

PubMed

Grau, Jan; Grosse, Ivo; Keilwagen, Jens

2015-08-01

Precision-recall (PR) and receiver operating characteristic (ROC) curves are valuable measures of classifier performance. Here, we present the R-package PRROC, which allows for computing and visualizing both PR and ROC curves. In contrast to available R-packages, PRROC allows for computing PR and ROC curves and areas under these curves for soft-labeled data using a continuous interpolation between the points of PR curves. In addition, PRROC provides a generic plot function for generating publication-quality graphics of PR and ROC curves. © The Author 2015. Published by Oxford University Press.

Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells.

PubMed

Nazarenko, Irina; Schäfer, Reinhold; Sers, Christine

2007-04-15

HRSL3 (also known as H-REV107-1) belongs to a class II tumor suppressor gene family and is downregulated in several human tumors including ovarian carcinomas. To unravel the mechanism of HRSL3 tumor suppressor action, we performed a yeast two-hybrid screen and identified the alpha-isoform of the regulatory subunit A of protein phosphatase 2A (PR65alpha) as a new interaction partner of HRSL3. Interaction between HRSL3 and PR65alpha was confirmed in vitro and by co-immunoprecipitation in mammalian cells. We demonstrate that HRSL3 binds to the endogenous PR65alpha, thereby partially sequestering the catalytic subunit PR36 from the PR65 protein complex, and inhibiting PP2A catalytic activity. Furthermore, binding of HRSL3 to PR65 induces apoptosis in ovarian carcinoma cells in a caspase-dependent manner. Using several mutant HRSL3 constructs, we identified the N-terminal proline-rich region within the HRSL3 protein as the domain that is relevant for both binding of PR65alpha and induction of programmed cell death. This suggests that the negative impact of HRSL3 onto PP2A activity is important for the HRSL3 pro-apoptotic function and indicates a role of PP2A in survival of human ovarian carcinomas. The analysis of distinct PP2A target molecules revealed PKCzeta as being involved in HRSL3 action. These data implicate HRSL3 as a signaling regulatory molecule, which is functionally involved in the oncogenic network mediating growth and survival of ovarian cancer cells.

Plant Pathogenesis-Related Proteins PR-10 and PR-14 as Components of Innate Immunity System and Ubiquitous Allergens.

PubMed

Finkina, Ekaterina I; Melnikova, Daria N; Bogdanov, Ivan V; Ovchinnikova, Tatiana V

2017-01-01

Pathogenesis-related (PR) proteins are components of innate immunity system in plants. They play an important role in plant defense against pathogens. Lipid transfer proteins (LTPs) and Bet v 1 homologs comprise of two separate families of PR-proteins. Both LTPs (PR-14) and Bet v 1 homologs (PR-10) are multifunctional small proteins involving in plant response to abiotic and biotic stress conditions. The representatives of these PR-protein families do not show any sequence similarity but have other common biochemical features such as low molecular masses, the presence of hydrophobic cavities, ligand binding properties, and antimicrobial activities. Besides, many members of PR-10 and PR-14 families are ubiquitous plant panallergens which are able to cause sensitization of human immune system and crossreactive allergic reactions to plant food and pollen. This review is aimed at comparative analysis of structure-functional and allergenic properties of the PR-10 and PR-14 families, as well as prospects for their medicinal application. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis.

PubMed

Millet, Arnaud; Martin, Katherine R; Bonnefoy, Francis; Saas, Philippe; Mocek, Julie; Alkan, Manal; Terrier, Benjamin; Kerstein, Anja; Tamassia, Nicola; Satyanarayanan, Senthil Kumaran; Ariel, Amiram; Ribeil, Jean-Antoine; Guillevin, Loïc; Cassatella, Marco A; Mueller, Antje; Thieblemont, Nathalie; Lamprecht, Peter; Mouthon, Luc; Perruche, Sylvain; Witko-Sarsat, Véronique

2015-11-02

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology.

The Amino-Terminal PrP Domain Is Crucial to Modulate Prion Misfolding and Aggregation

PubMed Central

Cordeiro, Yraima; Kraineva, Julia; Gomes, Mariana P. B.; Lopes, Marilene H.; Martins, Vilma R.; Lima, Luís M. T. R.; Foguel, Débora; Winter, Roland; Silva, Jerson L.

2005-01-01

The main hypothesis for prion diseases is that the cellular protein (PrPC) can be altered into a misfolded, β-sheet-rich isoform (PrPSc), which undergoes aggregation and triggers the onset of transmissible spongiform encephalopathies. Here, we investigate the effects of amino-terminal deletion mutations, rPrPΔ51–90 and rPrPΔ32–121, on the stability and the packing properties of recombinant murine PrP. The region lacking in rPrPΔ51–90 is involved physiologically in copper binding and the other construct lacks more amino-terminal residues (from 32 to 121). The pressure stability is dramatically reduced with decreasing N-domain length and the process is not reversible for rPrPΔ51–90 and rPrPΔ32–121, whereas it is completely reversible for the wild-type form. Decompression to atmospheric pressure triggers immediate aggregation for the mutants in contrast to a slow aggregation process for the wild-type, as observed by Fourier-transform infrared spectroscopy. The temperature-induced transition leads to aggregation of all rPrPs, but the unfolding temperature is lower for the rPrP amino-terminal deletion mutants. The higher susceptibility to pressure of the amino-terminal deletion mutants can be explained by a change in hydration and cavity distribution. Taken together, our results show that the amino-terminal region has a pivotal role on the development of prion misfolding and aggregation. PMID:16040743

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis

PubMed Central

Millet, Arnaud; Martin, Katherine R.; Bonnefoy, Francis; Saas, Philippe; Mocek, Julie; Alkan, Manal; Terrier, Benjamin; Kerstein, Anja; Tamassia, Nicola; Satyanarayanan, Senthil Kumaran; Ariel, Amiram; Ribeil, Jean-Antoine; Guillevin, Loïc; Cassatella, Marco A.; Mueller, Antje; Thieblemont, Nathalie; Lamprecht, Peter; Mouthon, Luc; Perruche, Sylvain; Witko-Sarsat, Véronique

2015-01-01

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology. PMID:26436651

Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions.

PubMed

Hu, Ping Ping; Morales, Rodrigo; Duran-Aniotz, Claudia; Moreno-Gonzalez, Ines; Khan, Uffaf; Soto, Claudio

2016-06-10

One intriguing feature of prion diseases is their strain variation. Prion strains are differentiated by the clinical consequences they generate in the host, their biochemical properties, and their potential to infect other animal species. The selective targeting of these agents to specific brain structures have been extensively used to characterize prion strains. However, the molecular basis dictating strain-specific neurotropism are still elusive. In this study, isolated brain structures from animals infected with four hamster prion strains (HY, DY, 139H, and SSLOW) were analyzed for their content of protease-resistant PrP(Sc) Our data show that these strains have different profiles of PrP deposition along the brain. These patterns of accumulation, which were independent of regional PrP(C) production, were not reproduced by in vitro replication when different brain regions were used as substrate for the misfolding-amplification reaction. On the contrary, our results show that in vitro replication efficiency depended exclusively on the amount of PrP(C) present in each part of the brain. Our results suggest that the variable regional distribution of PrP(Sc) in distinct strains is not determined by differences on prion formation, but on other factors or cellular pathways. Our findings may contribute to understand the molecular mechanisms of prion pathogenesis and strain diversity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Functional and morphological characteristics of neuronal substance P in the canine gastroesophageal junction.

PubMed

Sandler, A D; Maher, J W; Weinstock, J V; Schmidt, C D; Schlegel, J F; Jew, J Y; Williams, T H

1993-10-01

The specific functions of the numerous substance P (SP) nerve fibers present within the gastrointestinal tract are not clearly defined. This study examines both functional aspects and distribution of immunoreactive SP (IR-SP) in the canine gastroesophageal junctional (GEJ) region. Lower esophageal sphincter pressure (LESP), mean arterial pressure (MAP), pulse rate (PR), and respiratory rate (RR) were monitored before and after topical application of 2 ml capsaicin (8-methyl-N-vanillyl-6-nonenamide) to the distal esophageal mucosa of anesthetized dogs. Animals then underwent a capsaicin desensitization protocol over a 12-day period. The responses of monitored variables were compared on Day 1 and Day 12 of repetitive capsaicin application. Immunohistochemistry and radioimmunoassay (RIA) were performed on GEJ segments to study the distribution and content of IR-SP in both control (untreated) and capsaicin-treated dogs. The IR-SP was extracted from tissue for RIA and analysis by reverse-phase high-performance liquid chromatography (HPLC). On Day 1, a 2-ml capsaicin application stimulated increases in LESP (44.3 +/- 7.8 cm H2O; P < 0.05), MAP (48 +/- 8.7 mm Hg; P < 0.05), PR (52.6 +/- 20.5 beats/min; P < 0.05), and RR (26.3 +/- 15.6 breaths/min; P > 0.2). No response was observed on Day 12 of treatment. This was accompanied by a 43.3% decrease of IR-SP content in the mucosa of the distal esophagus of desensitized animals. Capsaicin applied at greater concentrations on Day 12 stimulated a return of responses (P < 0.05). Ganglia, cell bodies, nerve fascicles, and neurites stained positively for IR-SP. IR-SP content was markedly higher in esophageal mucosa than in gastric mucosa (P < 0.05). The authenticity of the IR-SP molecule was confirmed by elution time on HPLC. In conclusion, repetitive capsaicin application induced a state of homologous desensitization which was accompanied by a partial depletion of mucosal SP. The GEJ region contains a high SP content with a broad neural distribution. These findings are consistent with the hypothesis that SP may act as a neurotransmitter for chemonociceptive stimuli in the canine distal esophagus.

Benefits of Pulmonary Rehabilitation in Idiopathic Pulmonary Fibrosis

PubMed Central

Swigris, Jeffrey J.; Fairclough, Diane L.; Morrison, Marianne; Make, Barry; Kozora, Elizabeth; Brown, Kevin K.; Wamboldt, Frederick S.

2013-01-01

BACKGROUND Information on the benefits of pulmonary rehabilitation (PR) in patients with idiopathic pulmonary fibrosis (IPF) is growing, but PR’s effects on certain important outcomes is lacking. METHODS We conducted a pilot study of PR in IPF and analyzed changes in functional capacity, fatigue, anxiety, depression, sleep, and health status from baseline to after completion of a standard, 6-week PR program. RESULTS Six-min walk distance improved a mean ± standard error 202 ± 135 feet (P = .01) from baseline. Fatigue Severity Scale score also improved significantly, declining an average 1.5 ± 0.5 points from baseline. There were trends toward improvement in anxiety, depression, and health status. CONCLUSIONS PR improves functional capacity and fatigue in patients with IPF. (ClinicalTrials.gov registration NCT00692796.) PMID:21333082

Behavioral abnormalities in prion protein knockout mice and the potential relevance of PrPc for the cytoskeleton

USDA-ARS?s Scientific Manuscript database

The cellular prion protein (PrPC) is a highly conserved protein, which is anchored to the outer surface of the plasma membrane. Even though its physiological function has already been investigated in different cell or mouse models where PrPC expression is either up-regulated or depleted, its exact p...

Public Relations for Brazilian Libraries: Process, Principles, Program Planning, Planning Techniques and Suggestions.

ERIC Educational Resources Information Center

Kies, Cosette N.

A brief overview of the functions of public relations in libraries introduces this manual, which provides an explanation of the public relations (PR) process, including fact-finding, planning, communicating, evaluating, and marketing; some PR principles; a 10-step program that could serve as a model for planning a PR program; a discussion of PR…

Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population.

PubMed

Vestmar, Marie A; Andersson, Ehm A; Christensen, Charlotte R; Hauge, Maria; Glümer, Charlotte; Linneberg, Allan; Witte, Daniel R; Jørgensen, Marit E; Christensen, Cramer; Brandslund, Ivan; Lauritzen, Torsten; Pedersen, Oluf; Holst, Birgitte; Grarup, Niels; Schwartz, Thue W; Hansen, Torben

2016-09-01

p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gαq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucose-related traits in the Danish population. Surface expression, Gq and Gi coupled signalling as well as β-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals. p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect β-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population (p>0.05). We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PrPC Undergoes Basal to Apical Transcytosis in Polarized Epithelial MDCK Cells

PubMed Central

Arkhipenko, Alexander; Syan, Sylvie; Victoria, Guiliana Soraya

2016-01-01

The Prion Protein (PrP) is an ubiquitously expressed glycosylated membrane protein attached to the external leaflet of the plasma membrane via a glycosylphosphatidylinositol anchor (GPI). While the misfolded PrPSc scrapie isoform is the infectious agent of prion disease, the cellular isoform (PrPC) is an enigmatic protein with unclear function. Of interest, PrP localization in polarized MDCK cells is controversial and its mechanism of trafficking is not clear. Here we investigated PrP traffic in MDCK cells polarized on filters and in three-dimensional MDCK cysts, a more physiological model of polarized epithelia. We found that, unlike other GPI-anchored proteins (GPI-APs), PrP undergoes basolateral-to-apical transcytosis in fully polarized MDCK cells. Following this event full-length PrP and its cleavage fragments are segregated in different domains of the plasma membrane in polarized cells in both 2D and 3D cultures. PMID:27389581

Sakiadis flow of Maxwell fluid considering magnetic field and convective boundary conditions

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

Mustafa, M., E-mail: meraj-mm@hotmail.com; Khan, Junaid Ahmad; Hayat, T.

2015-02-15

In this paper we address the flow of Maxwell fluid due to constantly moving flat radiative surface with convective condition. The flow is under the influence of non-uniform transverse magnetic field. The velocity and temperature distributions have been evaluated numerically by shooting approach. The solution depends on various interesting parameters including local Deborah number De, magnetic field parameter M, Prandtl number Pr and Biot number Bi. We found that variation in velocity with an increase in local Deborah number De is non-monotonic. However temperature is a decreasing function of local Deborah number De.

Effects of home-based pulmonary rehabilitation with a metronome-guided walking pace in chronic obstructive pulmonary disease.

PubMed

Lee, Sung-soon; Kim, Changhwan; Jin, Young-Soo; Oh, Yeon-Mok; Lee, Sang-Do; Yang, Yun Jun; Park, Yong Bum

2013-05-01

Despite documented efficacy and recommendations, pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) has been underutilized. Home-based PR was proposed as an alternative, but there were limited data. The adequate exercise intensity was also a crucial issue. The aim of this study was to investigate the effects of home-based PR with a metronome-guided walking pace on functional exercise capacity and health-related quality of life (HRQOL) in COPD. The subjects participated in a 12-week home-based PR program. Exercise intensity was initially determined by cardiopulmonary exercise test, and was readjusted (the interval of metronome beeps was reset) according to submaximal endurance test. Six-minute walk test, pulmonary function test, cardiopulmonary exercise test, and St. George's Respiratory Questionnaire (SGRQ) were done before and after the 12-week program, and at 6 months after completion of rehabilitation. Thirty-three patients participated in the program. Six-minute walking distance was significantly increased (48.8 m; P = 0.017) and the SGRQ score was also improved (-15; P < 0.001) over the six-month follow-up period after rehabilitation. There were no significant differences in pulmonary function and peak exercise parameters. We developed an effective home-based PR program with a metronome-guided walking pace for COPD patients. This rehabilitation program may improve functional exercise capacity and HRQOL.

Proteorhodopsin-bearing bacteria in Antarctic sea ice.

PubMed

Koh, Eileen Y; Atamna-Ismaeel, Nof; Martin, Andrew; Cowie, Rebecca O M; Beja, Oded; Davy, Simon K; Maas, Elizabeth W; Ryan, Ken G

2010-09-01

Proteorhodopsins (PRs) are widespread bacterial integral membrane proteins that function as light-driven proton pumps. Antarctic sea ice supports a complex community of autotrophic algae, heterotrophic bacteria, viruses, and protists that are an important food source for higher trophic levels in ice-covered regions of the Southern Ocean. Here, we present the first report of PR-bearing bacteria, both dormant and active, in Antarctic sea ice from a series of sites in the Ross Sea using gene-specific primers. Positive PR sequences were generated from genomic DNA at all depths in sea ice, and these sequences aligned with the classes Alphaproteobacteria, Gammaproteobacteria, and Flavobacteria. The sequences showed some similarity to previously reported PR sequences, although most of the sequences were generally distinct. Positive PR sequences were also observed from cDNA reverse transcribed from RNA isolated from sea ice samples. This finding indicates that these sequences were generated from metabolically active cells and suggests that the PR gene is functional within sea ice. Both blue-absorbing and green-absorbing forms of PRs were detected, and only a limited number of blue-absorbing forms were found and were in the midsection of the sea ice profile in this study. Questions still remain regarding the protein's ecological functions, and ultimately, field experiments will be needed to establish the ecological and functional role of PRs in the sea ice ecosystem.

Progesterone receptor modulates estrogen receptor-α action in breast cancer

PubMed Central

Mohammed, Hisham; Russell, I. Alasdair; Stark, Rory; Rueda, Oscar M.; Hickey, Theresa E.; Tarulli, Gerard A.; Serandour, Aurelien A. A.; Birrell, Stephen N.; Bruna, Alejandra; Saadi, Amel; Menon, Suraj; Hadfield, James; Pugh, Michelle; Raj, Ganesh V.; Brown, Gordon D.; D’Santos, Clive; Robinson, Jessica L. L.; Silva, Grace; Launchbury, Rosalind; Perou, Charles M.; Stingl, John; Caldas, Carlos; Tilley, Wayne D.; Carroll, Jason S.

2015-01-01

Summary Progesterone receptor (PR) expression is employed as a biomarker of estrogen receptor-α (ERα) function and breast cancer prognosis. We now show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions. PMID:26153859

Prion protein induced signaling cascades in monocytes

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

Krebs, Bjarne; Dorner-Ciossek, Cornelia; Schmalzbauer, Ruediger

2006-02-03

Prion proteins play a central role in transmission and pathogenesis of transmissible spongiform encephalopathies. The cellular prion protein (PrP{sup C}), whose physiological function remains elusive, is anchored to the surface of a variety of cell types including neurons and cells of the lymphoreticular system. In this study, we investigated the response of a mouse monocyte/macrophage cell line to exposure with PrP{sup C} fusion proteins synthesized with a human Fc-tag. PrP{sup C} fusion proteins showed an attachment to the surface of monocyte/macrophages in nanomolar concentrations. This was accompanied by an increase of cellular tyrosine phosphorylation as a result of activated signalingmore » pathways. Detailed investigations exhibited activation of downstream pathways through a stimulation with PrP fusion proteins, which include phosphorylation of ERK{sub 1,2} and Akt kinase. Macrophages opsonize and present antigenic structures, contact lymphocytes, and deliver cytokines. The findings reported here may become the basis of understanding the molecular function of PrP{sup C} in monocytes and macrophages.« less

Hematological shift in goat kids naturally devoid of prion protein.

PubMed

Reiten, Malin R; Bakkebø, Maren K; Brun-Hansen, Hege; Lewandowska-Sabat, Anna M; Olsaker, Ingrid; Tranulis, Michael A; Espenes, Arild; Boysen, Preben

2015-01-01

The physiological role of the cellular prion protein (PrP(C)) is incompletely understood. The expression of PrP(C) in hematopoietic stem cells and immune cells suggests a role in the development of these cells, and in PrP(C) knockout animals altered immune cell proliferation and phagocytic function have been observed. Recently, a spontaneous nonsense mutation at codon 32 in the PRNP gene in goats of the Norwegian Dairy breed was discovered, rendering homozygous animals devoid of PrP(C). Here we report hematological and immunological analyses of homozygous goat kids lacking PrP(C) (PRNP(Ter/Ter) ) compared to heterozygous (PRNP (+/Ter)) and normal (PRNP (+/+)) kids. Levels of cell surface PrP(C) and PRNP mRNA in peripheral blood mononuclear cells (PBMCs) correlated well and were very low in PRNP (Ter/Ter), intermediate in PRNP (+/Ter) and high in PRNP (+/+) kids. The PRNP (Ter/Ter) animals had a shift in blood cell composition with an elevated number of red blood cells (RBCs) and a tendency toward a smaller mean RBC volume (P = 0.08) and an increased number of neutrophils (P = 0.068), all values within the reference ranges. Morphological investigations of blood smears and bone marrow imprints did not reveal irregularities. Studies of relative composition of PBMCs, phagocytic ability of monocytes and T-cell proliferation revealed no significant differences between the genotypes. Our data suggest that PrP(C) has a role in bone marrow physiology and warrant further studies of PrP(C) in erythroid and immune cell progenitors as well as differentiated effector cells also under stressful conditions. Altogether, this genetically unmanipulated PrP(C)-free animal model represents a unique opportunity to unveil the enigmatic physiology and function of PrP(C).

Pulmonary rehabilitation in patients with bronchiectasis: pulmonary function, arterial blood gases, and the 6-minute walk test.

PubMed

van Zeller, Mafalda; Mota, Patrícia Caetano; Amorim, Adelina; Viana, Paulo; Martins, Paula; Gaspar, Luís; Hespanhol, Venceslau; Gomes, Isabel

2012-01-01

Information regarding the effects of pulmonary rehabilitation (PR) on pulmonary function (PF), arterial blood gases (ABG), and 6-minute walk distance (6MWD) in patients with bronchiectasis is scant in the literature. To evaluate the effects of PR on these indices in this population, a retrospective evaluation of those who attended PR from 2007 to 2010, was made. Pulmonary rehabilitation lasted a mean of 12 weeks and included cycle ergometer exercise for 30 minutes, 3 times per week, with additional upper limbs and quadriceps training. PF, ABG, and 6MWD were evaluated before and after PR to determine the potential influence of gender, exacerbations, underlying cause of bronchiectasis, severity of obstruction, and colonization with bacteria. Forty-one patients (48.8% males; median age, 54 years) were included; 25 had severe obstruction and 19 were colonized with bacteria. Following PR, no significant changes were detected in PF or ABG. Median 6MWD before PR was 425 m and post-PR was 450 m (P = .431). Outcomes did not show any interaction with gender, colonization, or exacerbations. However, patients with idiopathic bronchiectasis did show a significant improvement in forced vital capacity in percent of predicted and residual volume after PR (P = .016 and .048, respectively). Patients with severe obstruction showed a statistically significant decrease in percent of predicted residual volume (P = .025). There appears to be a beneficial impact of PR on PF in certain groups of patients with bronchiectasis. In addition, PR indications and protocols for patients with bronchiectasis may need to be adapted to accommodate specific patients, so that expressive exercise capacity improvement can be achieved.

Overexpression of NtPR-Q Up-Regulates Multiple Defense-Related Genes in Nicotiana tabacum and Enhances Plant Resistance to Ralstonia solanacearum.

PubMed

Tang, Yuanman; Liu, Qiuping; Liu, Ying; Zhang, Linli; Ding, Wei

2017-01-01

Various classes of plant pathogenesis-related proteins have been identified in the past several decades. PR-Q, a member of the PR3 family encoding chitinases, has played an important role in regulating plant resistance and preventing pathogen infection. In this paper, we functionally characterized NtPR-Q in tobacco plants and found that the overexpression of NtPR-Q in tobacco Yunyan87 resulted in higher resistance to Ralstonia solanacearum inoculation. Surprisingly, overexpression of NtPR-Q led to the activation of many defense-related genes, such as salicylic acid (SA)-responsive genes NtPR1a/c , NtPR2 and NtCHN50 , JA-responsive gene NtPR1b and ET production-associated genes NtACC Oxidase and NtEFE26 . Consistent with the role of NtPR-Q in multiple stress responses, NtPR-Q transcripts were induced by the exogenous hormones SA, ethylene and methyl jasmonate, which could enhance the resistance of tobacco to R. solanacearum . Collectively, our results suggested that NtPR-Q overexpression led to the up-regulation of defense-related genes and enhanced plant resistance to R. solanacearum infection.

Changes in the endurance shuttle walk test in COPD patients with chronic respiratory failure after pulmonary rehabilitation: the minimal important difference obtained with anchor- and distribution-based method.

PubMed

Altenburg, Wytske A; Duiverman, Marieke L; Ten Hacken, Nick H T; Kerstjens, Huib A M; de Greef, Mathieu H G; Wijkstra, Peter J; Wempe, Johan B

2015-02-19

Although the endurance shuttle walk test (ESWT) has proven to be responsive to change in exercise capacity after pulmonary rehabilitation (PR) for COPD, the minimally important difference (MID) has not yet been established. We aimed to establish the MID of the ESWT in patients with severe COPD and chronic hypercapnic respiratory failure following PR. Data were derived from a randomized controlled trial, investigating the value of noninvasive positive pressure ventilation added to PR. Fifty-five patients with stable COPD, GOLD stage IV, with chronic respiratory failure were included (mean (SD) FEV1 31.1 (12.0) % pred, age 62 (9) y). MID estimates of the ESWT in seconds, percentage and meters change were calculated with anchor based and distribution based methods. Six minute walking distance (6MWD), peak work rate on bicycle ergometry (Wpeak) and Chronic Respiratory Questionnaire (CRQ) were used as anchors and Cohen's effect size was used as distribution based method. The estimated MID of the ESWT with the different anchors ranged from 186-199 s, 76-82% and 154-164 m. Using the distribution based method the MID was 144 s, 61% and 137 m. Estimates of the MID for the ESWT after PR showed only small differences using different anchors in patients with COPD and chronic respiratory failure. Therefore we recommend using a range of 186-199 s, 76-82% or 154-164 m as MID of the ESWT in COPD patients with chronic respiratory failure. Further research in larger populations should elucidate whether this cut-off value is also valid in other COPD populations and with other interventions. ClinicalTrials.Gov (ID NCT00135538).

The Physical Relationship between Infectivity and Prion Protein Aggregates Is Strain-Dependent

PubMed Central

Tixador, Philippe; Herzog, Laëtitia; Reine, Fabienne; Jaumain, Emilie; Chapuis, Jérôme; Le Dur, Annick; Laude, Hubert; Béringue, Vincent

2010-01-01

Prions are unconventional infectious agents thought to be primarily composed of PrPSc, a multimeric misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrPC). They cause fatal neurodegenerative diseases in both animals and humans. The disease phenotype is not uniform within species, and stable, self-propagating variations in PrPSc conformation could encode this ‘strain’ diversity. However, much remains to be learned about the physical relationship between the infectious agent and PrPSc aggregation state, and how this varies according to the strain. We applied a sedimentation velocity technique to a panel of natural, biologically cloned strains obtained by propagation of classical and atypical sheep scrapie and BSE infectious sources in transgenic mice expressing ovine PrP. Detergent-solubilized, infected brain homogenates were used as starting material. Solubilization conditions were optimized to separate PrPSc aggregates from PrPC. The distribution of PrPSc and infectivity in the gradient was determined by immunoblotting and mouse bioassay, respectively. As a general feature, a major proteinase K-resistant PrPSc peak was observed in the middle part of the gradient. This population approximately corresponds to multimers of 12–30 PrP molecules, if constituted of PrP only. For two strains, infectivity peaked in a markedly different region of the gradient. This most infectious component sedimented very slowly, suggesting small size oligomers and/or low density PrPSc aggregates. Extending this study to hamster prions passaged in hamster PrP transgenic mice revealed that the highly infectious, slowly sedimenting particles could be a feature of strains able to induce a rapidly lethal disease. Our findings suggest that prion infectious particles are subjected to marked strain-dependent variations, which in turn could influence the strain biological phenotype, in particular the replication dynamics. PMID:20419156

PrPC expression and prion seeding activity in the alimentary tract and lymphoid tissue of deer

PubMed Central

Davenport, Kristen A.; Hoover, Clare E.; Bian, Jifeng; Telling, Glenn C.; Mathiason, Candace K.; Hoover, Edward A.

2017-01-01

The agent responsible for prion diseases is a misfolded form of a normal protein (PrPC). The prion hypothesis stipulates that PrPC must be present for the disease to manifest. Cervid populations across the world are infected with chronic wasting disease, a horizontally-transmissible prion disease that is likely spread via oral exposure to infectious prions (PrPCWD). Though PrPCWD has been identified in many tissues, there has been little effort to characterize the overall PrPC expression in cervids and its relationship to PrPCWD accumulation. We used immunohistochemistry (IHC), western blot and enzyme-linked immunosorbent assay to describe PrPC expression in naïve white-tailed deer. We used real-time, quaking-induced conversion (RT-QuIC) to detect prion seeding activity in CWD-infected deer. We assessed tissues comprising the alimentary tract, alimentary-associated lymphoid tissue and systemic lymphoid tissue from 5 naïve deer. PrPC was expressed in all tissues, though expression was often very low compared to the level in the CNS. IHC identified specific cell types wherein PrPC expression is very high. To compare the distribution of PrPC to PrPCWD, we examined 5 deer with advanced CWD infection. Using RT-QuIC, we detected prion seeding activity in all 21 tissues. In 3 subclinical deer sacrificed 4 months post-inoculation, we detected PrPCWD consistently in alimentary-associated lymphoid tissue, irregularly in alimentary tract tissues, and not at all in the brain. Contrary to our hypothesis that PrPC levels dictate prion accumulation, PrPC expression was higher in the lower gastrointestinal tissues than in the alimentary-associated lymphoid system and was higher in salivary glands than in the oropharyngeal lymphoid tissue. These data suggest that PrPC expression is not the sole driver of prion accumulation and that alimentary tract tissues accumulate prions before centrifugal spread from the brain occurs. PMID:28880938

75 FR 51032 - National Fuel Gas Distribution Corporation; Notice of Baseline Filing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. PR10-79-000] National Fuel Gas Distribution Corporation; Notice of Baseline Filing August 12, 2010. Take notice that on August 10, 2010, National fuel Gas Distribution Corporation submitted a baseline filing of its Statement of...

Progesterone receptor isoforms in the mammary gland of cats and dogs.

PubMed

Gracanin, A; de Gier, J; Zegers, K; Bominaar, M; Rutteman, G R; Schaefers-Okkens, A C; Kooistra, H S; Mol, J A

2012-12-01

Progesterone exerts its effect by binding to specific progesterone receptors (PR) within the cell. In dogs and cats, no data are available on PR isoforms as found in other species. We therefore investigated the sequence of the PR gene and encoded protein in dogs and cats, the expression of PR isoforms in mammary tissue using Western blots and the presence of PR in mammary tissue using immunohistochemistry. Comparison of the amino acid sequence of the canine and feline PR with human PR revealed major differences in the PR-B-specific upstream segment (BUS). However, the essential activation function 3 (AF3) domain was intact in the cat but mutated in the dog. The DNA and ligand-binding domains were highly similar among the species. In cats with fibroadenomatous hyperplasia (FAH), high expression of PR mRNA together with growth hormone (GH), GH receptor (GHR) and IGF-I mRNA was found in comparison with feline mammary carcinomas. Immunohistochemical analysis showed strong nuclear as well as cytoplasmic staining for PR in FAH. Western blot analysis revealed expression of the PR-A and PR-B isoforms in the feline mammary gland. In canine mammary tissue, the most abundant PR staining was found in proliferative zones of the mammary gland. Western blot analyses showed mainly staining for PR-A with lower PR-B staining. It is concluded that in dogs and cats both PR isoforms are expressed. The role of mutations found in the canine PR-B is discussed. © 2012 Blackwell Verlag GmbH.

Associations among depression severity, painful physical symptoms, and social and occupational functioning impairment in patients with major depressive disorder: a 3-month, prospective, observational study.

PubMed

Harada, Eiji; Satoi, Yoichi; Kuga, Atsushi; Tokuoka, Hirofumi; Kikuchi, Toshiaki; Watanabe, Koichiro; Alev, Levent; Mimura, Masaru

2017-01-01

To investigate associations among depression severity, painful physical symptoms (PPS), and social and occupational functioning impairment in patients with major depressive disorder (MDD) who had achieved complete remission (CR) or partial remission (PR) after acute treatment. This was a 12-week, multicenter, prospective, observational study. Patients with MDD treated with an antidepressant medication for the previous 12 weeks (±3 weeks) who had achieved CR (defined as a 17-item Hamilton Rating Scale for Depression [HAM-D17] score ≤7) or PR (HAM-D17 score ≥8 and ≤18) were enrolled. Depression severity, PPS, and impairment in social and occupational functioning were assessed using the HAM-D17, the Brief Pain Inventory (Short Form) (BPI-SF), and the Social and Occupational Functioning Assessment Scale (SOFAS), respectively, at enrollment (Week 12) and after 12 weeks (Week 24). Overall, 323 Japanese patients with MDD were enrolled (CR n=158, PR n=165) and 288 patients completed the study (CR n=139, PR n=149). HAM-D17 and SOFAS scores were strongly and negatively correlated at enrollment (Week 12; P <0.0001) and Week 24 ( P <0.0001). A weak negative correlation between the BPI-SF and SOFAS was observed at Week 24 ( P =0.0011), but not at enrollment ( P =0.164). Remission status at enrollment (CR or PR) was associated with achieving normal social and occupational functioning (SOFAS score ≥80) at Week 24 in patients who had not achieved normal social and occupational functioning (SOFAS score <80) at enrollment (CR vs PR, OR=0.05 [95% CIs 0.01-0.18], P <0.0001). A greater proportion of patients with CR and no PPS at enrollment achieved SOFAS scores ≥80 at Week 24 than those with CR and PPS. Our results suggest that treating both depressive symptoms and PPS is important for achieving a normal level of functioning on a long-term basis in patients with MDD.

Guidelines for Use of the Approximate Beta-Poisson Dose-Response Model.

PubMed

Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

2017-07-01

For dose-response analysis in quantitative microbial risk assessment (QMRA), the exact beta-Poisson model is a two-parameter mechanistic dose-response model with parameters α>0 and β>0, which involves the Kummer confluent hypergeometric function. Evaluation of a hypergeometric function is a computational challenge. Denoting PI(d) as the probability of infection at a given mean dose d, the widely used dose-response model PI(d)=1-(1+dβ)-α is an approximate formula for the exact beta-Poisson model. Notwithstanding the required conditions α<β and β>1, issues related to the validity and approximation accuracy of this approximate formula have remained largely ignored in practice, partly because these conditions are too general to provide clear guidance. Consequently, this study proposes a probability measure Pr(0 < r < 1 | α̂, β̂) as a validity measure (r is a random variable that follows a gamma distribution; α̂ and β̂ are the maximum likelihood estimates of α and β in the approximate model); and the constraint conditions β̂>(22α̂)0.50 for 0.02<α̂<2 as a rule of thumb to ensure an accurate approximation (e.g., Pr(0 < r < 1 | α̂, β̂) >0.99) . This validity measure and rule of thumb were validated by application to all the completed beta-Poisson models (related to 85 data sets) from the QMRA community portal (QMRA Wiki). The results showed that the higher the probability Pr(0 < r < 1 | α̂, β̂), the better the approximation. The results further showed that, among the total 85 models examined, 68 models were identified as valid approximate model applications, which all had a near perfect match to the corresponding exact beta-Poisson model dose-response curve. © 2016 Society for Risk Analysis.

Alzheimer's Disease and Prion Protein

PubMed Central

Zhou, Jiayi; Liu, Bingqian

2013-01-01

Summary Alzheimer's disease (AD) is a devastating neurodegenerative disease with progressive loss of memory and cognitive function, pathologically hallmarked by aggregates of the amyloid-beta (Aβ) peptide and hyperphosphorylated tau in the brain. Aggregation of Aβ under the form of amyloid fibrils has long been considered central to the pathogenesis of AD. However, recent evidence has indicated that soluble Aβ oligomers, rather than insoluble fibrils, are the main neurotoxic species in AD. The cellular prion protein (PrPC) has newly been identified as a cell surface receptor for Aβ oligomers. PrPC is a cell surface glycoprotein that plays a key role in the propagation of prions, proteinaceous infectious agents that replicate by imposing their abnormal conformation to PrPC molecules. In AD, PrPC acts to transduce the neurotoxic signals arising from Aβ oligomers, leading to synaptic failure and cognitive impairment. Interestingly, accumulating evidence has also shown that aggregated Aβ or tau possesses prion-like activity, a property that would allow them to spread throughout the brain. In this article, we review recent findings regarding the function of PrPC and its role in AD, and discuss potential therapeutic implications of PrPC-based approaches in the treatment of AD. PMID:25343100

Signal transduction in neurons: effects of cellular prion protein on fyn kinase and ERK1/2 kinase.

PubMed

Tomasi, Vittorio

2010-12-16

It has been reported that cellular prion protein (PrPc) co-localizes with caveolin-1 and participates to signal transduction events by recruiting Fyn kinase. As PrPc is a secreted protein anchored to the outer surface membrane through a glycosylphosphatidylinositol (GPI) anchor (secPrP) and caveolin-1 is located in the inner leaflet of plasma membrane, there is a problem of how the two proteins can physically interact each other and transduce signals. By using the GST-fusion proteins system we observed that PrPc strongly interacts with caveolin-1 scaffolding domain and with a caveolin-1 hydrophilic C-terminal region, but not with the caveolin-1 N-terminal region. In vitro binding experiments were also performed to define the site(s) of PrPc interacting with cav-1. The results are consistent with a participation of PrPc octapeptide repeats motif in the binding to caveolin-1 scaffolding domain. The caveolar localization of PrPc was ascertained by co-immunoprecipitation, by co-localization after flotation in density gradients and by confocal microscopy analysis of PrPc and caveolin-1 distributions in a neuronal cell line (GN11) expressing caveolin-1 at high levels. We observed that, after antibody-mediated cross-linking or copper treatment, PrPc was internalized probably into caveolae. We propose that following translocation from rafts to caveolae or caveolae-like domains, secPrP could interact with caveolin-1 and induce signal transduction events.

Expression and Function of the Progesterone Receptor in Human Prostate Stroma Provide Novel Insights to Cell Proliferation Control

PubMed Central

Yu, Yue; Liu, Liangliang; Xie, Ning; Xue, Hui; Fazli, Ladan; Buttyan, Ralph; Wang, Yuzhuo; Gleave, Martin

2013-01-01

Context: Like other tissues, the prostate is an admixture of many different cell types that can be segregated into components of the epithelium or stroma. Reciprocal interactions between these 2 types of cells are critical for maintaining prostate homeostasis, whereas aberrant stromal cell proliferation can disrupt this balance and result in diseases such as benign prostatic hyperplasia. Although the androgen and estrogen receptors are relatively well studied for their functions in controlling stromal cell proliferation and differentiation, the role of the progesterone receptor (PR) remains unclear. Objective: The aim of the study was to investigate the expression and function of the PR in the prostate. Design and Setting: Human prostate biopsies, renal capsule xenografts, and prostate stromal cells were used. Immunohistochemistry, Western blotting, real-time quantitative PCR, cell proliferation, flow cytometry, and gene microarray analyses were performed. Results: Two PR isoforms, PRA and PRB, are expressed in prostate stromal fibroblasts and smooth muscle cells, but not in epithelial cells. Both PR isoforms suppress prostate stromal cell proliferation through inhibition of the expression of cyclinA, cyclinB, and cdc25c, thus delaying cell cycling through S and M phases. Gene microarray analyses further demonstrated that PRA and PRB regulated different transcriptomes. However, one of the major gene groups commonly regulated by both PR isoforms was the one associated with regulation of cell proliferation. Conclusion: PR plays an inhibitory role in prostate stromal cell proliferation. PMID:23666965

Aortic valve calcification as a predictor of location and severity of paravalvular regurgitation after transcatheter aortic valve implantation.

PubMed

Koh, Ezra Y; Lam, Kayan Y; Bindraban, Navin R; Cocchieri, Riccardo; Planken, R Nils; Koch, Karel T; Baan, Jan; de Mol, Bas A; Marquering, Henk A

2015-03-01

To determine whether the location of aortic valve calcium (AVC) influences the location of paravalvular regurgitation (PR). PR is an adverse effect of transcatheter aortic valve implantation (TAVI) with a negative effect on long-term patient survival. The relationship between AVC and the occurrence of PR has been documented. However, the relationship between the distribution of AVC and the location of PR is still sparsely studied. The purpose of this study was to correlate severity and location of AVC with PR in patients treated with TAVI. Fifty-six consecutive patients who underwent transaortic or transapical TAVI and had preoperative computed tomography scans were included in this retrospective study. The volume, mass and location of AVC was determined and compared between patients with and without PR using a non-parametric t-test. Postoperative echocardiography was performed to determine the presence and location of PR, which was associated with the cusp with highest AVC using a χ(2) test. Valve deployment was successful in all 56 patients. PR was present in 38 patients (68%) after TAVI. There was a non-significantly higher volume of AVC in the PR group [214 (70-418) vs 371 (254-606) cm(3), P = 0.15]. AVC mass was significantly higher in patients with PR than in patients without PR [282 (188-421) vs 142 (48-259) mg, respectively, P = 0.043]. The location of PR was determined in 36 of these patients. Of these 36 patients, PR occurred at the cusp with the highest AVC in 20 patients (56%, χ(2) P = 0.030). In our population, PR was associated with greater AVC mass. Moreover, the location of PR was associated with the cusp with the highest amount of AVC. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Comparisons of Rain Estimates from Ground Radar and Satellite Over Mountainous Regions

NASA Technical Reports Server (NTRS)

Lin, Xin; Kidd, Chris; Tao, Jing; Barros, Ana

2016-01-01

A high-resolution rainfall product merging surface radar and an enhanced gauge network is used as a reference to examine two operational surface radar rainfall products over mountain areas. The two operational rainfall products include radar-only and conventional-gauge-corrected radar rainfall products. Statistics of rain occurrence and rain amount including their geographical, seasonal, and diurnal variations are examined using 3-year data. It is found that the three surface radar rainfall products in general agree well with one another over mountainous regions in terms of horizontal mean distributions of rain occurrence and rain amount. Frequency of rain occurrence and fraction of rain amount also indicate similar distribution patterns as a function of rain intensity. The diurnal signals of precipitation over mountain ridges are well captured and joint distributions of coincident raining samples indicate reasonable correlations during both summer and winter. Factors including undetected low-level precipitation, limited availability of gauges for correcting the Z-R relationship over the mountains, and radar beam blocking by mountains are clearly noticed in the two conventional radar rainfall products. Both radar-only and conventional-gauge-corrected radar rainfall products underestimate the rain occurrence and fraction of rain amount at intermediate and heavy rain intensities. Comparison of PR and TMI against a surface radar-only rainfall product indicates that the PR performs equally well with the high-resolution radar-only rainfall product over complex terrains at intermediate and heavy rain intensities during the summer and winter. TMI, on the other hand, requires improvement to retrieve wintertime precipitation over mountain areas.

Microwave nonlinearity and photoresponse of superconducting resonators with columnar defect micro-channels

NASA Astrophysics Data System (ADS)

Remillard, S. K.; Kirkendall, D.; Ghigo, G.; Gerbaldo, R.; Gozzelino, L.; Laviano, F.; Yang, Z.; Mendelsohn, N. A.; Ghamsari, B. G.; Friedman, B.; Jung, P.; Anlage, S. M.

2014-09-01

Micro-channels of nanosized columnar tracks were planted by heavy-ion irradiation into superconducting microwave microstrip resonators that were patterned from YBa2Cu3O7 - x thin films on LaAlO3 substrates. Three different ion fluences were used, producing different column densities, with each fluence having a successively greater impact on the microwave nonlinearity of the device, as compared to a control sample. Photoresponse (PR) images made with a 638 nm rastered laser beam revealed that the channel is a location of enhanced PR and a hot spot for the generation of intermodulation distortion. The microwave PR technique was also advanced in this work by investigating the role of coupling strength on the distribution of PR between inductive and resistive components.

The effect of foot arch on plantar pressure distribution during standing.

PubMed

Periyasamy, R; Anand, Sneh

2013-07-01

The aim of this study was to explore how foot type affects plantar pressure distribution during standing. In this study, 32 healthy subjects voluntarily participated and the subject feet were classified as: normal feet (n = 23), flat feet (n = 14) and high arch feet (n = 27) according to arch index (AI) values obtained from foot pressure intensity image analysis. Foot pressure intensity images were acquired by a pedopowergraph system to obtain a foot pressure distribution parameter-power ratio (PR) during standing in eight different regions of the foot. Contact area and mean PR were analysed in hind foot, mid-foot and fore foot regions. One-way analysis of variance was used to determine statistical differences between groups. The contact area and mean PR value beneath the mid-foot was significantly increased in the low arch foot when compared to the normal arch foot and high arch foot (p < 0.001) in both feet. However, subjects with low-arch feet had significantly higher body mass index (BMI) compared to subjects with high-arch feet (p < 0.05) and subjects with normal arch feet (p < 0.05) in both feet. In addition, subjects with low-arch feet had significant differences in arch index (AI) value as compared to subjects with high-arch feet (p < 0.001) and subjects with normal arch feet (p < 0.05) in both feet. Mean mid-foot PR value were positively (r = 0.54) correlated with increased arch index (AI) value. A significant (p < 0.05) change was obtained in PR value beneath the mid-foot of low arch feet when compared with other groups in both feet. The findings suggest that there is an increased mid-foot PR value in the low arch foot as compared to the normal arch foot and high arch foot during standing. Therefore, individuals with low arch feet could be at high risk for mid-foot collapse and Charcot foot problems, indicating that foot type should be assessed when determining an individual's risk for foot injury.

Dielectric and electrical studies of Pr{sup 3+} doped nano CaSiO{sub 3} perovskite ceramics

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

Kulkarni, Sandhya, E-mail: pappu.sandhyakulkarni@gmail.com; Nagabhushana, B.M.; Parvatikar, Narsimha

2014-02-01

Highlights: • CaSiO{sub 3}:Pr{sup 3+} was prepared by facile low temperature solution combustion method. • The crystalline phase of the product is obtained by adopting sintering method. • Samples prepared at 500 °C and calcined at 900 °C for 3 h showed β-phase. • The Pr{sup 3+} doped CaSiO{sub 3} shows “unusual results”. • The electrical microstructure has been accepted to be of internal barrier layer capacitor. - Abstract: CaSiO{sub 3} nano-ceramic powder doped with Pr{sup 3+} has been prepared by solution combustion method. The powder Ca{sub 0.95}Pr{sub 0.05}SiO{sub 3} is investigated for its dielectric and electrical properties at roommore » temperature to study the effect of doping. The sample is characterized by X-ray diffraction and infrared spectroscopy. The size of either of volume elements of CaSiO{sub 3}:Pr{sup 3+} estimated from transmission electron microscopy is about 180–200 nm. The sample shows colossal dielectric response at room temperature. This colossal dielectric behaviour follows Debye-type relaxation and can be explained by Maxwell–Wagner (MW) polarization. However, analysis of impedance and electric modulus data using Cole–Cole plot shows that it deviates from ideal Debye behaviour resulting from the distribution of relaxation times. The distribution in the relaxation times may be attributed to existence of electrically heterogeneous grains, insulating grain boundary, and electrode contact regions. Doping, thus, results in substantial modifications in the dielectric and electrical properties of the nano-ceramic CaSiO{sub 3}.« less

Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy.

PubMed

Okada, Hiroyuki; Masujin, Kentaro; Miyazawa, Kohtaro; Iwamaru, Yoshihumi; Imamura, Morikazu; Matsuura, Yuichi; Arai, Shozo; Fukuda, Shigeo; Murayama, Yuichi; Yokoyama, Takashi

2017-11-01

H-type bovine spongiform encephalopathy (H-BSE) is an atypical form of BSE in cattle. During passaging of H-BSE in transgenic bovinized (TgBoPrP) mice, a novel phenotype of BSE, termed BSE-SW emerged and was characterized by a short incubation time and host weight loss. To investigate the biological and biochemical properties of the BSE-SW prion, a transmission study was conducted in cattle, which were inoculated intracerebrally with brain homogenate from BSE-SW-infected TgBoPrP mice. The disease incubation period was approximately 15 months. The animals showed characteristic neurological signs of dullness, and severe spongiform changes and a widespread, uniform distribution of disease-associated prion protein (PrP Sc ) were observed throughout the brain of infected cattle. Immunohistochemical PrP Sc staining of the brain revealed the presence of intraglial accumulations and plaque-like deposits. No remarkable differences were identified in vacuolar lesion scores, topographical distribution patterns, and staining types of PrP Sc in the brains of BSE-SW- vs H-BSE-infected cattle. PrP Sc deposition was detected in the ganglia, vagus nerve, spinal nerve, cauda equina, adrenal medulla, and ocular muscle. Western blot analysis revealed that the specific biochemical properties of the BSE-SW prion, with an additional 10- to 12-kDa fragment, were well maintained after transmission. These findings indicated that the BSE-SW prion has biochemical properties distinct from those of H-BSE in cattle, although clinical and pathologic features of BSW-SW in cattle are indistinguishable from those of H-BSE. The results suggest that the 2 infectious agents, BSE-SW and H-BSE, are closely related strains.

Prevalence and Correlates of Physical Disability and Functional Limitation among Elderly Rural Population in Nigeria

PubMed Central

Abdulraheem, I. S.; Oladipo, A. R.; Amodu, M. O.

2011-01-01

Background. The number of people surviving into old age is increasing, and it has now become a global phenomenon. Studies on the prevalence and correlates of physical disability and functional limitation among elderly Nigerians are scanty. Methodology. This is a community-based cross-sectional study conducted in 3 local government areas (LGAs) in Nigeria, using a multistage sampling technique. Functional limitations of 1824 elderly persons were tested using Tinetti performance-oriented mobility assessment tool (TPOMAT) and self-reported activities of daily living (ADL). ADL disability of ten, six, and five basic items were compared. Results. The prevalence ratios (PRs) of physical disability using the ten, six, and five basic ADL items were 28.3 (95% CI 25.2–31. 5), 15.7 (95% CI 13.4–19.8), and 12.1 (95% CI 9.8–15.3), respectively, while functional limitation was 22.5 (95% CI 18.1–24.4). Increased risk of disability was independently associated with female gender PR 3.6 (95% CI 1.5–7.4), advanced age ≥75 years; PR 22.2 (95% CI 14.5, 36.8), arthritis PR 3.7 (95% CI 2.6–4.6), stroke PR 4.8 (95% CI 3.7–7.9) and diabetes PR 6.1 (95% CI 4.3–7.1). Conclusions. The findings from this study are pointers to unmet needs of the elderly disabled Nigerians. PMID:21748005

Internal consistency of the Spanish health literacy test (TOFHLA-SPR) for Puerto Rico.

PubMed

Rivero-Méndez, Marta; Suárez, Erick; Solís-Báez, Solymar S; Hernández, Gloryvee; Cordero, Wanda; Vázquez, Irma; Medina, Zullettevy; Padilla, Raisa; Flores, Aida; Bonilla, José Luis; Holzemer, William L

2010-03-01

Low functional health literacy has been related to poor viral control, and lower levels of ART adherence in people living with HIV/AIDS. Research in functional health literacy among people living with HIV/AIDS in Puerto Rico (PR) is an unexplored area. The purpose of this paper is to describe how the full-length Spanish Version of the Test of Functional Health Literacy in Adults (TOFHLA-S) scale was adapted to PR. Thirty participants (women = 16, men = 14) completed a basic demographic questionnaire, the TOFHLA-S and participated in an interview. Analyses were performed to examine the information provided by participants and the internal consistency of the TOFHLA-S. The mean age was 47.7 years (range 34-77). Thirty-seven percent had less than 12 years of formal schooling and 43% reported having education above high school. Changes suggested by participants included: increasing font size from 14 to 16 points for better readability and changes/simplification of several words in order to make them colloquial and comprehensible for the PR context. The reliability coefficient obtained for this scale was strong (estimated alpha = 0.95) however, differences were observed by subtype: numeracy (estimated alpha(num) = .819 vs. comprehension (estimated alpha =. 953). Based on this process, we have adapted the original version of the TOFHLA-S and the new version of the full-length TOFHLA-S, PR is now valid for further research and testing levels of functional health literacy in a larger sample in PR.

Internal Consistency of the Spanish Health Literacy Test (TOFHLA-SPR) for Puerto Rico

PubMed Central

Rivero-Méndez, Marta; Suárez, Erick; Solís-Báez, Solymar S.; Hernández, Gloryvee; Cordero, Wanda; Vázquez, Irma; Medina, Zullettevy; Padilla, Raisa; Flores, Aida; Bonilla, José Luis; Holzemer, William L.

2010-01-01

Background Low functional health literacy has been related to poor viral control, and lower levels of ART adherence in people living with HIV/AIDS. Research in functional health literacy among people living with HIV/AIDS in Puerto Rico (PR) is an unexplored area. The purpose of this paper is to describe how the full-length Spanish Version of the Test of Functional Health Literacy in Adults (TOFHLA-S) scale was adapted to PR. Methods Thirty participants (women = 16, men = 14) completed a basic demographic questionnaire, the TOFHLA-S and participated in an interview. Analyses were performed to examine the information provided by participants and the internal consistency of the TOFHLA-S. Results The mean age was 47.7 years (range 34-77). Thirty-seven percent had less than 12 years of formal schooling and 43% reported having education above high school. Changes suggested by participants included: increasing font size from 14 to 16 points for better readability and changes/simplification of several words in order to make them colloquial and comprehensible for the PR context. The reliability coefficient obtained for this scale was strong (estimated alpha = 0.95) however, differences were observed by subtype: numeracy (estimated alphanum = .819 vs. comprehension (estimated alpha =. 953). Conclusions Based on this process, we have adapted the original version of the TOFHLA-S and the new version of the full-length TOFHLA-S, PR is now valid for further research and testing levels of functional health literacy in a larger sample in PR. PMID:20222334

Progesterone Receptor Scaffolding Function in Breast Cancer

DTIC Science & Technology

2010-10-28

regulated (BIRC3, HSD11β2, and HbEGF ) expression. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR...of a subset of PR target genes known to be involved in cell growth and prevention of apoptosis, including BIRC3, HSD11β2 and HbEGF (Appendix A, Fig...genes by PR-B also required Ser81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF ) expression. We conclude that phospho

Production of cattle lacking prion protein

PubMed Central

Richt, Jürgen A; Kasinathan, Poothappillai; Hamir, Amir N; Castilla, Joaquin; Sathiyaseelan, Thillai; Vargas, Francisco; Sathiyaseelan, Janaki; Wu, Hua; Matsushita, Hiroaki; Koster, Julie; Kato, Shinichiro; Ishida, Isao; Soto, Claudio; Robl, James M; Kuroiwa, Yoshimi

2010-01-01

Prion diseases are caused by propagation of misfolded forms of the normal cellular prion protein PrPC, such as PrPBSE in bovine spongiform encephalopathy (BSE) in cattle and PrPCJD in Creutzfeldt-Jakob disease (CJD) in humans1. Disruption of PrPC expression in mice, a species that does not naturally contract prion diseases, results in no apparent developmental abnormalities2–5. However, the impact of ablating PrPC function in natural host species of prion diseases is unknown. Here we report the generation and characterization of PrPC-deficient cattle produced by a sequential gene-targeting system6. At over 20 months of age, the cattle are clinically, physiologically, histopathologically, immunologically and reproductively normal. Brain tissue homogenates are resistant to prion propagation in vitro as assessed by protein misfolding cyclic amplification7. PrPC-deficient cattle may be a useful model for prion research and could provide industrial bovine products free of prion proteins. PMID:17195841

In utero transmission and tissue distribution of chronic wasting disease-associated prions in free-ranging Rocky Mountain elk.

PubMed

Selariu, Anca; Powers, Jenny G; Nalls, Amy; Brandhuber, Monica; Mayfield, Amber; Fullaway, Stephenie; Wyckoff, Christy A; Goldmann, Wilfred; Zabel, Mark M; Wild, Margaret A; Hoover, Edward A; Mathiason, Candace K

2015-11-01

The presence of disease-associated prions in tissues and bodily fluids of chronic wasting disease (CWD)-infected cervids has received much investigation, yet little is known about mother-to-offspring transmission of CWD. Our previous work demonstrated that mother-to-offspring transmission is efficient in an experimental setting. To address the question of relevance in a naturally exposed free-ranging population, we assessed maternal and fetal tissues derived from 19 elk dam-calf pairs collected from free-ranging Rocky Mountain elk from north-central Colorado, a known CWD endemic region. Conventional immunohistochemistry identified three of 19 CWD-positive dams, whereas a more sensitive assay [serial protein misfolding cyclic amplification (sPMCA)] detected CWD prion seeding activity (PrPCWD) in 15 of 19 dams. PrPCWD distribution in tissues was widespread, and included the central nervous system (CNS), lymphoreticular system, and reproductive, secretory, excretory and adipose tissues. Interestingly, five of 15 sPMCA-positive dams showed no evidence of PrPCWD in either CNS or lymphoreticular system, sites typically assessed in diagnosing CWD. Analysis of fetal tissues harvested from the 15 sPMCA-positive dams revealed PrPCWD in 80 % of fetuses (12 of 15), regardless of gestational stage. These findings demonstrated that PrPCWD is more abundant in peripheral tissues of CWD-exposed elk than current diagnostic methods suggest, and that transmission of prions from mother to offspring may contribute to the efficient transmission of CWD in naturally exposed cervid populations.

In utero transmission and tissue distribution of chronic wasting disease-associated prions in free-ranging Rocky Mountain elk

PubMed Central

Selariu, Anca; Powers, Jenny G.; Nalls, Amy; Brandhuber, Monica; Mayfield, Amber; Fullaway, Stephenie; Wyckoff, Christy A.; Goldmann, Wilfred; Zabel, Mark M.; Wild, Margaret A.; Hoover, Edward A.

2015-01-01

The presence of disease-associated prions in tissues and bodily fluids of chronic wasting disease (CWD)-infected cervids has received much investigation, yet little is known about mother-to-offspring transmission of CWD. Our previous work demonstrated that mother-to-offspring transmission is efficient in an experimental setting. To address the question of relevance in a naturally exposed free-ranging population, we assessed maternal and fetal tissues derived from 19 elk dam–calf pairs collected from free-ranging Rocky Mountain elk from north-central Colorado, a known CWD endemic region. Conventional immunohistochemistry identified three of 19 CWD-positive dams, whereas a more sensitive assay [serial protein misfolding cyclic amplification (sPMCA)] detected CWD prion seeding activity (PrPCWD) in 15 of 19 dams. PrPCWD distribution in tissues was widespread, and included the central nervous system (CNS), lymphoreticular system, and reproductive, secretory, excretory and adipose tissues. Interestingly, five of 15 sPMCA-positive dams showed no evidence of PrPCWD in either CNS or lymphoreticular system, sites typically assessed in diagnosing CWD. Analysis of fetal tissues harvested from the 15 sPMCA-positive dams revealed PrPCWD in 80 % of fetuses (12 of 15), regardless of gestational stage. These findings demonstrated that PrPCWD is more abundant in peripheral tissues of CWD-exposed elk than current diagnostic methods suggest, and that transmission of prions from mother to offspring may contribute to the efficient transmission of CWD in naturally exposed cervid populations. PMID:26358706

Influence of grafting solvents on the properties of polymer electrolyte membranes prepared by γ-ray preirradiation method

NASA Astrophysics Data System (ADS)

Kimura, Yosuke; Asano, Masaharu; Chen, Jinhua; Maekawa, Yasunari; Katakai, Ryoichi; Yoshida, Masaru

2008-07-01

The effect of grafting solvents, such as isopropanol (iPrOH), tetrachloroethane (TCE), tetrahydrofuran (THF), and toluene, on the preparation of poly(ethylene- co-tetrafluoroethylene)-graft-poly(styrene sulfonic acid) (ETFE-g-PSSA) electrolyte membranes by the γ-ray preirradiation grafting method was investigated. It was found that the iPrOH can drastically accelerate the grafting, resulting in a higher degree of grafting. However, for an appropriate degree of grafting of about 50%, the sulfonic acid groups in the ETFE-g-PSSA membrane prepared with the iPrOH were mainly distributed near the membrane surface, as shown by low proton conductivity in the membrane thickness direction. In contrast to this result, the ETFE-g-PSSA membranes prepared with the THF, toluene and TCE exhibited uniform distribution of the sulfonic acid groups in the membrane. Especially, in the case of the TCE grafting solvent, the chemical stability of the resultant electrolyte membrane was clearly higher than those prepared with the other grafting solvents.

Characterization and evolution of dissolved organic matter in acidic forest soil and its impact on the mobility of major and trace elements (case of the Strengbach watershed)

NASA Astrophysics Data System (ADS)

Gangloff, Sophie; Stille, Peter; Pierret, Marie-Claire; Weber, Tiphaine; Chabaux, François

2014-04-01

Dissolved Organic Carbon (DOC) plays an important role in the behavior of major and trace elements in the soil and influences their transfer from soil to soil solution. The first objective of this study is to characterize different organic functional groups for the Water Extractable Organic Carbon (WEOC) fractions of a forest soil as well as their evolution with depth. The second objective is to clarify the influence of these organic functional groups on the migration of the trace elements in WEOC fractions compared to those in the soil solution obtained by lysimeter plates. All experiments have been performed on an acidic forest soil profile (five depths in the first meter) of the experimental spruce parcel in the Stengbach catchment. The Infra-red spectra of the freeze-dried WEOC fractions show a modification of the molecular structure with depth, i.e. a decrease of the polar compounds such as polysaccharides and an increase of the less polar hydro-carbon functional groups with a maximum value of the aromaticity at 30 cm depth. A Hierarchical Ascending Classification (HAC) of the evolution of Water Extractable Chemical Elements (WECE) with the evolution of the organic functional groups in the organic matter (OM) enriched soil compartments permits recognition of relationships between trace element behavior and the organic functional group variations. More specifically, Pb is preferentially bound to the carboxylic acid function of DOC mainly present in the upper soil compartment and rare earth elements (REE) show similar behavior to Fe, V and Cr with a good affinity to carboxy-phenolic and phenolic groups of DOC. The experimental results show that heavy REE compared to light REE are preferentially bound to the aromatic functional group. This different behavior fractionates the REE pattern of soil solutions at 30 cm depth due to the here observed aromaticity enrichment of DOC. These different affinities for the organic functional groups of the DOC explain some aspects of the behavior of trace elements in soil solutions and in the soil profile but, also the competition between trace elements in complexation with DOC. The results of this study are important for the understanding of the mobility and the migration of pollutants (as heavy metals or radionuclides) as well as nutrients in natural ecosystems. WE PrN/YbN is constant between 3 and 16 cm depth whereas SS PrN/YbN slightly decreases from 0.80 at 5 cm depth to 0.74 at 10 cm depth. This results from Pr (LREE) enrichment in the soil solution of the upper soil compartment caused by vegetation controlled LREE recycling and/or atmospheric depositions (see above). WE PrN/YbN and SS PrN/YbN show similar depth dependent distributions including the enrichment at 30 cm depth. It results from Yb depletion at this depth and enrichment in the deeper soil compartment compared to Pr. Similar to Marsac et al. (2012, 2013) one might suggest that there is competition between Fe3+, Al3+ and REE for the binding with DOC. They have a high affinity with the same organic functional groups which is confirmed by the classification scheme (Fig. 8). The studies of Marsac et al. suggest that at acidic pH and low metal/DOC ratios, Fe3+and Al3+ compete more with HREE than LREE; moreover, at high metal/DOC ratios and acidic pH, Al3+ competes with LREE. The Fig. 13 showing the variations of WECEN for Al and Fe in function of WECEN LREE and HREE confirms Marsac et al.’s observations. The slope of the extrapolation line resulting from WECEN Al and HREE values remains rather unchanged for the OM depleted and enriched soil compartments; thus, the change in the metal/DOC ratio in the soil does not change the extraction behavior of Al and HREE. However, the WECEN Fe strongly increase compared to the corresponding HREE values in the OM enriched compartment pointing to the competition between Fe and HREE. Alternatively, one observes that the WECEN Fe and LREE values in the OM enriched compartment plot on the extrapolation line derived from OM depleted soil samples. Thus, in this case, the change in the metal/DOC ratio does not affect the extraction behavior of Fe and LREE. However, the WECEN values for Al and corresponding LREE of samples from the OM enriched soil compartment plot below the extrapolation line and point to the competition between Al and LREE. These results are also in agreement with the REE distribution pattern of the soil solutions from the same site which are at greater depth LREE depleted (Stille et al., 2009).

The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner.

PubMed

Leo, Joyce C L; Lin, Valerie C L

2008-01-01

It is known that progesterone receptor (PR) isoform A (PR-A) and isoform B (PR-B) may mediate different effects of progesterone. The objective of this study was to determine if the functions of PR isoforms also vary in response to different PR modulators (PRM). The effects of 7 synthetic PRM were tested in MDA-MB-231 cells engineered to express PR-A, PR-B, or both PR isoforms. The effects of progesterone were similar in cells expressing PR-A or PR-B in which it inhibited growth and induced focal adhesion. On the other hand, synthetic PRM modulated the activity of the PR isoforms differently. RU486, CDB4124, 17alpha-hydroxy CDB4124 and VA2914 exerted agonist activities on cell growth and adhesion via PR-B. Via PR-A, however, these compounds displayed agonist effect on cell growth but induced stellate morphology which was distinct from the agonist's effect. Their dual properties via PR-A were also displayed at the gene expression level: the compounds acted as agonists on cell cycle genes but exhibited antagonistic effect on cell adhesion genes. Introduction of ERalpha by adenoviral vector to these cells did not change PR-A or PR-B mediated effect of PRM radically, but it causes significant cell rounding and modified the magnitudes of the responses to PRM. The findings suggest that the activities of PR isoforms may be modulated by different PRM through gene-specific regulatory mechanisms. This raises an interesting possibility that PRM may be designed to be PR isoform and cellular pathway selective to achieve targeted therapy in breast cancer. Copyright 2007 Wiley-Liss, Inc.

[Molecular aspects of allergy to plant products. Part II. Pathogenesis-related proteins (PRs), apple allergenicity governed by Mal d 1 gene].

PubMed

Bokszczanin, Kamila Ł; Przybyła, Andrzej A

2012-03-01

Of the plant allergens listed in the Official Allergen Database of the International Union of Immunological Societies, approximately 25% belong to the group of pathogenesis-related proteins (PRs). They have been classified into 17 PR families based on similarities in their amino acid sequence, enzymatic activities, or other functional properties. Plant-derived allergens have been identified with sequence similarities to PR families 2, 3, 4, 5, 8, 10, and 14. The main birch allergen in northern Europe is a class 10 (PR-10) protein from the European white birch (Betula pendula) termed Bet v 1. Pollen of other Fagales species contains PR-10 homologues that share epitopes with Bet v 1, as do several fruits, nuts and vegetables. Among the plant food fruits of the Rosaceae family are the most frequently responsible for allergenic reactions. It is documented, that approximately 2% of European population is allergic to apples. The article presents molecular characterization of PR-10 proteins with regard to their structure and function as well as apple Mal d 1 gene-determined allergenicity.

Disability relating to basic and instrumental activities of daily living: a zopulation-based study with elderly in Pelotas, Rio Grande do Sul, Brazil, 2014.

PubMed

Farías-Antúnez, Simone; Lima, Natália Peixoto; Bierhals, Isabel Oliveira; Gomes, Ana Paula; Vieira, Luna Strieder; Tomasi, Elaine

2018-06-11

to estimate the prevalence of disability related to basic and instrumental activities of daily living and its association with socioeconomic, demographic, behavioral and health characteristics in the elderly. population-based cross-sectional study in Pelotas, Brazil, in 2014; Katz and Lawton scales were used to assess the outcomes using Poisson regression. the study included 1.451 elderly individuals; the prevalence of disability for basic and instrumental activities was 36.1% and 34.0%, respectively, and 18.1% in both; higher prevalence of functional disability were observed individuals ≥80 years (PR=3.01; 95%CI 2.17;4.18), not working (PR=2.02; 95%CI 1.13;3.60) and those with multiple morbidities (PR=3.28; 95%CI 1.38;7.79); and lower in individuals with ≥12 years of schooling (PR=0.40; 95%CI 0.24;0.66), and that were physically active (PR=0.42; 95%CI 0.21;0.82). functional disability was associated to individuals older than 80, with less schooling years and affected by multiple morbidities.

A dynamical systems model of progesterone receptor interactions with inflammation in human parturition.

PubMed

Brubaker, Douglas; Barbaro, Alethea; R Chance, Mark; Mesiano, Sam

2016-08-19

Progesterone promotes uterine relaxation and is essential for the maintenance of pregnancy. Withdrawal of progesterone activity and increased inflammation within the uterine tissues are key triggers for parturition. Progesterone actions in myometrial cells are mediated by two progesterone receptor (PR) isoforms, PR-A and PR-B, that function as ligand-activated transcription factors. PR-B mediates relaxatory actions of progesterone, in part, by decreasing myometrial cell responsiveness to pro-inflammatory stimuli. These same pro-inflammatory stimuli promote the expression of PR-A which inhibits the anti-inflammatory activity of PR-B. Competitive interaction between the progesterone receptors then augments myometrial responsiveness to pro-inflammatory stimuli. The interaction between PR-B transcriptional activity and inflammation in the pregnancy myometrium is examined using a dynamical systems model in which quiescence and labor are represented as phase-space equilibrium points. Our model shows that PR-B transcriptional activity and the inflammatory load determine the stability of the quiescent and laboring phenotypes. The model is tested using published transcriptome datasets describing the mRNA abundances in the myometrium before and after the onset of labor at term. Surrogate transcripts were selected to reflect PR-B transcriptional activity and inflammation status. The model coupling PR-B activity and inflammation predicts contractile status (i.e., laboring or quiescent) with high precision and recall and outperforms uncoupled single and two-gene classifiers. Linear stability analysis shows that phase space bifurcations exist in our model that may reflect the phenotypic states of the pregnancy uterus. The model describes a possible tipping point for the transition of the quiescent to the contractile laboring phenotype. Our model describes the functional interaction between the PR-A:PR-B hypothesis and tissue level inflammation in the pregnancy uterus and is a first step in more sophisticated dynamical systems modeling of human partition. The model explains observed biochemical dynamics and as such will be useful for the development of a range of systems-based models using emerging data to predict preterm birth and identify strategies for its prevention.

Pulmonary rehabilitation improves cardiovascular response to exercise in COPD.

PubMed

Ramponi, Sara; Tzani, Panagiota; Aiello, Marina; Marangio, Emilio; Clini, Enrico; Chetta, Alfredo

2013-01-01

Pulmonary rehabilitation (PR) has emerged as a recommended standard of care in symptomatic COPD. We now studied whether PR may affect cardiovascular response to exercise in these patients. Twenty-seven patients (9 females aged 69 ± 8 years) with moderate-to-severe airflow obstruction admitted to a 9-week PR course performed a pre-to-post evaluation of lung function test and symptom-limited cardiopulmonary exercise test (CPET). Oxygen uptake (VO2), tidal volume (V(T)), dyspnea and leg fatigue scores were measured during CPET. Cardiovas-cular response was assessed by means of oxygen pulse (O2Pulse), the oxygen uptake efficiency slope and heart rate recovery at the 1st min. A significant increase in peak VO2 and in all cardiovascular parameters (p < 0.05) was found following PR when compared to baseline. Leg fatigue (p < 0.05), but not dyspnea, was significantly reduced after PR. When assessed at metabolic and ventilatory iso levels [% VCO2max and % minute ventilation (VEmax)], O2Pulse and V(T) were significantly higher (p < 0.05) at submaximal exercise (75 and 50% of VCO2max and VEmax) after PR when compared to baseline. V(T) percent changes at 75% VCO2max and 75% VEmax after PR significantly correlated with corresponding changes in O2Pulse (p < 0.01). In COPD patients, a PR training program improved the cardiovascular response during exercise at submaximal exercise independent of the external workload. This change was associated with an enhanced ventilatory function during exercise. Copyright © 2013 S. Karger AG, Basel.

The prion protein has DNA strand transfer properties similar to retroviral nucleocapsid protein.

PubMed

Gabus, C; Auxilien, S; Péchoux, C; Dormont, D; Swietnicki, W; Morillas, M; Surewicz, W; Nandi, P; Darlix, J L

2001-04-06

The transmissible spongiform encephalopathies are fatal neurodegenerative diseases that are associated with the accumulation of a protease-resistant form of the cellular prion protein (PrP). Although PrP is highly conserved and widely expressed in vertebrates, its function remains a matter of speculation. Indeed PrP null mice develop normally and are healthy. Recent results show that PrP binds to nucleic acids in vitro and is found associated with retroviral particles. Furthermore, in mice the scrapie infectious process appears to be accelerated by MuLV replication. These observations prompted us to further investigate the interaction between PrP and nucleic acids, and compare it with that of the retroviral nucleocapsid protein (NC). As the major nucleic acid-binding protein of the retroviral particle, NC protein is tightly associated with the genomic RNA in the virion nucleocapsid, where it chaperones proviral DNA synthesis by reverse transcriptase. Our results show that the human prion protein (huPrP) functionally resembles NCp7 of HIV-1. Both proteins form large nucleoprotein complexes upon binding to DNA. They accelerate the hybridization of complementary DNA strands and chaperone viral DNA synthesis during the minus and plus DNA strand transfers necessary to generate the long terminal repeats. The DNA-binding and strand transfer properties of huPrP appear to map to the N-terminal fragment comprising residues 23 to 144, whereas the C-terminal domain is inactive. These findings suggest that PrP could be involved in nucleic acid metabolism in vivo. Copyright 2001 Academic Press.

The Prion Protein Modulates A-type K+ Currents Mediated by Kv4.2 Complexes through Dipeptidyl Aminopeptidase-like Protein 6*

PubMed Central

Mercer, Robert C. C.; Ma, Li; Watts, Joel C.; Strome, Robert; Wohlgemuth, Serene; Yang, Jing; Cashman, Neil R.; Coulthart, Michael B.; Schmitt-Ulms, Gerold; Jhamandas, Jack H.; Westaway, David

2013-01-01

Widely expressed in the adult central nervous system, the cellular prion protein (PrPC) is implicated in a variety of processes, including neuronal excitability. Dipeptidyl aminopeptidase-like protein 6 (DPP6) was first identified as a PrPC interactor using in vivo formaldehyde cross-linking of wild type (WT) mouse brain. This finding was confirmed in three cell lines and, because DPP6 directs the functional assembly of K+ channels, we assessed the impact of WT and mutant PrPC upon Kv4.2-based cell surface macromolecular complexes. Whereas a Gerstmann-Sträussler-Scheinker disease version of PrP with eight extra octarepeats was a loss of function both for complex formation and for modulation of Kv4.2 channels, WT PrPC, in a DPP6-dependent manner, modulated Kv4.2 channel properties, causing an increase in peak amplitude, a rightward shift of the voltage-dependent steady-state inactivation curve, a slower inactivation, and a faster recovery from steady-state inactivation. Thus, the net impact of wt PrPC was one of enhancement, which plays a critical role in the down-regulation of neuronal membrane excitability and is associated with a decreased susceptibility to seizures. Insofar as previous work has established a requirement for WT PrPC in the Aβ-dependent modulation of excitability in cholinergic basal forebrain neurons, our findings implicate PrPC regulation of Kv4.2 channels as a mechanism contributing to the effects of oligomeric Aβ upon neuronal excitability and viability. PMID:24225951

Mechanisms of Photoreceptor Patterning in Vertebrates and Invertebrates.

PubMed

Viets, Kayla; Eldred, Kiara; Johnston, Robert J

2016-10-01

Across the animal kingdom, visual systems have evolved to be uniquely suited to the environments and behavioral patterns of different species. Visual acuity and color perception depend on the distribution of photoreceptor (PR) subtypes within the retina. Retinal mosaics can be organized into three broad categories: stochastic/regionalized, regionalized, and ordered. We describe here the retinal mosaics of flies, zebrafish, chickens, mice, and humans, and the gene regulatory networks controlling proper PR specification in each. By drawing parallels in eye development between these divergent species, we identify a set of conserved organizing principles and transcriptional networks that govern PR subtype differentiation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Availability of High Quality TRMM Ground Validation Data from Kwajalein, RMI: A Practical Application of the Relative Calibration Adjustment Technique

NASA Technical Reports Server (NTRS)

Marks, David A.; Wolff, David B.; Silberstein, David S.; Tokay, Ali; Pippitt, Jason L.; Wang, Jianxin

2008-01-01

Since the Tropical Rainfall Measuring Mission (TRMM) satellite launch in November 1997, the TRMM Satellite Validation Office (TSVO) at NASA Goddard Space Flight Center (GSFC) has been performing quality control and estimating rainfall from the KPOL S-band radar at Kwajalein, Republic of the Marshall Islands. Over this period, KPOL has incurred many episodes of calibration and antenna pointing angle uncertainty. To address these issues, the TSVO has applied the Relative Calibration Adjustment (RCA) technique to eight years of KPOL radar data to produce Ground Validation (GV) Version 7 products. This application has significantly improved stability in KPOL reflectivity distributions needed for Probability Matching Method (PMM) rain rate estimation and for comparisons to the TRMM Precipitation Radar (PR). In years with significant calibration and angle corrections, the statistical improvement in PMM distributions is dramatic. The intent of this paper is to show improved stability in corrected KPOL reflectivity distributions by using the PR as a stable reference. Inter-month fluctuations in mean reflectivity differences between the PR and corrected KPOL are on the order of 1-2 dB, and inter-year mean reflectivity differences fluctuate by approximately 1 dB. This represents a marked improvement in stability with confidence comparable to the established calibration and uncertainty boundaries of the PR. The practical application of the RCA method has salvaged eight years of radar data that would have otherwise been unusable, and has made possible a high-quality database of tropical ocean-based reflectivity measurements and precipitation estimates for the research community.

Biological properties of prolactin-releasing peptide analogs with a modified aromatic ring of a C-terminal phenylalanine amide.

PubMed

Maletínská, Lenka; Spolcová, Andrea; Maixnerová, Jana; Blechová, Miroslava; Zelezná, Blanka

2011-09-01

Prolactin-releasing peptide (PrRP)-induced secretion of prolactin is not currently considered a primary function of PrRP, but the development of late-onset obesity in both PrRP and PrRP receptor knock-out mice indicates the unique anorexigenic properties of PrRP. In our recent study, we showed comparable potencies of peptides PrRP31 and PrRP20 in binding, intracellular signaling and prolactin release in pituitary RC-4B/C cells, and anorexigenic effect after central administration in fasted mice. In the present study, eight analogs of PrRP20 with C-terminal Phe amide modified with a bulky side chain or a halogenated aromatic ring revealed high binding potency, activation of mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK1/2) and cAMP response element-binding protein (CREB) and prolactin release in RC-4B/C cells. In particular, [PheNO(2)(31)]PrRP20, [1-Nal(31)]PrRP20, [2-Nal(31)]PrRP20 and [Tyr(31)]PrRP20 showed not only in vitro effects comparable or higher than those of PrRP20, but also a very significant and long-lasting anorexigenic effect after central administration in fasted mice. The design of potent and long-lasting PrRP analogs with selective anorexigenic properties promises to contribute to the study of food intake disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

Novel Loci Associated with PR Interval in a Genome-Wide Association Study of Ten African American Cohorts

PubMed Central

Butler, Anne M.; Yin, Xiaoyan; Evans, Daniel S.; Nalls, Michael A.; Smith, Erin N.; Tanaka, Toshiko; Li, Guo; Buxbaum, Sarah G.; Whitsel, Eric A.; Alonso, Alvaro; Arking, Dan E.; Benjamin, Emelia J.; Berenson, Gerald S.; Bis, Josh C.; Chen, Wei; Deo, Rajat; Ellinor, Patrick T.; Heckbert, Susan R.; Heiss, Gerardo; Hsueh, Wen-Chi; Keating, Brendan J.; Kerr, Kathleen F.; Li, Yun; Limacher, Marian C.; Liu, Yongmei; Lubitz, Steven A.; Marciante, Kristin D.; Mehra, Reena; Meng, Yan A.; Newman, Anne B.; Newton-Cheh, Christopher; North, Kari E.; Palmer, Cameron D.; Psaty, Bruce M.; Quibrera, P. Miguel; Redline, Susan; Reiner, Alex P.; Rotter, Jerome I.; Schnabel, Renate B.; Schork, Nicholas J.; Singleton, Andrew B.; Smith, J. Gustav; Soliman, Elsayed Z.; Srinivasan, Sathanur R.; Zhang, Zhu-ming; Zonderman, Alan B.; Ferrucci, Luigi; Murray, Sarah S.; Evans, Michele K.; Sotoodehnia, Nona; Magnani, Jared W.; Avery, Christy L.

2013-01-01

Background The PR interval (PR) as measured by the resting, standard 12-lead electrocardiogram (ECG) reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at nine loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. Methods and Results We present results from the largest genome-wide association study to date of PR in 13,415 adults of African descent from ten cohorts. We tested for association between PR (ms) and approximately 2.8 million genotyped and imputed single nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (lambda range: 0.9–1.1), although not after genomic control correction was applied to the overall meta-analysis (lambda: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0×10−8), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained two additional independent secondary signals influencing PR (P<5.0×10−8). Conclusions This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European and Asian descent. PMID:23139255

First principle study of structural, electronic and fermi surface properties of aluminum praseodymium

NASA Astrophysics Data System (ADS)

Shugani, Mani; Aynyas, Mahendra; Sanyal, S. P.

2018-05-01

We present a structural, Electronic and Fermi surface properties of Aluminum Praseodymium (AlPr) using First-principles density functional calculation by using full potential linearized augmented plane wave (FP-LAPW) method within generalized gradient approximation (GGA). The ground state properties along with electronic and Fermi surface properties are studied. It is found that AlPr is metallic and the bonding between Al and Pr is covalent.

Progesterone Receptor-A and -B Have Opposite Effects on Proinflammatory Gene Expression in Human Myometrial Cells: Implications for Progesterone Actions in Human Pregnancy and Parturition

PubMed Central

Tan, Huiqing; Yi, Lijuan; Rote, Neal S.; Hurd, William W.

2012-01-01

Context: Progesterone promotes uterine relaxation during pregnancy and its withdrawal induces labor. Progesterone withdrawal in human parturition is mediated in part by changes in the relative levels of the nuclear progesterone receptor isoforms, PR-A and PR-B, in myometrial cells. Parturition also involves myometrial inflammation; however, the functional link between nuclear PR-mediated progesterone actions and inflammation in human myometrial cells is unclear. Objective: Our objective was to determine how PR-A and PR-B regulate progesterone action in human myometrial cells and specifically the expression of genes encoding contraction-associated proteins and proinflammatory mediators. Design: Effects of PR-A and PR-B on the capacity for progesterone to modulate gene expression was determined using an immortalized human myometrial cell line stably transfected with inducible PR-A and PR-B expression transgenes and conditioned to express various PR-A and PR-B levels. Gene expression was assessed by genome wide transcriptome analysis, quantitative RT-PCR and immunoblotting. Results: PR-A and PR-B were each transcriptionally active in response to progesterone and affected the expression of distinct gene cohorts. The capacity for progesterone to affect gene expression was dependent on the PR-A to PR-B ratio. This was especially apparent for the expression of proinflammatory genes. Progesterone decreased proinflammatory gene expression when the PR-A to PR-B ratio favored PR-B and increased proinflammatory gene expression when the ratio favored PR-A. Progesterone via PR-B increased expression of inhibitor-κBα, a repressor of the nuclear factor-κB transcription factor, and inhibited basal and lipopolysaccharide-induced proinflammatory gene expression. Both of those PR-B-mediated effects were inhibited by PR-A. Conclusions: Our data suggest that during most of human pregnancy, when myometrial cells are PR-B dominant, progesterone promotes myometrial quiescence through PR-B-mediated antiinflammatory actions. At parturition, the rise in PR-A expression promotes labor by inhibiting the antiinflammatory actions of PR-B and stimulating proinflammatory gene expression in response to progesterone. PMID:22419721

Effect of Surface Coverage of Gold Nanoparticles on the Refractive Index Sensitivity in Fiber-Optic Nanoplasmonic Sensing.

PubMed

Wu, Wei-Te; Chen, Chien-Hsing; Chiang, Chang-Yue; Chau, Lai-Kwan

2018-05-31

A simple theoretical model was developed to analyze the extinction spectrum of gold nanoparticles (AuNPs) on the fiber core and glass surfaces in order to aid the determination of the surface coverage and surface distribution of the AuNPs on the fiber core surface for sensitivity optimization of the fiber optic particle plasmon resonance (FOPPR) sensor. The extinction spectrum of AuNPs comprises of the interband absorption of AuNPs, non-interacting plasmon resonance (PR) band due to isolated AuNPs, and coupled PR band of interacting AuNPs. When the surface coverage is smaller than 12.2%, the plasmon coupling effect can almost be ignored. This method is also applied to understand the refractive index sensitivity of the FOPPR sensor with respect to the non-interacting PR band and the coupled PR band. In terms of wavelength sensitivity at a surface coverage of 18.6%, the refractive index sensitivity of the coupled PR band (205.5 nm/RIU) is greater than that of the non-interacting PR band (349.1 nm/RIU). In terms of extinction sensitivity, refractive index sensitivity of the coupled PR band (-3.86/RIU) is similar to that of the non-interacting PR band (-3.93/RIU). Both maximum wavelength and extinction sensitivities were found at a surface coverage of 15.2%.

Transition-metal prion protein attachment: Competition with copper

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Bernholc, Jerry

2012-02-01

Prion protein, PrP, is a protein capable of binding copper ions in multiple modes depending on their concentration. Misfolded PrP is implicated in a group of neurodegenerative diseases, which include ``mad cow disease'' and its human form, variant Creutzfeld-Jacob disease. An increasing amount of evidence suggests that attachment of non-copper metal ions to PrP triggers transformations to abnormal forms similar to those observed in prion diseases. In this work, we use hybrid Kohn-Sham/orbital-free density functional theory simulations to investigate copper replacement by other transition metals that bind to PrP, including zinc, iron and manganese. We consider all known copper binding modes in the N-terminal domain of PrP. Our calculations identify modes most susceptible to copper replacement and reveal metals that can successfully compete with copper for attachment to PrP.

TRMM Precipitation Radar Reflectivity Profiles Compared to High-Resolution Airborne and Ground-Based Radar Measurements

NASA Technical Reports Server (NTRS)

Heymsfield, G. M.; Geerts, B.; Tian, L.

1999-01-01

In this paper, TRMM (Tropical Rainfall Measuring Mission Satellite) Precipitation Radar (PR) products are evaluated by means of simultaneous comparisons with data from the high-altitude ER-2 Doppler Radar (EDOP), as well as ground-based radars. The comparison is aimed primarily at the vertical reflectivity structure, which is of key importance in TRMM rain type classification and latent heating estimation. The radars used in this study have considerably different viewing geometries and resolutions, demanding non-trivial mapping procedures in common earth-relative coordinates. Mapped vertical cross sections and mean profiles of reflectivity from the PR, EDOP, and ground-based radars are compared for six cases. These cases cover a stratiform frontal rainband, convective cells of various sizes and stages, and a hurricane. For precipitating systems that are large relative to the PR footprint size, PR reflectivity profiles compare very well to high-resolution measurements thresholded to the PR minimum reflectivity, and derived variables such as bright band height and rain types are accurate, even at high PR incidence angles. It was found that for, the PR reflectivity of convective cells small relative to the PR footprint is weaker than in reality. Some of these differences can be explained by non-uniform beam filling. For other cases where strong reflectivity gradients occur within a PR footprint, the reflectivity distribution is spread out due to filtering by the PR antenna illumination pattern. In these cases, rain type classification may err and be biased towards the stratiform type, and the average reflectivity tends to be underestimated. The limited sensitivity of the PR implies that the upper regions of precipitation systems remain undetected and that the PR storm top height estimate is unreliable, usually underestimating the actual storm top height. This applies to all cases but the discrepancy is larger for smaller cells where limited sensitivity is compounded by incomplete beam filling. Users of level three TRMM PR products should be aware of this scale dependency.

Drug transporters in tissues and cells relevant to sexual transmission of HIV: Implications for drug delivery.

PubMed

Hu, Minlu; Patel, Sravan Kumar; Zhou, Tian; Rohan, Lisa C

2015-12-10

Efflux and uptake transporters of drugs are key regulators of the pharmacokinetics of many antiretroviral drugs. A growing body of literature has revealed the expression and functionality of multiple transporters in female genital tract (FGT), colorectal tissue, and immune cells. Drug transporters could play a significant role in the efficacy of preventative strategies for HIV-1 acquisition. Pre-exposure prophylaxis (PrEP) is a promising strategy, which utilizes topically (vaginally or rectally), orally or other systemically administered antiretroviral drugs to prevent the sexual transmission of HIV to receptive partners. The drug concentration in the receptive mucosal tissues and target immune cells for HIV is critical for PrEP effectiveness. Hence, there is an emerging interest in utilizing transporter information to explain tissue disposition patterns of PrEP drugs, to interpret inter-individual variability in PrEP drug pharmacokinetics and effectiveness, and to improve tissue drug exposure through modulation of the cervicovaginal, colorectal, or immune cell transporters. In this review, the existing literature on transporter expression, functionality and regulation in the transmission-related tissues and cells is summarized. In addition, the relevance of transporter function for drug delivery and strategies that could exploit transporters for increased drug concentration at target locales is discussed. The overall goal is to facilitate an understanding of drug transporters for PrEP optimization. Copyright © 2015 Elsevier B.V. All rights reserved.

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules.

PubMed

Linden, Rafael

2017-01-01

The prion glycoprotein (PrP C ) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrP C is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer's Disease (AD). PrP C is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrP C at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrP C , despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrP C with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrP C serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.

Targeting the membrane-anchored serine protease testisin with a novel engineered anthrax toxin prodrug to kill tumor cells and reduce tumor burden

PubMed Central

Martin, Erik W.; Buzza, Marguerite S.; Driesbaugh, Kathryn H.; Liu, Shihui; Fortenberry, Yolanda M.; Leppla, Stephen H.; Antalis, Toni M.

2015-01-01

The membrane-anchored serine proteases are a unique group of trypsin-like serine proteases that are tethered to the cell surface via transmembrane domains or glycosyl-phosphatidylinositol-anchors. Overexpressed in tumors, with pro-tumorigenic properties, they are attractive targets for protease-activated prodrug-like anti-tumor therapies. Here, we sought to engineer anthrax toxin protective antigen (PrAg), which is proteolytically activated on the cell surface by the proprotein convertase furin to instead be activated by tumor cell-expressed membrane-anchored serine proteases to function as a tumoricidal agent. PrAg's native activation sequence was mutated to a sequence derived from protein C inhibitor (PCI) that can be cleaved by membrane-anchored serine proteases, to generate the mutant protein PrAg-PCIS. PrAg-PCIS was resistant to furin cleavage in vitro, yet cytotoxic to multiple human tumor cell lines when combined with FP59, a chimeric anthrax toxin lethal factor-Pseudomonas exotoxin fusion protein. Molecular analyses showed that PrAg-PCIS can be cleaved in vitro by several serine proteases including the membrane-anchored serine protease testisin, and mediates increased killing of testisin-expressing tumor cells. Treatment with PrAg-PCIS also potently attenuated the growth of testisin-expressing xenograft tumors in mice. The data indicates PrAg can be engineered to target tumor cell-expressed membrane-anchored serine proteases to function as a potent tumoricidal agent. PMID:26392335

Estimation of sensitivity and specificity of pregnancy diagnosis using transrectal ultrasonography and ELISA for pregnancy-associated glycoprotein in dairy cows using a Bayesian latent class model.

PubMed

Shephard, R W; Morton, J M

2018-01-01

To determine the sensitivity (Se) and specificity (Sp) of pregnancy diagnosis using transrectal ultrasonography and an ELISA for pregnancy-associated glycoprotein (PAG) in milk, in lactating dairy cows in seasonally calving herds approximately 85-100 days after the start of the herd's breeding period. Paired results were used from pregnancy diagnosis using transrectal ultrasonography and ELISA for PAG in milk carried out approximately 85 and 100 days after the start of the breeding period, respectively, from 879 cows from four herds in Victoria, Australia. A Bayesian latent class model was used to estimate the proportion of cows pregnant, the Se and Sp of each test, and covariances between test results in pregnant and non-pregnant cows. Prior probability estimates were defined using beta distributions for the expected proportion of cows pregnant, Se and Sp for each test, and covariances between tests. Markov Chain Monte Carlo iterations identified posterior distributions for each of the unknown variables. Posterior distributions for each parameter were described using medians and 95% probability (i.e. credible) intervals (PrI). The posterior median estimates for Se and Sp for each test were used to estimate positive predictive and negative predictive values across a range of pregnancy proportions. The estimate for proportion pregnant was 0.524 (95% PrI = 0.485-0.562). For pregnancy diagnosis using transrectal ultrasonography, Se and Sp were 0.939 (95% PrI = 0.890-0.974) and 0.943 (95% PrI = 0.885-0.984), respectively; for ELISA, Se and Sp were 0.963 (95% PrI = 0.919-0.990) and 0.870 (95% PrI = 0.806-0.931), respectively. The estimated covariance between test results was 0.033 (95% PrI = 0.008-0.046) and 0.035 (95% PrI = 0.018-0.078) for pregnant and non-pregnant cows, respectively. Pregnancy diagnosis results using transrectal ultrasonography had a higher positive predictive value but lower negative predictive value than results from the ELISA across the range of pregnancy proportions assessed. Pregnancy diagnosis using transrectal ultrasonography and ELISA for PAG in milk had similar Se but differed in predictive values. Pregnancy diagnosis in seasonally calving herds around 85-100 days after the start of the breeding period using the ELISA is expected to result in a higher negative predictive value but lower positive predictive value than pregnancy diagnosis using transrectal ultrasonography. Thus, with the ELISA, a higher proportion of the cows with negative results will be non-pregnant, relative to results from transrectal ultrasonography, but a lower proportion of cows with positive results will be pregnant.

Pyruvate in oral rehydration salt improves hemodynamics, vasopermeability and survival after burns in dogs.

PubMed

Liu, Rui; Hu, Xiao-Hang; Wang, Shu-Ming; Guo, Si-Jia; Li, Zong-Yu; Bai, Xiao-Dong; Zhou, Fang-Qiang; Hu, Sen

2016-06-01

To investigate whether pyruvate-enriched oral rehydration solution (Pyr-ORS), compared with citrate-enriched ORS (Cit-ORS), improves hemodynamics and organ function by alleviating vasopermeability and plasma volume loss during intra-gastric fluid rehydration in dogs with severe burn. Forty dogs subjected to severe burn were randomly divided into four groups (n=10): two oral rehydrated groups with Pyr-ORS and Cit-ORS (group PR and group CR), respectively, according to the Parkland formula during the first 24h after burns. Other two groups were the intravenous (IV) resuscitation (group VR) with lactated Ringer's solution with the same dosage and no fluid rehydration (group NR). During the next 24h, all groups received the same IV infusion. The hemodynamics, plasma volume, vasopermeability and water contents and function of various organs were determined. Plasma levels of vascular endothelial growth factor (VEGF) and platelet activating factor (PAF) were detected by ELISA. Hemodynamics parameters were significantly improved in group PR superior to group CR after burns. Levels of VEGF and PAF were significantly lower in group PR than in group CR. Organ function parameters were also greatly preserved in group PR, relative to groups CR and NR. Lactic acidosis was fully corrected and survival increased in group PR (50.0%), compared to group CR (20.0%). Pyr-ORS was more effective than Cit-ORS in improving hemodynamics, visceral blood perfusion and organ function by alleviating vasopermeability-induced visceral edema and plasma volume loss in dogs with severe burn. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

Structural, electronic and magnetic properties of Pr-based filled skutterudites: A first principle study

NASA Astrophysics Data System (ADS)

Yadav, Priya; Nautiyal, Shashank; Verma, U. P.

2018-04-01

Ternary skutterudites materials exhibit good electronic properties due to the unpaired d- and f- electrons of the transition and rare-earth metals, respectively. In this communication, we have performed the structural optimization of Pr-based filled skutterudite (PrCo4P12) for the first time and obtained the electronic band structure, density of states and magnetic moments by using the full-potential linearized augmented plane wave (FP-LAPW) method based on density functional theory (DFT). Our obtained magnetic moment of PrCo4P12 is ˜ 1.8 µB in which main contribution is due to Pr atom. Behavior of this material is metallic and it is most stable in body centered cubic (BCC) structure.

Beyond policy analysis: the raw politics behind opposition to healthy public policy.

PubMed

Raphael, Dennis

2015-06-01

Despite evidence that public policy that equitably distributes the prerequisites/social determinants of health (PrH/SDH) is a worthy goal, progress in achieving such healthy public policy (HPP) has been uneven. This has especially been the case in nations where the business sector dominates the making of public policy. In response, various models of the policy process have been developed to create what Kickbusch calls a health political science to correct this situation. In this article I examine an aspect of health political science that is frequently neglected: the raw politics of power and influence. Using Canada as an example, I argue that aspects of HPP related to the distribution of key PrH/SDH are embedded within issues of power, influence, and competing interests such that key sectors of society oppose and are successful in blocking such HPP. By identifying these opponents and understanding why and how they block HPP, these barriers can be surmounted. These efforts to identify opponents of HPP that provide an equitable distribution of the PrH/SDH will be especially necessary where a nation's political economy is dominated by the business and corporate sector. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

New insights on the synthesis and electronic transport in bulk polycrystalline Pr-doped SrTiO3-δ

NASA Astrophysics Data System (ADS)

Dehkordi, Arash Mehdizadeh; Bhattacharya, Sriparna; Darroudi, Taghi; Alshareef, Husam N.; Tritt, Terry M.

2015-02-01

Recently, we have reported a significant enhancement in the electronic and thermoelectric properties of bulk polycrystalline SrTiO3 ceramics via praseodymium doping. This improvement was originated from the simultaneous enhancement in the thermoelectric power factor and reduction in thermal conductivity, which was contributed to the non-uniform distribution of Pr dopants. In order to further understand the underlying mechanism, we herein investigate the role of praseodymium doping source (Pr2O3 versus Pr6O11) on the synthesis and electronic transport in Pr-doped SrTiO3 ceramics. It was observed that the high-temperature electronic transport properties are independent of the choice of praseodymium doping source for samples prepared following our synthesis strategy. Theoretical calculations were also performed in order to estimate the maximum achievable power factor and the corresponding optimal carrier concentration. The result suggests the possibility of further improvement of the power factor. This study should shed some light on the superior electronic transport in bulk polycrystalline Pr-doped SrTiO3 ceramics and provide new insight on further improvement of the thermoelectric power factor.

Saccharomyces cerevisiae proteinase A excretion and wine making.

PubMed

Song, Lulu; Chen, Yefu; Du, Yongjing; Wang, Xibin; Guo, Xuewu; Dong, Jian; Xiao, Dongguang

2017-11-09

Proteinase A (PrA), the major protease in Saccharomyces cerevisiae, plays an essential role in zymogen activation, sporulation, and other physiological processes in vivo. The extracellular secretion of PrA often occurs during alcoholic fermentation, especially in the later stages when the yeast cells are under stress conditions, and affects the quality and safety of fermented products. Thus, the mechanism underlying PrA excretion must be explored to improve the quality and safety of fermented products. This paper briefly introduces the structure and physiological function of PrA. Two transport routes of PrA, namely, the Golgi-to-vacuole pathway and the constitutive Golgi-to-plasma membrane pathway, are also discussed. Moreover, the research history and developments on the mechanism of extracellular PrA secretion are described. In addition, it is briefly discussed that calcium homeostasis plays an important role in the secretory pathway of proteins, implying that the regulation of PrA delivery to the plasma membrane requires the involvement of calcium ion. Finally, this review focuses on the effects of PrA excretion on wine making (including Chinese rice wine, grape wine, and beer brewage) and presents strategies to control PrA excretion.

Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

PubMed Central

Lau, Agnes; McDonald, Alex; Daude, Nathalie; Mays, Charles E; Walter, Eric D; Aglietti, Robin; Mercer, Robert CC; Wohlgemuth, Serene; van der Merwe, Jacques; Yang, Jing; Gapeshina, Hristina; Kim, Chae; Grams, Jennifer; Shi, Beipei; Wille, Holger; Balachandran, Aru; Schmitt-Ulms, Gerold; Safar, Jiri G; Millhauser, Glenn L; Westaway, David

2015-01-01

The cellular prion protein (PrPC) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrPSc in Creutzfeldt-Jakob disease. PrPC β-endoproteolysis to the C2 fragment allows PrPSc formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, ‘S1’ and ‘S3’, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrPSc and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrPSc and infectivity can either uncouple or engage to drive the onset of clinical disease. PMID:25661904

Geomicrobiology of the Ocean Crust: The Phylogenetic Diversity, Abundance, and Distribution of Microbial Communities Inhabiting Basalt and Implications for Rock Alteration Processes

DTIC Science & Technology

2007-06-01

AF317741) 93 EPR3970- MOlA -Bc32 gamma-Proteobacteria Uncultured gamma proteobacterium clone AT-s80 (AY225635) 99 FPR3970-MO IA-Bc33 Actinobacteria...bacterium partial I AJ966584) 99 1iPR3970- MOlA -Bc65 Unidentified Uncultured bacterium clone CV90 (DQ499320) 89 1iPR3970- MOlA -Bc66 Unidentified Uncultured

Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa.

PubMed

Petit, Lolita; Ma, Shan; Cipi, Joris; Cheng, Shun-Yun; Zieger, Marina; Hay, Nissim; Punzo, Claudio

2018-05-29

Aerobic glycolysis accounts for ∼80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic stress conditions such as those encountered in retinitis pigmentosa, where the loss of rods causes a nutrient shortage in cones. The data support a model where aerobic glycolysis in PRs is not a necessity but rather a metabolic choice that maximizes PR function and adaptability to nutrient stress conditions. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

ck2-dependent phosphorylation of progesterone receptors (PR) on Ser81 regulates PR-B isoform-specific target gene expression in breast cancer cells.

PubMed

Hagan, Christy R; Regan, Tarah M; Dressing, Gwen E; Lange, Carol A

2011-06-01

Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. Herein, we show that phosphorylation of PR Ser81 is ck2 dependent and progestin regulated in intact cells but also occurs in the absence of PR ligands when cells enter the G(1)/S phase of the cell cycle. T47D breast cancer cells stably expressing a PR-B mutant receptor that cannot be phosphorylated at Ser79/81 (S79/81A) formed fewer soft agar colonies. Regulation of selected genes by PR-B, but not PR-A, also required Ser79/81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF) expression. Additionally, wild-type (wt) PR-B, but not S79/81A mutant PR, was robustly recruited to a progesterone response element (PRE)-containing transcriptional enhancer region of BIRC3; abundant ck2 also associated with this region in cells expressing wt but not S79/81A PR. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR-B target genes. Understanding how ligand-independent PRs function in the context of high levels of kinase activities characteristic of breast cancer is critical to understanding the basis of tumor-specific changes in gene expression and will speed the development of highly selective treatments.

ck2-Dependent Phosphorylation of Progesterone Receptors (PR) on Ser81 Regulates PR-B Isoform-Specific Target Gene Expression in Breast Cancer Cells ▿

PubMed Central

Hagan, Christy R.; Regan, Tarah M.; Dressing, Gwen E.; Lange, Carol A.

2011-01-01

Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. Herein, we show that phosphorylation of PR Ser81 is ck2 dependent and progestin regulated in intact cells but also occurs in the absence of PR ligands when cells enter the G1/S phase of the cell cycle. T47D breast cancer cells stably expressing a PR-B mutant receptor that cannot be phosphorylated at Ser79/81 (S79/81A) formed fewer soft agar colonies. Regulation of selected genes by PR-B, but not PR-A, also required Ser79/81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF) expression. Additionally, wild-type (wt) PR-B, but not S79/81A mutant PR, was robustly recruited to a progesterone response element (PRE)-containing transcriptional enhancer region of BIRC3; abundant ck2 also associated with this region in cells expressing wt but not S79/81A PR. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR-B target genes. Understanding how ligand-independent PRs function in the context of high levels of kinase activities characteristic of breast cancer is critical to understanding the basis of tumor-specific changes in gene expression and will speed the development of highly selective treatments. PMID:21518957

Analysis of nucleic acid chaperoning by the prion protein and its inhibition by oligonucleotides.

PubMed

Guichard, Cécile; Ivanyi-Nagy, Roland; Sharma, Kamal Kant; Gabus, Caroline; Marc, Daniel; Mély, Yves; Darlix, Jean-Luc

2011-10-01

Prion diseases are unique neurodegenerative illnesses associated with the conversion of the cellular prion protein (PrP(C)) into the aggregated misfolded scrapie isoform, named PrP(Sc). Recent studies on the physiological role of PrP(C) revealed that this protein has probably multiple functions, notably in cell-cell adhesion and signal transduction, and in assisting nucleic acid folding. In fact, in vitro findings indicated that the human PrP (huPrP) possesses nucleic acid binding and annealing activities, similarly to nucleic acid chaperone proteins that play essential roles in cellular DNA and RNA metabolism. Here, we show that a peptide, representing the N-terminal domain of huPrP, facilitates nucleic acid annealing by two parallel pathways nucleated through the stem termini. We also show that PrP of human or ovine origin facilitates DNA strand exchange, ribozyme-directed cleavage of an RNA template and RNA trans-splicing in a manner similar to the nucleocapsid protein of HIV-1. In an attempt to characterize inhibitors of PrP-chaperoning in vitro we discovered that the thioaptamer 5'-GACACAAGCCGA-3' was extensively inhibiting the PrP chaperoning activities. At the same time a recently characterized methylated oligoribonucleotide inhibiting the chaperoning activity of the HIV-1 nucleocapsid protein was poorly impairing the PrP chaperoning activities.

Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing

NASA Astrophysics Data System (ADS)

Su, Tao; Tan, Yong; Tsui, Man-Shan; Yi, Hua; Fu, Xiu-Qiong; Li, Ting; Chan, Chi Leung; Guo, Hui; Li, Ya-Xi; Zhu, Pei-Li; Tse, Anfernee Kai Wing; Cao, Hui; Lu, Ai-Ping; Yu, Zhi-Ling

2016-10-01

Pinelliae Rhizoma (PR) is a commonly used Chinese medicinal herb, but it has been frequently reported about its toxicity. According to the traditional Chinese medicine theory, processing can reduce the toxicity of the herbs. Here, we aim to determine if processing reduces the toxicity of raw PR, and to explore the underlying mechanisms of raw PR-induced toxicities and the toxicity-reducing effect of processing. Biochemical and histopathological approaches were used to evaluate the toxicities of raw and processed PR. Rat serum metabolites were analyzed by LC-TOF-MS. Ingenuity pathway analysis of the metabolomics data highlighted the biological pathways and network functions involved in raw PR-induced toxicities and the toxicity-reducing effect of processing, which were verified by molecular approaches. Results showed that raw PR caused cardiotoxicity, and processing reduced the toxicity. Inhibition of mTOR signaling and activation of the TGF-β pathway contributed to raw PR-induced cardiotoxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on the mechanisms of raw PR-induced cardiotoxicity and the toxicity-reducing effect of processing. This study provides scientific justifications for the traditional processing theory of PR, and should help in optimizing the processing protocol and clinical combinational application of PR.

Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation

PubMed Central

Alleaume-Butaux, Aurélie; Nicot, Simon; Pietri, Mathéa; Baudry, Anne; Dakowski, Caroline; Tixador, Philippe; Ardila-Osorio, Hector; Haeberlé, Anne-Marie; Bailly, Yannick; Peyrin, Jean-Michel; Launay, Jean-Marie; Kellermann, Odile; Schneider, Benoit

2015-01-01

In prion diseases, synapse dysfunction, axon retraction and loss of neuronal polarity precede neuronal death. The mechanisms driving such polarization defects, however, remain unclear. Here, we examined the contribution of RhoA-associated coiled-coil containing kinases (ROCK), key players in neuritogenesis, to prion diseases. We found that overactivation of ROCK signaling occurred in neuronal stem cells infected by pathogenic prions (PrPSc) and impaired the sprouting of neurites. In reconstructed networks of mature neurons, PrPSc-induced ROCK overactivation provoked synapse disconnection and dendrite/axon degeneration. This overactivation of ROCK also disturbed overall neurotransmitter-associated functions. Importantly, we demonstrated that beyond its impact on neuronal polarity ROCK overactivity favored the production of PrPSc through a ROCK-dependent control of 3-phosphoinositide-dependent kinase 1 (PDK1) activity. In non-infectious conditions, ROCK and PDK1 associated within a complex and ROCK phosphorylated PDK1, conferring basal activity to PDK1. In prion-infected neurons, exacerbated ROCK activity increased the pool of PDK1 molecules physically interacting with and phosphorylated by ROCK. ROCK-induced PDK1 overstimulation then canceled the neuroprotective α-cleavage of normal cellular prion protein PrPC by TACE α-secretase, which physiologically precludes PrPSc production. In prion-infected cells, inhibition of ROCK rescued neurite sprouting, preserved neuronal architecture, restored neuronal functions and reduced the amount of PrPSc. In mice challenged with prions, inhibition of ROCK also lowered brain PrPSc accumulation, reduced motor impairment and extended survival. We conclude that ROCK overactivation exerts a double detrimental effect in prion diseases by altering neuronal polarity and triggering PrPSc accumulation. Eventually ROCK emerges as therapeutic target to combat prion diseases. PMID:26241960

Antiviral activities of 2,6-diaminopurine-based acyclic nucleoside phosphonates against herpesviruses: In vitro study results with pseudorabies virus (PrV, SuHV-1).

PubMed

Zouharova, Darina; Lipenska, Ivana; Fojtikova, Martina; Kulich, Pavel; Neca, Jiri; Slany, Michal; Kovarcik, Kamil; Turanek-Knotigova, Pavlina; Hubatka, Frantisek; Celechovska, Hana; Masek, Josef; Koudelka, Stepan; Prochazka, Lubomir; Eyer, Ludek; Plockova, Jana; Bartheldyova, Eliska; Miller, Andrew D; Ruzek, Daniel; Raska, Milan; Janeba, Zlatko; Turanek, Jaroslav

2016-02-29

Pseudorabies virus (PrV), a causative agent of Aujeszky's disease, is deadly to most mammals with the exception of higher primates and men. This disease causes serious economic loses among farm animals, especially pigs, yet many European countries are today claimed to be Aujeszky's disease free because of the discovery of an efficient vaccination for pigs. In reality, the virus is still present in wild boar. Current vaccines are neither suitable for dogs nor are there anti-PrV drugs approved for veterinary use. Therefore, the disease still represents a high threat, particularly for expensive hunting dogs that can come into close contact with infected boars. Here we report on the anti-PrV activities of a series of synthetic diaminopurine-based acyclic nucleoside phosphonate (DAP-ANP) analogues. Initially, all synthetic DAP-ANPs under investigation are shown to exhibit minimal cytotoxicity by MTT and XTT tests (1-100μM range). Thereafter in vitro infection models are established using PrV virus SuHV-1, optimized on PK-15 and RK-13 cell lines. Out of the six DAP-ANP analogues tested, analogue VI functionalized with a cyclopropyl group on the 6-amino position of the purine ring proves the most effective antiviral DAP-ANP analogue against PrV infection, aided by sufficient hydrophobic character to enhance bioavailability to its cellular target viral DNA-polymerase. Four other DAP-ANP analogues with functional groups introduced to the C2'position are shown ineffective against PrV infection, even with favourable hydrophobic properties. Cidofovir(®), a drug approved against various herpesvirus infections, is found to exert only low activity against PrV in these same in vitro models. Copyright © 2016 Elsevier B.V. All rights reserved.

The prenyl-binding protein PrBP/δ: a chaperone participating in intracellular trafficking

PubMed Central

Zhang, Houbin; Constantine, Ryan; Frederick, Jeanne M.; Baehr, Wolfgang

2012-01-01

Expressed ubiquitously, PrBP/δ functions as chaperone/co-factor in the transport of a subset of prenylated proteins. PrBP/δ features an immunoglobulin-like β-sandwich fold for lipid binding, and interacts with diverse partners. PrBP/δ binds both C-terminal C15 and C20 prenyl side chains of phototransduction polypeptides and small GTP-binding (G) proteins of the Ras superfamily. PrBP/δ also interacts with the small GTPases, ARL2 and ARL3, which act as release factors (GDFs) for prenylated cargo. Targeted deletion of the mouse Pde6d gene encoding PrBP/δ resulted in impeded trafficking to the outer segments of GRK1 and cone PDE6 which are predicted to be farnesylated and geranylgeranylated, respectively. Rod and cone transducin trafficking was largely unaffected. These trafficking defects produce progressive cone-rod dystrophy in the Pde6d−/− mouse. PMID:22960045

Epithelial and endothelial expression of the green fluorescent protein reporter gene under the control of bovine prion protein (PrP) gene regulatory sequences in transgenic mice

NASA Astrophysics Data System (ADS)

Lemaire-Vieille, Catherine; Schulze, Tobias; Podevin-Dimster, Valérie; Follet, Jérome; Bailly, Yannick; Blanquet-Grossard, Françoise; Decavel, Jean-Pierre; Heinen, Ernst; Cesbron, Jean-Yves

2000-05-01

The expression of the cellular form of the prion protein (PrPc) gene is required for prion replication and neuroinvasion in transmissible spongiform encephalopathies. The identification of the cell types expressing PrPc is necessary to understanding how the agent replicates and spreads from peripheral sites to the central nervous system. To determine the nature of the cell types expressing PrPc, a green fluorescent protein reporter gene was expressed in transgenic mice under the control of 6.9 kb of the bovine PrP gene regulatory sequences. It was shown that the bovine PrP gene is expressed as two populations of mRNA differing by alternative splicing of one 115-bp 5' untranslated exon in 17 different bovine tissues. The analysis of transgenic mice showed reporter gene expression in some cells that have been identified as expressing PrP, such as cerebellar Purkinje cells, lymphocytes, and keratinocytes. In addition, expression of green fluorescent protein was observed in the plexus of the enteric nervous system and in a restricted subset of cells not yet clearly identified as expressing PrP: the epithelial cells of the thymic medullary and the endothelial cells of both the mucosal capillaries of the intestine and the renal capillaries. These data provide valuable information on the distribution of PrPc at the cellular level and argue for roles of the epithelial and endothelial cells in the spread of infection from the periphery to the brain. Moreover, the transgenic mice described in this paper provide a model that will allow for the study of the transcriptional activity of the PrP gene promoter in response to scrapie infection.

Quantitative estimation of Tropical Rainfall Mapping Mission precipitation radar signals from ground-based polarimetric radar observations

NASA Astrophysics Data System (ADS)

Bolen, Steven M.; Chandrasekar, V.

2003-06-01

The Tropical Rainfall Mapping Mission (TRMM) is the first mission dedicated to measuring rainfall from space using radar. The precipitation radar (PR) is one of several instruments aboard the TRMM satellite that is operating in a nearly circular orbit with nominal altitude of 350 km, inclination of 35°, and period of 91.5 min. The PR is a single-frequency Ku-band instrument that is designed to yield information about the vertical storm structure so as to gain insight into the intensity and distribution of rainfall. Attenuation effects on PR measurements, however, can be significant and as high as 10-15 dB. This can seriously impair the accuracy of rain rate retrieval algorithms derived from PR signal returns. Quantitative estimation of PR attenuation is made along the PR beam via ground-based polarimetric observations to validate attenuation correction procedures used by the PR. The reflectivity (Zh) at horizontal polarization and specific differential phase (Kdp) are found along the beam from S-band ground radar measurements, and theoretical modeling is used to determine the expected specific attenuation (k) along the space-Earth path at Ku-band frequency from these measurements. A theoretical k-Kdp relationship is determined for rain when Kdp ≥ 0.5°/km, and a power law relationship, k = a Zhb, is determined for light rain and other types of hydrometers encountered along the path. After alignment and resolution volume matching is made between ground and PR measurements, the two-way path-integrated attenuation (PIA) is calculated along the PR propagation path by integrating the specific attenuation along the path. The PR reflectivity derived after removing the PIA is also compared against ground radar observations.

Oral immunization of wild boar and domestic pigs with attenuated live vaccine protects against Pseudorabies virus infection.

PubMed

Maresch, Christina; Lange, Elke; Teifke, Jens P; Fuchs, Walter; Klupp, Barbara; Müller, Thomas; Mettenleiter, Thomas C; Vahlenkamp, Thomas W

2012-12-28

In domestic pigs strict control measures and the use of gene-deleted marker vaccines resulted in the elimination of pseudorabies virus (PrV) infections in many parts of Europe and North America. In free-roaming feral pigs and wild boar populations, however, serological surveys and monitoring in The Americas, Europe and North Africa provided serological and virological evidence that PrV is more widely distributed than previously assumed. Thus, there is a constant risk of spillover of PrV infection from wild pig populations to domestic animals which could require intervention to limit the infection in wild pigs. To investigate whether oral immunization of wild boar by live-attenuated PrV could be an option, wild boar and domestic pigs were orally immunized with 2×10(6) TCID(50) of the attenuated live PrV vaccine strain Bartha supplied either with a syringe or within a blister, and subsequently intranasally challenged with 10(6) TCID(50) of the highly virulent PrV strain NIA-3. Oral immunization with live-attenuated PrV was able to confer protection against clinical signs in wild boar and against transmission of challenge virus to naïve contact animals. Only two vaccinated domestic pigs developed neurological signs after challenge infection. Our results demonstrate that oral immunization against PrV infection in wild boar is possible. In case increasing PrV infection rates in wild boar may enhance the risk for spillover into domestic pig populations, oral immunization of wild boar against PrV in endemic areas might be a feasible control strategy. Copyright © 2012 Elsevier B.V. All rights reserved.

Development of Semi-distributed ecohydrological model in the Rio Grande De Manati River Basin, Puerto Rico

NASA Astrophysics Data System (ADS)

Setegn, S. G.; Ortiz, J.; Melendez, J.; Barreto, M.; Torres-Perez, J. L.; Guild, L. S.

2015-12-01

There are limited studies in Puerto Rico that shows the water resources availability and variability with respect to changing climates and land use. The main goal of the HICE-PR (Human Impacts to Coastal Ecosystems in Puerto Rico (HICE-PR): the Río Loco Watershed (southwest coast PR) project which was funded by NASA is to evaluate the impacts of land use/land cover changes on the quality and extent of coastal and marine ecosystems (CMEs) in two priority watersheds in Puerto Rico (Manatí and Guánica).The main objective of this study is to set up a physically based spatially distributed hydrological model, Soil and Water Assessment Tool (SWAT) for the analysis of hydrological processes in the Rio Grande de Manati river basin. SWAT (soil and water assessment tool) is a spatially distributed watershed model developed to predict the impact of land management practices on water, sediment and agricultural chemical yields in large complex watersheds. For efficient use of distributed models for hydrological and scenario analysis, it is important that these models pass through a careful calibration and uncertainty analysis. The model was calibrated and validated using Sequential Uncertainty Fitting (SUFI-2) calibration and uncertainty analysis algorithms. The model evaluation statistics for streamflows prediction shows that there is a good agreement between the measured and simulated flows that was verified by coefficients of determination and Nash Sutcliffe efficiency greater than 0.5. Keywords: Hydrological Modeling; SWAT; SUFI-2; Rio Grande De Manati; Puerto Rico

Allyl Ligand Reactivity in Tantalum(V) Compounds: Experimental and Computational Evidence for Allyl Transfer to the Formamidinate Ligand in fac-Ta(NMe2)3( 1-allyl)[iPrNC(H)NHiPr] via a Metallo-Claisen Rearrangement

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

Huang, Shih-Huang Huang; Wang, Xiaoping; Nesterov, Vladimir

2011-01-01

Treatment of TaCl(NMe{sub 2})4 (1) with allyl MgCl furnishes the allyl-substituted compound Ta(NMe{sub 2})4({eta}{sup 1}-allyl) (2) in moderate yield. The X-ray structure of 2 reveals a trigonal-bipyramidal geometry at the tantalum center with an equatorially situated {eta}{sup 1}-allyl moiety. VT {sup 1}H NMR measurements confirm that the molecule is fluxional in solution over the temperature range 298-193 K, and DFT calculations indicate that the time-averaged environment exhibited by the allyl moiety in fluid solution derives from a rapid {eta}{sup 1}-to-{eta}{sup 3} equilibration, with Ta(NMe{sub 2})4({eta}{sup 3}-allyl) serving as the transition state for this process. 1 reacts rapidly with the formamidinemore » {sup i}PrNC(H)N{sup i}Pr to yield fac-TaCl(NMe{sub 2}){sub 3}[{sup i}PrNC(H)N{sup i}Pr] (5) and Me{sub 2}NH, and the tantalum product has been characterized by NMR spectroscopy and X-ray diffraction analysis. The five-coordinate compound Ta(NMe{sub 2}){sub 3}[{sup i}PrNCH(allyl)N{sup i}Pr] (7), whose origin is traced to the putative octahedral species fac-Ta(NMe{sub 2}){sub 3}({eta}{sup 1}-allyl)[{sup i}PrNC(H)N{sup i}Pr] (6), has been obtained from the reaction of 2 with {sup i}PrNC(H)N{sup i}Pr; 7 may also be prepared from the reaction of 5 with allylMgCl. The rearrangement of the allyl moiety in fac-Ta(NMe{sub 2}){sub 3}({eta}{sup 1}-allyl)[{sup i}PrNC(H)N{sup i}Pr] to the formamidinate carbon atom in 7 has been investigated by DFT calculations. Here the DFT calculations have provided crucial insight into the reaction mechanism and the composition of those transient species that do not lend themselves to direct spectroscopic observation. The computed barrier for this metallo-Claisen rearrangement is sensitive to the nature of the density functional employed, and the barrier computed using the meta-GGA TPSS functional provides the best agreement with the experimental conditions. The related alkenyl derivatives Ta(NMe{sub 2})4({eta}{sup 1}-3-butenyl) (3) and Ta(NMe{sub 2}){sub 3}({eta}{sup 1}-3-butenyl)[{sup i}PrNC(H)N{sup i}Pr] (8) have been synthesized, and their reactivity is contrasted with the corresponding allyl-substituted analogues.« less

Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells.

PubMed

Hamanaka, Taichi; Nishizawa, Keiko; Sakasegawa, Yuji; Oguma, Ayumi; Teruya, Kenta; Kurahashi, Hiroshi; Hara, Hideyuki; Sakaguchi, Suehiro; Doh-Ura, Katsumi

2017-03-15

Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear. IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Aβ oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region. Copyright © 2017 American Society for Microbiology.

Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells

PubMed Central

Hamanaka, Taichi; Nishizawa, Keiko; Sakasegawa, Yuji; Oguma, Ayumi; Teruya, Kenta; Kurahashi, Hiroshi; Hara, Hideyuki; Sakaguchi, Suehiro

2017-01-01

ABSTRACT Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear. IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Aβ oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region. PMID:28077650

Modeling transport kinetics in clinoptilolite-phosphate rock systems

NASA Technical Reports Server (NTRS)

Allen, E. R.; Ming, D. W.; Hossner, L. R.; Henninger, D. L.

1995-01-01

Nutrient release in clinoptilolite-phosphate rock (Cp-PR) systems occurs through dissolution and cation-exchange reactions. Investigating the kinetics of these reactions expands our understanding of nutrient release processes. Research was conducted to model transport kinetics of nutrient release in Cp-PR systems. The objectives were to identify empirical models that best describe NH4, K, and P release and define diffusion-controlling processes. Materials included a Texas clinoptilolite (Cp) and North Carolina phosphate rock (PR). A continuous-flow thin-disk technique was used. Models evaluated included zero order, first order, second order, parabolic diffusion, simplified Elovich, Elovich, and power function. The power-function, Elovich, and parabolic-diffusion models adequately described NH4, K, and P release. The power-function model was preferred because of its simplicity. Models indicated nutrient release was diffusion controlled. Primary transport processes controlling nutrient release for the time span observed were probably the result of a combination of several interacting transport mechanisms.

Acceptability of an "on-demand" pre-exposure HIV prophylaxis trial among men who have sex with men living in France.

PubMed

Lorente, Nicolas; Fugon, Lionel; Carrieri, Maria Patrizia; Andreo, Christian; Le Gall, Jean-Marie; Cook, Emmanuel; Aboulker, Jean-Pierre; Capitant, Catherine; Molina, Jean-Michel; Spire, Bruno

2012-01-01

Although predictors of willingness to take daily, self-administered pre-exposure HIV prophylaxis (PrEP) for men who have sex with men (MSM) have been studied in the context of several PrEP trials internationally, little is known about MSM interested in participating in a trial on the use of PrEP on an "on -demand" basis, i.e., taking a first dose of combined tenofovir/emtricitabine a few hours before possible HIV sexual exposure and a second dose a few hours afterwards. A double-blind placebo randomized PrEP trial will soon begin in France to evaluate the effectiveness of PrEP in terms of reducing HIV infection rates, among MSM self-administering "on-demand" PrEP. To assess potential participants' characteristics associated with willingness to participate in the trial and identify barriers and facilitators to implementation, MSM completed a self-administered questionnaire, distributed via gay venues and community websites. Among the 443 respondents who reported being HIV-negative, 40% reported being interested in participating. Factors independently associated with interest included: reporting lower educational level, more than 20 male sexual partners in the previous year, reporting unprotected anal sex with casual partners and preferring PrEP follow-up visits in a devoted area within a hospital. There is great interest in participating in a future "on-demand" PrEP trial among HIV-negative MSM and particularly in those at potentially high risk of HIV exposure. Providing confidentiality and tailored counseling during PrEP follow-up are important issues.

Prandtl-number Effects in High-Rayleigh-number Spherical Convection

NASA Astrophysics Data System (ADS)

Orvedahl, Ryan J.; Calkins, Michael A.; Featherstone, Nicholas A.; Hindman, Bradley W.

2018-03-01

Convection is the predominant mechanism by which energy and angular momentum are transported in the outer portion of the Sun. The resulting overturning motions are also the primary energy source for the solar magnetic field. An accurate solar dynamo model therefore requires a complete description of the convective motions, but these motions remain poorly understood. Studying stellar convection numerically remains challenging; it occurs within a parameter regime that is extreme by computational standards. The fluid properties of the convection zone are characterized in part by the Prandtl number \\Pr = ν/κ, where ν is the kinematic viscosity and κ is the thermal diffusion; in stars, \\Pr is extremely low, \\Pr ≈ 10‑7. The influence of \\Pr on the convective motions at the heart of the dynamo is not well understood since most numerical studies are limited to using \\Pr ≈ 1. We systematically vary \\Pr and the degree of thermal forcing, characterized through a Rayleigh number, to explore its influence on the convective dynamics. For sufficiently large thermal driving, the simulations reach a so-called convective free-fall state where diffusion no longer plays an important role in the interior dynamics. Simulations with a lower \\Pr generate faster convective flows and broader ranges of scales for equivalent levels of thermal forcing. Characteristics of the spectral distribution of the velocity remain largely insensitive to changes in \\Pr . Importantly, we find that \\Pr plays a key role in determining when the free-fall regime is reached by controlling the thickness of the thermal boundary layer.

Genetic diversity in Capsicum baccatum is significantly influenced by its ecogeographical distribution

USDA-ARS?s Scientific Manuscript database

The structure of genetic diversity in a plant germplasm collection is significantly influenced by its ecogeographical distribution. Improved understanding of the combined effects of geology, ecology and human intervention is essential for efficient conservation and use of plant germplasm. In the pr...

Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity*

PubMed Central

Haldar, Swati; Tripathi, Ajai; Qian, Juan; Beserra, Amber; Suda, Srinivas; McElwee, Matthew; Turner, Jerrold; Hopfer, Ulrich; Singh, Neena

2015-01-01

Brain iron-dyshomeostasis is an important cause of neurotoxicity in prion disorders, a group of neurodegenerative conditions associated with the conversion of prion protein (PrPC) from its normal conformation to an aggregated, PrP-scrapie (PrPSc) isoform. Alteration of iron homeostasis is believed to result from impaired function of PrPC in neuronal iron uptake via its ferrireductase activity. However, unequivocal evidence supporting the ferrireductase activity of PrPC is lacking. Kidney provides a relevant model for this evaluation because PrPC is expressed in the kidney, and ∼370 μg of iron are reabsorbed daily from the glomerular filtrate by kidney proximal tubule cells (PT), requiring ferrireductase activity. Here, we report that PrPC promotes the uptake of transferrin (Tf) and non-Tf-bound iron (NTBI) by the kidney in vivo and mainly NTBI by PT cells in vitro. Thus, uptake of 59Fe administered by gastric gavage, intravenously, or intraperitoneally was significantly lower in PrP-knock-out (PrP−/−) mouse kidney relative to PrP+/+ controls. Selective in vivo radiolabeling of plasma NTBI with 59Fe revealed similar results. Expression of exogenous PrPC in immortalized PT cells showed localization on the plasma membrane and intracellular vesicles and increased transepithelial transport of 59Fe-NTBI and to a smaller extent 59Fe-Tf from the apical to the basolateral domain. Notably, the ferrireductase-deficient mutant of PrP (PrPΔ51–89) lacked this activity. Furthermore, excess NTBI and hemin caused aggregation of PrPC to a detergent-insoluble form, limiting iron uptake. Together, these observations suggest that PrPC promotes retrieval of iron from the glomerular filtrate via its ferrireductase activity and modulates kidney iron metabolism. PMID:25572394

Identification and functional analysis of a novel mutation in the PAX3 gene associated with Waardenburg syndrome type I.

PubMed

Niu, Zhijie; Li, Jiada; Tang, Fen; Sun, Jie; Wang, Xueping; Jiang, Lu; Mei, Lingyun; Chen, Hongsheng; Liu, Yalan; Cai, Xinzhang; Feng, Yong; He, Chufeng

2018-02-05

Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant genetic disorder of neural crest cells (NCC) characterized by congenital sensorineural hearing loss, dystopia canthorum, and abnormal iris pigmentation. WS1 is due to loss-of-function mutations in paired box gene 3 (PAX3). Here, we identified a novel PAX3 mutation (c.808C>G, p.R270G) in a three-generation Chinese family with WS1, and then analyzed its in vitro activities. The R270G PAX3 retained nuclear distribution and normal DNA-binding ability; however, it failed to activate MITF promoter, suggesting that haploinsufficiency may be the underlying mechanism for the mild WS1 phenotype of the study family. Copyright © 2017 Elsevier B.V. All rights reserved.

A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function.

PubMed

Catling, A D; Schaeffer, H J; Reuter, C W; Reddy, G R; Weber, M J

1995-10-01

Mammalian MEK1 and MEK2 contain a proline-rich (PR) sequence that is absent both from the yeast homologs Ste7 and Byr1 and from a recently cloned activator of the JNK/stress-activated protein kinases, SEK1/MKK4. Since this PR sequence occurs in MEKs that are regulated by Raf family enzymes but is missing from MEKs and SEKs activated independently of Raf, we sought to investigate the role of this sequence in MEK1 and MEK2 regulation and function. Deletion of the PR sequence from MEK1 blocked the ability of MEK1 to associate with members of the Raf family and markedly attenuated activation of the protein in vivo following growth factor stimulation. In addition, this sequence was necessary for efficient activation of MEK1 in vitro by B-Raf but dispensable for activation by a novel MEK1 activator which we have previously detected in fractionated fibroblast extracts. Furthermore, we found that a phosphorylation site within the PR sequence of MEK1 was required for sustained MEK1 activity in response to serum stimulation of quiescent fibroblasts. Consistent with this observation, we observed that MEK2, which lacks a phosphorylation site at the corresponding position, was activated only transiently following serum stimulation. Finally, we found that deletion of the PR sequence from a constitutively activated MEK1 mutant rendered the protein nontransforming in Rat1 fibroblasts. These observations indicate a critical role for the PR sequence in directing specific protein-protein interactions important for the activation, inactivation, and downstream functioning of the MEKs.

A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function.

PubMed Central

Catling, A D; Schaeffer, H J; Reuter, C W; Reddy, G R; Weber, M J

1995-01-01

Mammalian MEK1 and MEK2 contain a proline-rich (PR) sequence that is absent both from the yeast homologs Ste7 and Byr1 and from a recently cloned activator of the JNK/stress-activated protein kinases, SEK1/MKK4. Since this PR sequence occurs in MEKs that are regulated by Raf family enzymes but is missing from MEKs and SEKs activated independently of Raf, we sought to investigate the role of this sequence in MEK1 and MEK2 regulation and function. Deletion of the PR sequence from MEK1 blocked the ability of MEK1 to associate with members of the Raf family and markedly attenuated activation of the protein in vivo following growth factor stimulation. In addition, this sequence was necessary for efficient activation of MEK1 in vitro by B-Raf but dispensable for activation by a novel MEK1 activator which we have previously detected in fractionated fibroblast extracts. Furthermore, we found that a phosphorylation site within the PR sequence of MEK1 was required for sustained MEK1 activity in response to serum stimulation of quiescent fibroblasts. Consistent with this observation, we observed that MEK2, which lacks a phosphorylation site at the corresponding position, was activated only transiently following serum stimulation. Finally, we found that deletion of the PR sequence from a constitutively activated MEK1 mutant rendered the protein nontransforming in Rat1 fibroblasts. These observations indicate a critical role for the PR sequence in directing specific protein-protein interactions important for the activation, inactivation, and downstream functioning of the MEKs. PMID:7565670

Breast Cancer Risk Factors Defined by Estrogen and Progesterone Receptor Status

PubMed Central

Monroe, Kristine R.; Wilkens, Lynne R.; Kolonel, Laurence N.; Pike, Malcolm C.; Henderson, Brian E.

2009-01-01

Prospective data on ethnic differences in hormone receptor-defined subtypes of breast cancer and their risk factor profiles are scarce. The authors examined the joint distributions of estrogen receptor (ER) and progesterone receptor (PR) status across 5 ethnic groups and the associations of established risk factors with ER/PR status in the Multiethnic Cohort Study (Hawaii and Los Angeles, California). During an average of 10.4 years of follow-up of 84,427 women between 1993–1996 and 2004/2005, 2,543 breast cancer cases with data on ER/PR status were identified: 1,672 estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+); 303 ER+/progesterone receptor-negative (PR−); 77 estrogen receptor-negative (ER−)/PR+; and 491 ER−/PR−. ER/PR status varied significantly across racial/ethnic groups even within the same tumor stage (for localized tumors, P < 0.0001; for advanced tumors, P = 0.01). The highest fraction of ER−/PR− tumors was observed in African Americans (31%), followed by Latinas (25%), Whites (18%), Japanese (14%), and Native Hawaiians (14%). Associations differed between ER+/PR+ and ER−/PR− cases for postmenopausal obesity (P = 0.02), age at menarche (P = 0.05), age at first birth (P = 0.04), and postmenopausal hormone use (P < 0.0001). African Americans are more likely to be diagnosed with ER−/PR− tumors independently of stage at diagnosis, and there are disparate risk factor profiles across the ER/PR subtypes of breast cancer. PMID:19318616

Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells

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

Lin, Y.-J.; Department of Biotechnology, Asia University, Taichung, Taiwan; Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan

2009-01-23

Puerariae radix (PR) is a popular natural herb and a traditional food in Asia, which has antithrombotic and anti-allergic properties and stimulates estrogenic activity. In the present study, we investigated the effects of the PR isoflavones puerarin, daidzein, and genistein on the growth of breast cancer cells. Our data revealed that after treatment with PR isoflavones, a dose-dependent inhibition of cell growth occurred in HS578T, MDA-MB-231, and MCF-7 cell lines. Results from cell cycle distribution and apoptosis assays revealed that PR isoflavones induced cell apoptosis through a caspase-3-dependent pathway and mediated cell cycle arrest in the G2/M phase. Furthermore, wemore » observed that the serum metabolites of PR (daidzein sulfates/glucuronides) inhibited proliferation of the breast cancer cells at a 50% cell growth inhibition (GI{sub 50}) concentration of 2.35 {mu}M. These results indicate that the daidzein constituent of PR can be metabolized to daidzein sulfates or daidzein glucuronides that exhibit anticancer activities. The protein expression levels of the active forms of caspase-9 and Bax in breast cancer cells were significantly increased by treatment with PR metabolites. These metabolites also increased the protein expression levels of p53 and p21. We therefore suggest that PR may act as a chemopreventive and/or chemotherapeutic agent against breast cancer by reducing cell viability and inducing apoptosis.« less

Yeast prions assembly and propagation

PubMed Central

2011-01-01

Yeast prions are self-perpetuating protein aggregates that are at the origin of heritable and transmissible non-Mendelian phenotypic traits. Among these, [PSI+], [URE3] and [PIN+] are the most well documented prions and arise from the assembly of Sup35p, Ure2p and Rnq1p, respectively, into insoluble fibrillar assemblies. Fibril assembly depends on the presence of N- or C-terminal prion domains (PrDs) which are not homologous in sequence but share unusual amino-acid compositions, such as enrichment in polar residues (glutamines and asparagines) or the presence of oligopeptide repeats. Purified PrDs form amyloid fibrils that can convert prion-free cells to the prion state upon transformation. Nonetheless, isolated PrDs and full-length prion proteins have different aggregation, structural and infectious properties. In addition, mutations in the “non-prion” domains (non-PrDs) of Sup35p, Ure2p and Rnq1p were shown to affect their prion properties in vitro and in vivo. Despite these evidences, the implication of the functional non-PrDs in fibril assembly and prion propagation has been mostly overlooked. In this review, we discuss the contribution of non-PrDs to prion assemblies, and the structure-function relationship in prion infectivity in the light of recent findings on Sup35p and Ure2p assembly into infectious fibrils from our laboratory and others. PMID:22052349

Large-Scale Conformational Changes of Trypanosoma cruzi Proline Racemase Predicted by Accelerated Molecular Dynamics Simulation

PubMed Central

McCammon, J. Andrew

2011-01-01

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is a life-threatening illness affecting 11–18 million people. Currently available treatments are limited, with unacceptable efficacy and safety profiles. Recent studies have revealed an essential T. cruzi proline racemase enzyme (TcPR) as an attractive candidate for improved chemotherapeutic intervention. Conformational changes associated with substrate binding to TcPR are believed to expose critical residues that elicit a host mitogenic B-cell response, a process contributing to parasite persistence and immune system evasion. Characterization of the conformational states of TcPR requires access to long-time-scale motions that are currently inaccessible by standard molecular dynamics simulations. Here we describe advanced accelerated molecular dynamics that extend the effective simulation time and capture large-scale motions of functional relevance. Conservation and fragment mapping analyses identified potential conformational epitopes located in the vicinity of newly identified transient binding pockets. The newly identified open TcPR conformations revealed by this study along with knowledge of the closed to open interconversion mechanism advances our understanding of TcPR function. The results and the strategy adopted in this work constitute an important step toward the rationalization of the molecular basis behind the mitogenic B-cell response of TcPR and provide new insights for future structure-based drug discovery. PMID:22022240

Large-scale conformational changes of Trypanosoma cruzi proline racemase predicted by accelerated molecular dynamics simulation.

PubMed

de Oliveira, César Augusto F; Grant, Barry J; Zhou, Michelle; McCammon, J Andrew

2011-10-01

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is a life-threatening illness affecting 11-18 million people. Currently available treatments are limited, with unacceptable efficacy and safety profiles. Recent studies have revealed an essential T. cruzi proline racemase enzyme (TcPR) as an attractive candidate for improved chemotherapeutic intervention. Conformational changes associated with substrate binding to TcPR are believed to expose critical residues that elicit a host mitogenic B-cell response, a process contributing to parasite persistence and immune system evasion. Characterization of the conformational states of TcPR requires access to long-time-scale motions that are currently inaccessible by standard molecular dynamics simulations. Here we describe advanced accelerated molecular dynamics that extend the effective simulation time and capture large-scale motions of functional relevance. Conservation and fragment mapping analyses identified potential conformational epitopes located in the vicinity of newly identified transient binding pockets. The newly identified open TcPR conformations revealed by this study along with knowledge of the closed to open interconversion mechanism advances our understanding of TcPR function. The results and the strategy adopted in this work constitute an important step toward the rationalization of the molecular basis behind the mitogenic B-cell response of TcPR and provide new insights for future structure-based drug discovery.

Nitrogen-doped partially reduced graphene oxide rewritable nonvolatile memory.

PubMed

Seo, Sohyeon; Yoon, Yeoheung; Lee, Junghyun; Park, Younghun; Lee, Hyoyoung

2013-04-23

As memory materials, two-dimensional (2D) carbon materials such as graphene oxide (GO)-based materials have attracted attention due to a variety of advantageous attributes, including their solution-processability and their potential for highly scalable device fabrication for transistor-based memory and cross-bar memory arrays. In spite of this, the use of GO-based materials has been limited, primarily due to uncontrollable oxygen functional groups. To induce the stable memory effect by ionic charges of a negatively charged carboxylic acid group of partially reduced graphene oxide (PrGO), a positively charged pyridinium N that served as a counterion to the negatively charged carboxylic acid was carefully introduced on the PrGO framework. Partially reduced N-doped graphene oxide (PrGODMF) in dimethylformamide (DMF) behaved as a semiconducting nonvolatile memory material. Its optical energy band gap was 1.7-2.1 eV and contained a sp2 C═C framework with 45-50% oxygen-functionalized carbon density and 3% doped nitrogen atoms. In particular, rewritable nonvolatile memory characteristics were dependent on the proportion of pyridinum N, and as the proportion of pyridinium N atom decreased, the PrGODMF film lost memory behavior. Polarization of charged PrGODMF containing pyridinium N and carboxylic acid under an electric field produced N-doped PrGODMF memory effects that followed voltage-driven rewrite-read-erase-read processes.

Emission factors for PM2.5, CO, CO2, NOx, SO2 and particle size distributions from the combustion of wood species using a new controlled combustion chamber 3CE.

PubMed

Cereceda-Balic, Francisco; Toledo, Mario; Vidal, Victor; Guerrero, Fabian; Diaz-Robles, Luis A; Petit-Breuilh, Ximena; Lapuerta, Magin

2017-04-15

The objective of this research was to determine emission factors (EF) for particulate matter (PM 2.5 ), combustion gases and particle size distribution generated by the combustion of Eucalyptus globulus (EG), Nothofagus obliqua (NO), both hardwoods, and Pinus radiata (PR), softwood, using a controlled combustion chamber (3CE). Additionally, the contribution of the different emissions stages associated with the combustion of these wood samples was also determined. Combustion experiments were performed using shaving size dried wood (0% humidity). The emission samples were collected with a tedlar bag and sampling cartridges containing quartz fiber filters. High reproducibility was achieved between experiment repetitions (CV<10%, n=3). The EF for PM 2.5 was 1.06gkg -1 for EG, 1.33gkg -1 for NO, and 0.84gkg -1 for PR. Using a laser aerosol spectrometer (0.25-34μm), the contribution of particle emissions (PM 2.5 ) in each stage of emission process (SEP) was sampled in real time. Particle size of 0.265μm were predominant during all stages, and the percentages emitted were PR (33%), EG (29%), and NO (21%). The distributions of EF for PM 2.5 in pre-ignition, flame and smoldering stage varied from predominance of the flame stage for PR (77%) to predominance of the smoldering stage for NO (60%). These results prove that flame phase is not the only stage contributing to emissions and on the contrary, pre-ignition and in especial post-combustion smoldering have also very significant contributions. This demonstrates that particle concentrations measured only in stationary state during flame stage may cause underestimation of emissions. Copyright © 2017 Elsevier B.V. All rights reserved.

Experiments on Pool-riffle Sequences with Multi-fractional Sediment Bed During Floods

NASA Astrophysics Data System (ADS)

Rodriguez, J. F.; Vahidi, E.; Bayat, E.; de Almeida, G. A. M.; Saco, P. M.

2017-12-01

The morphodynamics of pools and riffles has been the subject of research for over a century and has more recently attracted intense attention for their central role in providing habitat diversity conditions, both in terms of flow and substrate. Initial efforts to explain the long-term stability of the pool-riffle (PR) sequences (often referred to as self-maintenance) focused almost exclusively on cross sectional flow characteristics (either average or near bed velocity or shear stress), using episodic shifts in higher shear stress or velocities from riffles to pools during floods (i.e. reversal conditions) as an indication of the long-term self-maintenance of the structures.. However, less attention has been paid to the interactions of flow unsteadiness, sediment supply and sedimentological contrasts as the drivers for maintaining PR sequences. Here we investigate these effects through laboratory experiments on a scaled-down PR sequence of an existing gravel bed river. Froude similitude and equality of Shields' number were applied to scale one- to four-year recurrence flood events and sediment size distributions, respectively. We conducted experiments with different hydrographs and different sedimentological conditions. In each experiment we continuously measured velocities and shear stresses (using acoustic velocity profilers) bed levels (using a bed profiler) and bed grain size distribution (using an automatic digital technique on the painted bed sediments) during the hydrographs. Our results show that the most important factors for self-maintenance were the sediment bed composition, the level of infilling of the pool and the sediment supply grainsize distribution. These results highlight the need to consider the time varying sedimentological characteristics of a PR sequence to assess its capacity for self-maintenance.

A Functional Interplay between Human Immunodeficiency Virus Type 1 Protease Residues 77 and 93 Involved in Differential Regulation of Precursor Autoprocessing and Mature Protease Activity

PubMed Central

Counts, Christopher J.; Ho, P. Shing; Donlin, Maureen J.; Tavis, John E.; Chen, Chaoping

2015-01-01

HIV-1 protease (PR) is a viral enzyme vital to the production of infectious virions. It is initially synthesized as part of the Gag-Pol polyprotein precursor in the infected cell. The free mature PR is liberated as a result of precursor autoprocessing upon virion release. We previously described a model system to examine autoprocessing in transfected mammalian cells. Here, we report that a covariance analysis of miniprecursor (p6*-PR) sequences derived from drug naïve patients identified a series of amino acid pairs that vary together across independent viral isolates. These covariance pairs were used to build the first topology map of the miniprecursor that suggests high levels of interaction between the p6* peptide and the mature PR. Additionally, several PR-PR covariance pairs are located far from each other (>12 Å Cα to Cα) relative to their positions in the mature PR structure. Biochemical characterization of one such covariance pair (77–93) revealed that each residue shows distinct preference for one of three alkyl amino acids (V, I, and L) and that a polar or charged amino acid at either of these two positions abolishes precursor autoprocessing. The most commonly observed 77V is preferred by the most commonly observed 93I, but the 77I variant is preferred by other 93 variances (L, V, or M) in supporting precursor autoprocessing. Furthermore, the 77I93V covariant enhanced precursor autoprocessing and Gag polyprotein processing but decreased the mature PR activity. Therefore, both covariance and biochemical analyses support a functional association between residues 77 and 93, which are spatially distant from each other in the mature PR structure. Our data also suggests that these covariance pairs differentially regulate precursor autoprocessing and the mature protease activity. PMID:25893662

Prolactin-releasing peptide affects gastric motor function in rat by modulating synaptic transmission in the dorsal vagal complex.

PubMed

Grabauskas, Gintautas; Zhou, Shi-Yi; Das, Sudipto; Lu, Yuanxu; Owyang, Chung; Moises, Hylan C

2004-12-15

Prolactin-releasing peptide (PrRP) is a recently discovered neuropeptide implicated in the central control of feeding behaviour and autonomic homeostasis. PrRP-containing neurones and PrRP receptor mRNA are found in abundance in the caudal portion of the nucleus tractus solitarius (NTS), an area which together with the dorsal motor nucleus of the vagus (DMV) comprises an integrated structure, the dorsal vagal complex (DVC) that processes visceral afferent signals from and provides parasympathetic motor innervation to the gastrointestinal tract. In this study, microinjection experiments were conducted in vivo in combination with whole-cell recording from neurones in rat medullary slices to test the hypothesis that PrRP plays a role in the central control of gastric motor function, acting within the DVC to modulate the activity of preganglionic vagal motor neurones that supply the stomach. Microinjection of PrRP (0.2 pmol (20 nl)(-1)) into the DMV at the level of the area postrema (+0.2 to +0.6 mm from the calamus scriptorius, CS) markedly stimulated gastric contractions and increased intragastric pressure (IGP). Conversely, administration of peptide into the DMV at sites caudal to the obex (0.0 to -0.3 mm from the CS) decreased IGP and reduced phasic contractions. These effects occurred without change in mean arterial pressure and were abolished by ipsilateral vagotomy, indicating mediation via a vagal-dependent mechanism(s). The pattern of gastric motor responses evoked by PrRP mimicked that produced by administration of L-glutamate at the same sites, and both the effects of L-glutamate and PrRP were abolished following local administration of NMDA and non-NMDA-type glutamate receptor antagonists. On the other hand, microinjection of PrRP into the medial or comissural nucleus of the solitary tract (mNTS and comNTS, respectively) resulted in less robust changes in IGP in a smaller percentage of animals, accompanied by marked alterations in arterial pressure. Superfusion of brain slices with PrRP (100-300 nm) produced a small depolarization and increased spontaneous firing in 10 of 30 retrogradely labelled gastric-projecting DMV neurones. The excitatory effects were blocked by administration of TTX (2 mum) or specific glutamate receptor antagonists, indicating that they resulted from interactions of PrRP at a presynaptic site. Congruent with this, PrRP increased the amplitude of excitatory postsynaptic currents (EPSCs, 154 +/- 33%, 12 of 25 neurones) evoked by electrical stimulation in mNTS or comNTS. In addition, administration of PrRP decreased the paired-pulse ratio of EPSCs evoked by two identical stimuli delivered 100 ms apart (from 0.95 +/- 0.08 to 0.71 +/- 0.11, P < 0.05), whereas it did not affect the amplitude of inward currents evoked by exogenous application of L-glutamate to the slice. The frequency, but not amplitude of spontaneous EPSCs and action potential-independent miniature EPSCs was also increased by administration of PrRP, suggesting that the peptide was acting at least in part at receptors on presynaptic nerve terminals to enhance glutamatergic transmission. In recordings obtained from a separate group of slices, we did not observe any direct effects of PrRP on spontaneous discharge or postsynaptic excitability in either mNTS or comNTS neurones (n = 31). These data indicate that PrRP may act within the DVC to regulate gastric motor function by modulating the efficacy of conventional excitatory synaptic inputs from the NTS onto gastric-projecting vagal motor neurones.

Prolactin-releasing peptide affects gastric motor function in rat by modulating synaptic transmission in the dorsal vagal complex

PubMed Central

Grabauskas, Gintautas; Zhou, Shi-Yi; Das, Sudipto; Lu, Yuanxu; Owyang, Chung; Moises, Hylan C

2004-01-01

Prolactin-releasing peptide (PrRP) is a recently discovered neuropeptide implicated in the central control of feeding behaviour and autonomic homeostasis. PrRP-containing neurones and PrRP receptor mRNA are found in abundance in the caudal portion of the nucleus tractus solitarius (NTS), an area which together with the dorsal motor nucleus of the vagus (DMV) comprises an integrated structure, the dorsal vagal complex (DVC) that processes visceral afferent signals from and provides parasympathetic motor innervation to the gastrointestinal tract. In this study, microinjection experiments were conducted in vivo in combination with whole-cell recording from neurones in rat medullary slices to test the hypothesis that PrRP plays a role in the central control of gastric motor function, acting within the DVC to modulate the activity of preganglionic vagal motor neurones that supply the stomach. Microinjection of PrRP (0.2 pmol (20 nl)−1) into the DMV at the level of the area postrema (+0.2 to +0.6 mm from the calamus scriptorius, CS) markedly stimulated gastric contractions and increased intragastric pressure (IGP). Conversely, administration of peptide into the DMV at sites caudal to the obex (0.0 to −0.3 mm from the CS) decreased IGP and reduced phasic contractions. These effects occurred without change in mean arterial pressure and were abolished by ipsilateral vagotomy, indicating mediation via a vagal-dependent mechanism(s). The pattern of gastric motor responses evoked by PrRP mimicked that produced by administration of l-glutamate at the same sites, and both the effects of l-glutamate and PrRP were abolished following local administration of NMDA and non-NMDA-type glutamate receptor antagonists. On the other hand, microinjection of PrRP into the medial or comissural nucleus of the solitary tract (mNTS and comNTS, respectively) resulted in less robust changes in IGP in a smaller percentage of animals, accompanied by marked alterations in arterial pressure. Superfusion of brain slices with PrRP (100–300 nm) produced a small depolarization and increased spontaneous firing in 10 of 30 retrogradely labelled gastric-projecting DMV neurones. The excitatory effects were blocked by administration of TTX (2 μm) or specific glutamate receptor antagonists, indicating that they resulted from interactions of PrRP at a presynaptic site. Congruent with this, PrRP increased the amplitude of excitatory postsynaptic currents (EPSCs, 154 ± 33%, 12 of 25 neurones) evoked by electrical stimulation in mNTS or comNTS. In addition, administration of PrRP decreased the paired-pulse ratio of EPSCs evoked by two identical stimuli delivered 100 ms apart (from 0.95 ± 0.08 to 0.71 ± 0.11, P < 0.05), whereas it did not affect the amplitude of inward currents evoked by exogenous application of l-glutamate to the slice. The frequency, but not amplitude of spontaneous EPSCs and action potential-independent miniature EPSCs was also increased by administration of PrRP, suggesting that the peptide was acting at least in part at receptors on presynaptic nerve terminals to enhance glutamatergic transmission. In recordings obtained from a separate group of slices, we did not observe any direct effects of PrRP on spontaneous discharge or postsynaptic excitability in either mNTS or comNTS neurones (n = 31). These data indicate that PrRP may act within the DVC to regulate gastric motor function by modulating the efficacy of conventional excitatory synaptic inputs from the NTS onto gastric-projecting vagal motor neurones. PMID:15486017

Nutritional status, physical performance and functional capacity in an elderly population in southern Brazil.

PubMed

Danielewicz, Ana Lúcia; Barbosa, Aline Rodrigues; Del Duca, Giovâni Firpo

2014-01-01

To investigate the association between nutritional status and functional limitation and disability in an elderly population in southern Brazil. Epidemiological, cross-sectional household-based study carried out with 477 elderly of both sexes (60 to 100 years). Body mass index (BMI) served to assess the nutritional status: underweight (BMI < 22 kg/m2) and overweight (BMI > 27 kg/m2). The sum score (0-5) obtained in three tests: "chair stand" and "pick up a pen" (measured by time) and standing balance (four static measurements) assessed the functional limitation. The disability was evaluated by the difficulty in performing one or more self-reported tasks related to basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs). Crude and adjusted analyzes (3 models) were carried out using Poisson regression; prevalence ratios (PR) and 95% confidence intervals (CI) were calculated. Crude analyzes showed a positive association between underweight and functional limitation (PR = 2.71, 95% CI = 1.63 to 4.51); overweight and disability in ADLs (PR = 2.20, CI 95% = 1.44 to 3.35); overweight and disability in IADLs (PR = 1.56, CI 95% = 1.20 to 2.03). The additional adjustments for gender, age, level of education, living arrangements, current work, cognitive function and number of morbidities reduced the strength of the associations, without changing the statistical strength. Nutritional status is a factor that is independently and positively associated with functional limitation and disability. We recommend the use of this indicator to monitor the health of the elderly.

Pulmonary stenosis and pulmonary regurgitation: both ends of the spectrum in residual hemodynamic impairment after tetralogy of Fallot repair.

PubMed

Yoo, Byung Won; Park, Han Ki

2013-06-01

Repair of tetralogy of Fallot (TOF) has shown excellent outcomes. However it leaves varying degrees of residual hemodynamic impairment, with severe pulmonary stenosis (PS) and free pulmonary regurgitation (PR) at both ends of the spectrum. Since the 1980s, studies evaluating late outcomes after TOF repair revealed the adverse impacts of residual chronic PR on RV volume and function; thus, a turnaround of operational strategies has occurred from aggressive RV outflow tract (RVOT) reconstruction for complete relief of RVOT obstruction to conservative RVOT reconstruction for limiting PR. This transformation has raised the question of how much residual PS after conservative RVOT reconstruction is acceptable. Besides, as pulmonary valve replacement (PVR) increases in patients with RV deterioration from residual PR, there is concern regarding when it should be performed. Regarding residual PS, several studies revealed that PS in addition to PR was associated with less PR and a small RV volume. This suggests that PS combined with PR makes RV diastolic property to protect against dilatation through RV hypertrophy and supports conservative RVOT enlargement despite residual PS. Also, several studies have revealed the pre-PVR threshold of RV parameters for the normalization of RV volume and function after PVR, and based on these results, the indications for PVR have been revised. Although there is no established strategy, better understanding of RV mechanics, development of new surgical and interventional techniques, and evidence for the effect of PVR on RV reverse remodeling and its late outcome will aid us to optimize the management of TOF.

Inhibiting Inosine Hydrolase and Alanine Racemase to Enhance the Germination of Bacillus anthracis Sterne Spores: Potential Spore Decontamination Strategies

DTIC Science & Technology

2015-06-19

animal waste an~ decompositiOn DISTRIBUTION STATEMENT A: Approved for public release; distribution is unlimited. UNCLASSIFIED PR-15-306 Anthrax...influx of water. Ungerminated spore Germination Germinated spore Spore hydratation ~ Non-refractile spore Refractile spore • Fluorescence

Significant enhancement in thermoelectric properties of polycrystalline Pr-doped SrTiO{sub 3−δ} ceramics originating from nonuniform distribution of Pr dopants

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

Dehkordi, Arash Mehdizadeh, E-mail: amehdiz@g.clemson.edu; Bhattacharya, Sriparna; He, Jian

2014-05-12

Recently, we have reported a significant enhancement (>70% at 500 °C) in the thermoelectric power factor (PF) of bulk polycrystalline Pr-doped SrTiO{sub 3} ceramics employing a novel synthesis strategy which led to the highest ever reported values of PF among doped polycrystalline SrTiO{sub 3}. It was found that the formation of Pr-rich grain boundary regions gives rise to an enhancement in carrier mobility. In this Letter, we investigate the electronic and thermal transport in Sr{sub 1−x}Pr{sub x}TiO{sub 3} ceramics in order to determine the optimum doping concentration and to evaluate the overall thermoelectric performance. Simultaneous enhancement in the thermoelectric power factormore » and reduction in thermal conductivity in these samples resulted in more than 30% improvement in the dimensionless thermoelectric figure of merit (ZT) for the whole temperature range over all previously reported maximum values. Maximum ZT value of 0.35 was obtained at 500 °C.« less

The Identification and Structure of an N-Terminal PR Domain Show that FOG1 Is a Member of the PRDM Family of Proteins

PubMed Central

Clifton, Molly K.; Westman, Belinda J.; Thong, Sock Yue; O’Connell, Mitchell R.; Webster, Michael W.; Shepherd, Nicholas E.; Quinlan, Kate G.; Crossley, Merlin; Blobel, Gerd A.; Mackay, Joel P.

2014-01-01

FOG1 is a transcriptional regulator that acts in concert with the hematopoietic master regulator GATA1 to coordinate the differentiation of platelets and erythrocytes. Despite considerable effort, however, the mechanisms through which FOG1 regulates gene expression are only partially understood. Here we report the discovery of a previously unrecognized domain in FOG1: a PR (PRD-BF1 and RIZ) domain that is distantly related in sequence to the SET domains that are found in many histone methyltransferases. We have used NMR spectroscopy to determine the solution structure of this domain, revealing that the domain shares close structural similarity with SET domains. Titration with S-adenosyl-L-homocysteine, the cofactor product synonymous with SET domain methyltransferase activity, indicated that the FOG PR domain is not, however, likely to function as a methyltransferase in the same fashion. We also sought to define the function of this domain using both pulldown experiments and gel shift assays. However, neither pulldowns from mammalian nuclear extracts nor yeast two-hybrid assays reproducibly revealed binding partners, and we were unable to detect nucleic-acid-binding activity in this domain using our high-diversity Pentaprobe oligonucleotides. Overall, our data demonstrate that FOG1 is a member of the PRDM (PR domain containing proteins, with zinc fingers) family of transcriptional regulators. The function of many PR domains, however, remains somewhat enigmatic for the time being. PMID:25162672

Enhanced stability of monomer fold correlates with extreme drug resistance of HIV-1 protease.

PubMed

Louis, John M; Tözsér, József; Roche, Julien; Matúz, Krisztina; Aniana, Annie; Sayer, Jane M

2013-10-29

During treatment, mutations in HIV-1 protease (PR) are selected rapidly that confer resistance by decreasing affinity to clinical protease inhibitors (PIs). As these unique drug resistance mutations can compromise the fitness of the virus to replicate, mutations that restore conformational stability and activity while retaining drug resistance are selected on further evolution. Here we identify several compensating mechanisms by which an extreme drug-resistant mutant bearing 20 mutations (PR20) with >5-fold increased Kd and >4000-fold decreased affinity to the PI darunavir functions. (1) PR20 cleaves, albeit poorly, Gag polyprotein substrates essential for viral maturation. (2) PR20 dimer, which exhibits distinctly enhanced thermal stability, has highly attenuated autoproteolysis, thus likely prolonging its lifetime in vivo. (3) The enhanced stability of PR20 results from stabilization of the monomer fold. Both monomeric PR20(T26A) and dimeric PR20 exhibit Tm values 6-7.5 °C higher than those for their PR counterparts. Two specific mutations in PR20, L33F and L63P at sites of autoproteolysis, increase the Tm of monomeric PR(T26A) by ~8 °C, similar to PR20(T26A). However, without other compensatory mutations as seen in PR20, L33F and L63P substitutions, together, neither restrict autoproteolysis nor significantly reduce binding affinity to darunavir. To determine whether dimer stability contributes to binding affinity for inhibitors, we examined single-chain dimers of PR and PR(D25N) in which the corresponding identical monomer units were covalently linked by GGSSG sequence. Linking of the subunits did not appreciably change the ΔTm on inhibitor binding; thus stabilization by tethering appears to have little direct effect on enhancing inhibitor affinity.

Effect of progesterone receptor status on maspin synthesis via nitric oxide production in neutrophils in human breast cancer.

PubMed

Ganguly Bhattacharjee, Karabi; Bhattacharyya, Mau; Halder, Umesh Chandra; Jana, Pradipta; Sinha, Asru K

2014-09-01

Although progesterone receptor (PR) status, similarly to estrogen receptor status, is of prognostic importance in breast cancer, the involvement of the PR in breast cancer remains obscure. Studies were conducted to determine the function of the PR in neutrophils in the nitric oxide-induced synthesis of maspin, an anti-breast-cancer protein produced in nonmalignant mammary cells and in neutrophils in the circulation. PR status was determined by immunohistochemistry. Maspin synthesis was determined by in-vitro translation of messenger RNA and quantified by enzyme-linked immunosorbent assay. Nitric oxide was determined by the methemoglobin method. It was found that PR status in neutrophils was identical with that in malignant breast tissues. A Scatchard plot for progesterone binding to normal and PR-positive (PR+) neutrophils revealed that whereas normal neutrophils had 11.5 × 10(10) PR sites/cell with K d = 47.619 nM, PR+ neutrophils had 6.6 × 10(10) PR sites/cell with K d = 47.619 nM. The progesterone negative (PR-) neutrophils failed to bind to progesterone. Incubation of normal and PR+ neutrophils with 25 nM progesterone produced 1.317 μM NO and 2.329 nM maspin; the PR+ neutrophils produced 0.72 μM NO and 1.138 nM maspin. The PR- neutrophils failed to produce any NO or maspin in the presence of progesterone. Inhibition of progesterone-induced NO synthesis led to complete inhibition of maspin synthesis in all neutrophils. These results suggest that estrogen and progesterone complement each other in NO-induced maspin synthesis, and do not necessarily antagonize in the synthesis of the anti-breast-cancer protein.

Sequencing ASMT identifies rare mutations in Chinese Han patients with autism.

PubMed

Wang, Lifang; Li, Jun; Ruan, Yanyan; Lu, Tianlan; Liu, Chenxing; Jia, Meixiang; Yue, Weihua; Liu, Jing; Bourgeron, Thomas; Zhang, Dai

2013-01-01

Melatonin is involved in the regulation of circadian and seasonal rhythms and immune function. Prior research reported low melatonin levels in autism spectrum disorders (ASD). ASMT located in pseudo-autosomal region 1 encodes the last enzyme of the melatonin biosynthesis pathway. A previous study reported an association between ASD and single nucleotide polymorphisms (SNPs) rs4446909 and rs5989681 located in the promoter of ASMT. Furthermore, rare deleterious mutations were identified in a subset of patients. To investigate the association between ASMT and autism, we sequenced all ASMT exons and its neighboring region in 398 Chinese Han individuals with autism and 437 healthy controls. Although our study did not detect significant differences of genotypic distribution and allele frequencies of the common SNPs in ASMT between patients with autism and healthy controls, we identified new rare coding mutations of ASMT. Among these rare variants, 4 were exclusively detected in patients with autism including a stop mutation (p.R115W, p.V166I, p.V179G, and p.W257X). These four coding variants were observed in 6 of 398 (1.51%) patients with autism and none in 437 controls (Chi-Square test, Continuity Correction p = 0.032, two-sided). Functional prediction of impact of amino acid showed that p.R115W might affect protein function. These results indicate that ASMT might be a susceptibility gene for autism. Further studies in larger samples are needed to better understand the degree of variation in this gene as well as to understand the biochemical and clinical impacts of ASMT/melatonin deficiency.

Changes in Protein Structure and Distribution Observed at Pre-Clinical Stages of Scrapie Pathogenesis

PubMed Central

Kretlow, Ariane; Wang, Qi; Beekes, Michael; Naumann, Dieter; Miller, Lisa M.

2011-01-01

Scrapie is a neurodegenerative disorder that involves the misfolding, aggregation and accumulation of the prion protein (PrP). The normal cellular PrP (PrPC) is rich in α-helical secondary structure, whereas the disease-associated pathogenic form of the protein (PrPSc) has an anomalously high β-sheet content. In this study, protein structural changes were examined in situ in the dorsal root ganglia from perorally 263K scrapie-infected and mock-infected hamsters using synchrotron Fourier Transform InfraRed Microspectroscopy (FTIRM) at four time points over the course of the disease (preclinical, 100 & 130 days post-infection (dpi); first clinical signs (~145 dpi); and terminal (~170 dpi)). Results showed clear changes in the total protein content, structure, and distribution as the disease progressed. At pre-clinical time points, the scrapie-infected animals exhibited a significant increase in protein expression, but the β-sheet protein content was significantly lower than controls. Based on these findings, we suggest that the pre-clinical stages of scrapie are characterized by an overexpression of proteins low in β-sheet content. As the disease progressed, the β-sheet content increased significantly. Immunostaining with a PrP-specific antibody, 3F4, confirmed that this increase was partly – but not solely – due to the formation of PrPSc in the tissue and indicated that other proteins high in β-sheet were produced, either by overexpression or misfolding. Elevated β-sheet was observed near the cell membrane at pre-clinical time points and also in the cytoplasm of infected neurons at later stages of infection. At the terminal stage of the disease, the protein expression declined significantly, likely due to degeneration and death of neurons. These dramatic changes in protein content and structure, especially at pre-clinical time points, emphasize the possibility for identifying other proteins involved in early pathogenesis, which are important for further understanding the disease. PMID:18625306

Distribution épidémiologique de l'infection à VIH chez les femmes enceintes dans les dix régions du Cameroun et implications stratégiques pour les programmes de prévention

PubMed Central

Billong, Serge-Clotaire; Fokam, Joseph; Billong, Edson-Joan; Nguefack-Tsague, Georges; Essi, Marie-Josée; Fodjo, Raoul; Sosso, Samuel-Martin; Gomba, Armelle; Mosoko-Jembia, Joseph; Loni-Ekali, Gabriel; Colizzi, Vittorio; Bissek, Anne-Cécile Zoung-Kani; Monebenimp, Francisca; Nfetam, Jean-Bosco Elat

2015-01-01

Introduction Le Cameroun se situe dans un contexte d’épidémie généralisée du VIH. La sous-population des femmes enceintes, facilement accessible au sein de la population générale, représente une cible probante pour mener la surveillance du VIH et estimer l’évolution épidémiologique. L'objectif de notre étude était d’évaluer la distribution épidémiologique du VIH chez les femmes enceintes. Méthodes Étude transversale menée en 2012 chez 6521 femmes enceintes (49,3% âgées de 15-24 ans) en première consultation prénatale (CPN1) dans 60 sites des 10 régions Camerounaises. L'algorithme en série a été utilisé pour le sérodiagnostic du VIH. Résultats La prévalence du VIH était de 7,8% (508/6521), avec une différence non significative (p = 0,297) entre milieu rural (7,4%) et milieu urbain (8,1%). En zone rurale, cette prévalence variait de 0,7% à l'Extrême-Nord à 11,8% au Sud. Cependant, en zone urbaine elle variait de 4% à l'Ouest à 11,1% au Sud-Ouest. Suivant l’âge, la prévalence était plus élevée (11,3%) chez les femmes de 35-39 ans. Suivant le niveau de scolarisation, la prévalence du VIH était plus faible (4,4%) chez celles non-scolarisées, et plus élevée (9,3%) chez celles ayant un niveau primaire. Selon la profession, l'infection était plus élevée chez les coiffeuses (15,5%), secrétaires (14,8%), commerçantes (12,9%) et institutrices/enseignantes (10,8%). Conclusion La prévalence du VIH reste élevée chez les femmes enceintes au Cameroun, sans distinction entre milieux rural et urbain. Les stratégies de prévention devraient s'orienter préférentiellement chez les femmes enceintes âgées, celles du niveau d'instruction primaire, et celles du secteur des petites et moyennes entreprises. PMID:26090037

Cellular prion protein promotes glucose uptake through the Fyn-HIF-2α-Glut1 pathway to support colorectal cancer cell survival.

PubMed

Li, Qing-Quan; Sun, Yan-Ping; Ruan, Can-Ping; Xu, Xin-Yun; Ge, Jun-Hui; He, Jin; Xu, Zu-De; Wang, Qiang; Gao, Wen-Chao

2011-02-01

Cellular prion protein (PrPc) is a glycosylphosphatidylinositol-anchored membrane protein that has various physical functions, including protection against apoptotic and oxidative stress, cellular uptake of copper ions, transmembrane signaling, and adhesion to the extracellular matrix. In this study, we show that PrPc is highly expressed in colorectal adenocarcinomas. Transcriptome profiling of PrPc-depleted DLD-1 cells revealed downregulation of glucose transporter 1 (Glut1). PrPc is shown to be involved in regulating Glut1 expression through the Fyn-HIF-2α pathway. As Glut1 is the natural transporter of glucose and is required for the high glycolytic rate seen in colorectal tumors, silencing of PrPc reduced the proliferation and survival rate of colorectal cancer cells in vitro. In vivo, knockdown of PrPc by hydrodynamic injection with a cocktail of PrPc-shRNA-encoding plasmids also inhibited tumorigenicity in a xenograft model in nude mice. In summary, our data characterize a novel molecular mechanism that links PrPc expression to the regulation of glycolysis. Targeting PrPc will therefore be a promising strategy to overcome the growth and survival advantage in colorectal tumors. © 2010 Japanese Cancer Association.

Memory Impairment in Transgenic Alzheimer Mice Requires Cellular Prion Protein

PubMed Central

Gimbel, David A.; Nygaard, Haakon B.; Coffey, Erin E.; Gunther, Erik C.; Laurén, Juha; Gimbel, Zachary A.; Strittmatter, Stephen M.

2012-01-01

Soluble oligomers of the amyloid-β (Aβ) peptide are thought to play a key role in the pathophysiology of Alzheimer’s disease (AD). Recently, we reported that synthetic Aβ oligomers bind to cellular prion protein (PrPC) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Aβ peptide. We hypothesized that PrPC is essential for the ability of brain-derived Aβ to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1ΔE9 into Prnp−/− mice to examine the necessity of PrPC for AD-related phenotypes. Neither APP expression nor Aβ level is altered by PrPC absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrPC expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1ΔE9 transgenic mice. The AD transgenic mice with intact PrPC expression exhibit deficits in spatial learning and memory. Mice lacking PrPC, but containing Aβ plaque derived from APPswe/PSen1ΔE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrPC expression dissociates Aβ accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrPC. PMID:20445063

Views of policymakers, healthcare workers and NGOs on HIV pre-exposure prophylaxis (PrEP): a multinational qualitative study

PubMed Central

Eisingerich, Andreas B; Gomez, Gabriela B; Gray, Emily; Dybul, Mark R; Piot, Peter

2012-01-01

Objectives To examine policymakers and providers' views on pre-exposure prophylaxis (PrEP) and their willingness to support its introduction, to inform policy and practice in this emerging field. Design Semistructured qualitative interview study. Setting Peru, Ukraine, India, Kenya, Uganda, Botswana and South Africa. Participants 35 policymakers, 35 healthcare workers and 21 non-governmental organisation representatives involved in HIV prevention. Results Six themes emerged from the data: (1) perceived HIV prevention landscape: prevention initiatives needed to be improved and expanded; (2) PrEP awareness: 50 of 91 participants had heard of PrEP; (3) benefits of PrEP: one component of the combination prevention arsenal that could help prioritise HIV prevention, empower key populations and result in economic gains; (4) challenges of PrEP: regimen complexity, cost and cost-effectiveness, risk compensation, efficacy and effectiveness, stigmatisation and criminalisation, information and training and healthcare system capacity; (5) programmatic considerations: user eligibility, communication strategy, cost, distribution, medication and HIV testing compliance and (6) early versus late implementation: participants were divided as to whether they would support an early introduction of PrEP in their country or would prefer to wait until it has been successfully implemented in other countries, with around half of those we spoke to supporting each option. Very few said they would not support PrEP at all. Conclusions Despite the multiple challenges identified, there was general willingness to support the introduction of PrEP. Yet, strengthening existing HIV prevention efforts was also deemed necessary. Our results suggest that an effective PrEP programme would be delivered in healthcare facilities and involve non-governmental organisations and the community and consider the needs of mobile populations. Comprehensive information packages and training for users and providers would be critical. The cost of PrEP would be affordable and possibly segmented. Extensive counselling and innovative monitoring measures ought to be considered. PMID:22761288

Winter precipitation characteristics in western US related to atmospheric river landfalls: observations and model evaluations

NASA Astrophysics Data System (ADS)

Kim, J.; Guan, B.; Waliser, D. E.; Ferraro, R. D.; Case, J. L.; Iguchi, T.; Kemp, E.; Putman, W.; Wang, W.; Wu, D.; Tian, B.

2018-01-01

Winter precipitation (PR) characteristics in western United States (WUS) related to atmospheric river (AR) landfalls are examined using the observation-based PRISM data. The observed AR-related precipitation characteristics are in turn used to evaluate model precipitation data from the NASA MERRA2 reanalysis and from seven dynamical downscaling simulations driven by the MERRA2. Multiple metrics including mean bias, Taylor diagram, and two skill scores are used to measure model performance for three climatological sub-regions in WUS, Pacific Northwest (PNW), Pacific Southwest (PSW) and Great Basin (GB). All model data well represent the winter-mean PR with spatial pattern correlations of 0.8 or higher with PRISM for the three sub-regions. Higher spatial resolutions and/or the use of spectral nudging generally yield higher skill scores in simulating the geographical distribution of PR for the entire winter. The PRISM data shows that the AR-related fraction of winter PR and associated daily PR PDFs in each region vary strongly for landfall locations; AR landfalls in the northern WUS coast (NC) affect mostly PNW while those in the southern WUS coast (SC) affect both PSW and GB. NC (SC) landfalls increase the frequency of heavy PR in PNW (PSW and GB) but reduce it in PSW (PNW). All model data reasonably represent these observed variations in the AR-related winter PR fractions and the daily PR PDFs according to AR landfall locations. However, unlike for the entire winter period, no systematic effects of resolution and/or spectral nudging are identified in these AR-related PR characteristics. Dynamical downscaling in this study generally yield positive added values to the MERRA2 PR in the AR-related PR fraction for most sub-regions and landfall locations, most noticeably for PSW by NU-WRF. The downscaling also generate positive added value in p95 for PNW, but negative values for PSW and GB due to overestimation of heavy precipitation events.

Analysis of nucleic acid chaperoning by the prion protein and its inhibition by oligonucleotides

PubMed Central

Guichard, Cécile; Ivanyi-Nagy, Roland; Sharma, Kamal Kant; Gabus, Caroline; Marc, Daniel; Mély, Yves; Darlix, Jean-Luc

2011-01-01

Prion diseases are unique neurodegenerative illnesses associated with the conversion of the cellular prion protein (PrPC) into the aggregated misfolded scrapie isoform, named PrPSc. Recent studies on the physiological role of PrPC revealed that this protein has probably multiple functions, notably in cell–cell adhesion and signal transduction, and in assisting nucleic acid folding. In fact, in vitro findings indicated that the human PrP (huPrP) possesses nucleic acid binding and annealing activities, similarly to nucleic acid chaperone proteins that play essential roles in cellular DNA and RNA metabolism. Here, we show that a peptide, representing the N-terminal domain of huPrP, facilitates nucleic acid annealing by two parallel pathways nucleated through the stem termini. We also show that PrP of human or ovine origin facilitates DNA strand exchange, ribozyme-directed cleavage of an RNA template and RNA trans-splicing in a manner similar to the nucleocapsid protein of HIV-1. In an attempt to characterize inhibitors of PrP-chaperoning in vitro we discovered that the thioaptamer 5′-GACACAAGCCGA-3′ was extensively inhibiting the PrP chaperoning activities. At the same time a recently characterized methylated oligoribonucleotide inhibiting the chaperoning activity of the HIV-1 nucleocapsid protein was poorly impairing the PrP chaperoning activities. PMID:21737432

Lipid Rafts and Clathrin Cooperate in the Internalization of PrPC in Epithelial FRT Cells

PubMed Central

Casanova, Philippe; Puri, Claudia; Paladino, Simona; Tivodar, Simona S.; Campana, Vincenza; Tacchetti, Carlo; Zurzolo, Chiara

2009-01-01

Background The cellular prion protein (PrPC) plays a key role in the pathogenesis of Transmissible Spongiform Encephalopathies in which the protein undergoes post-translational conversion to the infectious form (PrPSc). Although endocytosis appears to be required for this conversion, the mechanism of PrPC internalization is still debated, as caveolae/raft- and clathrin-dependent processes have all been reported to be involved. Methodology/Principal Findings We have investigated the mechanism of PrPC endocytosis in Fischer Rat Thyroid (FRT) cells, which lack caveolin-1 (cav-1) and caveolae, and in FRT/cav-1 cells which form functional caveolae. We show that PrPC internalization requires activated Cdc-42 and is sensitive to cholesterol depletion but not to cav-1 expression suggesting a role for rafts but not for caveolae in PrPC endocytosis. PrPC internalization is also affected by knock down of clathrin and by the expression of dominant negative Eps15 and Dynamin 2 mutants, indicating the involvement of a clathrin-dependent pathway. Notably, PrPC co-immunoprecipitates with clathrin and remains associated with detergent-insoluble microdomains during internalization thus indicating that PrPC can enter the cell via multiple pathways and that rafts and clathrin cooperate in its internalization. Conclusions/Significance These findings are of particular interest if we consider that the internalization route/s undertaken by PrPC can be crucial for the ability of different prion strains to infect and to replicate in different cell lines. PMID:19503793

The prion protein has RNA binding and chaperoning properties characteristic of nucleocapsid protein NCP7 of HIV-1.

PubMed

Gabus, C; Derrington, E; Leblanc, P; Chnaiderman, J; Dormont, D; Swietnicki, W; Morillas, M; Surewicz, W K; Marc, D; Nandi, P; Darlix, J L

2001-06-01

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases associated with the accumulation of a protease-resistant form of the prion protein (PrP). Although PrP is conserved in vertebrates, its function remains to be identified. In vitro PrP binds large nucleic acids causing the formation of nucleoprotein complexes resembling human immunodeficiency virus type 1 (HIV-1) nucleocapsid-RNA complexes and in vivo MuLV replication accelerates the scrapie infectious process, suggesting possible interactions between retroviruses and PrP. Retroviruses, including HIV-1 encode a major nucleic acid binding protein (NC protein) found within the virus where 2000 NC protein molecules coat the dimeric genome. NC is required in virus assembly and infection to chaperone RNA dimerization and packaging and in proviral DNA synthesis by reverse transcriptase (RT). In HIV-1, 5'-leader RNA/NC interactions appear to control these viral processes. This prompted us to compare and contrast the interactions of human and ovine PrP and HIV-1 NCp7 with HIV-1 5'-leader RNA. Results show that PrP has properties characteristic of NCp7 with respect to viral RNA dimerization and proviral DNA synthesis by RT. The NC-like properties of huPrP map to the N-terminal region of huPrP. Interestingly, PrP localizes in the membrane and cytoplasm of PrP-expressing cells. These findings suggest that PrP is a multifunctional protein possibly participating in nucleic acid metabolism.

Versatile application of indirect Fourier transformation to structure factor analysis: from X-ray diffraction of molecular liquids to small angle scattering of protein solutions.

PubMed

Fukasawa, Toshiko; Sato, Takaaki

2011-02-28

We highlight versatile applicability of a structure-factor indirect Fourier transformation (IFT) technique, hereafter called SQ-IFT. The original IFT aims at the pair distance distribution function, p(r), of colloidal particles from small angle scattering of X-rays (SAXS) and neutrons (SANS), allowing the conversion of the experimental form factor, P(q), into a more intuitive real-space spatial autocorrelation function. Instead, SQ-IFT is an interaction potential model-free approach to the 'effective' or 'experimental' structure factor to yield the pair correlation functions (PCFs), g(r), of colloidal dispersions like globular protein solutions for small-angle scattering data as well as the radial distribution functions (RDFs) of molecular liquids in liquid diffraction (LD) experiments. We show that SQ-IFT yields accurate RDFs of liquid H(2)O and monohydric alcohol reflecting their local intermolecular structures, in which q-weighted structure function, qH(q), conventionally utilized in many LD studies out of necessity of performing direct Fourier transformation, is no longer required. We also show that SQ-IFT applied to theoretically calculated structure factors for uncharged and charged colloidal dispersions almost perfectly reproduces g(r) obtained as a solution of the Ornstein-Zernike (OZ) equation. We further demonstrate the relevance of SQ-IFT in its practical applications, using SANS effective structure factors of lysozyme solutions reported in recent literatures which revealed the equilibrium cluster formation due to coexisting long range electrostatic repulsion and short range attraction between the proteins. Finally, we present SAXS experiments on human serum albumin (HSA) at different ionic strength and protein concentration, in which we discuss the real space picture of spatial distributions of the proteins via the interaction potential model-free route.

Genetic polymorphisms of 15 STR loci in two Tibetan populations from Tibet Changdu and Naqu, China.

PubMed

Kang, LongLi; Yuan, Dongya; Yang, Fengying; Liu, Kai; Za, Xi

2007-07-04

The allelic distribution of 15 short tandem repeat (STR) loci included in the AmpFl STR Identifiler kit was examined in 100 Changdu Tibetan and 118 Naqu Tibetan unrelated individuals living in the Tibet Province, PR China. The distribution of these observed genotypes was not significantly different from the expected distribution according to Hardy-Weinberg equilibrium.

Normal Cellular Prion Protein Protects against Manganese-induced Oxidative Stress and Apoptotic Cell Death

PubMed Central

Choi, Christopher J.; Anantharam, Vellareddy; Saetveit, Nathan J.; Houk, Robert. S.; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

2012-01-01

The normal prion protein is abundantly expressed in the CNS, but its biological function remains unclear. The prion protein has octapeptide repeat regions that bind to several divalent metals, suggesting that the prion proteins may alter the toxic effect of environmental neurotoxic metals. In the present study, we systematically examined whether prion protein modifies the neurotoxicity of manganese (Mn) by comparing the effect of Mn on mouse neural cells expressing prion protein (PrPC -cells) and prion-knockout (PrPKO -cells). Exposure to Mn (10 μM-1 mM) for 24 hr produced a dose-dependent cytotoxic response in both PrPC -cells and PrPKO -cells. Interestingly, PrPC -cells (EC50 117.6μM) were more resistant to Mn-induced cytotoxicity, as compared to PrPKO -cells (EC50 59.9μM), suggesting a protective role for PrPC against Mn neurotoxicity. Analysis of intracellular Mn levels showed less Mn accumulation in PrPC -cells as compared to PrPKO -cells. Furthermore, Mn-induced mitochondrial depolarization and ROS generation were significantly attenuated in PrPC -cells as compared to PrPKO -cells. Measurement of antioxidant status revealed similar basal levels of glutathione (GSH) in PrPC -cells and PrPKO -cells; however, Mn treatment caused greater depletion of GSH in PrPKO -cells. Mn-induced mitochondrial depolarization and ROS production were followed by time- and dose-dependent activation of the apoptotic cell death cascade involving caspase-9 and -3. Notably, DNA fragmentation induced by both Mn treatment and oxidative stress-inducer hydrogen peroxide (100μM) was significantly suppressed in PrPC -cells as compared to PrPKO -cells. Together, these results demonstrate that prion protein interferes with divalent metal Mn uptake and protects against Mn-induced oxidative stress and apoptotic cell death. PMID:17483122

Atomically layer-by-layer diffusion of oxygen/hydrogen in highly epitaxial PrBaCo2O5.5+δ thin films

NASA Astrophysics Data System (ADS)

Bao, Shanyong; Xu, Xing; Enriquez, Erik; Mace, Brennan E.; Chen, Garry; Kelliher, Sean P.; Chen, Chonglin; Zhang, Yamei; Whangbo, Myung-Hwan; Dong, Chuang; Zhang, Qinyu

2015-12-01

Single-crystalline epitaxial thin films of PrBaCo2O5.5+δ (PrBCO) were prepared, and their resistance R(t) under a switching flow of oxidizing and reducing gases were measured as a function of the gas flow time t in the temperature range of 200-800 °C. During the oxidation cycle under O2, the PrBCO films exhibit fast oscillations in their dR(t)/dt vs. t plots, which reflect the oxidation processes, Co2+/Co3+ → Co3+ and Co3+ → Co3+/Co4+, that the Co atoms of PrBCO undergo. Each oscillation consists of two peaks, with larger and smaller peaks representing the oxygen/hydrogen diffusion through the (BaO)(CoO2)(PrO)(CoO2) layers of PrBCO via the oxygen-vacancy-exchange mechanism. This finding paves a significant avenue for cathode materials operating in low-temperature solid-oxide-fuel-cell devices and for chemical sensors with wide range of operating temperature.

S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3.

PubMed

Priceman, Saul J; Shen, Shudan; Wang, Lin; Deng, Jiehui; Yue, Chanyu; Kujawski, Maciej; Yu, Hua

2014-03-27

S1PR1 signaling has been shown to restrain the number and function of regulatory T (Treg) cells in the periphery under physiological conditions and in colitis models, but its role in regulating tumor-associated T cells is unknown. Here, we show that S1PR1 signaling in T cells drives Treg accumulation in tumors, limits CD8(+) T cell recruitment and activation, and promotes tumor growth. T-cell-intrinsic S1PR1 affects Treg cells, but not CD8(+) T cells, as demonstrated by adoptive transfer models and transient pharmacological S1PR1 modulation. An increase in S1PR1 in CD4(+) T cells promotes STAT3 activation and JAK/STAT3-dependent Treg tumor migration, whereas STAT3 ablation in T cells diminishes tumor-associated Treg accumulation and tumor growth. Our study demonstrates a stark contrast between the consequences of S1PR1 signaling in Treg cells in the periphery versus tumors. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

A single amino acid (Asp159) from the dog prion protein suppresses the toxicity of the mouse prion protein in Drosophila

PubMed Central

Sanchez-Garcia, J; Jensen, K; Zhang, Y; Rincon-Limas, DE; Fernandez-Funez, P

2016-01-01

Misfolding of the prion protein (PrP) is the key step in the transmission of spongiform pathologies in humans and several animals. Although PrP is highly conserved in mammals, a few changes in the sequence of endogenous PrP are proposed to confer protection to dogs, which were highly exposed to prion during the mad-cow epidemics. D159 is a unique amino acid found in PrP from dogs and other canines that was shown to alter surface charge, but its functional relevance has never been tested in vivo. Here, we show in transgenic Drosophila that introducing the N159D substitution on mouse PrP decreases its turnover. Additionally, mouse PrP-N159D demonstrates no toxicity and accumulates no pathogenic conformations, suggesting that a single D159 substitution is sufficient to prevent PrP conformational change and pathogenesis. Understanding the mechanisms mediating the protective activity of D159 is likely to lessen the burden of prion diseases in humans and domestic animals. PMID:27477054

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

PubMed Central

Singhal, Hari; Greene, Marianne E.; Tarulli, Gerard; Zarnke, Allison L.; Bourgo, Ryan J.; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G.; Raj, Ganesh V.; Hickey, Theresa E.; Tilley, Wayne D.; Greene, Geoffrey L.

2016-01-01

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored. PMID:27386569

Variations in abundance and size distribution of carbohydrates in the lower Mississippi River, Pearl River and Bay of St Louis

NASA Astrophysics Data System (ADS)

Wang, Xuri; Cai, Yihua; Guo, Laodong

2013-07-01

Riverine export of dissolved and particulate organic matter to the sea is one of the major components in marine carbon cycles, affecting biogeochemical processes in estuarine and coastal regions. However, the detailed composition of organic material and the relative partitioning among the dissolved, colloidal, and particulate phases are poorly quantified. The abundance of carbohydrate species and their partitioning among dissolved, colloidal, and particulate phases were examined in the waters from the lower Mississippi River (MR), the lower Pearl River (PR), and the Bay of St. Louis (BSL). Particulate carbohydrates (PCHO) represented a small fraction of the particulate organic carbon (POC) pool, with 4.7 ± 3.1%, 4.5 ± 2.4% and 1.8 ± 0.83% in the MR, PR, and BSL, respectively. Dissolved carbohydrates (DCHO) were a major component of the bulk dissolved organic carbon (DOC) pool, comprising 23%, 35%, and 18% in the MR, PR, and BSL, respectively. Differences in the DCHO/DOC ratio between the MR, PR, and BSL were related to their distinct characteristics in drainage basins, anthropogenic impacts, and hydrological conditions, reflecting differences in sources and composition of organic matter in different aquatic environments. Within the total carbohydrates (TCHO) pool, the high-molecular-weight carbohydrates (HMW-CHO, 1 kDa-0.45 μm) were the dominant species, representing 52-71% of the TCHO pool, followed by the low-molecular-weight carbohydrates (LMW-CHO, <1 kDa), representing 14-44% of the TCHO. The PCHO accounted for 4-16% of the bulk TCHO. Variations in the size distribution of carbohydrates among the MR, PR, and BSL were closely linked to the cycling pathway of organic matter and the interactions between different size fractions of the carbohydrates.

Disruption of an EAAT-Mediated Chloride Channel in a Drosophila Model of Ataxia.

PubMed

Parinejad, Neda; Peco, Emilie; Ferreira, Tiago; Stacey, Stephanie M; van Meyel, Donald J

2016-07-20

Patients with Type 6 episodic ataxia (EA6) have mutations of the excitatory amino acid transporter EAAT1 (also known as GLAST), but the underlying pathophysiological mechanism for EA6 is not known. EAAT1 is a glutamate transporter expressed by astrocytes and other glia, and it serves dual function as an anion channel. One EA6-associated mutation is a P>R substitution (EAAT1(P>R)) that in transfected cells has a reduced rate of glutamate transport and an abnormal anion conductance. We expressed this EAAT1(P>R) mutation in glial cells of Drosophila larvae and found that these larvae exhibit episodic paralysis, and their astrocytes poorly infiltrate the CNS neuropil. These defects are not seen in Eaat1-null mutants, and so they cannot be explained by loss of glutamate transport. We instead explored the role of the abnormal anion conductance of the EAAT1(P>R) mutation, and to do this we expressed chloride cotransporters in astrocytes. Like the EAAT1(P>R) mutation, the chloride-extruding K(+)-Cl(-) cotransporter KccB also caused astroglial malformation and paralysis, supporting the idea that the EAAT1(P>R) mutation causes abnormal chloride flow from CNS glia. In contrast, the Na(+)-K(+)-Cl(-) cotransporter Ncc69, which normally allows chloride into cells, rescued the effects of the EAAT1(P>R) mutation. Together, our results indicate that the cytopathology and episodic paralysis in our Drosophila EA6 model stem from a gain-of-function chloride channelopathy of glial cells. We studied a mutation found in episodic ataxia of the dual-function glutamate transporter/anion channel EAAT1, and discovered it caused malformation of astrocytes and episodes of paralysis in a Drosophila model. These effects were mimicked by a chloride-extruding cotransporter and were rescued by restoring chloride homeostasis to glial cells with a Na(+)-K(+)-2Cl(-) cotransporter. Our findings reveal a new pathophysiological mechanism in which astrocyte cytopathology and neural circuit dysfunction arise via disruption of the ancillary function of EAAT1 as a chloride channel. In some cases, this mechanism might also be important for neurological diseases related to episodic ataxia, such as hemiplegia, migraine, and epilepsy. Copyright © 2016 the authors 0270-6474/16/367640-08$15.00/0.

Cross section measurements of radiative KL2,3 RRS in 24Cr and L3M4,5 RRS in 59Pr for Mn Kα1,2 X-rays

NASA Astrophysics Data System (ADS)

Sharma, Veena; Upmanyu, Arun; Singh, Ranjit; Singh, Gurjot; Sharma, Hitesh; Kumar, Sanjeev; Mehta, D.

2017-06-01

The KL2,3 and L3M4,5 radiative resonant Raman scattering (RRS) cross sections have been measured for the quasimonochromatic Mn Kα1,2 X-rays (5.895 keV) in 24Cr (K-shell level width (ΓK) =1.08 eV) and 59 Pr (L3-subshell level width (ΓL3) =3.60 eV), respectively, using targets in metallic and various chemical forms. The incident Mn Kα1,2 X-ray energy is lower than the K-shell binding energy of 24Cr and L3-subshell binding energy of 59Pr by 94 ΓK (Cr) and 94 ΓL3 (Pr), respectively. The experimental measurements were performed with a low energy Ge detector (LEGe) and a radioactive 55Fe annular source in conjunction with 24Cr absorber. The measured cross section values for the 24Cr and 59 Pr elements in their various oxidation states are found to be same within experimental errors. The measurements were further extended to investigate alignment of the intermediate L3-subshell (J =3/2) virtual vacancy states in 59Pr through angular distribution measurements for RRS photon emission, which is found to be isotropic within experimental errors.

Determinants of tobacco use by students

PubMed Central

Vargas, Lorena Silva; Lucchese, Roselma; da Silva, Andrécia Cósmem; Guimarães, Rafael Alves; Vera, Ivânia; de Castro, Paulo Alexandre

2017-01-01

ABSTRACT OBJECTIVE Estimate the prevalence and determinants of tobacco use by students. METHODS This cross-sectional study, carried out between 2013 and 2014, evaluates 701 public school students between 10 and 79 years of age living in a city in the countryside of the State of Goias, Midwest of Brazil. A structured questionnaire collected the data and the predictor variables were demographic data, family nucleus, religion, physical activity practice, family functionality and parental smoking. Two multivariable models were implemented, the first for occasional tobacco use and the second for regular use, acquiring the measure of prevalence ratio (PR) and their respective 95%CI. Variables with p < 0.10 were included in Poisson regression models with robust variance to obtain the adjusted PR (adPR) and 95%CI. The Wald Chi-Squared test examined the differences between proportions, and values with p < 0.05 were statistically significant. RESULTS The prevalence of occasional and regular tobacco use were 33.4% (95%CI 29.8–36.9) and 6.7% (95%CI 5.0–8.8), respectively. The factors associated with occasional tobacco consumption were age of 15 to 17 years (adPR = 1.98) and above 18 years (adPR = 3.87), male gender (adPR = 1.23), moderate family dysfunction (adPR = 1.30), high family dysfunction (adPR = 1.97) and parental smoking (adPR = 1.60). In regards to regular consumption of tobacco, age above 18 years (adPR = 4.63), lack of religion (adPR = 2.08), high family dysfunction (adPR = 2.35) and parental smoking (adPR = 2.89) remained associated. CONCLUSIONS Students exhibit a high prevalence of occasional and regular tobacco use. This consumption relates to sociodemographic variables and family dysfunction. PMID:28492760

Distribution and mode of occurrence of radionuclides in phosphogypsum derived from Aqaba and Eshidiya Fertilizer Industry, South Jordan

USGS Publications Warehouse

Al-Hwaiti, M. S.; Zielinski, R.A.; Bundham, J.R.; Ranville, J.F.; Ross, P.E.

2010-01-01

Phosphogypsum (PG) is a by-product of the chemical reaction called the "wet process" whereby sulphuric acid reacts with phosphate rock (PR) to produce phosphoric acid, needed for fertilizer production. Through the wet process, some impurities naturally present in the PR become incorporated in PG, including U decay-series radionuclides, are the main important concern which could have an effect on the surrounding environment and prevent its safe utilization. In order to determine the distribution and bioavailability of radionuclides to the surrounding environment, we used a sequential leaching of PG samples from Aqaba and Eshidiya fertilizer industry. The results showed that the percentages of 226Ra and 210Pb in PG are over those in the corresponding phosphate rocks (PG/PR), where 85% of the 226Ra and 85% of the 210Pb fractionate to PG. The sequential extraction results exhibited that most of 226Ra and 210Pb are bound in the residual phase (non-CaSO4) fraction ranging from 45-65% and 55%-75%, respectively, whereas only 10%-15% and 10%-20% respectively of these radionuclides are distributed in the most labile fraction. The results obtained from this study showed that radionuclides are not incorporated with gypsum itself and may not form a threat to the surrounding environment. ?? 2010 Science Press, Institute of Geochemistry, CAS and Springer Berlin Heidelberg.

Evaluation of Absolute and Relative Reinforcer Value Using Progressive-Ratio Schedules

PubMed Central

Francisco, Monica T; Borrero, John C; Sy, Jolene R

2008-01-01

We evaluated behavior exhibited by individuals with developmental disabilities using progressive-ratio (PR) schedules. High- and low-preference stimuli were determined based on the results of a paired-stimulus preference assessment and were evaluated in subsequent reinforcer and PR assessments using concurrent and single schedules of presentation. In Experiment 1, results showed that for 2 of 3 participants, stimuli determined to be low-preference functioned as reinforcers when evaluated independent of high-preference stimuli. Further, the results from Experiment 2 showed that low-preference stimuli also functioned as reinforcers under gradually increasing PR requirements. Results suggest that for cases in which a high-preference stimulus is unavailable or impractical, the contingent delivery of relatively less preferred stimuli may maintain appropriate behavior, even as schedule requirements increase. PMID:18595283

Yeast two-hybrid and pull-down assays propose an interaction between P50 of apple chlorotic leaf spot virus and PR-10 of Malus sylvestris cv. R12740-7A.

PubMed

Wang, Y; Li, N; Zhao, X; Hu, J; He, Y; Hu, T; Wang, S; Wang, Y; Cao, K

Apple chlorotic leaf spot virus (ACLSV) movement protein (P50) is involved in cell-to-cell transport and influences the long-distance spread of silencing activity. Previously, we obtained 69 P50-interacting proteins from Malus sylvestris cv. R12740-7A and using bioinformatics analyzed their biological functions. In this study, we used the GAL4-based two-hybrid yeast system and His pull-down assays to confirm an interaction between PR-10 of M. sylvestris cv. R12740-7A and ACLSV P50. Our results provide a theoretical basis for further research on the biological function of PR-10 in ACLSV infection and the interacting mechanism between host and virus.

A new species of Haliotis (Gastropoda) from São Tomé & Príncipe Islands, Gulf of Guinea, with comparisons to other Haliotis found in the Eastern Atlantic and Mediterranean.

PubMed

Owen, Buzz

2014-07-16

The Haliotidae from the Gulf of Guinea, West Africa are reviewed. The distribution of the mainland species Haliotis marmorata Linnaeus, 1758 is confirmed and compared to the insular species from the island nation of São Tomé and Príncipe which is described as Haliotis geigeri n. sp. Both species are illustrated and compared to the other known Haliotidae from the eastern Atlantic.

Progress and developments in the turbo Grignard reagent i-PrMgCl·LiCl: a ten-year journey.

PubMed

Bao, Robert Li-Yuan; Zhao, Rong; Shi, Lei

2015-04-25

Over the past decade, the effectiveness of i-PrMgCl·LiCl has been constantly highlighted by a number of research groups. Its enhanced nucleophilicity brings prosperity to highly functionalized Grignard reagents, other useful bimetallic (alkali-metal) agents and nucleophilic alkylation products under mild reaction conditions. In this feature article, a comprehensive, systematical and in-depth overview of i-PrMgCl·LiCl is provided in a multidisciplinary idea. It involves the structural and kinetic perspectives of i-PrMgCl·LiCl as well as its unique reactivity and selectivity, with knowledge of the former helping to rationalize trends of the later.

The prenyl-binding protein PrBP/δ: a chaperone participating in intracellular trafficking.

PubMed

Zhang, Houbin; Constantine, Ryan; Frederick, Jeanne M; Baehr, Wolfgang

2012-12-15

Expressed ubiquitously, PrBP/δ functions as chaperone/co-factor in the transport of a subset of prenylated proteins. PrBP/δ features an immunoglobulin-like β-sandwich fold for lipid binding, and interacts with diverse partners. PrBP/δ binds both C-terminal C15 and C20 prenyl side chains of phototransduction polypeptides and small GTP-binding (G) proteins of the Ras superfamily. PrBP/δ also interacts with the small GTPases, ARL2 and ARL3, which act as release factors (GDFs) for prenylated cargo. Targeted deletion of the mouse Pde6d gene encoding PrBP/δ resulted in impeded trafficking to the outer segments of GRK1 and cone PDE6 which are predicted to be farnesylated and geranylgeranylated, respectively. Rod and cone transducin trafficking was largely unaffected. These trafficking defects produce progressive cone-rod dystrophy in the Pde6d(-/-) mouse. Copyright © 2012 Elsevier Ltd. All rights reserved.

Sequential Right and Left Ventricular Assessment in Posttetralogy of Fallot Patients with Significant Pulmonary Regurgitation.

PubMed

Wijesekera, Vishva A; Raju, Rekha; Precious, Bruce; Berger, Adam J; Kiess, Marla C; Leipsic, Jonathon A; Grewal, Jasmine

2016-12-01

The natural history of right ventricular (RV) and left ventricular (LV) size and function among adults with tetralogy of Fallot (TOF) repair and hemodynamically significant pulmonary regurgitation (PR) is not known. The main aim of this study was to determine changes in RV and LV size and function over time in an adult population with TOF repair and hemodynamically significant pulmonary regurgitation. Forty patients with repaired TOF and hemodynamically significant PR were included. These patients were identified on the basis of having more than one CMR between January 2008 and 2015. Patients with a prosthetic pulmonary valve or any cardiac intervention between CMR studies were excluded. Rate of progression (ROP) of RV dilation was determined for both indexed right ventricular end-systolic volume (RVESVi) and indexed right ventricular end-diastolic volume (RVEDVi), and calculated as the difference between the last and first volumes divided by the number of years between CMR#1 and CMR#2. Subjects were also divided into two groups based on the distribution of the ROP of RV dilation: Group I-rapid ROP (>50th percentile) and Group II-slower ROP (≤50th percentile). The interval between CMR#1 and CMR#2 was 3.9 ± 1.7 years (range 1-8 years). We did find a significant change in RVEDVi and RVESVi over this time period, although the magnitude of change was small. Nine patients (23%) had a reduction in right ventricular ejection fraction (RVEF) by greater than 5%, 13 patients (33%) had an increase in RVEDVi by greater than 10 mL/m 2 and seven patients (18%) had an increase in RVESVi by greater than 10 mL/m 2 . Median ROP for RVEDVi was 1.8 (range -10.4 to 21.8) mL/(m 2 year); RVESVi 1.1 (range -5.8 to 24.5) mL/(m 2 year) and RVEF -0.5 (range -8 to 4)%/year. Patients with a rapid ROP had significantly larger RV volumes at the time of CMR#1 and lower RVEF as compared to the slow ROP group. There was no overall significant change in LVEDVi, LVESVi, or LVEF over this time period. We have demonstrated, in a small population of patients with hemodynamically significant PR, that there is a small increase in RV volumes and decrease in RVEF over a mean 4-year period. We believe it to be reasonable practice to perform CMR at least every 4 years in asymptomatic patients with repaired TOF and hemodynamically significant PR. We found that LV volumes and function remained stable during the study period, suggesting that significant progressive LV changes are less likely to occur over a shorter time period. Our results inform a safe standardized approach to monitoring adults with hemodynamically significant PR post TOF repair and assist in planning allocation of this expensive and limited resource. © 2016 Wiley Periodicals, Inc.

Yeast prions assembly and propagation: contributions of the prion and non-prion moieties and the nature of assemblies.

PubMed

Kabani, Mehdi; Melki, Ronald

2011-01-01

Yeast prions are self-perpetuating protein aggregates that are at the origin of heritable and transmissible non-Mendelian phenotypic traits. Among these, [PSI+], [URE3] and [PIN+] are the most well documented prions and arise from the assembly of Sup35p, Ure2p and Rnq1p, respectively, into insoluble fibrillar assemblies. Fibril assembly depends on the presence of N- or C-terminal prion domains (PrDs) which are not homologous in sequence but share unusual amino-acid compositions, such as enrichment in polar residues (glutamines and asparagines) or the presence of oligopeptide repeats. Purified PrDs form amyloid fibrils that can convert prion-free cells to the prion state upon transformation. Nonetheless, isolated PrDs and full-length prion proteins have different aggregation, structural and infectious properties. In addition, mutations in the "non-prion" domains (non-PrDs) of Sup35p, Ure2p and Rnq1p were shown to affect their prion properties in vitro and in vivo. Despite these evidences, the implication of the functional non-PrDs in fibril assembly and prion propagation has been mostly overlooked. In this review, we discuss the contribution of non-PrDs to prion assemblies, and the structure-function relationship in prion infectivity in the light of recent findings on Sup35p and Ure2p assembly into infectious fibrils from our laboratory and others.

Sensorimotor development in neonatal progesterone receptor knockout mice.

PubMed

Willing, Jari; Wagner, Christine K

2014-01-01

Early exposure to steroid hormones can permanently and dramatically alter neural development. This is best understood in the organizational effects of hormones during development of brain regions involved in reproductive behaviors or neuroendocrine function. However, recent evidence strongly suggests that steroid hormones play a vital role in shaping brain regions involved in cognitive behavior such as the cerebral cortex. The most abundantly expressed steroid hormone receptor in the developing rodent cortex is the progesterone receptor (PR). In the rat, PR is initially expressed in the developmentally-critical subplate at E18, and subsequently in laminas V and II/III through the first three postnatal weeks (Quadros et al. [2007] J Comp Neurol 504:42-56; Lopez & Wagner [2009]: J Comp Neurol 512:124-139), coinciding with significant periods of dendritic maturation, the arrival of afferents and synaptogenesis. In the present study, we investigated PR expression in the neonatal mouse somatosensory cortex. Additionally, to investigate the potential role of PR in developing cortex, we examined sensorimotor function in the first two postnatal weeks in PR knockout mice and their wildtype (WT) and heterozygous (HZ) counterparts. While the three genotypes were similar in most regards, PRKO and HZ mice lost the rooting reflex 2-3 days earlier than WT mice. These studies represent the first developmental behavioral assessment of PRKO mice and suggest PR expression may play an important role in the maturation of cortical connectivity and sensorimotor integration. Copyright © 2013 Wiley Periodicals, Inc.

LIA at TREC 2012 Web Track: Unsupervised Search Concepts Identification from General Sources of Information

DTIC Science & Technology

2012-11-01

use in this work the variational approximation algo- rithm implemented and distributed by Pr . Blei1. Each learned multinomial distribution φk is tra...4,111,240 newswire articles collected from four distinct international sources including the New York Times (Graff and Cieri, 2003). The New York Times

Impact of obesity and physical activity on functional outcomes in the elderly: data from NHANES 2005-2010.

PubMed

Vásquez, Elizabeth; Batsis, John A; Germain, Cassandra M; Shaw, Benjamin A

2014-09-01

The objective of this study was to (a) to examine whether the association between obesity and physical functioning among older adults is moderated by physical activity (PA) and (b) to test whether this moderating effect varies by gender. Data from adults (aged >60 years) who participated in the National Health and Nutrition Examination Surveys (2005-2010) were analyzed. Using multivariate logistic regression, we estimated the prevalence ratio (PR) of functional limitations and impairment in activities of daily living and instrumental activities of daily living, by body mass index and PA, while adjusting for age, educational level, and a comorbidity index. The sample included 5,304 subjects (mean age = 70.4 years), and 50.5% were female. Overweight and obesity were associated with higher levels of functional limitations when compared with normal weight individuals regardless of the PA status (PR = 1.47, 95% confidence interval [CI] [1.17, 1.85], and PR = 2.71, 95% CI [2.00, 3.67], respectively) even after adjustment for confounders. Overweight and obesity are associated with impairment in functional outcomes irrespective of PA. © The Author(s) 2014.

Electronic conductivity of Ce0.9Gd0.1O(1.95-δ) and Ce0.8Pr0.2O(2-δ): Hebb-Wagner polarisation in the case of redox active dopants and interference.

PubMed

Chatzichristodoulou, C; Hendriksen, P V

2011-12-28

The electronic conductivity of Ce(0.9)Gd(0.1)O(1.95-δ) and Ce(0.8)Pr(0.2)O(2-δ) under suppressed ionic flow was measured as a function of pO(2) in the range from 10(3) atm to 10(-17) atm for temperatures between 600 °C and 900 °C by means of Hebb-Wagner polarisation. The steady state I-V curve of Ce(0.9)Gd(0.1)O(1.95-δ) could be well described by the standard Hebb-Wagner equation [M. H. Hebb, J. Chem. Phys., 1952, 20, 185; C. Wagner, Z. Elektrochem., 1956, 60, 4], yielding expressions for the n- and p-type conductivity as a function of pO(2). On the other hand, significant deviation of the steady state I-V curve from the standard Hebb-Wagner equation was observed for the case of Ce(0.8)Pr(0.2)O(2-δ). It is shown that the I-V curve can be successfully reproduced when the presence of the redox active dopant, Pr(3+)/Pr(4+), is taken into account, whereas even better agreement can be reached when further taking into account the interference between the ionic and electronic flows [C. Chatzichristodoulou, W.-S. Park, H.-S. Kim, P. V. Hendriksen and H.-I. Yoo, Phys. Chem. Chem. Phys., 2010, 12, 33]. Expressions are deduced for the small polaron mobilities in the Ce 4f and Pr 4f bands of Ce(0.8)Pr(0.2)O(2-δ).

2D-QSAR study of fullerene nanostructure derivatives as potent HIV-1 protease inhibitors

NASA Astrophysics Data System (ADS)

Barzegar, Abolfazl; Jafari Mousavi, Somaye; Hamidi, Hossein; Sadeghi, Mehdi

2017-09-01

The protease of human immunodeficiency virus1 (HIV-PR) is an essential enzyme for antiviral treatments. Carbon nanostructures of fullerene derivatives, have nanoscale dimension with a diameter comparable to the diameter of the active site of HIV-PR which would in turn inhibit HIV. In this research, two dimensional quantitative structure-activity relationships (2D-QSAR) of fullerene derivatives against HIV-PR activity were employed as a powerful tool for elucidation the relationships between structure and experimental observations. QSAR study of 49 fullerene derivatives was performed by employing stepwise-MLR, GAPLS-MLR, and PCA-MLR models for variable (descriptor) selection and model construction. QSAR models were obtained with higher ability to predict the activity of the fullerene derivatives against HIV-PR by a correlation coefficient (R2training) of 0.942, 0.89, and 0.87 as well as R2test values of 0.791, 0.67and 0.674 for stepwise-MLR, GAPLS-MLR, and PCA -MLR models, respectively. Leave-one-out cross-validated correlation coefficient (R2CV) and Y-randomization methods confirmed the models robustness. The descriptors indicated that the HIV-PR inhibition depends on the van der Waals volumes, polarizability, bond order between two atoms and electronegativities of fullerenes derivatives. 2D-QSAR simulation without needing receptor's active site geometry, resulted in useful descriptors mainly denoting ;C60 backbone-functional groups; and ;C60 functional groups; properties. Both properties in fullerene refer to the ligand fitness and improvement van der Waals interactions with HIV-PR active site. Therefore, the QSAR models can be used in the search for novel HIV-PR inhibitors based on fullerene derivatives.

[USE OF PROTECTIVE LUNG VENTILATION REGIMEN IN CARDIAC SURGERY PATIENTS.

PubMed

Pshenichniy, T A; Akselrod, B A; Titova, I V; Trekova, N A; Khrustaleva, M V

2017-09-01

In cardiac surgery, protective lung ventilation and/or preventive brdnchoscopy (PB) are able to decrease lung injury effects of cardiopulmonary bypass (CPB) and mechanical ventilation. define lung complication risks, evaluate the effect ofprotective lung ventilation (PLV) on lung functioning, and investigate the feasibility ofpreventive PB in higher pulmonary risk (PR) patients. 66 patients participated in prospective randomized research. Allocation was based on PR and intraoperative mechanical ventilation type. PLV includedfollowing parameters: PCK PIP - up to 20 cm H20, Vt - 6 ml/ kg of PBW, PEEP - 5-10 cm H20, IE ratio - 1:1.5-1:1, EtCO2 - 35-42 mm Hg, FiO2 - 45-60%, lung ventilation during CPB, alveolar recruitment. Four groups were formed: A - higher PR plus PLV- B - higher PR plus conventional LV (CLV), C - lower PR plus PLV- D - lower PR plus CLV PIP PEEP dynamic compliance, p/f ratio and intrapulmonary shunt (Qs/Qt) were recorded. Seventeen patients of group A underwent PB. Advanced dynamic compliance, higher p/f ratio and lower Qs/Qt were seen in group A, in comparison with group B (p< 0.05). Lower Qs/Qt was seen in group C, in comparison with group D (p<0.05). Mucus obstruction of subsegmental bronchi was observed in 53.3% of higher PR patients. More than half ofpatients without PB sufferedfrom postoperative lung complications (70.4 vs. 34.2 7%, p

Theobroma cacao L. pathogenesis-related gene tandem array members show diverse expression dynamics in response to pathogen colonization.

PubMed

Fister, Andrew S; Mejia, Luis C; Zhang, Yufan; Herre, Edward Allen; Maximova, Siela N; Guiltinan, Mark J

2016-05-17

The pathogenesis-related (PR) group of proteins are operationally defined as polypeptides that increase in concentration in plant tissues upon contact with a pathogen. To date, 17 classes of highly divergent proteins have been described that act through multiple mechanisms of pathogen resistance. Characterizing these families in cacao, an economically important tree crop, and comparing the families to those in other species, is an important step in understanding cacao's immune response. Using publically available resources, all members of the 17 recognized pathogenesis-related gene families in the genome of Theobroma cacao were identified and annotated resulting in a set of ~350 members in both published cacao genomes. Approximately 50 % of these genes are organized in tandem arrays scattered throughout the genome. This feature was observed in five additional plant taxa (three dicots and two monocots), suggesting that tandem duplication has played an important role in the evolution of the PR genes in higher plants. Expression profiling captured the dynamics and complexity of PR genes expression at basal levels and after induction by two cacao pathogens (the oomycete, Phytophthora palmivora, and the fungus, Colletotrichum theobromicola), identifying specific genes within families that are more responsive to pathogen challenge. Subsequent qRT-PCR validated the induction of several PR-1, PR-3, PR-4, and PR-10 family members, with greater than 1000 fold induction detected for specific genes. We describe candidate genes that are likely to be involved in cacao's defense against Phytophthora and Colletotrichum infection and could be potentially useful for marker-assisted selection for breeding of disease resistant cacao varieties. The data presented here, along with existing cacao-omics resources, will enable targeted functional genetic screening of defense genes likely to play critical functions in cacao's defense against its pathogens.

Impact of Radiotherapy When Added to Androgen-Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes From the NCIC CTG PR3/MRC PR07 Randomized Trial

PubMed Central

Brundage, Michael; Sydes, Matthew R.; Parulekar, Wendy R.; Warde, Padraig; Cowan, Richard; Bezjak, Andrea; Kirkbride, Peter; Parliament, Matthew; Moynihan, Clare; Bahary, Jean-Paul; Parmar, Mahesh K.B.; Sanders, Karen; Chen, Bingshu E.; Mason, Malcolm D.

2015-01-01

Purpose The NCIC CTG PR3/MRC PR07 randomized phase III trial compared androgen-deprivation therapy (ADT) alone versus ADT with radiotherapy (RT) for patients with locally advanced prostate cancer. This article reports the health-related quality-of-life (HRQOL) outcomes of this trial. Patients and Methods A total of 1,205 patients were randomly allocated to either ADT alone or ADT with RT. HRQOL was assessed at baseline and every 6 months thereafter using the European Organisation for Research and Treatment of Cancer Core Questionnaire and a prostate cancer–specific checklist or the Functional Assessment of Cancer Therapy–Prostate questionnaire. Mean changes from baseline scores for five function domains and nine symptom domains were analyzed as those most relevant to ADT and RT. The proportions of patients with improved, stable, or worsened HRQOL scores according to instrument-specific minimal important differences were calculated. Results Baseline questionnaires were completed by 1,028 patients (88%). At 6 months, RT had a statistically significant impact on mean score for bowel symptoms (P = .02), diarrhea (P < .001), urinary function (P = .003), and erectile dysfunction (P = .008); by 3 years, however, there were no significant between-group differences in any domain. Generalized linear mixed modeling revealed no significant between-arm differences in any of the function scales but showed significant deterioration in both arms over time for Functional Assessment of Cancer Therapy–Prostate total score, treatment outcome index, and physical and functional well-being. Conclusion The addition of RT to ADT for patients with locally advanced prostate cancer significantly improved overall survival and had only modest and transient negative impact on relevant domains of HRQOL. PMID:26014295

A 4-dimethylaminobenzoate-functionalized Ti6-oxo cluster with a narrow band gap and enhanced photoelectrochemical activity: a combined experimental and computational study.

PubMed

Lv, Hai-Ting; Cui, Ying; Zhang, Yu-Min; Li, Hua-Min; Zou, Guo-Dong; Duan, Rui-Huan; Cao, Jun-Tao; Jing, Qiang-Shan; Fan, Yang

2017-09-28

Organic donor-π-bridge-acceptor (D-π-A) dyes with arylamines as an electron donor have been widely used as photosensitizers for dye-sensitized solar cells (DSSCs). However, titanium-oxo clusters (TOCs) functionalized with this kind of D-π-A structured dye-molecule have rarely been explored. In the present study, the 4-dimethylaminobenzoate-functionalized titanium-oxo cluster [Ti 6 (μ 3 -O) 6 (OiPr) 6 (DMABA) 6 ]·2C 6 H 5 CH 3 (DMABA = 4-dimethylaminobenzoate) was synthesized and structurally characterized by single-crystal X-ray diffraction. For comparison, two other Ti 6 -oxo clusters, namely [Ti 6 (μ 3 -O) 6 (OiPr) 6 (AD) 6 ] (AD = 1-adamantanecarboxylate) and [Ti 6 (μ 3 -O) 2 (μ 2 -O)(μ 2 -OiPr) 4 (OiPr) 10 (DMM) 2 ] (DMM = dimethylmalonate), were also studied. The DMABA-functionalized cluster exhibits a remarkably reduced band gap of ∼2.5 eV and much enhanced photocurrent response in comparison with the other two clusters. The electronic structures and electronic transitions of the clusters were studied by DFT and TDDFT calculations. The computational results suggest that the low-energy transitions of the DMABA-functionalized cluster have a substantial charge-transfer character arising from the DMABA → {Ti 6 } cluster core ligand-to-core charge transfer (LCCT), along with the DMABA-based intra-ligand charge transfer (ILCT). These low-energy charge transfer transitions provide efficient electron injection pathways for photon-to-electron conversion.

Pulmonary Rehabilitation in Ontario: A Cross-Sectional Survey

PubMed Central

Bowen, James M; Campbell, Kaitryn; Sutherland, Simone; Bartlett, Ann; Brooks, Dina; Qureshi, Riaz; Goldstein, Roger; Gershon, Andrea S; Prevost, Shelley; Samis, Lorelei; Kaplan, Alan G; Hopkins, Robert B; MacDougald, Craig; Nunes, Erica; O'Reilly, Daria J; Goeree, Ron

2015-01-01

Background Pulmonary rehabilitation (PR) is a comprehensive intervention of exercise training, education, and behaviour change to improve the physical and psychological condition of people with chronic respiratory disorders, such as chronic obstructive pulmonary disease (COPD) and to promote long-term adherence to health-enhancing behaviours. Although PR is considered the standard of care for patients with COPD who remain symptomatic despite bronchodilator therapies, current evidence suggests that only 1.15% of COPD patients across Canada have access to PR facilities for care. Objectives The objectives of this study were to identify the number of health care facilities across Ontario providing PR services for patients with COPD, describe the scope of those services, and determine the province's current capacity to provide PR services relative to need, for the province as a whole and by local health integration network (LHIN). Methods The Pulmonary Rehabilitation Programs in Ontario (PRO) Survey was a province-wide, descriptive, cross-sectional survey of health care facilities (hospitals, family health teams, and community health centres). It was distributed to 409 facilities to collect information on various aspects of PR services in the province. Results Between April 2013 and February 2014, 187 facilities responded to the survey (46% response rate). Most responding centres (144) did not offer PR services, and only 43 were full PR sites providing a comprehensive program. Hospital-based programs made up the majority of sites offering full PR services (67%), followed by programs based at family health teams (19%) and community health centres (14%). More than 90% of PR programs are outpatient-based. The average wait time for outpatient PR was 6.9 weeks, and 58% of programs provide services 5 days per week. More than 80% of patients attending PR complete the full program. Across all program types, the total estimated provincial capacity for PR outpatient care is 4,524 patients per year, or 0.66% to 1.78% of patients with COPD, depending on the estimated prevalence of disease. Limitations These results are representative of 12 of the 14 LHINs in Ontario due to low response rates in facilities in 2 LHINs. Conclusions Although some increase in capacity has occurred since a similar survey in 2005, PR resources in Ontario are insufficient to support the delivery of care to people with COPD in accordance with clinical practice guideline recommendations. PMID:26366242

Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f

PubMed Central

Morimoto, Megumi; Amano, Yuichiro; Oka, Masahiro; Harada, Ayako; Fujita, Hisashi; Hikichi, Yukiko; Tozawa, Ryuichi; Yamaoka, Masuo

2017-01-01

Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia. PMID:29216311

Placental restriction of fetal growth reduces cutaneous responses to antigen after sensitization in sheep.

PubMed

Wooldridge, Amy L; Bischof, Robert J; Meeusen, Els N; Liu, Hong; Heinemann, Gary K; Hunter, Damien S; Giles, Lynne C; Kind, Karen L; Owens, Julie A; Clifton, Vicki L; Gatford, Kathryn L

2014-04-01

Prenatal and early childhood exposures are implicated as causes of allergy, but the effects of intrauterine growth restriction on immune function and allergy are poorly defined. We therefore evaluated effects of experimental restriction of fetal growth on immune function and allergic sensitization in adolescent sheep. Immune function (circulating total red and white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and the antibody response to Clostridial vaccination) and responses to house dust mite (HDM) allergen and ovalbumin (OVA) antigen sensitization (specific total Ig, IgG1, and IgE antibodies, and cutaneous hypersensitivity) were investigated in adolescent sheep from placentally restricted (PR, n = 23) and control (n = 40) pregnancies. Increases in circulating HDM-specific IgE (P = 0.007) and OVA-specific IgE (P = 0.038) were greater in PR than control progeny. PR did not alter total Ig, IgG1, or IgM responses to either antigen. PR increased OVA-specific but not HDM-specific IgA responses in females only (P = 0.023). Multiple birth increased Ig responses to OVA in a sex-specific manner. PR decreased the proportion of positive cutaneous hypersensitivity responders to OVA at 24 h (P = 0.030) but had no effect on cutaneous responses to HDM. Acute wheal responses to intradermal histamine correlated positively with birth weight in singletons (P = 0.023). Intrauterine growth restriction may suppress inflammatory responses in skin downstream of IgE induction, without impairment in antibody responses to a nonpolysaccharide vaccine. Discord between cutaneous and IgE responses following sensitization suggests new mechanisms for prenatal allergy programming.

Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice.

PubMed

Hara, Hideyuki; Miyata, Hironori; Das, Nandita Rani; Chida, Junji; Yoshimochi, Tatenobu; Uchiyama, Keiji; Watanabe, Hitomi; Kondoh, Gen; Yokoyama, Takashi; Sakaguchi, Suehiro

2018-01-01

Conformational conversion of the cellular isoform of prion protein, PrP C , into the abnormally folded, amyloidogenic isoform, PrP Sc , is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrP C into PrP Sc after infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/ Prnp 0 / 0 mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrP Sc ΔOR in their brains. We show here that Tg(PrPΔOR)/ Prnp 0 / 0 mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrP Sc ΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrP C into PrP Sc after infection with BSE prions. However, Tg(PrPΔOR)/ Prnp 0 / 0 mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrP Sc ΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/ Prnp 0 / 0 mice than PrP Sc in control wild-type mice. Taken together, these results indicate that the OR region of PrP C could play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions. IMPORTANCE Structure-function relationship studies of PrP C conformational conversion into PrP Sc are worthwhile to understand the mechanism of the conversion of PrP C into PrP Sc We show here that, by inoculating Tg(PrPΔOR)/ Prnp 0 / 0 mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrP C into PrP Sc after infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrP Sc ΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrP Sc ΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrP C into PrP Sc after infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions. Copyright © 2017 American Society for Microbiology.

The expression of sphingosine-1 phosphate receptor-1 in chronic lymphocytic leukemia cells is impaired by tumor microenvironmental signals and enhanced by piceatannol and R406.

PubMed

Borge, Mercedes; Remes Lenicov, Federico; Nannini, Paula R; de los Ríos Alicandú, María M; Podaza, Enrique; Ceballos, Ana; Fernández Grecco, Horacio; Cabrejo, María; Bezares, Raimundo F; Morande, Pablo E; Oppezzo, Pablo; Giordano, Mirta; Gamberale, Romina

2014-09-15

Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of clonal B lymphocytes. Proliferation occurs in lymphoid tissues upon interaction of leukemic cells with a supportive microenvironment. Therefore, the mobilization of tissue-resident CLL cells into the circulation is a useful therapeutic strategy to minimize the reservoir of tumor cells within survival niches. Because the exit of normal lymphocytes from lymphoid tissues depends on the presence of sphingosine-1 phosphate (S1P) and the regulated expression of S1P receptor-1 (S1PR1), we investigated whether the expression and function of S1PR1 can be modulated by key microenvironment signals. We found that activation of CLL cells with CXCL12, fibroblast CD40L(+), BCR cross-linking, or autologous nurse-like cells reduces their S1PR1 expression and the migratory response toward S1P. Moreover, we found that S1PR1 expression was reduced in the proliferative/activated subset of leukemic cells compared with the quiescent subset from the same patient. Similarly, bone marrow-resident CLL cells expressing high levels of the activation marker CD38 showed a lower expression of S1PR1 compared with CD38(low) counterparts. Finally, given that treatment with BCR-associated kinase inhibitors induces a transient redistribution of leukemic cells from lymphoid tissues to circulation, we studied the effect of the Syk inhibitors piceatannol and R406 on S1PR1 expression and function. We found that they enhance S1PR1 expression in CLL cells and their migratory response toward S1P. Based on our results, we suggest that the regulated expression of S1PR1 might modulate the egress of the leukemic clone from lymphoid tissues. Copyright © 2014 by The American Association of Immunologists, Inc.

pH-Sensitive PEGylated liposomes functionalized with a fibronectin-mimetic peptide show enhanced intracellular delivery to colon cancer cell.

PubMed

Garg, Ashish; Kokkoli, Efrosini

2011-08-01

pH-sensitive liposomes undergo rapid destabilization under mildly acidic conditions such as those found in endocytotic vesicles. Though this makes them promising drug carriers, their application is limited due to their rapid clearance from circulation by the reticulo-endothelial system. Researchers have therefore used pH-sensitive liposomes that are sterically stabilized by polyethylene glycol (PEG) molecules (stealth liposomes) on the liposome surface. The goal of this study is to bring bio-functionality to pH-sensitive PEGylated liposomes in order to facilitate their potential use as a targeted drug delivery agent. To improve the selectivity of these nanoparticles, we included a targeting moiety, PR_b which specifically recognizes and binds to integrin α(5)β(1) expressing cells. PR_b (KSSPHSRN(SG)(5)RGDSP) is a novel fibronectin-mimetic peptide sequence that mimics the cell adhesion domain of fibronectin. Integrin α(5)β(1) is expressed on several types of cancer cells, including colon cancer, and plays an important role in tumor growth and metastasis. We have thoroughly studied the release of calcein from pH-sensitive PEGylated liposomes by varying the lipid composition of the liposomes in the absence and presence of the targeting peptide, PR_b, and accounting for the first time for the effect of both pH and time (photo-bleaching effect) on the fluorescence signal of calcein. We have demonstrated that we can design PR_b-targeted pH-sensitive PEGylated liposomes, which can undergo destabilization under mildly acidic conditions and have shown that incorporating the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b-targeted pH-sensitive PEGylated liposomes bind to CT26.WT colon carcinoma cells that express integrin α(5)β(1), undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. Our studies demonstrate that PR_b-functionalized pH-sensitive targeted delivery systems have the potential to deliver a payload directly to cancer cells in an efficient and specific manner.

Exploring Flexibility of Progesterone Receptor Ligand Binding Domain Using Molecular Dynamics

PubMed Central

Zheng, Liangzhen; Mu, Yuguang

2016-01-01

Progesterone receptor (PR), a member of nuclear receptor (NR) superfamily, plays a vital role for female reproductive tissue development, differentiation and maintenance. PR ligand, such as progesterone, induces conformation changes in PR ligand binding domain (LBD), thus mediates subsequent gene regulation cascades. PR LBD may adopt different conformations upon an agonist or an antagonist binding. These different conformations would trigger distinct transcription events. Therefore, the dynamics of PR LBD would be of general interest to biologists for a deep understanding of its structure-function relationship. However, no apo-form (non-ligand bound) of PR LBD model has been proposed either by experiments or computational methods so far. In this study, we explored the structural dynamics of PR LBD using molecular dynamics simulations and advanced sampling tools in both ligand-bound and the apo-forms. Resolved by the simulation study, helix 11, helix 12 and loop 895–908 (the loop between these two helices) are quite flexible in antagonistic conformation. Several residues, such as Arg899 and Glu723, could form salt-bridging interaction between helix 11 and helix 3, and are important for the PR LBD dynamics. And we also propose that helix 12 in apo-form PR LBD, not like other NR LBDs, such as human estrogen receptor α (ERα) LBD, may not adopt a totally extended conformation. With the aid of umbrella sampling and metadynamics simulations, several stable conformations of apo-form PR LBD have been sampled, which may work as critical structural models for further large scale virtual screening study to discover novel PR ligands for therapeutic application. PMID:27824891

An automatic method for skeletal patterns classification using craniomaxillary variables on a Colombian population.

PubMed

Niño-Sandoval, Tania Camila; Guevara Perez, Sonia V; González, Fabio A; Jaque, Robinson Andrés; Infante-Contreras, Clementina

2016-04-01

The mandibular bone is an important part of the forensic facial reconstruction and it has the possibility of getting lost in skeletonized remains; for this reason, it is necessary to facilitate the identification process simulating the mandibular position only through craniomaxillary measures, for this task, different modeling techniques have been performed, but they only contemplate a straight facial profile that belong to skeletal pattern Class I, but the 24.5% corresponding to the Colombian skeletal patterns Class II and III are not taking into account, besides, craniofacial measures do not follow a parametric trend or a normal distribution. The aim of this study was to employ an automatic non-parametric method as the Support Vector Machines to classify skeletal patterns through craniomaxillary variables, in order to simulate the natural mandibular position on a contemporary Colombian sample. Lateral cephalograms (229) of Colombian young adults of both sexes were collected. Landmark coordinates protocols were used to create craniomaxillary variables. A Support Vector Machine with a linear kernel classifier model was trained on a subset of the available data and evaluated over the remaining samples. The weights of the model were used to select the 10 best variables for classification accuracy. An accuracy of 74.51% was obtained, defined by Pr-A-N, N-Pr-A, A-N-Pr, A-Te-Pr, A-Pr-Rhi, Rhi-A-Pr, Pr-A-Te, Te-Pr-A, Zm-A-Pr and PNS-A-Pr angles. The Class Precision and the Class Recall showed a correct distinction of the Class II from the Class III and vice versa. Support Vector Machines created an important model of classification of skeletal patterns using craniomaxillary variables that are not commonly used in the literature and could be applicable to the 24.5% of the contemporary Colombian sample. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In vivo functional analysis of polyglutamic acid domains in recombinant bone sialoprotein.

PubMed

Wazen, Rima M; Tye, Coralee E; Goldberg, Harvey A; Hunter, Graeme K; Smith, Charles E; Nanci, Antonio

2007-01-01

Bone sialoprotein (BSP) is an anionic phosphoprotein expressed in mineralizing connective tissues that binds to hydroxyapatite and nucleates its formation in vitro. Two polyglutamic acid regions (poly [E]) are believed to participate in these activities. The aim of this study was to evaluate the contribution of these acidic regions to the binding of prokaryote recombinant BSP (prBSP(E)) within an actual in vivo environment. Full-length prBSP(E) and prBSP(E) in which the poly [E] domains were replaced by polyalanine (prBSP(A)) were tagged with dinitrophenol (DNP). Tagged preparations comprised intact molecules and some fragmented forms. They were infused through a surgically created hole in the bone of rat hemimandibles and detected using immunogold labeling with anti-DNP antibodies. prBSP(E)-DNP was consistently immunodetected along exposed mineralized bone surfaces and osteocyte canaliculi at the surgical site. Few gold particles were observed on these surfaces when prBSP(A)-DNP was infused. Quantitative analyses showed significant differences in labeling between prBSP(E)-DNP (5.04 +/- 0.73 particles/micro m2) and prBSP(A)-DNP (1.37 +/- 0.35 particles/micro m2). These results indicate that poly [E] domains influence binding of prBSP(E) to surfaces presenting a mixture of mineral and proteins bathed by tissue fluids and suggest that they may similarly mediate the interaction of native BSP in the bone environment.

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells.

PubMed

Corsaro, Alessandro; Bajetto, Adriana; Thellung, Stefano; Begani, Giulia; Villa, Valentina; Nizzari, Mario; Pattarozzi, Alessandra; Solari, Agnese; Gatti, Monica; Pagano, Aldo; Würth, Roberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio

2016-06-21

Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.

Memory impairment in transgenic Alzheimer mice requires cellular prion protein.

PubMed

Gimbel, David A; Nygaard, Haakon B; Coffey, Erin E; Gunther, Erik C; Laurén, Juha; Gimbel, Zachary A; Strittmatter, Stephen M

2010-05-05

Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

PubMed Central

Corsaro, Alessandro; Bajetto, Adriana; Thellung, Stefano; Begani, Giulia; Villa, Valentina; Nizzari, Mario; Pattarozzi, Alessandra; Solari, Agnese; Gatti, Monica; Pagano, Aldo; Würth, Roberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio

2016-01-01

Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype. PMID:27229535

Investigation of Hill's optical turbulence model by means of direct numerical simulation.

PubMed

Muschinski, Andreas; de Bruyn Kops, Stephen M

2015-12-01

For almost four decades, Hill's "Model 4" [J. Fluid Mech. 88, 541 (1978) has played a central role in research and technology of optical turbulence. Based on Batchelor's generalized Obukhov-Corrsin theory of scalar turbulence, Hill's model predicts the dimensionless function h(κl(0), Pr) that appears in Tatarskii's well-known equation for the 3D refractive-index spectrum in the case of homogeneous and isotropic turbulence, Φn(κ)=0.033C2(n)κ(-11/3) h(κl(0), Pr). Here we investigate Hill's model by comparing numerical solutions of Hill's differential equation with scalar spectra estimated from direct numerical simulation (DNS) output data. Our DNS solves the Navier-Stokes equation for the 3D velocity field and the transport equation for the scalar field on a numerical grid containing 4096(3) grid points. Two independent DNS runs are analyzed: one with the Prandtl number Pr=0.7 and a second run with Pr=1.0 . We find very good agreement between h(κl(0), Pr) estimated from the DNS output data and h(κl(0), Pr) predicted by the Hill model. We find that the height of the Hill bump is 1.79 Pr(1/3), implying that there is no bump if Pr<0.17 . Both the DNS and the Hill model predict that the viscous-diffusive "tail" of h(κl(0), Pr) is exponential, not Gaussian.

C-Terminal HIV-1 Transframe p6* Tetrapeptide Blocks Enhanced Gag Cleavage Incurred by Leucine Zipper Replacement of a Deleted p6* Domain.

PubMed

Yu, Fu-Hsien; Huang, Kuo-Jung; Wang, Chin-Tien

2017-05-15

HIV-1 protease (PR) functions as a homodimer mediating virus maturation following virus budding. Gag-Pol dimerization is believed to trigger embedded PR activation by promoting PR dimer formation. Early PR activation can lead to markedly reduced virus yields due to premature Gag cleavage. The p6* peptide, located between Gag and PR, is believed to ensure virus production by preventing early PR maturation. Studies aimed at finding supporting evidence for this proposal are limited due to a reading frame overlap between p6* and the p6gag budding domain. To determine if p6* affects virus production via the modulation of PR activation, we engineered multiple constructs derived from Dp6*PR (an assembly- and processing-competent construct with Pol fused at the inactivated PR C terminus). The data indicated that a p6* deletion adjacent to active PR significantly impaired virus processing. We also observed that the insertion of a leucine zipper (LZ) dimerization motif in the deleted region eliminated virus production in a PR activity-dependent manner, suggesting that the LZ insertion triggered premature PR activation by facilitating PR dimer formation. As few as four C-terminal p6* residues remaining at the p6*/PR junction were sufficient to restore virus yields, with a Gag processing profile similar to that of the wild type. Our study provides supporting evidence in a virus assembly context that the C-terminal p6* tetrapeptide plays a role in preventing premature PR maturation. IMPORTANCE Supporting evidence for the assumption that p6* retards PR maturation in the context of virus assembly is lacking. We found that replacing p6* with a leucine zipper peptide abolished virus assembly due to the significant enhancement of Gag cleavage. However, as few as four C-terminal p6* residues remaining in the deleted region were sufficient for significant PR release, as well as for counteracting leucine zipper-incurred premature Gag cleavage. Our data provide evidence that (i) p6* ensures virus assembly by preventing early PR activation and (ii) four C-terminal p6* residues are critical for modulating PR activation. Current PR inhibitor development efforts are aimed largely at mature PR, but there is a tendency for HIV-1 variants that are resistant to multiple protease inhibitors to emerge. Our data support the idea of modulating PR activation by targeting PR precursors as an alternative approach to controlling HIV-1/AIDS. Copyright © 2017 American Society for Microbiology.

Fluoride-induced thyroid dysfunction in rats: roles of dietary protein and calcium level.

PubMed

Wang, H; Yang, Z; Zhou, B; Gao, H; Yan, X; Wang, J

2009-02-01

To assess the roles of dietary protein (Pr) and calcium (Ca) level associated with excessive fluoride (F) intake and the impact of dietary Pr, Ca, and F on thyroid function, 144 30-day-old Wistar albino rats were randomly allotted to six groups of 24 (female:male = 1:1). The six groups were fed (1) a normal control (NC) diet (17.92% Pr, 0.85% Ca = NC group); (2) the NC diet and high F (338 mg NaF [=150 mg F ion]/L in their drinking water = NC+F group); (3) low Pr and low Ca diet (10.01% Pr, 0.24% Ca = LPrLCa group); (4) low Pr and low Ca diet plus high F = LPrLCa+F group; (5) high Pr and low Ca diet plus high F (25.52% Pr, 0.25% Ca = HPrLCa+F group); and (6) low Pr and high Ca diet plus high F (10.60% Pr, 1.93% Ca = LPrHCa+F group). The areas of thyroid follicles were determined by Image-Proplus 5.1, and triiodothyronine (T3), free T3 (FT3), thyroxine (T4), and free T4 (FT4) levels in serum were measured by radioimmunoassay. The histopathological study revealed obviously flatted follicular epithelia cells and hyperplastic nodules, consisting of thyroid parafollicular cells that appeared by excessive F ingestion, on the 120th day. Pr or Ca supplementation reverses the F-induced damage in malnutrition. The serum T3, FT3, T4, and FT4 levels in the NC+F group were significantly decreased and significantly increased in the LPrLCa+F group. Thus, excessive F administration induces thyroid dysfunction in rats; dietary Pr and Ca level play key roles in F-induced thyroid dysfunction.

Salicylic acid-dependent and -independent impact of an RNA-binding protein on plant immunity.

PubMed

Hackmann, Christian; Korneli, Christin; Kutyniok, Magdalene; Köster, Tino; Wiedenlübbert, Matthias; Müller, Caroline; Staiger, Dorothee

2014-03-01

Plants overexpressing the RNA-binding protein AtGRP7 (AtGRP7-ox plants) constitutively express the PR-1 (PATHOGENESIS-RELATED-1), PR-2 and PR-5 transcripts associated with salicylic acid (SA)-mediated immunity and show enhanced resistance against Pseudomonas syringae pv. tomato (Pto) DC3000. Here, we investigated whether the function of AtGRP7 in plant immunity depends on SA. Endogenous SA was elevated fivefold in AtGRP7-ox plants. The elevated PR-1, PR-2 and PR-5 levels were eliminated upon expression of the salicylate hydroxylase nahG in AtGRP7-ox plants and elevated PR-1 levels were suppressed by sid (salicylic acid deficient) 2-1 that is impaired in SA biosynthesis. RNA immunoprecipitation showed that AtGRP7 does not bind the PR-1 transcript in vivo, whereas it binds PDF1.2. Constitutive or inducible AtGRP7 overexpression increases PR-1 promoter activity, indicating that AtGRP7 affects PR-1 transcription. In line with this, the effect of AtGRP7 on PR-1 is suppressed by npr (non-expressor of PR genes) 1. Whereas AtGRP7-ox plants restricted growth of Pto DC3000 compared with wild type (wt), sid2-1 AtGRP7-ox plants allowed more growth than AtGRP7-ox plants. Furthermore, we show an enhanced hypersensitive response triggered by avirulent Pto DC3000 (AvrRpt2) in AtGRP7-ox compared with wt. In sid2-1 AtGRP7-ox, an intermediate phenotype was observed. Thus, AtGRP7 has both SA-dependent and SA-independent effects on plant immunity. © 2013 John Wiley & Sons Ltd.

Ionic mechanisms of action of prion protein fragment PrP(106-126) in rat basal forebrain neurons.

PubMed

Alier, Kwai; Li, Zongming; Mactavish, David; Westaway, David; Jhamandas, Jack H

2010-08-01

Prion diseases are neurodegenerative disorders that are characterized by the presence of the misfolded prion protein (PrP). Neurotoxicity in these diseases may result from prion-induced modulation of ion channel function, changes in neuronal excitability, and consequent disruption of cellular homeostasis. We therefore examined PrP effects on a suite of potassium (K(+)) conductances that govern excitability of basal forebrain neurons. Our study examined the effects of a PrP fragment [PrP(106-126), 50 nM] on rat neurons using the patch clamp technique. In this paradigm, PrP(106-126) peptide, but not the "scrambled" sequence of PrP(106-126), evoked a reduction of whole-cell outward currents in a voltage range between -30 and +30 mV. Reduction of whole-cell outward currents was significantly attenuated in Ca(2+)-free external media and also in the presence of iberiotoxin, a blocker of calcium-activated potassium conductance. PrP(106-126) application also evoked a depression of the delayed rectifier (I(K)) and transient outward (I(A)) potassium currents. By using single cell RT-PCR, we identified the presence of two neuronal chemical phenotypes, GABAergic and cholinergic, in cells from which we recorded. Furthermore, cholinergic and GABAergic neurons were shown to express K(v)4.2 channels. Our data establish that the central region of PrP, defined by the PrP(106-126) peptide used at nanomolar concentrations, induces a reduction of specific K(+) channel conductances in basal forebrain neurons. These findings suggest novel links between PrP signalling partners inferred from genetic experiments, K(+) channels, and PrP-mediated neurotoxicity.

Star-pseudopolyrotaxane organized in nanoplatelets for poly(ε-caprolactone)-based nanofibrous scaffolds with enhanced surface reactivity.

PubMed

Oster, Murielle; Hébraud, Anne; Gallet, Sébastien; Lapp, Alain; Pollet, Eric; Avérous, Luc; Schlatter, Guy

2015-02-01

Herein, it is demonstrated that star pseudopolyrotaxanes (star-pPRs) obtained from the inclusion complexation of α-cyclodextrin (CD) and four-branched star poly(ε-caprolactone) (star-PCL) organize into nanoplatelets in dimethyl sulfoxide at 35 °C. This peculiar property, not observed for linear pseudopolyrotaxanes, allows the processing of star-pPRs while preserving their supramolecular assembly. Thus, original PCL:star-pPR core:shell nanofibers are elaborated by coaxial electrospinning. The star-pPR shell ensures the presence of available CD hydroxyl functions on the fiber surface allowing its postfunctionalization. As proof of concept, fluorescein isothiocyanate is grafted. Moreover, the morphology of the fibers is maintained due to the star-pPR shell that acts as a shield, preventing the fiber dissolution during chemical modification. The proposed strategy is simple and avoids the synthesis of polyrotaxanes, i.e., pPR end-capping to prevent the CD dethreading. As PCL is widely used for biomedical applications, this strategy paves the way for simple functionalization with any bioactive molecules. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Precise integration of inducible transcriptional elements (PrIITE) enables absolute control of gene expression.

PubMed

Pinto, Rita; Hansen, Lars; Hintze, John; Almeida, Raquel; Larsen, Sylvester; Coskun, Mehmet; Davidsen, Johanne; Mitchelmore, Cathy; David, Leonor; Troelsen, Jesper Thorvald; Bennett, Eric Paul

2017-07-27

Tetracycline-based inducible systems provide powerful methods for functional studies where gene expression can be controlled. However, the lack of tight control of the inducible system, leading to leakiness and adverse effects caused by undesirable tetracycline dosage requirements, has proven to be a limitation. Here, we report that the combined use of genome editing tools and last generation Tet-On systems can resolve these issues. Our principle is based on precise integration of inducible transcriptional elements (coined PrIITE) targeted to: (i) exons of an endogenous gene of interest (GOI) and (ii) a safe harbor locus. Using PrIITE cells harboring a GFP reporter or CDX2 transcription factor, we demonstrate discrete inducibility of gene expression with complete abrogation of leakiness. CDX2 PrIITE cells generated by this approach uncovered novel CDX2 downstream effector genes. Our results provide a strategy for characterization of dose-dependent effector functions of essential genes that require absence of endogenous gene expression. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

PubMed

Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W; Ingles, Sue A; Kittles, Rick A; Strom, Sara S; Rybicki, Benjamin A; Nemesure, Barbara; Isaacs, William B; Zheng, Wei; Pettaway, Curtis A; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; John, Esther M; Murphy, Adam B; Signorello, Lisa B; Carpten, John; Leske, M Cristina; Wu, Suh-Yuh; Hennis, Anslem J M; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Witte, John S; Casey, Graham; Kaggwa, Sam; Cook, Michael B; Stram, Daniel O; Blot, William J; Eeles, Rosalind A; Easton, Douglas; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel M; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L J; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K; Arndt, Volker; Park, Jong Y; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A; Teixeira, Manuel R; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Conti, David V; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I; Campa, Daniele; Crawford, E David; Diver, W Ryan; Gapstur, Susan M; Gaziano, J Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R; Price, Alkes L; Freedman, Matthew L; Haiman, Christopher A; Pasaniuc, Bogdan

2016-04-07

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

A closer look at prion strains

PubMed Central

Solforosi, Laura; Milani, Michela; Mancini, Nicasio; Clementi, Massimo; Burioni, Roberto

2013-01-01

Prions are infectious proteins that are responsible for transmissible spongiform encephalopathies (TSEs) and consist primarily of scrapie prion protein (PrPSc), a pathogenic isoform of the host-encoded cellular prion protein (PrPC). The absence of nucleic acids as essential components of the infectious prions is the most striking feature associated to these diseases. Additionally, different prion strains have been isolated from animal diseases despite the lack of DNA or RNA molecules. Mounting evidence suggests that prion-strain-specific features segregate with different PrPSc conformational and aggregation states. Strains are of practical relevance in prion diseases as they can drastically differ in many aspects, such as incubation period, PrPSc biochemical profile (e.g., electrophoretic mobility and glycoform ratio) and distribution of brain lesions. Importantly, such different features are maintained after inoculation of a prion strain into genetically identical hosts and are relatively stable across serial passages. This review focuses on the characterization of prion strains and on the wide range of important implications that the study of prion strains involves. PMID:23357828

Properties of Lu3Al5O12, Lu3Al5O12:Pr, Lu3Al5O12:Pr,Mo, and (Lu1-x Y x )3Al5O12:Pr scintillator crystals

NASA Astrophysics Data System (ADS)

Talik, E.; Kusz, J.; Guzik, A.; Szubka, M.; Balin, K.; Kisielewski, J.; Wierzchowski, W.; Malinowska, A.; Strojny-Nedza, A.; Pajaczkowska, A.; Drozdowski, W.

2017-05-01

Lattice parameters, magnetic susceptibility, electronic structure, distribution of the elements and thermal properties were examined for single crystals of Lu3Al5O12 (LuAG) and (Lu1-x Y x )3Al5O12 (LuYAG) (x  =  0.25, 0.50, 0.75), either pure or doped with Pr and optionally co-doped with Mo, which are predicted as potential fast and efficient scintillators. It was indicated that specific cage-like surrounding of rare earth and aluminum ions built from oxygen ions and proper doping can influence the thermal conductivity and the emission process. Maximum light emission (LY) was observed at praseodymium concentration about 0.3 at.%. The growth atmosphere (Ar or N2) influences the crystal quality. Additional molybdenum doping below 0.01 at% concentration increases LY.

Systematic evaluation of NASA precipitation radar estimates using NOAA/NSSL National Mosaic QPE products

NASA Astrophysics Data System (ADS)

Kirstetter, P.; Hong, Y.; Gourley, J. J.; Chen, S.; Flamig, Z.; Zhang, J.; Howard, K.; Petersen, W. A.

2011-12-01

Proper characterization of the error structure of TRMM Precipitation Radar (PR) quantitative precipitation estimation (QPE) is needed for their use in TRMM combined products, water budget studies and hydrological modeling applications. Due to the variety of sources of error in spaceborne radar QPE (attenuation of the radar signal, influence of land surface, impact of off-nadir viewing angle, etc.) and the impact of correction algorithms, the problem is addressed by comparison of PR QPEs with reference values derived from ground-based measurements (GV) using NOAA/NSSL's National Mosaic QPE (NMQ) system. An investigation of this subject has been carried out at the PR estimation scale (instantaneous and 5 km) on the basis of a 3-month-long data sample. A significant effort has been carried out to derive a bias-corrected, robust reference rainfall source from NMQ. The GV processing details will be presented along with preliminary results of PR's error characteristics using contingency table statistics, probability distribution comparisons, scatter plots, semi-variograms, and systematic biases and random errors.

Significant enhancement in thermoelectric properties of polycrystalline Pr-doped SrTiO3-δ ceramics originating from nonuniform distribution of Pr dopants

NASA Astrophysics Data System (ADS)

Dehkordi, Arash Mehdizadeh; Bhattacharya, Sriparna; He, Jian; Alshareef, Husam N.; Tritt, Terry M.

2014-05-01

Recently, we have reported a significant enhancement (>70% at 500 °C) in the thermoelectric power factor (PF) of bulk polycrystalline Pr-doped SrTiO3 ceramics employing a novel synthesis strategy which led to the highest ever reported values of PF among doped polycrystalline SrTiO3. It was found that the formation of Pr-rich grain boundary regions gives rise to an enhancement in carrier mobility. In this Letter, we investigate the electronic and thermal transport in Sr1-xPrxTiO3 ceramics in order to determine the optimum doping concentration and to evaluate the overall thermoelectric performance. Simultaneous enhancement in the thermoelectric power factor and reduction in thermal conductivity in these samples resulted in more than 30% improvement in the dimensionless thermoelectric figure of merit (ZT) for the whole temperature range over all previously reported maximum values. Maximum ZT value of 0.35 was obtained at 500 °C.

Genetic Evidence That the Red-Absorbing Form of Phytochrome B Modulates Gravitropism in Arabidopsis thaliana.

PubMed Central

Liscum, E.; Hangarter, R. P.

1993-01-01

Hypocotyls of dark-grown Arabidopsis seedlings exhibit strong negative gravitropism, whereas in red light, gravitropism is strongly reduced. Red/far-red light-pulse experiments and analysis of specific phytochrome-deficient mutants indicate that the red-absorbing (Pr) form of phytochrome B regulates normal hypocotyl gravitropism in darkness, and depletion of Pr by photoconversion to the far-red-absorbing form attenuates hypocotyl gravitropism. These studies provide genetic evidence that the Pr form of phytochrome has an active function in plant development. PMID:12231913

Retroviral proteases and their roles in virion maturation.

PubMed

Konvalinka, Jan; Kräusslich, Hans-Georg; Müller, Barbara

2015-05-01

Proteolytic processing of viral polyproteins is essential for retrovirus infectivity. Retroviral proteases (PR) become activated during or after assembly of the immature, non-infectious virion. They cleave viral polyproteins at specific sites, inducing major structural rearrangements termed maturation. Maturation converts retroviral enzymes into their functional form, transforms the immature shell into a metastable state primed for early replication events, and enhances viral entry competence. Not only cleavage at all PR recognition sites, but also an ordered sequence of cleavages is crucial. Proteolysis is tightly regulated, but the triggering mechanisms and kinetics and pathway of morphological transitions remain enigmatic. Here, we outline PR structures and substrate specificities focusing on HIV PR as a therapeutic target. We discuss design and clinical success of HIV PR inhibitors, as well as resistance development towards these drugs. Finally, we summarize data elucidating the role of proteolysis in maturation and highlight unsolved questions regarding retroviral maturation. Copyright © 2015 Elsevier Inc. All rights reserved.

The down-conversion and up-conversion photoluminescence properties of Na{sub 0.5}Bi{sub 0.5}TiO{sub 3}:Yb{sup 3+}/Pr{sup 3+} ceramics

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

Huang, Yinpeng; Luo, Laihui, E-mail: luolaihui@nbu.edu.cn; Wang, Jia

2015-07-28

Na{sub 0.5}Bi{sub 0.5−x−y}Yb{sub x}Pr{sub y}TiO{sub 3} (NBT:xYb/yPr) ceramics with different Yb and Pr contents are prepared. Both the down-conversion (DC) and up-conversion (UC) photoluminescence (PL) of the ceramics via 453 and 980 nm excitation, respectively, are investigated. The effect of Yb{sup 3+} and Pr{sup 3+} doping contents on the DC and UC PL is significantly different from each other. Furthermore, the UC PL of the ceramics as a function of temperatures is measured to investigate the UC process in detail. Based on energy level diagram of Pr{sup 3+} and Yb{sup 3+} ions and the DC and UC PL spectra, the DCmore » and UC PL mechanisms of Pr{sup 3+} and Yb{sup 3+} ions are discussed. Especially, the UC PL mechanism is clarified, which is different from the previously reported literature. Also, the temperature sensing properties of the ceramics are studied based on the photoluminescence ratio technique, using the thermal coupling energy levels of Pr{sup 3+}.« less

Prion potency in stem cells biology.

PubMed

Lopes, Marilene H; Santos, Tiago G

2012-01-01

Prion protein (PrP) can be considered a pivotal molecule because it interacts with several partners to perform a diverse range of critical biological functions that might differ in embryonic and adult cells. In recent years, there have been major advances in elucidating the putative role of PrP in the basic biology of stem cells in many different systems. Here, we review the evidence indicating that PrP is a key molecule involved in driving different aspects of the potency of embryonic and tissue-specific stem cells in self-perpetuation and differentiation in many cell types. It has been shown that PrP is involved in stem cell self-renewal, controlling pluripotency gene expression, proliferation, and neural and cardiomyocyte differentiation. PrP also has essential roles in distinct processes that regulate tissue-specific stem cell biology in nervous and hematopoietic systems and during muscle regeneration. Results from our own investigations have shown that PrP is able to modulate self-renewal and proliferation in neural stem cells, processes that are enhanced by PrP interactions with stress inducible protein 1 (STI1). Thus, the available data reveal the influence of PrP in acting upon the maintenance of pluripotent status or the differentiation of stem cells from the early embryogenesis through adulthood.

A maximum entropy thermodynamics of small systems.

PubMed

Dixit, Purushottam D

2013-05-14

We present a maximum entropy approach to analyze the state space of a small system in contact with a large bath, e.g., a solvated macromolecular system. For the solute, the fluctuations around the mean values of observables are not negligible and the probability distribution P(r) of the state space depends on the intricate details of the interaction of the solute with the solvent. Here, we employ a superstatistical approach: P(r) is expressed as a marginal distribution summed over the variation in β, the inverse temperature of the solute. The joint distribution P(β, r) is estimated by maximizing its entropy. We also calculate the first order system-size corrections to the canonical ensemble description of the state space. We test the development on a simple harmonic oscillator interacting with two baths with very different chemical identities, viz., (a) Lennard-Jones particles and (b) water molecules. In both cases, our method captures the state space of the oscillator sufficiently well. Future directions and connections with traditional statistical mechanics are discussed.

Interaction between GPR120 p.R270H loss-of-function variant and dietary fat intake on incident type 2 diabetes risk in the D.E.S.I.R. study.

PubMed

Lamri, A; Bonnefond, A; Meyre, D; Balkau, B; Roussel, R; Marre, M; Froguel, P; Fumeron, F

2016-10-01

GPR120 (encoded by FFAR4) is a lipid sensor that plays an important role in the control of energy balance. GPR120 is activated by long chain fatty acids (FAs) including omega-3 FAs. In humans, the loss of function p.R270H variant of the gene FFAR4 has been associated with a lower protein activity, an increased risk of obesity and higher fasting plasma glucose levels. The aim of this study was to investigate whether p.R270H interacts with dietary fat intake to modulate the risk of type 2 diabetes (T2D, 198 incident; 368 prevalent cases) and overweight (787 incident and 2891 prevalent cases) in the prospective D.E.S.I.R. study (n = 5,212, 9 years follow-up). The association of p.R270H with dietary fat and total calories was assessed by linear mixed models. The interaction between p.R270H and dietary fat on T2D and overweight was assessed by logistic regression analysis. The p.R270H variant had a minor allele frequency of 1.45% and was not significantly associated with total calories intake, fat intake or the total calories derived from fat (%). However, there was a significant interaction between p.R270H and dietary fat modulating the incidence of T2D (Pinteraction = 0.02) where the H-carriers had a higher risk of T2D than RR homozygotes in the low fat intake category only. The interaction between p.R270H and fat intake modulating the incidence and prevalence of overweight was not significant. The p.R270H variant of GPR120 modulates the risk of T2D in interaction with dietary fat intake in the D.E.S.I.R. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Real reproduction and evaluation of color based on BRDF method

NASA Astrophysics Data System (ADS)

Qin, Feng; Yang, Weiping; Yang, Jia; Li, Hongning; Luo, Yanlin; Long, Hongli

2013-12-01

It is difficult to reproduce the original color of targets really in different illuminating environment using the traditional methods. So a function which can reconstruct the characteristics of reflection about every point on the surface of target is required urgently to improve the authenticity of color reproduction, which known as the Bidirectional Reflectance Distribution Function(BRDF). A method of color reproduction based on the BRDF measurement is introduced in this paper. Radiometry is combined with the colorimetric theories to measure the irradiance and radiance of GretagMacbeth 24 ColorChecker by using PR-715 Radiation Spectrophotometer of PHOTO RESEARCH, Inc, USA. The BRDF and BRF (Bidirectional Reflectance Factor) values of every color piece corresponding to the reference area are calculated according to irradiance and radiance, thus color tristimulus values of 24 ColorChecker are reconstructed. The results reconstructed by BRDF method are compared with values calculated by the reflectance using PR-715, at last, the chromaticity coordinates in color space and color difference between each other are analyzed. The experimental result shows average color difference and sample standard deviation between the method proposed in this paper and traditional reconstruction method depended on reflectance are 2.567 and 1.3049 respectively. The conclusion indicates that the method of color reproduction based on BRDF has the more obvious advantages to describe the color information of object than the reflectance in hemisphere space through the theoretical and experimental analysis. This method proposed in this paper is effective and feasible during the research of reproducing the chromaticity.

Pre-Exposure Prophylaxis for HIV Prevention: Safety Concerns.

PubMed

Tetteh, Raymond A; Yankey, Barbara A; Nartey, Edmund T; Lartey, Margaret; Leufkens, Hubert G M; Dodoo, Alexander N O

2017-04-01

Available evidence supports the efficacy of pre-exposure prophylaxis (PrEP) in decreasing the incidence of human immunodeficiency virus (HIV) infection among high-risk individuals, especially when used in combination with other behavioural preventive methods. Safety concerns about PrEP present challenges in the implementation and use of PrEP. The aim of this review is to discuss safety concerns observed in completed clinical trials on the use of PrEP. We performed a literature search on PrEP in PubMed, global advocacy for HIV prevention (Aids Vaccine Advocacy Coalition) database, clinical trials registry " http://www.clinicaltrials.gov " and scholar.google, using combination search terms 'pre-exposure prophylaxis', 'safety concerns in the use of pre-exposure prophylaxis', 'truvada use as PrEP', 'guidelines for PrEP use', 'HIV pre-exposure prophylaxis' and 'tenofovir' to identify clinical trials and literature on PrEP. We present findings associated with safety issues on the use of PrEP based on a review of 11 clinical trials on PrEP with results on safety and efficacy as at April 2016. We also reviewed findings from routine real-life practice reports. The pharmacological intervention for PrEP was tenofovir disoproxil fumarate/emtricitabine in a combined form as Truvada ® or tenofovir as a single entity. Both products are efficacious for PrEP and seem to have a good safety profile. Regular monitoring is recommended to prevent long-term toxic effects. The main adverse effects observed with PrEP are gastrointestinal related; basically mild to moderate nausea, vomiting and diarrhea. Other adverse drug effects worth monitoring are liver enzymes, renal function and bone mineral density. PrEP as an intervention to reduce HIV transmission appears to have a safe benefit-risk profile in clinical trials. It is recommended for widespread use but adherence monitoring and real-world safety surveillance are critical in the post-marketing phase to ensure that the benefits observed in clinical trials are maintained in real-world use.

Influence of minor combined addition of Cr and Pr on microstructure, mechanical properties and corrosion behaviors of an ultrahigh strength Al-Zn-Mg-Cu-Zr alloy.

PubMed

Wang, Ming; Huang, Lanping; Chen, Kanghua; Liu, Wensheng

2018-01-01

This work focuses on controlling grain boundary structure in an ultra-high strength Al-8.6Zn-2.5Mg-2.2Cu-0.16Zr (wt.%) alloy by the combined addition of trace Cr (0.1wt.%) and Pr (0.14wt.%), and evaluating mechanical properties and localized corrosion behaviors of the alloy in the peak aged condition. The introduction of trace Cr and Pr leads to the formation of nanoscale Cr, Pr-containing Al 3 Zr and Zr-containing PrCr 2 Al 20 dispersoids which can obviously inhibit the recrystallization and sub-grain growth of the super-high strength Al-Zn-Mg-Cu alloys, and retain the deformation-recovery microstructure dominated by low-angle grain boundaries. The nearly ellipsoidal dispersoids with a size of 10-35nm are discretely distributed and precipitate free zones are hardly formed in low-angle grain boundaries. This new alloy composition exhibits better combined properties, higher resistance to stress corrosion, exfoliation corrosion and inter-granular corrosion with the undamaged strength, ductility and fracture toughness. Copyright © 2017 Elsevier Ltd. All rights reserved.

Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility.

PubMed

Sun, Xiaoguang; Ma, Shwu-Fan; Wade, Michael S; Flores, Carlos; Pino-Yanes, Maria; Moitra, Jaideep; Ober, Carole; Kittles, Rick; Husain, Aliya N; Ford, Jean G; Garcia, Joe G N

2010-08-01

The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma, and the sphingosine-1-phosphate receptor (S1PR1) is an essential participant regulating lung vascular integrity and responses to lung inflammation. We explored the contribution of polymorphisms in the S1PR1 gene to asthma susceptibility. A combination of gene resequencing for single nucleotide polymorphism (SNP) discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was used. Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in lungs of asthmatic patients compared with those of nonasthmatic subjects (P < .05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in 3 case-control cohorts from Chicago and New York totaling 1,061 subjects (502 cases and 559 control subjects). The promoter SNP rs2038366 (-1557G/T) was found to be associated with asthma (P = .03) in European Americans. In African Americans an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.-164+170A/G; P = .006 and P = .040, respectively) and for promoter SNP rs59317557 (-532C/G) with severe asthma (P = .028). Consistent with predicted in silico functionality, alleles of the promoter SNPs rs2038366 (-1557G/T) and rs59317557 (-532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor) known to be increased in asthmatic airways. These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Progesterone receptor knockout mice have an improved glucose homeostasis secondary to -cell proliferation

NASA Astrophysics Data System (ADS)

Picard, Frédéric; Wanatabe, Mitsuhiro; Schoonjans, Kristina; Lydon, John; O'Malley, Bert W.; Auwerx, Johan

2002-11-01

Gestational diabetes coincides with elevated circulating progesterone levels. We show that progesterone accelerates the progression of diabetes in female db/db mice. In contrast, RU486, an antagonist of the progesterone receptor (PR), reduces blood glucose levels in both female WT and db/db mice. Furthermore, female, but not male, PR-/- mice had lower fasting glycemia than PR+/+ mice and showed higher insulin levels on glucose injection. Pancreatic islets from female PR-/- mice were larger and secreted more insulin consequent to an increase in -cell mass due to an increase in -cell proliferation. These findings demonstrate an important role of progesterone signaling in insulin release and pancreatic function and suggest that it affects the susceptibility to diabetes.

Disorder and Quantum Spin Ice

NASA Astrophysics Data System (ADS)

Martin, N.; Bonville, P.; Lhotel, E.; Guitteny, S.; Wildes, A.; Decorse, C.; Ciomaga Hatnean, M.; Balakrishnan, G.; Mirebeau, I.; Petit, S.

2017-10-01

We report on diffuse neutron scattering experiments providing evidence for the presence of random strains in the quantum spin-ice candidate Pr2Zr2O7 . Since Pr3 + is a non-Kramers ion, the strain deeply modifies the picture of Ising magnetic moments governing the low-temperature properties of this material. It is shown that the derived strain distribution accounts for the temperature dependence of the specific heat and of the spin-excitation spectra. Taking advantage of mean-field and spin-dynamics simulations, we argue that the randomness in Pr2Zr2O7 promotes a new state of matter, which is disordered yet characterized by short-range antiferroquadrupolar correlations, and from which emerge spin-ice-like excitations. Thus, this study gives an original research route in the field of quantum spin ice.

Expression of nuclear progesterone receptor and progesterone receptor membrane components 1 and 2 in the oviduct of cyclic and pregnant cows during the post-ovulation period

PubMed Central

2012-01-01

Background Progesterone (P4) may modulate oviductal functions to promote early embryo development in cattle. In addition to its nuclear receptor (PR), P4 may mediate its actions through P4 receptor membrane component 1 (PGRMC1) and its relative, PGRMC2. Two successive experiments were undertaken to characterise the expression of PR, PGRMC1 and PGRMC2 in the bovine oviduct during the post-ovulation period, and to relate their expression to the presence of an embryo, the proximity of the CL and to the region of the oviduct. Methods In the first experiment (Exp. I), whole oviduct sections were collected from Holstein cows at Day 1.5, Day 4 and Day 5 post-ovulation (n = 2 cows per stage). The expression of PR, PGRMC1 and PGRMC2 was studied in the ampulla and isthmus by RT-PCR, western-blot and immunohistochemistry. In Exp. II, oviduct epithelial cells were collected from cyclic and pregnant Charolais cows (n = 4 cows per status) at Day 3.5 post-ovulation and mRNA expression of PR, PGRMC1 and PGRMC2 was examined in the ampulla and isthmus by real-time quantitative PCR. Results In Exp. I, PR, PGRMC1 and PGRMC2 were expressed in all oviduct samples. PGRMC1 was mainly localised in the luminal epithelium whereas PR and PGRMC2 were localised in the epithelium as well as in the muscle and stroma layers of the oviduct. The expression was primarily nuclear for PR, primarily cytoplasmic for PGRMC1 and both nuclear and cytoplasmic for PGRMC2. In Exp. II, mRNA levels for PR, PGRMC1 and PGRMC2 were not affected by either the pregnancy status or the side relative to the CL. However, the expression of PR and PGRMC2 varied significantly with the region of the oviduct: PR was more highly expressed in the isthmus whereas PGRMC2 was more highly expressed in the ampulla. Conclusions This is the first evidence of PGRMC2 expression in the bovine oviduct. Our findings suggest that P4 regulates the functions of the bovine oviduct in a region-specific manner and through both classical and non classical pathways during the post-ovulation period. PMID:22958265

Pathways of Prion Spread during Early Chronic Wasting Disease in Deer

PubMed Central

Hoover, Clare E.; Davenport, Kristen A.; Henderson, Davin M.; Denkers, Nathaniel D.; Mathiason, Candace K.; Soto, Claudio; Zabel, Mark D.

2017-01-01

ABSTRACT Among prion infections, two scenarios of prion spread are generally observed: (i) early lymphoid tissue replication or (ii) direct neuroinvasion without substantial antecedent lymphoid amplification. In nature, cervids are infected with chronic wasting disease (CWD) prions by oral and nasal mucosal exposure, and studies of early CWD pathogenesis have implicated pharyngeal lymphoid tissue as the earliest sites of prion accumulation. However, knowledge of chronological events in prion spread during early infection remains incomplete. To investigate this knowledge gap in early CWD pathogenesis, we exposed white-tailed deer to CWD prions by mucosal routes and performed serial necropsies to assess PrPCWD tissue distribution by real-time quaking-induced conversion (RT-QuIC) and tyramide signal amplification immunohistochemistry (TSA-IHC). Although PrPCWD was not detected by either method in the initial days (1 and 3) postexposure, we observed PrPCWD seeding activity and follicular immunoreactivity in oropharyngeal lymphoid tissues at 1 and 2 months postexposure (MPE). At 3 MPE, PrPCWD replication had expanded to all systemic lymphoid tissues. By 4 MPE, the PrPCWD burden in all lymphoid tissues had increased and approached levels observed in terminal disease, yet there was no evidence of nervous system invasion. These results indicate the first site of CWD prion entry is in the oropharynx, and the initial phase of prion amplification occurs in the oropharyngeal lymphoid tissues followed by rapid dissemination to systemic lymphoid tissues. This lymphoid replication phase appears to precede neuroinvasion. IMPORTANCE Chronic wasting disease (CWD) is a universally fatal transmissible spongiform encephalopathy affecting cervids, and natural infection occurs through oral and nasal mucosal exposure to infectious prions. Terminal disease is characterized by PrPCWD accumulation in the brain and lymphoid tissues of affected animals. However, the initial sites of prion accumulation and pathways of prion spread during early CWD infection remain unknown. To investigate the chronological events of early prion pathogenesis, we exposed deer to CWD prions and monitored the tissue distribution of PrPCWD over the first 4 months of infection. We show CWD uptake occurs in the oropharynx with initial prion replication in the draining oropharyngeal lymphoid tissues, rapidly followed by dissemination to systemic lymphoid tissues without evidence of neuroinvasion. These data highlight the two phases of CWD infection: a robust prion amplification in systemic lymphoid tissues prior to neuroinvasion and establishment of a carrier state. PMID:28250130

Branched-chain Amino Acids are Beneficial to Maintain Growth Performance and Intestinal Immune-related Function in Weaned Piglets Fed Protein Restricted Diet.

PubMed

Ren, M; Zhang, S H; Zeng, X F; Liu, H; Qiao, S Y

2015-12-01

As a novel approach for disease control and prevention, nutritional modulation of the intestinal health has been proved. However, It is still unknown whether branched-chain amino acid (BCAA) is needed to maintain intestinal immune-related function. The objective of this study was to determine whether BCAA supplementation in protein restricted diet affects growth performance, intestinal barrier function and modulates post-weaning gut disorders. One hundred and eight weaned piglets (7.96±0.26 kg) were randomly fed one of the three diets including a control diet (21% crude protein [CP], CON), a protein restricted diet (17% CP, PR) and a BCAA diet (BCAA supplementation in the PR diet) for 14 d. The growth performance, plasma amino acid concentrations, small intestinal morphology and intestinal immunoglobulins were tested. First, average daily gain (ADG) (p<0.05) and average daily feed intake (ADFI) (p<0.05) of weaned pigs in PR group were lower, while gain:feed ratio was lower than the CON group (p<0.05). Compared with PR group, BCAA group improved ADG (p<0.05), ADFI (p<0.05) and feed:gain ratio (p<0.05) of piglets. The growth performance data between CON and BCAA groups was not different (p>0.05). The PR and BCAA treatments had a higher (p<0.05) plasma concentration of methionine and threonine than the CON treatment. The level of some essential and functional amino acids (such as arginine, phenylalanine, histidine, glutamine etc.) in plasma of the PR group was lower (p<0.05) than that of the CON group. Compared with CON group, BCAA supplementation significantly increased BCAA concentrations (p<0.01) and decreased urea concentration (p<0.01) in pig plasma indicating that the efficiency of dietary nitrogen utilization was increased. Compared with CON group, the small intestine of piglets fed PR diet showed villous atrophy, increasing of intra-epithelial lymphocytes (IELs) number (p<0.05) and declining of the immunoglobulin concentration, including jejunal immunoglobulin A (IgA) (p = 0.04), secreted IgA (sIgA) (p = 0.03) and immunoglobulin M (p = 0.08), and ileal IgA (p = 0.01) and immunoglobulin G (p = 0.08). The BCAA supplementation increased villous height in the duodenum (p<0.01), reversed the trend of an increasing IELs number. Notably, BCAA supplementation increased levels of jejunal and ileal immunoglobulin mentioned above. In conclusion, BCAA supplementation to protein restricted diet improved intestinal immune defense function by protecting villous morphology and by increasing levels of intestinal immunoglobulins in weaned piglets. Our finding has the important implication that BCAA may be used to reduce the negative effects of a protein restricted diet on growth performance and intestinal immunity in weaned piglets.

Magnetic study of the low temperature anomalies in the underdoped PrBCO compound

NASA Astrophysics Data System (ADS)

Lahoubi, Mahieddine

2018-05-01

The low temperature anomalous magnetic properties of a non-superconducting PrBCO6+x compound in an underdoped oxygen state of concentration (x = 0.44) are characterized by paraprocess magnetic susceptibility χH(T) measurements carried out as a function of temperature T under different values of a DC magnetic field H up to 110 kOe. The derivatives dχH(T)/dT curves reveal a significant reduction with increasing H in the Néel temperature TN = 9 K of the Pr antiferromagnetic (AFM) ordering for which the transition subsists at 100 kOe. The small anomaly at T2 = 6-7 K is confirmed at 20 kOe and the previous spin reorientation attributed to this transition temperature seems to be suppressed above 60 kOe. The well defined anomaly in the vicinity of the low-critical point Tcr = 4-5 K which occurs simultaneously, is still present when the strength of H is increased up to 100 kOe. Weak field induced phase transitions are observed between T2 and TN at a low transition-field (Ht<11 kOe) in the differential magnetic susceptibility dMT(H)/dH as a function of H deduced from the isothermal magnetizations MT(H) with H up to 21 kOe, whereas a weak ferromagnetic behavior of the Pr sublattice appears below Tcr. The magnetic field effects give rise to more evidence for the Pr-Cu(2) coupling with 'exchange-frustrated AFM' interactions and ascertain the main role of the Pr sublattice whereas the Cu(2) sublattice seems to be less efficient.

Neuroglobin and prion cellular localization: investigation of a potential interaction.

PubMed

Lechauve, Christophe; Rezaei, Human; Celier, Chantal; Kiger, Laurent; Corral-Debrinski, Marisol; Noinville, Sylvie; Chauvierre, Cédric; Hamdane, Djemel; Pato, Christine; Marden, Michael C

2009-05-22

Neuroglobin (Ngb) and the cellular prion protein (PrP(c)), proteins of unknown function in the nervous system, are known to be expressed in the retina and have been observed in different rat retinal cells. The retina is the site of the highest concentration for Ngb, a heme protein of similar size and conformation to myoglobin. In this study, we demonstrated by immunohistochemical analysis of retinal colocalization of Ngb and PrP(c) in the ganglion cell layer. Considering for these two a common protective role in relation to oxidative stress and a possible transient contact during migration of PrP(c) through the eye or upon neuronal degradation, we undertook in vitro studies of the interaction of the purified proteins. Mixing these two proteins leads to rapid aggregation, even at submicromolar concentrations. As observed with the use of dynamic light scattering, particles comprising both proteins evolve to hundreds of nanometers within several seconds, a first report showing that PrP(c) is able to form aggregates without major structural changes. The main effect would then appear to be a protein-protein interaction specific to the surface charge of the Ngb protein with PrP(c) N-terminal sequence. A dominant parameter is the solvent ionic force, which can significantly modify the final state of aggregation. PrP(c), normally anchored to the cell membrane, is toxic in the cytoplasm, where Ngb is present; this could suggest an Ngb function of scavenging proteins capable of forming deleterious aggregates considering a charge complementarity in the complex.

Differences in change in coping styles between good responders, moderate responders and non-responders to pulmonary rehabilitation.

PubMed

Stoilkova-Hartmann, Ana; Janssen, Daisy J A; Franssen, Frits M E; Wouters, Emiel F M

2015-12-01

Pulmonary rehabilitation (PR) improves exercise tolerance and health status in patients with chronic obstructive pulmonary disease (COPD). Data on the effects of PR on coping styles are limited. Aim of the present study was to compare changes in coping styles between patients who had a good, moderate and no improvement in either exercise tolerance or health status after PR. Coping styles of 439 COPD patients undergoing PR were assessed by the Utrecht Coping List (UCL) at baseline and after PR. Patients' pulmonary function, six-minute walking distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) and Hospital Anxiety and Depression Scale (HADS-A and HADS-D) were recorded. Good, moderate and non-responders were defined on the basis of minimally clinically important difference (MCID) for SGRQ total score and/or 6MWD. Overall, 54.0% of the patients fulfilled the criteria for good responders, while 22.1% were moderate responders. Change in passive reaction pattern coping style differed significantly between good responders and non-responders following PR (p < 0.001). Moreover, within the groups, changes in coping styles after PR occurred among the good responders, whereas the majority of moderate responders' and non-responders' coping styles were not significantly influenced by PR. Good responders decreased their passive reaction pattern coping style in contrast to non-responders after PR. In general, PR did not change the coping among moderate and non-responders. Further research is warranted to determine whether including interventions targeting coping styles may modify coping behaviour of COPD patients, as well as improvement in exercise tolerance or health status after PR. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reply to Comment on X-ray resonant scattering studies of orbital and charge ordering in Pr[sub 1-x]Ca[sub x]MnO[sub 3].

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

Zimmermann, M. V.; Grenier, S.; Nelson, C. S.

2003-09-01

The interpretation given in our recent x-ray scattering study of Pr{sub 1-x}Ca{sub x}MnO{sub 3} in terms of charge and orbital ordering is questioned in the preceding Comment by Garcia and Subias. They argue that anisotropy of the charge distribution induced by local distortions gives rise to the so-called charge order reflections. In this Reply we suggest that the two different pictures are reconcilable.

Controlling Spatial Confinement Effects in La0.3Pr0.4Ca0.3MnO3 Microbridges via Post Ar and Air Annealing

NASA Astrophysics Data System (ADS)

Jeon, Jaechun; Jung, Jan; Chow, Kim H.

2017-08-01

We report the effects of post Ar and air annealing of La0.3Pr0.4Ca0.3MnO3 microbridges which do not initially show spatial confinement effects. The removal or addition of oxygen via the post annealing changes the sizes and distribution of the metallic and insulating phase domains within these films and can create spatial confinement effects such as percolation induced resistance jumps and tunneling magnetoresistance.

Similarity law for Widom lines and coexistence lines

NASA Astrophysics Data System (ADS)

Banuti, D. T.; Raju, M.; Ihme, M.

2017-05-01

The coexistence line of a fluid separates liquid and gaseous states at subcritical pressures, ending at the critical point. Only recently, it became clear that the supercritical state space can likewise be divided into regions with liquidlike and gaslike properties, separated by an extension to the coexistence line. This crossover line is commonly referred to as the Widom line, and is characterized by large changes in density or enthalpy, manifesting as maxima in the thermodynamic response functions. Thus, a reliable representation of the coexistence line and the Widom line is important for sub- and supercritical applications that depend on an accurate prediction of fluid properties. While it is known for subcritical pressures that nondimensionalization with the respective species critical pressures pcr and temperatures Tcr only collapses coexistence line data for simple fluids, this approach is used for Widom lines of all fluids. However, we show here that the Widom line does not adhere to the corresponding states principle, but instead to the extended corresponding states principle. We resolve this problem in two steps. First, we propose a Widom line functional based on the Clapeyron equation and derive an analytical, species specific expression for the only parameter from the Soave-Redlich-Kwong equation of state. This parameter is a function of the acentric factor ω and compares well with experimental data. Second, we introduce the scaled reduced pressure pr* to replace the previously used reduced pressure pr=p /pcr . We show that pr* is a function of the acentric factor only and can thus be readily determined from fluid property tables. It collapses both subcritical coexistence line and supercritical Widom line data over a wide range of species with acentric factors ranging from -0.38 (helium) to 0.34 (water), including alkanes up to n-hexane. By using pr*, the extended corresponding states principle can be applied within corresponding states principle formalism. Furthermore, pr* provides a theoretical foundation to compare Widom lines of different fluids.

Functional studies of p.R132C, p.R149C, p.M283V, p.E431K, and a novel c.652-2A>G mutations of the CYP21A2 gene.

PubMed

Taboas, Melisa; Gómez Acuña, Luciana; Scaia, María Florencia; Bruque, Carlos D; Buzzalino, Noemí; Stivel, Mirta; Ceballos, Nora R; Dain, Liliana

2014-01-01

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism and accounts for 90-95% of CAH cases. In the present work, we analyzed the functional consequence of four novel previously reported point CYP21A2 mutations -p.R132C, p.R149C, p.M283V, p.E431K- found in Argentinean 21-hydroxylase deficient patients. In addition, we report an acceptor splice site novel point mutation, c.652-2A>G, found in a classical patient in compound heterozygosity with the rare p.R483Q mutation. We performed bioinformatic and functional assays to evaluate the biological implication of the novel mutation. Our analyses revealed that the residual enzymatic activity of the isolated mutants coding for CYP21A2 aminoacidic substitutions was reduced to a lesser than 50% of the wild type with both progesterone and 17-OH progesterone as substrates. Accordingly, all the variants would predict mild non-classical alleles. In one non-classical patient, the p.E431K mutation was found in cis with the p.D322G one. The highest decrease in enzyme activity was obtained when both mutations were assayed in the same construction, with a residual activity most likely related to the simple virilizing form of the disease. For the c.652-2A>G mutation, bioinformatic tools predicted the putative use of two different cryptic splicing sites. Nevertheless, functional analyses revealed the use of only one cryptic splice acceptor site located within exon 6, leading to the appearance of an mRNA with a 16 nt deletion. A severe allele is strongly suggested due to the presence of a premature stop codon in the protein only 12 nt downstream.

Functional Studies of p.R132C, p.R149C, p.M283V, p.E431K, and a Novel c.652-2A>G Mutations of the CYP21A2 Gene

PubMed Central

Taboas, Melisa; Gómez Acuña, Luciana; Scaia, María Florencia; Bruque, Carlos D.; Buzzalino, Noemí; Stivel, Mirta

2014-01-01

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism and accounts for 90–95% of CAH cases. In the present work, we analyzed the functional consequence of four novel previously reported point CYP21A2 mutations -p.R132C, p.R149C, p.M283V, p.E431K- found in Argentinean 21-hydroxylase deficient patients. In addition, we report an acceptor splice site novel point mutation, c.652-2A>G, found in a classical patient in compound heterozygosity with the rare p.R483Q mutation. We performed bioinformatic and functional assays to evaluate the biological implication of the novel mutation. Our analyses revealed that the residual enzymatic activity of the isolated mutants coding for CYP21A2 aminoacidic substitutions was reduced to a lesser than 50% of the wild type with both progesterone and 17-OH progesterone as substrates. Accordingly, all the variants would predict mild non-classical alleles. In one non-classical patient, the p.E431K mutation was found in cis with the p.D322G one. The highest decrease in enzyme activity was obtained when both mutations were assayed in the same construction, with a residual activity most likely related to the simple virilizing form of the disease. For the c.652-2A>G mutation, bioinformatic tools predicted the putative use of two different cryptic splicing sites. Nevertheless, functional analyses revealed the use of only one cryptic splice acceptor site located within exon 6, leading to the appearance of an mRNA with a 16 nt deletion. A severe allele is strongly suggested due to the presence of a premature stop codon in the protein only 12 nt downstream. PMID:24667412

Differential effects of power rehabilitation on physical performance and higher-level functional capacity among community-dwelling older adults with a slight degree of frailty.

PubMed

Ota, Atsuhiko; Yasuda, Nobufumi; Horikawa, Shunichi; Fujimura, Takashi; Ohara, Hiroshi

2007-03-01

Evidence is still insufficient regarding the effects of Power Rehabilitation (PR) on physical performance and higher-level functional capacity of community-dwelling frail elderly people. This nonrandomized controlled interventional trial consisted of 46 community-dwelling elderly individuals with light levels of long-term care needs. They were allocated to the intervention (I-group, n = 24) and control (C-group, n = 22) groups. Of them, 32 persons (17 in the I-group; 15 in the C-group) (median age, 77 years; sex, 28% male) completed the study. The I-group subjects underwent PR twice a week for 12 weeks. The outcomes were physical performance (muscle strength, balance, flexibility, and mobility) and higher-level functional capacity as evaluated by the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) and the level of long-term care need as certified by the public long-term care insurance. The I-group demonstrated a significant improvement in the measured value of the timed up-and-go test (median change, a decrease of 4.4 seconds versus a decrease of 0.2 seconds, p = 0.033) and the timed 10-meter walk (a decrease of 3.0 seconds versus an increase of 0.2 seconds, p = 0.007) in comparison with the C-group. No significant change was observed in the TMIG-IC scores or in the level of long-term care need in the I-group. PR improved mobility of community-dwelling frail elderly people; however, such improvement did not translate into higher-level functional capacity. Our findings demonstrate the difficulty in transferring the positive effects associated with PR into an improvement in higher-level functional capacity.

The pathogenesis-related protein PR-4b from Theobroma cacao presents RNase activity, Ca(2+) and Mg(2+) dependent-DNase activity and antifungal action on Moniliophthora perniciosa.

PubMed

Pereira Menezes, Sara; de Andrade Silva, Edson Mario; Matos Lima, Eline; Oliveira de Sousa, Aurizângela; Silva Andrade, Bruno; Santos Lima Lemos, Livia; Peres Gramacho, Karina; da Silva Gesteira, Abelmon; Pirovani, Carlos Priminho; Micheli, Fabienne

2014-06-11

The production and accumulation of pathogenesis-related proteins (PR proteins) in plants in response to biotic or abiotic stresses is well known and is considered as a crucial mechanism for plant defense. A pathogenesis-related protein 4 cDNA was identified from a cacao-Moniliophthora perniciosa interaction cDNA library and named TcPR-4b. TcPR-4b presents a Barwin domain with six conserved cysteine residues, but lacks the chitin-binding site. Molecular modeling of TcPR-4b confirmed the importance of the cysteine residues to maintain the protein structure, and of several conserved amino acids for the catalytic activity. In the cacao genome, TcPR-4b belonged to a small multigene family organized mainly on chromosome 5. TcPR-4b RT-qPCR analysis in resistant and susceptible cacao plants infected by M. perniciosa showed an increase of expression at 48 hours after infection (hai) in both cacao genotypes. After the initial stage (24-72 hai), the TcPR-4b expression was observed at all times in the resistant genotypes, while in the susceptible one the expression was concentrated at the final stages of infection (45-90 days after infection). The recombinant TcPR-4b protein showed RNase, and bivalent ions dependent-DNase activity, but no chitinase activity. Moreover, TcPR-4b presented antifungal action against M. perniciosa, and the reduction of M. perniciosa survival was related to ROS production in fungal hyphae. To our knowledge, this is the first report of a PR-4 showing simultaneously RNase, DNase and antifungal properties, but no chitinase activity. Moreover, we showed that the antifungal activity of TcPR-4b is directly related to RNase function. In cacao, TcPR-4b nuclease activities may be related to the establishment and maintenance of resistance, and to the PCD mechanism, in resistant and susceptible cacao genotypes, respectively.

Superoxide dismutase activity of Cu-bound prion protein

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Lu, Wenchang; Bernholc, Jerry

2009-03-01

Misfolding of the prion protein, PrP, has been linked to a group of neurodegenerative diseases, including the mad cow disease in cattle and the Creutzfeldt-Jakob disease in humans. The normal function of PrP is still unknown, but it was found that the PrP can efficiently bind Cu(II) ions. Early experiments suggested that Cu-PrP complex possesses significant superoxide dismutase (SOD) activity, but later experiments failed to confirm it and at present this issue remains unresolved. Using a recently developed hybrid DFT/DFT method, which combines Kohn-Sham DFT for the solute and its first solvation shells with orbital-free DFT for the remainder of the solvent, we have investigated SOD activity of PrP. The PrP is capable of incorporating Cu(II) ions in several binding modes and our calculations find that each mode has a different SOD activity. The highest activity found is comparable to those of well-known SOD proteins, suggesting that the conflicting experimental results may be due to different bindings of Cu(II) in those experiments.

Progesterone action in breast, uterine, and ovarian cancers

PubMed Central

Diep, Caroline H.; Daniel, Andrea R.; Mauro, Laura J.; Knutson, Todd P.; Lange, Carol A.

2015-01-01

Progesterone and progesterone receptors (PR) are essential for the development and cyclical regulation of hormone-responsive tissues including the breast and reproductive tract. Altered functions of PR isoforms contribute to the pathogenesis of tumors that arise in these tissues. In the breast, progesterone acts in concert with estrogen to promote proliferative and pro-survival gene programs. In sharp contrast, progesterone inhibits estrogen-driven growth in the uterus and protects the ovary from neoplastic transformation. Progesterone-dependent actions and associated biology in diverse tissues and tumors are mediated by two progesterone receptor isoforms, PR-A and PR-B. These isoforms are subject to altered transcriptional activity or expression levels, differential cross-talk with growth factor signaling pathways, and distinct post-translational modifications and cofactor binding partners. Herein, we summarize and discuss the recent literature focused on progesterone and PR isoform-specific actions in breast, uterine, and ovarian cancers. Understanding the complexity of context-dependent PR actions in these tissues is critical to developing new models that will allow us to advance our knowledge base with the goal of revealing novel and efficacious therapeutic regimens for these hormone-responsive diseases. PMID:25587053

Synthesis and structural studies of heterobimetallic alkoxide complexes supported by bis(phenolate) ligands: efficient catalysts for ring-opening polymerization of L-lactide.

PubMed

Chen, Hsuan-Ying; Liu, Mei-Yu; Sutar, Alekha Kumar; Lin, Chu-Chieh

2010-01-18

A series of heterobimetallic titanium(IV) complexes [LTi(O(i)Pr)(mu-O(i)Pr)(2)Li(THF)(2)], [LTi(O(i)Pr)(mu-O(i)Pr)(2)Na(THF)(2)], [LTi(mu-O(i)Pr)(2)Zn(O(i)Pr)(2)], and [LTi(mu-O(i)Pr)(2)Mg(O(i)Pr)(2)] (where L = bidentate bisphenol ligands) have been synthesized and characterized including a structural determination of [L(1)Ti(mu(2)-O(i)Pr)(2)(O(i)Pr)Li(THF)(2)] (1a). These complexes were investigated for their utility in the ring-opening polymerization (ROP) of l-lactide (LA). Polymerization activities have been shown to correlate with the electronic properties of the substituent within the bisphenol ligand. In contrast to monometallic titanium initiator 1e, all the heterobimetallic titanium initiators (Ti-Li, Ti-Na, Ti-Zn, and Ti-Mg) show enhanced catalytic activity toward ring-opening polymerization (ROP) of l-LA. In addition, the use of electron-donating methoxy or methylphenylsulfonyl functional ligands reveals the highest activity. The bisphenol bimetallic complexes give rise to controlled ring-opening polymerization, as shown by the linear relationship between the percentage conversion and the number-average molecular weight. The polymerization kinetics using 2c as an initiator were also studied, and the experimental results indicate that the reaction rate is first-order with respect to both monomer and catalyst concentration with a polymerization rate constant, k = 81.64 M(-1) min(-1).

Hox proteins activate the IGFBP-1 promoter and suppress the function of hPR in human endometrial cells.

PubMed

Gao, Jiaguo; Mazella, James; Tseng, Linda

2002-11-01

Previous studies have shown that progestin activates the transcription of IGFBP-1 (insulin-like growth factor binding protein-1). Four regions in the IGFBP-1 promotor have been identified to enhance the transcription. Two of the regions, located at -73 to -65 bp and -319 to -311 bp formed identical DNA-protein complexes with the nuclear extracts of endometrial stromal/decidual cells. To identify the binding protein(s) in endometrial cells that interact with these two regions, we have used the TGTCAATTA repeats (-319 to -11 bp of the IGFBP-1 promoter) to screen the human decidual cDNA library by yeast one-hybrid system. We found that Hox A10, HoxA11, HoxB2, HoxB4, and HoxD11 interacted with the TGTCAATTA repeats in yeast cells. Among these hox genes, the full-length coding region of HoxA10, HoxA11, and HoxB4 were used for functional analysis in three types of endometrial cells, undifferentiated endometrial stromal cells, decidual cells (differentiated stromal cells) and endometrial adenocarcinoma cell line (HEC1-B). All these endometrial cells produce IGFBP-1. Transient transfection assay showed that HoxA10 expression vector increased the promoter activity (the IGFBP-1 proximal promoter containing TGC/TCAATTA and two functional PRE sites) in endometrial stromal cells and in HEC-1B cells, but not in decidual cells. HoxB4 enhanced the promoter activity only in decidual cells, while HoxA11 had no apparent effect in all three types of cells. To evaluate whether Hox proteins would interact with progesterone receptor (hPR), cells were transfected with the promoter construct, Hox and hPR expression vectors. hPR alone activated the IGFBP-1 promoter activity, but expression of Hox gene suppressed the activation. Hox proteins also suppressed the hPR enhanced promoter activities of MMTV (containing consensus-PRE sites) and glycodelin (GdA, containing Sp1 site which mediates the hPR function). These data showed that Hox genes selectively activate the transcription of the IGFBP-1 and GdA genes in different types of endometrial cells. Hox genes, however, suppress the hPR enhanced activities. In addition, we found that HoxB4 expression was induced by estrogen and progestin. Other investigators have shown that HoxA10 and 11 were stimulated by progestin. These findings show that Hox proteins are molecular mediators of the steroid hormones during endometrial cell development.

The effect of novel mutations on the structure and enzymatic activity of unconventional myosins associated with autosomal dominant non-syndromic hearing loss.

PubMed

Kwon, Tae-Jun; Oh, Se-Kyung; Park, Hong-Joon; Sato, Osamu; Venselaar, Hanka; Choi, Soo Young; Kim, SungHee; Lee, Kyu-Yup; Bok, Jinwoong; Lee, Sang-Heun; Vriend, Gert; Ikebe, Mitsuo; Kim, Un-Kyung; Choi, Jae Young

2014-07-01

Mutations in five unconventional myosin genes have been associated with genetic hearing loss (HL). These genes encode the motor proteins myosin IA, IIIA, VI, VIIA and XVA. To date, most mutations in myosin genes have been found in the Caucasian population. In addition, only a few functional studies have been performed on the previously reported myosin mutations. We performed screening and functional studies for mutations in the MYO1A and MYO6 genes in Korean cases of autosomal dominant non-syndromic HL. We identified four novel heterozygous mutations in MYO6. Three mutations (p.R825X, p.R991X and Q918fsX941) produce a premature truncation of the myosin VI protein. Another mutation, p.R205Q, was associated with diminished actin-activated ATPase activity and actin gliding velocity of myosin VI in an in vitro analysis. This finding is consistent with the results of protein modelling studies and corroborates the pathogenicity of this mutation in the MYO6 gene. One missense variant, p.R544W, was found in the MYO1A gene, and in silico analysis suggested that this variant has deleterious effects on protein function. This finding is consistent with the results of protein modelling studies and corroborates the pathogenic effect of this mutation in the MYO6 gene.

The effect of novel mutations on the structure and enzymatic activity of unconventional myosins associated with autosomal dominant non-syndromic hearing loss

PubMed Central

Kwon, Tae-Jun; Oh, Se-Kyung; Park, Hong-Joon; Sato, Osamu; Venselaar, Hanka; Choi, Soo Young; Kim, SungHee; Lee, Kyu-Yup; Bok, Jinwoong; Lee, Sang-Heun; Vriend, Gert; Ikebe, Mitsuo; Kim, Un-Kyung; Choi, Jae Young

2014-01-01

Mutations in five unconventional myosin genes have been associated with genetic hearing loss (HL). These genes encode the motor proteins myosin IA, IIIA, VI, VIIA and XVA. To date, most mutations in myosin genes have been found in the Caucasian population. In addition, only a few functional studies have been performed on the previously reported myosin mutations. We performed screening and functional studies for mutations in the MYO1A and MYO6 genes in Korean cases of autosomal dominant non-syndromic HL. We identified four novel heterozygous mutations in MYO6. Three mutations (p.R825X, p.R991X and Q918fsX941) produce a premature truncation of the myosin VI protein. Another mutation, p.R205Q, was associated with diminished actin-activated ATPase activity and actin gliding velocity of myosin VI in an in vitro analysis. This finding is consistent with the results of protein modelling studies and corroborates the pathogenicity of this mutation in the MYO6 gene. One missense variant, p.R544W, was found in the MYO1A gene, and in silico analysis suggested that this variant has deleterious effects on protein function. This finding is consistent with the results of protein modelling studies and corroborates the pathogenic effect of this mutation in the MYO6 gene. PMID:25080041

Male breast cancer according to tumor subtype and race: a population-based study.

PubMed

Chavez-Macgregor, Mariana; Clarke, Christina A; Lichtensztajn, Daphne; Hortobagyi, Gabriel N; Giordano, Sharon H

2013-05-01

Breast cancer occurs rarely in men. To the authors' knowledge, no population-based estimates of the incidence of human epidermal growth factor receptor 2 (HER2)-positive breast cancer or of the distribution of breast cancer subtypes among male breast cancer patients have been published to date. Therefore, the objective of the current study was to explore breast tumor subtype distribution by race/ethnicity among men in the large, ethnically diverse population of California. This study included men who were diagnosed with invasive breast cancer between 2005 and 2009 with known estrogen receptor (ER) and progesterone receptor (PR) (together, hormone receptor [HR]) status and HER2 status reported to the California Cancer Registry. Among the men with HR-positive tumors, survival probabilities between groups were compared using log-rank tests. Six hundred six patients were included. The median age at diagnosis was 68 years. Four hundred ninety-four men (81.5%) had HR-positive tumors (defined as ER-positive and/or PR-positive and HER2-negative). Ninety men (14.9%) had HER2-positive tumors, and 22 (3.6%) had triple receptor-negative (TN) tumors. Among the patients with HR-positive tumors, non-Hispanic black men and Hispanic men were more likely to have PR-negative tumors than non-Hispanic white men. No statistically significant differences in survival were observed according to tumor subtype (P = .08). Differences in survival according to race/ethnicity were observed among all patients (P = .087) and among those with HR-positive tumors (P = .0170), and non-Hispanic black men had poorer outcomes. In this large, representative cohort of men with breast cancer, the distribution of tumor subtypes was different from that reported for women and varied by patient race/ethnicity. Non-Hispanic black men were more likely to have TN tumors and ER-positive/PR-negative tumors than white men. Copyright © 2013 American Cancer Society.

Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats

PubMed Central

Molenda-Figueira, Heather A.; Williams, Casey A.; Griffin, Andreana L.; Rutledge, Eric M.; Blaustein, Jeffrey D.; Tetel, Marc J.

2008-01-01

The ovarian hormones, estradiol (E) and progesterone (P) facilitate the expression of sexual behavior in female rats. E and P mediate many of these behavioral effects by binding to their respective intracellular receptors in specific brain regions. Nuclear receptor coactivators, including Steroid Receptor Coactivator-1 (SRC-1) and CREB Binding Protein (CBP), dramatically enhance ligand-dependent steroid receptor transcriptional activity in vitro. Previously, our lab has shown that SRC-1 and CBP modulate estrogen receptor (ER)-mediated induction of progestin receptor (PR) gene expression in the ventromedial nucleus of the hypothalamus (VMN) and hormone-dependent sexual receptivity in female rats. Female sexual behaviors can be activated by high doses of E alone in ovariectomized rats, and thus are believed to be ER-dependent. However, the full repertoire of female sexual behavior, in particular, proceptive behaviors such as hopping, darting and ear wiggling, are considered to be PR-dependent. In the present experiments, the function of SRC-1 and CBP in distinct ER- (Exp. 1) and PR- (Exp. 2) dependent aspects of female sexual behavior was investigated. In Exp. 1, infusion of antisense oligodeoxynucleotides to SRC-1 and CBP mRNA into the VMN decreased lordosis intensity in rats treated with E alone, suggesting that these coactivators modulate ER-mediated female sexual behavior. In Exp. 2, antisense to SRC-1 and CBP mRNA around the time of P administration reduced PR-dependent ear wiggling and hopping and darting. Taken together, these data suggest that SRC-1 and CBP modulate ER and PR action in brain and influence distinct aspects of hormone-dependent sexual behaviors. These findings support our previous studies and provide further evidence that SRC-1 and CBP function together to regulate ovarian hormone action in behaviorally-relevant brain regions. PMID:16769066

Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth and Protects against Subsequent Stroke

PubMed Central

Ichijo, Masahiko; Ishibashi, Satoru; Li, Fuying; Yui, Daishi; Miki, Kazunori; Mizusawa, Hidehiro; Yokota, Takanori

2015-01-01

Background and Purpose Collateral growth after acute occlusion of an intracranial artery is triggered by increasing shear stress in preexisting collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1) on endothelial cells was reported to be essential in sensing fluid shear stress. Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral growth and subsequent ischemic damage after focal ischemia. Methods In C57Bl/6 mice (n = 133) subjected to unilateral common carotid occlusion (CCAO) and sham surgery. The first series examined the time course of collateral growth, cell proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO. The second series examined the relationship between pharmacological regulation of S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly assigned to one of the following groups: LtCCAO and daily intraperitoneal (ip) injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day); sham surgery and daily ip injection for 7 days of SEW2871 after surgery; LtCCAO and daily ip injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg); LtCCAO and daily ip injection of DMSO for 7 days after surgery; and sham surgery and daily ip injection of DMSO for 7 days. Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex perfusion method, and a set of animals underwent subsequent permanent middle cerebral artery occlusion (pMCAO) 7days after the treatment termination. Neurological functions 1hour, 1, 4, and 7days and infarction volume 7days after pMCAO were evaluated. Results In parallel with the increase in S1PR1 mRNA levels, S1PR1 expression colocalized with endothelial cell markers in the leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7 days after CCAO. Mitotic cell numbers in the leptomeningeal arteries increased after CCAO. Administration of the S1PR1 selective agonist significantly increased cerebral blood flow (CBF) and the diameter of leptomeningeal collateral vessels (42.9 ± 2.6 μm) compared with the controls (27.6 ± 5.7 μm; P < 0.01). S1PR1 inverse agonist administration diminished the effect of the S1PR1 agonist (P < 0.001). After pMCAO, S1PR1 agonist pretreated animals showed significantly smaller infarct volume (17.5% ± 4.0% vs. 7.7% ± 4.0%, P < 0.01) and better functional recovery than vehicle-treated controls. Conclusions These results suggest that S1PR1 is one of the principal regulators of leptomeningeal collateral recruitment at the site of increased shear stress and provide evidence that an S1PR1 selective agonist has a role in promoting collateral growth and preventing of ischemic damage and neurological dysfunction after subsequent stroke in patients with intracranial major artery stenosis or occlusion. PMID:26367258

Sphingosine-1-phosphate receptor 1 regulates neointimal growth in a humanized model for restenosis.

PubMed

Braetz, Julian; Becker, Astrid; Geissen, Markus; Larena-Avellaneda, Axel; Schrepfer, Sonja; Daum, Guenter

2018-05-24

The main objective of this study was to define a role of sphingosine-1-phosphate receptor 1 (S1PR1) in the arterial injury response of a human artery. The hypotheses were tested that injury induces an expansion of S1PR1-positive cells and that these cells accumulate toward the lumen because they follow the sphingosine-1-phosphate gradient from arterial wall tissue (low) to plasma (high). A humanized rat model was used in which denuded human internal mammary artery (IMA) was implanted into the position of the abdominal aorta of immunosuppressed Rowett nude rats. This injury model is characterized by medial as well as intimal hyperplasia, whereby intimal cells are of human origin. At 7, 14, and 28 days after implantation, grafts were harvested and processed for fluorescent immunostaining for S1PR1 and smooth muscle α-actin. Nuclei were stained with 4',6-diamidine-2'-phenylindole dihydrochloride. Using digitally reconstructed, complete cross sections of grafts, intimal and medial areas were measured, whereby the medial area had virtually been divided into an outer (toward adventitia) and inner (toward lumen) layer. The fraction of S1PR1-positive cells was determined in each layer by counting S1PR1-positive and S1PR1-negative cells. The fraction of S1PR1-postive cells in naive IMA is 58.9% ± 6.0% (mean ± standard deviation). At day 28 after implantation, 81.6% ± 4.4% of medial cells were scored S1PR1 positive (P < .01). At day 14, the ratio between S1PR1-positive and S1PR1-negative cells was significantly higher in the lumen-oriented inner layer (9.3 ± 2.1 vs 6.0 ± 1.0; P < .01). Cells appearing in the intima at day 7 and day 14 were almost all S1PR1 positive. At day 28, however, about one-third of intimal cells were scored S1PR1 negative. From these data, we conclude that denudation of IMA specifically induces the expansion of S1PR1-positive cells. Based on the nonrandom distribution of S1PR1-positive cells, we consider the possibility that much like lymphocytes, S1PR1-positive smooth muscle cells also use S1PR1 to recognize the sphingosine-1-phosphate gradient from tissue (low) to plasma (high) and so migrate out of the media toward the intima of the injured IMA. Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Synthesis and luminescence characterization of Pr3+ doped Sr1.5Ca0.5SiO4 phosphor

NASA Astrophysics Data System (ADS)

Vidyadharan, Viji; Mani, Kamal P.; Sajna, M. S.; Joseph, Cyriac; Unnikrishnan, N. V.; Biju, P. R.

2014-12-01

Luminescence properties of Pr3+ activated Sr1.5Ca0.5SiO4 phosphors synthesized by solid state reaction method are reported in this work. Blue, orange red and red emissions were observed in the Pr3+ doped sample under 444 nm excitation and these emissions are assigned as 3P0 → 3H4, 3P0 → 3H6 and 3P0 → 3F4 transitions. The emission intensity shows a maximum corresponding to the 0.5 wt% Pr3+ ion. The decay analysis was done for 0.05 and 0.5 wt% Pr3+ doped samples for the transition 3P0 → 3H6. The life times of 0.05 and 0.5 wt% Pr3+ doped samples were calculated by fitting to exponential and non-exponential curve respectively, and are found to be 156 and 105 μs respectively. The non-exponential behaviour arises due to the statistical distribution of the distances between the ground state Pr3+ ions and excited state Pr3+ ions, which cause the inhomogeneous energy transfer rate. The XRD spectrum confirmed the triclinic phase of the prepared phosphors. The compositions of the samples were determined by the energy dispersive X-ray spectra. From the SEM images it is observed that the particles are agglomerated and are irregularly shaped. IR absorption bands were assigned to different vibrational modes. The well resolved peaks shown in the absorption spectra are identical to the excitation spectra of the phosphor samples. Pr3+ activated Sr1.5Ca0.5SiO4 phosphors can be efficiently excited with 444 nm irradiation and emit multicolour visible emissions. From the CIE diagram it can be seen that the prepared phosphor samples give yellowish-green emission.

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

PubMed

Lin, Honghuang; van Setten, Jessica; Smith, Albert V; Bihlmeyer, Nathan A; Warren, Helen R; Brody, Jennifer A; Radmanesh, Farid; Hall, Leanne; Grarup, Niels; Müller-Nurasyid, Martina; Boutin, Thibaud; Verweij, Niek; Lin, Henry J; Li-Gao, Ruifang; van den Berg, Marten E; Marten, Jonathan; Weiss, Stefan; Prins, Bram P; Haessler, Jeffrey; Lyytikäinen, Leo-Pekka; Mei, Hao; Harris, Tamara B; Launer, Lenore J; Li, Man; Alonso, Alvaro; Soliman, Elsayed Z; Connell, John M; Huang, Paul L; Weng, Lu-Chen; Jameson, Heather S; Hucker, William; Hanley, Alan; Tucker, Nathan R; Chen, Yii-Der Ida; Bis, Joshua C; Rice, Kenneth M; Sitlani, Colleen M; Kors, Jan A; Xie, Zhijun; Wen, Chengping; Magnani, Jared W; Nelson, Christopher P; Kanters, Jørgen K; Sinner, Moritz F; Strauch, Konstantin; Peters, Annette; Waldenberger, Melanie; Meitinger, Thomas; Bork-Jensen, Jette; Pedersen, Oluf; Linneberg, Allan; Rudan, Igor; de Boer, Rudolf A; van der Meer, Peter; Yao, Jie; Guo, Xiuqing; Taylor, Kent D; Sotoodehnia, Nona; Rotter, Jerome I; Mook-Kanamori, Dennis O; Trompet, Stella; Rivadeneira, Fernando; Uitterlinden, André; Eijgelsheim, Mark; Padmanabhan, Sandosh; Smith, Blair H; Völzke, Henry; Felix, Stephan B; Homuth, Georg; Völker, Uwe; Mangino, Massimo; Spector, Timothy D; Bots, Michiel L; Perez, Marco; Kähönen, Mika; Raitakari, Olli T; Gudnason, Vilmundur; Arking, Dan E; Munroe, Patricia B; Psaty, Bruce M; van Duijn, Cornelia M; Benjamin, Emelia J; Rosand, Jonathan; Samani, Nilesh J; Hansen, Torben; Kääb, Stefan; Polasek, Ozren; van der Harst, Pim; Heckbert, Susan R; Jukema, J Wouter; Stricker, Bruno H; Hayward, Caroline; Dörr, Marcus; Jamshidi, Yalda; Asselbergs, Folkert W; Kooperberg, Charles; Lehtimäki, Terho; Wilson, James G; Ellinor, Patrick T; Lubitz, Steven A; Isaacs, Aaron

2018-05-01

Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction ( P <1.2×10 -6 ), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 ( P =5.9×10 -11 ) and SCN5A ( P =1.1×10 -7 ) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health. © 2018 American Heart Association, Inc.

Photoluminescent emission of Pr 3+ ions in different zirconia crystalline forms

NASA Astrophysics Data System (ADS)

Ramos-Brito, F.; Alejo-Armenta, C.; García-Hipólito, M.; Camarillo, E.; Hernández A, J.; Murrieta S, H.; Falcony, C.

2008-08-01

Polycrystalline praseodymium doped-zirconia powders were synthesized by crystallization of a saturated solution and annealed in air at T a = 950 °C. Monoclinic, tetragonal and cubic crystalline phases of zirconia were obtained. EDS studies showed homogeneous chemical composition over all the powders particles and chemical elemental contents in good agreement with the incorporation of Pr 3+ ion in Zr 4+ sites. XRD patterns showed stabilization of tetragonal and cubic phases at 1.28 and 2.87 at.% of Pr 3+ doping concentrations, respectively. Both unit cells expand when Pr 3+ content increases. All samples showed a crystallite size lower than 27 nm. Diffuse reflectance studies exhibited the presence of the 4f5d absorption band of Pr 3+, and absorption peaks in 440-610 nm region associated with 4f inter-level electronic transitions in Pr 3+ ion. Low temperature (20 K) photo-luminescent spectroscopic measurements over excitation of 488 nm for praseodymium doped zirconia, showed multiple emission peaks in the 520-900 nm range of the electromagnetic spectrum, associated with typical 4f inter-level electronic transition in Pr 3+. Incorporation of Pr 3+ in more than one zirconia crystalline phase and the incorporation in cubic C 2 sites, were observed. Zirconia powders presented significant differences in its emission spectra as a function of the type of crystalline phase compounds.

High-temperature fcc phase of Pr:  Negative thermal expansion and intermediate valence state

NASA Astrophysics Data System (ADS)

Kuznetsov, A. Yu.; Dmitriev, V. P.; Bandilet, O. I.; Weber, H.-P.

2003-08-01

A high-temperature angle-dispersive synchrotron radiation diffraction study has revealed the double hexagonal-close-packed-to-face-centered-cubic (dhcp-to-fcc) transformation in the Pr metal occurring martensitically between 575 and 1035 K. The high-temperature fcc phase shows a negative thermal expansion in the range 600 800 K, attributed to the 4f-electron delocalization. A phenomenological theory is developed, which explains consistently the observed effect in terms of the mean valence variation of the metal as a function of temperature; it also predicts the existence of an isostructural phase transition and of a critical end point of a gas-liquid type in compressed Pr. The analysis of published data on P-T variation of conductivity of Pr supports this prediction.

Well behaved anisotropic compact star models in general relativity

NASA Astrophysics Data System (ADS)

Jasim, M. K.; Maurya, S. K.; Gupta, Y. K.; Dayanandan, B.

2016-11-01

Anisotropic compact star models have been constructed by assuming a particular form of a metric function e^{λ}. We solved the Einstein field equations for determining the metric function e^{ν}. For this purpose we have assumed a physically valid expression of radial pressure (pr). The obtained anisotropic compact star model is representing the realistic compact objects such as PSR 1937 +21. We have done an extensive study about physical parameters for anisotropic models and found that these parameters are well behaved throughout inside the star. Along with these we have also determined the equation of state for compact star which gives the radial pressure is purely the function of density i.e. pr=f(ρ).

PREDICTIONS IN AN INVADED WORLD - PART I: USING NICHE MODELS TO PREDICT DISTRIBUTIONS OF MARINE/ESTUARINE SPECIES AT THE HABITAT SCALE

EPA Science Inventory

Niche models can be used to predict the distributions of marine/estuarine nonindigenous species (NIS) over three spatial scales. The goal at the biogeographic scale is to predict whether a species is likely to invade a geographic region. At the regional scale, the goal is to pr...

[Public relations in institutions and establishments of the health administration system].

PubMed

Martynenko, A V

2002-01-01

The article is dedicated to development of directions and specific functions of the health system bodies/institutions public relations (PR) activities. Priorities are set forth depending on the form of property thereof. A complex use of approaches toward carrying out of PR activities permits optimizing work both within the system itself and relations with the society as a whole.

Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis.

PubMed

Chaudhry, Burhan Z; Cohen, Jeffrey A; Conway, Devon S

2017-10-01

Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.

Shadoo/PrP (Sprn0/0/Prnp0/0) double knockout mice

PubMed Central

Daude, Nathalie; Westaway, David

2012-01-01

Shadoo (Sho) is a brain glycoprotein with similarities to the unstructured region of PrPC. Frameshift alleles of the Sho gene, Sprn, are reported in variant Creutzfeldt-Jakob disease (vCJD) patients while Sprn mRNA knockdown in PrP-null (Prnp0/0) embryos produces lethality, advancing Sho as the hypothetical PrP-like “pi” protein. Also, Sho levels are reduced as misfolded PrP accumulates during prion infections. To penetrate these issues we created Sprn null alleles (Daude et al., Proc. Natl. Acad. Sci USA 2012; 109(23): 9035–40). Results from the challenge of Sprn null and TgSprn transgenic mice with rodent-adapted prions coalesce to define downregulation of Sho as a “tracer” for the formation of misfolded PrP. However, classical BSE and rodent-adapted BSE isolates may behave differently, as they do for other facets of the pathogenic process, and this intriguing variation warrants closer scrutiny. With regards to physiological function, double knockout mice (Sprn0/0/Prnp0/0) mice survived to over 600 d of age. This suggests that Sho is not pi, or, given the accumulating data for many activities for PrPC, that the pi hypothesis invoking a discrete signaling pathway to maintain neuronal viability is no longer tenable. PMID:22929230

Microsecond Unfolding Kinetics of Sheep Prion Protein Reveals an Intermediate that Correlates with Susceptibility to Classical Scrapie

PubMed Central

Chen, Kai-Chun; Xu, Ming; Wedemeyer, William J.; Roder, Heinrich

2011-01-01

The microsecond folding and unfolding kinetics of ovine prion proteins (ovPrP) were measured under various solution conditions. A fragment comprising residues 94–233 of the full-length ovPrP was studied for four variants with differing susceptibilities to classical scrapie in sheep. The observed biexponential unfolding kinetics of ovPrP provides evidence for an intermediate species. However, in contrast to previous results for human PrP, there is no evidence for an intermediate under refolding conditions. Global analysis of the kinetic data, based on a sequential three-state mechanism, quantitatively accounts for all folding and unfolding data as a function of denaturant concentration. The simulations predict that an intermediate accumulates under both folding and unfolding conditions, but is observable only in unfolding experiments because the intermediate is optically indistinguishable from the native state. The relative population of intermediates in two ovPrP variants, both transiently and under destabilizing equilibrium conditions, correlates with their propensities for classical scrapie. The variant susceptible to classical scrapie has a larger population of the intermediate state than the resistant variant. Thus, the susceptible variant should be favored to undergo the PrPC to PrPSc conversion and oligomerization. PMID:21889460

A class III chitinase without disulfide bonds from the fern, Pteris ryukyuensis: crystal structure and ligand-binding studies.

PubMed

Kitaoku, Yoshihito; Umemoto, Naoyuki; Ohnuma, Takayuki; Numata, Tomoyuki; Taira, Toki; Sakuda, Shohei; Fukamizo, Tamo

2015-10-01

We first solved the crystal structure of class III catalytic domain of a chitinase from fern (PrChiA-cat), and found a structural difference between PrChiA-cat and hevamine. PrChiA-cat was found to have reduced affinities to chitin oligosaccharides and allosamidin. Plant class III chitinases are subdivided into enzymes with three disulfide bonds and those without disulfide bonds. We here referred to the former enzymes as class IIIa chitinases and the latter as class IIIb chitinases. In this study, we solved the crystal structure of the class IIIb catalytic domain of a chitinase from the fern Pteris ryukyuensis (PrChiA-cat), and compared it with that of hevamine, a class IIIa chitinase from Hevea brasiliensis. PrChiA-cat was found to adopt an (α/β)8 fold typical of GH18 chitinases in a similar manner to that of hevamine. However, PrChiA-cat also had two large loops that extruded from the catalytic site, and the corresponding loops in hevamine were markedly smaller than those of PrChiA-cat. An HPLC analysis of the enzymatic products revealed that the mode of action of PrChiA-cat toward chitin oligosaccharides, (GlcNAc) n (n = 4-6), differed from those of hevamine and the other class IIIa chitinases. The binding affinities of (GlcNAc)3 and (GlcNAc)4 toward the inactive mutant of PrChiA-cat were determined by isothermal titration calorimetry, and were markedly lower than those toward other members of the GH18 family. The affinity and the inhibitory activity of allosamidin toward PrChiA-cat were also lower than those toward the GH18 chitinases investigated to date. Several hydrogen bonds found in the crystal structure of hevamine-allosamidin complex were missing in the modeled structure of PrChiA-cat-allosamidin complex. The structural findings for PrChiA-cat successfully interpreted the functional data presented.

Evidence for a postreproductive phase in female false killer whales Pseudorca crassidens.

PubMed

Photopoulou, Theoni; Ferreira, Ines M; Best, Peter B; Kasuya, Toshio; Marsh, Helene

2017-01-01

A substantial period of life after reproduction ends, known as postreproductive lifespan (PRLS), is at odds with classical life history theory and its causes and mechanisms have puzzled evolutionary biologists for decades. Prolonged PRLS has been confirmed in only two non-human mammals, both odontocete cetaceans in the family Delphinidae. We investigate the evidence for PRLS in a third species, the false killer whale, Pseudorca crassidens , using a quantitative measure of PRLS and morphological evidence from reproductive tissues. We examined specimens from false killer whales from combined strandings (South Africa, 1981) and harvest (Japan 1979-80) and found morphological evidence of changes in the activity of the ovaries in relation to age. Ovulation had ceased in 50% of whales over 45 years, and all whales over 55 years old had ovaries classified as postreproductive. We also calculated a measure of PRLS, known as postreproductive representation (PrR) as an indication of the effect of inter-population demographic variability. PrR for the combined sample was 0.14, whereas the mean of the simulated distribution for PrR under the null hypothesis of no PRLS was 0.02. The 99th percentile of the simulated distribution was 0.08 and no simulated value exceeded 0.13. These results suggest that PrR was convincingly different from the measures simulated under the null hypothesis. We found morphological and statistical evidence for PRLS in South African and Japanese pods of false killer whales, suggesting that this species is the third non-human mammal in which this phenomenon has been demonstrated in wild populations. Nonetheless, our estimate for PrR in false killer whales (0.14) is lower than the single values available for the short-finned pilot whale (0.28) and the killer whale (0.22) and is more similar to working Asian elephants (0.13).

Olfactory behavior and physiology are disrupted in prion protein knockout mice.

PubMed

Le Pichon, Claire E; Valley, Matthew T; Polymenidou, Magdalini; Chesler, Alexander T; Sagdullaev, Botir T; Aguzzi, Adriano; Firestein, Stuart

2009-01-01

The prion protein PrP(C) is infamous for its role in disease, but its normal physiological function remains unknown. Here we found a previously unknown behavioral phenotype of Prnp(-/-) mice in an odor-guided task. This phenotype was manifest in three Prnp knockout lines on different genetic backgrounds, which provides strong evidence that the phenotype is caused by a lack of PrP(C) rather than by other genetic factors. Prnp(-/-) mice also showed altered behavior in a second olfactory task, suggesting that the phenotype is olfactory specific. Furthermore, PrP(C) deficiency affected oscillatory activity in the deep layers of the main olfactory bulb, as well as dendrodendritic synaptic transmission between olfactory bulb granule and mitral cells. Notably, both the behavioral and electrophysiological alterations found in Prnp(-/-) mice were rescued by transgenic neuronal-specific expression of PrP(C). These data suggest that PrP(C) is important in the normal processing of sensory information by the olfactory system.

Steroid hormone receptors ERalpha and PR characterised by immunohistochemistry in the mare adrenal gland.

PubMed

Alm, Ylva Hedberg; Sukjumlong, Sayamon; Kindahl, Hans; Dalin, Anne-Marie

2009-07-22

Sex steroid hormone receptors have been identified in the adrenal gland of rat, sheep and rhesus monkey, indicating a direct effect of sex steroids on adrenal gland function. In the present study, immunohistochemistry using two different mouse monoclonal antibodies was employed to determine the presence of oestrogen receptor alpha (ERalpha) and progesterone receptor (PR) in the mare adrenal gland. Adrenal glands from intact (n = 5) and ovariectomised (OVX) (n = 5) mares, as well as uterine tissue (n = 9), were collected after euthanasia. Three of the OVX mares were treated with a single intramuscular injection of oestradiol benzoate (2.5 mg) 18-22 hours prior to euthanasia and tissue collection (OVX+Oe). Uterine tissue was used as a positive control and showed positive staining for both ERalpha and PR. ERalpha staining was detected in the adrenal zona glomerulosa, fasciculata and reticularis of all mare groups. Ovariectomy increased cortical ERalpha staining intensity. In OVX mares and one intact mare, positive ERalpha staining was also detected in adrenal medullary cells. PR staining of weak intensity was present in a low proportion of cells in the zona fasciculata and reticularis of all mare groups. Weak PR staining was also found in a high proportion of adrenal medullary cells. In contrast to staining in the adrenal cortex, which was always located within the cell nuclei, medullary staining for both ERalpha and PR was observed only in the cell cytoplasm. The present results show the presence of ERalpha in the adrenal cortex, indicating oestradiol may have a direct effect on mare adrenal function. However, further studies are needed to confirm the presence of PR as staining in the present study was only weak and/or minor. Also, any possible effect of oestradiol treatment on the levels of steroid receptors cannot be determined by the present study, as treatment time was of a too short duration.

Imaging characteristics of scintimammography using parallel-hole and pinhole collimators

NASA Astrophysics Data System (ADS)

Tsui, B. M. W.; Wessell, D. E.; Zhao, X. D.; Wang, W. T.; Lewis, D. P.; Frey, E. C.

1998-08-01

The purpose of the study is to investigate the imaging characteristics of scintimammography (SM) using parallel-hole (PR) and pinhole (PN) collimators in a clinical setting. Experimental data were acquired from a phantom that models the breast with small lesions using a low energy high resolution (LEHR) PR and a PN collimator. At close distances, the PN collimator provides better spatial resolution and higher detection efficiency than the PR collimator, at the expense of a smaller field-of-view (FOV). Detection of small breast lesions can be further enhanced by noise smoothing, field uniformity correction, scatter subtraction and resolution recovery filtering. Monte Carlo (MC) simulation data were generated from the 3D MCAT phantom that realistically models the Tc-99m sestamibi uptake and attenuation distributions in an average female patient. For both PR and PN collimation, the scatter to primary ratio (S/P) decreases from the base of the breast to the nipple and is higher in the left than right breast due to scatter of photons from the heart. Results from the study add to understanding of the imaging characteristics of SM using PR and PN collimators and assist in the design of data acquisition and image processing methods to enhance the detection of breast lesions using SM.

Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

PubMed Central

Ramos, Emilio; Ruchala, Piotr; Goodnough, Julia B.; Kautz, Léon; Preza, Gloria C.; Nemeth, Elizabeta

2012-01-01

The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation. PMID:22990014

The inhibition of functional expression of calcium channels by prion protein demonstrates competition with α2δ for GPI-anchoring pathways

PubMed Central

Alvarez-Laviada, Anita; Kadurin, Ivan; Senatore, Assunta; Chiesa, Roberto; Dolphin, Annette C.

2013-01-01

It has been shown recently that PrP (prion protein) and the calcium channel auxiliary α2δ subunits interact in neurons and expression systems [Senatore, Colleoni, Verderio, Restelli, Morini, Condliffe, Bertani, Mantovani, Canovi, Micotti, Forloni, Dolphin, Matteoli, Gobbi and Chiesa (2012) Neuron 74, 300–313]. In the present study we examined whether there was an effect of PrP on calcium currents. We have shown that when PrP is co-expressed with calcium channels formed from CaV2.1/β and α2δ-1 or α2δ-2, there is a consistent decrease in calcium current density. This reduction was absent when a PrP construct was used lacking its GPI (glycosylphosphatidylinositol) anchor. We have reported previously that α2δ subunits are able to form GPI-anchored proteins [Davies, Kadurin, Alvarez-Laviada, Douglas, Nieto-Rostro, Bauer, Pratt and Dolphin (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 1654–1659] and show further evidence in the present paper. We have characterized recently a C-terminally truncated α2δ-1 construct, α2δ-1ΔC, and found that, despite loss of its membrane anchor, it still shows a partial ability to increase calcium currents [Kadurin, Alvarez-Laviada, Ng, Walker-Gray, D’Arco, Fadel, Pratt and Dolphin (2012) J. Biol. Chem. 1287, 33554–33566]. We now find that PrP does not inhibit CaV2.1/β currents formed with α2δ-1ΔC, rather than α2δ-1. It is possible that PrP and α2δ-1 compete for GPI-anchor intermediates or trafficking pathways, or that interaction between PrP and α2δ-1 requires association in cholesterol-rich membrane microdomains. Our additional finding that CaV2.1/β1b/α2δ-1 currents were inhibited by GPI–GFP, but not cytosolic GFP, indicates that competition for limited GPI-anchor intermediates or trafficking pathways may be involved in PrP suppression of α2δ subunit function. PMID:24329154

Genomic assessment of the evolution of the prion protein gene family in vertebrates.

PubMed

Harrison, Paul M; Khachane, Amit; Kumar, Manish

2010-05-01

Prion diseases are devastating neurological disorders caused by the propagation of particles containing an alternative beta-sheet-rich form of the prion protein (PrP). Genes paralogous to PrP, called Doppel and Shadoo, have been identified, that also have neuropathological relevance. To aid in the further functional characterization of PrP and its relatives, we annotated completely the PrP gene family (PrP-GF), in the genomes of 42 vertebrates, through combined strategic application of gene prediction programs and advanced remote homology detection techniques (such as HMMs, PSI-TBLASTN and pGenThreader). We have uncovered several previously undescribed paralogous genes and pseudogenes. We find that current high-quality genomic evidence indicates that the PrP relative Doppel, was likely present in the last common ancestor of present-day Tetrapoda, but was lost in the bird lineage, since its divergence from reptiles. Using the new gene annotations, we have defined the consensus of structural features that are characteristic of the PrP and Doppel structures, across diverse Tetrapoda clades. Furthermore, we describe in detail a transcribed pseudogene derived from Shadoo that is conserved across primates, and that overlaps the meiosis gene, SYCE1, thus possibly regulating its expression. In addition, we analysed the locus of PRNP/PRND for significant conservation across the genomic DNA of eleven mammals, and determined the phylogenetic penetration of non-coding exons. The genomic evidence indicates that the second PRNP non-coding exon found in even-toed ungulates and rodents, is conserved in all high-coverage genome assemblies of primates (human, chimp, orang utan and macaque), and is, at least, likely to have fallen out of use during primate speciation. Furthermore, we have demonstrated that the PRNT gene (at the PRNP human locus) is conserved across at least sixteen mammals, and evolves like a long non-coding RNA, fashioned from fragments of ancient, long, interspersed elements. These annotations and evolutionary analyses will be of further use for functional characterisation of the PrP-GF, and will be updatable in a semi-automated fashion as more genomes accumulate. Copyright 2010 Elsevier Inc. All rights reserved.

Intelligent ePR system for evidence-based research in radiotherapy: proton therapy for prostate cancer.

PubMed

Le, Anh H; Liu, Brent; Schulte, Reinhard; Huang, H K

2011-11-01

Proton therapy (PT) utilizes high energy particle proton beam to kill cancer cells at the target region for target cancer therapy. Due to the physical properties of the proton beam, PT delivers dose with higher precision and no exit dose compared to conventional radiotherapy. In PT, patient data are distributed among multiple systems, a hindrance to research on efficacy and effectiveness. A data mining method and a treatment plan navigator utilizing the infrastructure and data repository of a PT electronic patient record (ePR) was developed to minimize radiation toxicity and improve outcomes in prostate cancer treatment. MATERIALS/METHOD(S): The workflow of a proton therapy treatment in a radiation oncology department was reviewed, and a clinical data model and data flow were designed. A prototype PT ePR system with DICOM compliance was developed to manage prostate cancer patient images, treatment plans, and related clinical data. The ePR system consists of four main components: (1) Data Gateway; (2) ePR Server; (3) Decision Support Tools; and (4) Visualization and Display Tools. Decision support and visualization tools are currently developed based on DICOM images, DICOM-RT and DICOM-RT-ION objects data from prostate cancer patients treated with hypofractionation protocol proton therapy were used for evaluating ePR system effectiveness. Each patient data set includes a set of computed tomography (CT) DICOM images and four DICOM-RT and RT-ION objects. In addition, clinical outcomes data collected from PT cases were included to establish a knowledge base for outcomes analysis. A data mining search engine and an intelligent treatment plan navigator (ITPN) were developed and integrated with the ePR system. Evaluation was based on a data set of 39 PT patients and a hypothetical patient. The ePR system was able to facilitate the proton therapy workflow. The PT ePR system was feasible for prostate cancer patient treated with hypofractionation protocol in proton therapy. This ePR system improves efficiency in data collection and integration to facilitate outcomes analysis.

The Impact of Cognitive Impairment on Efficacy of Pulmonary Rehabilitation in Patients With COPD.

PubMed

Cleutjens, Fiona A H M; Spruit, Martijn A; Ponds, Rudolf W H M; Vanfleteren, Lowie E G W; Franssen, Frits M E; Dijkstra, Jeanette B; Gijsen, Candy; Wouters, Emiel F M; Janssen, Daisy J A

2017-05-01

To compare changes in pulmonary rehabilitation (PR) dropout and outcomes between chronic obstructive pulmonary disease (COPD) patients with and without cognitive impairment. A cross-sectional observational study. Patients with COPD were recruited from a PR centre in the Netherlands. The study population consisted of 157 patients with clinically stable COPD who were referred for and completed PR. A comprehensive neuropsychological examination before start of PR was administered. Changes from baseline to PR completion in functional exercise capacity [6-minute walk test (6MWT)], disease-specific health status [COPD Assessment Test (CAT) and St George's Respiratory Questionnaire-COPD specific (SGRQ-C)], psychological well-being [Hospital Anxiety and Depression Scale (HADS)], COPD-related knowledge, and their need for information [Lung Information Needs Questionnaire (LINQ)] were compared between patients with and without cognitive impairment using independent samples t tests or Mann-Whitney U tests. Out of 157 patients with COPD [mean age 62.9 (9.4) years, forced expiratory volume in the first second 54.6% (22.9%) predicted], 24 patients (15.3%) did not complete PR. The dropout rate was worse in patients with cognitive impairment compared to those without cognitive impairment (23.3% and 10.3%, P = .03). Mean changes in PR outcomes after PR did not differ between completers with and without cognitive impairment. The proportion of patients with a clinically relevant improvement in 6MWT, CAT, SGRQ-C, HADS, and LINQ scores was comparable for patients with and without cognitive impairment. PR is an effective treatment for patients with COPD and cognitive impairment. Yet patients with cognitive impairment are at increased risk for not completing the PR program. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

African American men's understanding and perceptions about prostate cancer: why multiple dimensions of health literacy are important in cancer communication.

PubMed

Friedman, Daniela B; Corwin, Sara J; Dominick, Gregory M; Rose, India D

2009-10-01

Prostate cancer (PrCA) is the most diagnosed cancer among men in the United States, especially among African American (AA) men. The purpose of this formative study was to explore the implications of applying Nutbeam's multidimensional health literacy framework to AA men's understanding of PrCA information. Participants were 25 AA men aged 45 and older in South Carolina. Their functional health literacy was assessed using two modified Cloze tests and the Shortened Test of Functional Health Literacy in Adults (S-TOFHLA). Men also participated in interviews or focus groups during which they were asked questions about PrCA risk, prevention, and screening. Transcripts were reviewed for recurrent themes and analyzed qualitatively using NVivo7. Mean S-TOFHLA was 28.28 (+/-1.98), implying "adequate" comprehension. Mean Cloze was .71 (+/-.05) for a Grade 8 document and .66 (+/-.04) for a Grade 13 document, also showing "adequate" comprehension. Cloze scores for the Grade 8 resource were lower for participants with less education (P = .047). Despite having satisfactory literacy test scores, results from interviews and focus groups revealed participants' limited understanding and misconceptions about PrCA risk. Many wanted information about screening and family history delivered word-of-mouth by AA women and church pastors as few of them had ever received or actively sought out PrCA resources. Using Nutbeam's framework, gaps in health literacy which were not adequately captured by the validated tools emerged during the interviews and focus groups. Study findings provide important implications for PrCA communication with AA men to correct misperceptions about cancer risk and motivate preventive behaviors.

Structural motif screening reveals a novel, conserved carbohydrate-binding surface in the pathogenesis-related protein PR-5d.

PubMed

Doxey, Andrew C; Cheng, Zhenyu; Moffatt, Barbara A; McConkey, Brendan J

2010-08-03

Aromatic amino acids play a critical role in protein-glycan interactions. Clusters of surface aromatic residues and their features may therefore be useful in distinguishing glycan-binding sites as well as predicting novel glycan-binding proteins. In this work, a structural bioinformatics approach was used to screen the Protein Data Bank (PDB) for coplanar aromatic motifs similar to those found in known glycan-binding proteins. The proteins identified in the screen were significantly associated with carbohydrate-related functions according to gene ontology (GO) enrichment analysis, and predicted motifs were found frequently within novel folds and glycan-binding sites not included in the training set. In addition to numerous binding sites predicted in structural genomics proteins of unknown function, one novel prediction was a surface motif (W34/W36/W192) in the tobacco pathogenesis-related protein, PR-5d. Phylogenetic analysis revealed that the surface motif is exclusive to a subfamily of PR-5 proteins from the Solanaceae family of plants, and is absent completely in more distant homologs. To confirm PR-5d's insoluble-polysaccharide binding activity, a cellulose-pulldown assay of tobacco proteins was performed and PR-5d was identified in the cellulose-binding fraction by mass spectrometry. Based on the combined results, we propose that the putative binding site in PR-5d may be an evolutionary adaptation of Solanaceae plants including potato, tomato, and tobacco, towards defense against cellulose-containing pathogens such as species of the deadly oomycete genus, Phytophthora. More generally, the results demonstrate that coplanar aromatic clusters on protein surfaces are a structural signature of glycan-binding proteins, and can be used to computationally predict novel glycan-binding proteins from 3 D structure.

ERK1/2 and p38 MAP kinases control prion protein fragment 90-231-induced astrocyte proliferation and microglia activation.

PubMed

Thellung, Stefano; Villa, Valentina; Corsaro, Alessandro; Pellistri, Francesca; Venezia, Valentina; Russo, Claudio; Aceto, Antonio; Robello, Mauro; Florio, Tullio

2007-11-01

Astrogliosis and microglial activation are a common feature during prion diseases, causing the release of chemoattractant and proinflammatory factors as well as reactive free radicals, involved in neuronal degeneration. The recombinant protease-resistant domain of the prion protein (PrP90-231) displays in vitro neurotoxic properties when refolded in a beta-sheet-rich conformer. Here, we report that PrP90-231 induces the secretion of several cytokines, chemokines, and nitric oxide (NO) release, in both type I astrocytes and microglial cells. PrP90-231 elicited in both cell types the activation of ERK1/2 MAP kinase that displays, in astrocytes, a rapid kinetics and a proliferative response. Conversely, in microglia, PrP90-231-dependent MAP kinase activation was delayed and long lasting, inducing functional activation and growth arrest. In microglial cells, NO release, dependent on the expression of the inducible NO synthase (iNOS), and the secretion of the chemokine CCL5 were Ca(2+) dependent and under the control of the MAP kinases ERK1/2 and p38: ERK1/2 inhibition, using PD98059, reduced iNOS expression, while p38 blockade by PD169316 inhibited CCL5 release. In summary, we demonstrate that glial cells are activated by extracellular misfolded PrP90-231 resulting in a proliferative/secretive response of astrocytes and functional activation of microglia, both dependent on MAP kinase activation. In particular, in microglia, PrP90-231 activated a complex signalling cascade involved in the regulation of NO and chemokine release. These data argue in favor of a causal role for misfolded prion protein in sustaining glial activation and, possibly, glia-mediated neuronal death.

Phosphorylation enhances recombinant HSP27 neuroprotection against focal cerebral ischemia in mice.

PubMed

Shimada, Y; Tanaka, R; Shimura, H; Yamashiro, K; Urabe, T; Hattori, N

2014-10-10

Heat shock protein 27 (HSP27) exerts cytoprotection against many cellular insults including cerebral ischemia. We previously indicated that intravenous injection of HSP27 purified from human lymphocytes (hHSP27) significantly reduced infarct volume following cerebral ischemia-reperfusion injury, while recombinant HSP27 (rHSP27) was less effective. Phosphorylation is important for HSP27 function, and hHSP27 was more highly phosphorylated than rHSP27. We hypothesized that MAPKAP kinase 2 in vitro-phosphorylated rHSP27 (prHSP27) might increase its brain protection. Mice underwent transient 1-h middle cerebral artery occlusion (MCAO), and then received tail-vein injections of one of the following 1h after reperfusion: hHSP27 as positive control, rHSP27, prHSP27, or bovine serum albumin (BSA) as control. We measured infarct volume, neurological deficits, neurological severity, physiological parameters, cell-death, oxidative stress, and inflammatory response. Compared with BSA controls (30.7±3.1mm(3), n=5), infarct volume was reduced by 67% in the hHSP27 positive-control group (10.1±4.6mm(3), P<0.001, n=5), 17% following rHSP27 (25.4±3.6mm(3), P<0.05, n=5), and 46% following prHSP27 (16.5±4.0mm(3), P<0.001, n=9). Compared to the rHSP27 and BSA-treated groups, prHSP27 also reduced functional deficits, and significantly suppressed apoptosis, oxidative stress, and inflammatory responses. Here, we showed the superior neuroprotective effects of phosphorylated HSP27 by administering prHSP27. prHSP27 may be a useful therapeutic agent to protect against acute cerebral ischemic stroke. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

A closer look at prion strains: characterization and important implications.

PubMed

Solforosi, Laura; Milani, Michela; Mancini, Nicasio; Clementi, Massimo; Burioni, Roberto

2013-01-01

Prions are infectious proteins that are responsible for transmissible spongiform encephalopathies (TSEs) and consist primarily of scrapie prion protein (PrP (Sc) ), a pathogenic isoform of the host-encoded cellular prion protein (PrP (C) ). The absence of nucleic acids as essential components of the infectious prions is the most striking feature associated to these diseases. Additionally, different prion strains have been isolated from animal diseases despite the lack of DNA or RNA molecules. Mounting evidence suggests that prion-strain-specific features segregate with different PrP (Sc) conformational and aggregation states. Strains are of practical relevance in prion diseases as they can drastically differ in many aspects, such as incubation period, PrP (Sc) biochemical profile (e.g., electrophoretic mobility and glycoform ratio) and distribution of brain lesions. Importantly, such different features are maintained after inoculation of a prion strain into genetically identical hosts and are relatively stable across serial passages. This review focuses on the characterization of prion strains and on the wide range of important implications that the study of prion strains involves.

The mechanism of monomer transfer between two structurally distinct PrP oligomers

PubMed Central

Armiento, Aurora; Martin, Davy; Lepejova, Nad’a

2017-01-01

In mammals, Prion pathology refers to a class of infectious neuropathologies whose mechanism is based on the self-perpetuation of structural information stored in the pathological conformer. The characterisation of the PrP folding landscape has revealed the existence of a plethora of pathways conducing to the formation of structurally different assemblies with different biological properties. However, the biochemical interconnection between these diverse assemblies remains unclear. The PrP oligomerisation process leads to the formation of neurotoxic and soluble assemblies called O1 oligomers with a high size heterodispersity. By combining the measurements in time of size distribution and average size with kinetic models and data assimilation, we revealed the existence of at least two structurally distinct sets of assemblies, termed Oa and Ob, forming O1 assemblies. We propose a kinetic model representing the main processes in prion aggregation pathway: polymerisation, depolymerisation, and disintegration. The two groups interact by exchanging monomers through a disintegration process that increases the size of Oa. Our observations suggest that PrP oligomers constitute a highly dynamic population. PMID:28746342

The mechanism of monomer transfer between two structurally distinct PrP oligomers.

PubMed

Armiento, Aurora; Moireau, Philippe; Martin, Davy; Lepejova, Nad'a; Doumic, Marie; Rezaei, Human

2017-01-01

In mammals, Prion pathology refers to a class of infectious neuropathologies whose mechanism is based on the self-perpetuation of structural information stored in the pathological conformer. The characterisation of the PrP folding landscape has revealed the existence of a plethora of pathways conducing to the formation of structurally different assemblies with different biological properties. However, the biochemical interconnection between these diverse assemblies remains unclear. The PrP oligomerisation process leads to the formation of neurotoxic and soluble assemblies called O1 oligomers with a high size heterodispersity. By combining the measurements in time of size distribution and average size with kinetic models and data assimilation, we revealed the existence of at least two structurally distinct sets of assemblies, termed Oa and Ob, forming O1 assemblies. We propose a kinetic model representing the main processes in prion aggregation pathway: polymerisation, depolymerisation, and disintegration. The two groups interact by exchanging monomers through a disintegration process that increases the size of Oa. Our observations suggest that PrP oligomers constitute a highly dynamic population.

A multimedia electronic patient record (ePR) system for image-assisted minimally invasive spinal surgery.

PubMed

Documet, Jorge; Le, Anh; Liu, Brent; Chiu, John; Huang, H K

2010-05-01

This paper presents the concept of bridging the gap between diagnostic images and image-assisted surgical treatment through the development of a one-stop multimedia electronic patient record (ePR) system that manages and distributes the real-time multimodality imaging and informatics data that assists the surgeon during all clinical phases of the operation from planning Intra-Op to post-care follow-up. We present the concept of this multimedia ePR for surgery by first focusing on image-assisted minimally invasive spinal surgery as a clinical application. Three clinical phases of minimally invasive spinal surgery workflow in Pre-Op, Intra-Op, and Post-Op are discussed. The ePR architecture was developed based on the three-phased workflow, which includes the Pre-Op, Intra-Op, and Post-Op modules and four components comprising of the input integration unit, fault-tolerant gateway server, fault-tolerant ePR server, and the visualization and display. A prototype was built and deployed to a minimally invasive spinal surgery clinical site with user training and support for daily use. A step-by-step approach was introduced to develop a multimedia ePR system for imaging-assisted minimally invasive spinal surgery that includes images, clinical forms, waveforms, and textual data for planning the surgery, two real-time imaging techniques (digital fluoroscopic, DF) and endoscope video images (Endo), and more than half a dozen live vital signs of the patient during surgery. Clinical implementation experiences and challenges were also discussed.

PROMIS Peer Relationships Short Form: How Well Does Self-Report Correlate With Data From Peers?

PubMed

Devine, Katie A; Willard, Victoria W; Hocking, Matthew C; Stapleton, Jerod L; Rotter, David; Bukowski, William M; Noll, Robert B

2018-05-24

To examine the psychometric properties of the Patient-Reported Outcomes Measurement Information System (PROMIS®) peer relationships short form (PR-SF), including association with peer-reported friendships, likeability, and social reputation. 203 children (Mage = 10.12 years, SD = 2.37, range = 6-14) in Grades 1-8 completed the 8-item PR-SF and friendship nominations, like ratings, and social reputation measures about their peers during 2 classroom visits approximately 4 months apart, as part of a larger study. A confirmatory factor analysis, followed by an exploratory factor analysis, was conducted to examine the factor structure of the PR-SF. Spearman correlations between the PR-SF and peer-reported outcomes evaluated construct validity. For the PR-SF, a 2-factor solution demonstrated better fit than a 1-factor solution. The 2 factors appear to assess friendship quality (3 items) and peer acceptance (5 items). Reliability was marginal for the friendship quality factor (.66) but adequate for the acceptance factor (.85); stability was .34 for the PR-SF over 4 months. The PR-SF (8 items) and acceptance factor (5 items) both had modest but significant correlations with measures of friendship (rs = .25-.27), likeability (rs = .21-.22), and social reputation (rs = .29-.44). The PR-SF appears to be measuring two distinct aspects of social functioning. The 5-item peer acceptance scale is modestly associated with peer-reported friendship, likeability, and social reputation. Although not a replacement for peer-reported outcomes, the PR-SF is a promising patient-reported outcome for peer relationships in youth.

Pulmonary effects of exposure to fine fibreglass: irregular opacities and small airways obstruction.

PubMed Central

Kilburn, K H; Powers, D; Warshaw, R H

1992-01-01

OBJECTIVE--Man made mineral fibres imitate asbestos and produce tumours of the pleura in animals. To answer the question, Does prolonged exposure to fibreglass adversely affect pulmonary function or produce radiographic abnormalities in human subjects? we studied workers in a midwestern appliance plant where refrigerator doors and previously entire cabinets were insulated with fibreglass sheeting and loose rotary spun fibreglass. METHODS--Spirometry and lung volumes were measured, respiratory and occupational questionnaires were administered, and chest x-ray films were read for pneumoconiosis using International Labour Office (ILO) 1980 criteria in 284 workers with exposure of 20 years or more. RESULTS--Expiratory flows were reduced including FEV1 (mean 90.3% of predicted (pr), FEF25-75 (85.5% pr), and FEF75-85 (76.2% pr). Forced vital capacity was significantly reduced (92.8% pr) and total lung capacity was significantly increased (109.2% pr). In white male smokers, a group large enough for comparisons, parameters of pulmonary function were reduced further in the presence of irregular opacities. Forty three workers (15.1%) had evidence of pneumoconiosis on chest radiographs: 26 of these (9.1%), had no known exposure to asbestos and 17 (6.0%) had some exposure. The best judgement was that in 36 (13.0%), pulmonary opacities or pleural abnormalities were due to fibreglass. CONCLUSION--Commercial rotary spun fibreglass used for insulating appliances appears to produce human disease that is similar to asbestosis. PMID:1419860

Cloning and Characterization of the Gene Encoding Alpha-Pinene Oxide Lyase Enzyme (Prα-POL) from Pseudomonas rhodesiae CIP 107491 and Production of the Recombinant Protein in Escherichia coli.

PubMed

Dubessay, Pascal; Larroche, Christian; Fontanille, Pierre

2017-12-28

The alpha-pinene oxide lyase (Prα-POL) from Pseudomonas rhodesiae CIP107491 belongs to catabolic alpha-pinene degradation pathway. In this study, the gene encoding Prα-POL has been identified using mapping approach combined to inverse PCR (iPCR) strategy. The Prα-POL gene included a 609-bp open reading frame encoding 202 amino acids and giving rise to a 23.7 kDa protein, with a theoretical isoelectric point (pI) of 5.23. The amino acids sequence analysis showed homologies with those of proteins with unknown function from GammaProteobacteria group. Identification of a conserved domain in amino acid in positions 18 to 190 permitted to classify Prα-POL among the nuclear transport factor 2 (NTF2) protein superfamily. Heterologous expression of Prα-POL, both under its native form and with a histidin tag, was successfully performed in Escherichia coli, and enzymatic kinetics were analyzed. Bioconversion assay using recombinant E. coli strain allowed to reach a rate of isonovalal production per gramme of biomass about 40-fold higher than the rate obtained with P. rhodesiae.

7 CFR 1710.207 - RUS criteria for approval of load forecasts by distribution borrowers not required to maintain an...

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 11 2010-01-01 2010-01-01 false RUS criteria for approval of load forecasts by distribution borrowers not required to maintain an approved load forecast on an ongoing basis. 1710.207 Section 1710.207 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE GENERAL AND PR...

A Three-Stage Colonel Blotto Game with Applications to Cyber-Physical Security

DTIC Science & Technology

2014-03-15

joint measure over the space Ri. Let µi ∈ ℘(Ri) be the strategy of Player i. Then, we let Prk #µi denote the marginal of µi on the k th battlefield. A...solely on the marginal distributions ( Prk #µ1,Pr k #µ2). The resources available to the players and the number of battlefields are common knowledge...Ri) → 2℘(Ri) denote a set-valued map (correspon- dence), defined as Ψi(µi) := { µ̃i ∈ ℘(Ri) : supp(µ̃i) = supp(µi) and Prk #µ̃i = Pr k #µi for all k

Fate of prions in soil: trapped conformation of full-length ovine prion protein induced by adsorption on clays.

PubMed

Revault, M; Quiquampoix, H; Baron, M H; Noinville, S

2005-08-05

Studying the mechanism of retention of ovine prion protein in soils will tackle the environmental aspect of potential dissemination of scrapie infectious agent. We consider the surface-induced conformational changes that the recombinant ovine prion protein (ovPrP) may undergo under different pH conditions when interacting with soil minerals of highly adsorptive capacities such as montmorillonite. The conformational states of the full-length ovine prion protein adsorbed on the electronegative clay surface are compared to its solvated state in deuterated buffer in the pD range 3.5-9, using FTIR spectroscopy. The in vitro pH-induced conversion of the alpha-helical monomer of ovPrP into oligomers of beta-like structure prone to self-aggregation does not occur when the protein is adsorbed on the clay surface. The conformation of the trapped ovPrP molecules on montmorillonite is pH-independent and looks like that of the ovPrP solvated state at pD higher than 7, suggesting the major role of Arg and Lys residues in the electrostatic origin of adsorption. The uneven distribution of positively and negatively charged residues of the ovPrP protein would promote a favored orientation of the protein towards the clay, so that not only the basic residues embedded in the N-terminal flexible part but also external basic residues in the globular part of the protein might participate to the attractive interaction. From these results, it appears unlikely that the interaction of normal prions (PrP(C)) with soil clay surfaces could induce a change of conformation leading to the pathogenic form of prions (PrP(Sc)).

NMR structure of the bovine prion protein

PubMed Central

López García, Francisco; Zahn, Ralph; Riek, Roland; Wüthrich, Kurt

2000-01-01

The NMR structures of the recombinant 217-residue polypeptide chain of the mature bovine prion protein, bPrP(23–230), and a C-terminal fragment, bPrP(121–230), include a globular domain extending from residue 125 to residue 227, a short flexible chain end of residues 228–230, and an N-terminal flexibly disordered “tail” comprising 108 residues for the intact protein and 4 residues for bPrP(121–230), respectively. The globular domain contains three α-helices comprising the residues 144–154, 173–194, and 200–226, and a short antiparallel β-sheet comprising the residues 128–131 and 161–164. The best-defined parts of the globular domain are the central portions of the helices 2 and 3, which are linked by the only disulfide bond in bPrP. Significantly increased disorder and mobility is observed for helix 1, the loop 166–172 leading from the β-strand 2 to helix 2, the end of helix 2 and the following loop, and the last turn of helix 3. Although there are characteristic local differences relative to the conformations of the murine and Syrian hamster prion proteins, the bPrP structure is essentially identical to that of the human prion protein. On the other hand, there are differences between bovine and human PrP in the surface distribution of electrostatic charges, which then appears to be the principal structural feature of the “healthy” PrP form that might affect the stringency of the species barrier for transmission of prion diseases between humans and cattle. PMID:10899999

Prostate cancer incidence and tumor severity in Georgia: descriptive epidemiology, racial disparity, and geographic trends.

PubMed

Wagner, Sara E; Bauer, Sarah E; Bayakly, A Rana; Vena, John E

2013-01-01

Limited research has been conducted to describe the geographical clustering and distribution of prostate cancer (PrCA) incidence in Georgia (GA). This study describes and compares the temporal and geographic trends of PrCA incidence in GA with a specific focus on racial disparities. GA Comprehensive Cancer Registry PrCA incidence data were obtained for 1998-2008. Directly standardized age-adjusted PrCA incidence rates per 100,000 were analyzed by race, stage, grade, and county. County-level hotspots of PrCA incidence were analyzed with the Getis-Ord Gi* statistic in a geographic information system; a census tract-level cluster analysis was performed with a Discrete Poisson model and implemented in SaTScan(®) software. Significant (p < 0.05) hotspots of PrCA incidence were observed in nine southwestern counties and six centrally located counties among men of both races. Six significant (p < 0.1) clusters of PrCA incidence rates were detected for men of both races in north and northwest central Georgia. When stratified by race, clusters among white and black men were similar, although centroids were slightly shifted. Most notably, a large (122 km radius) cluster in northwest central Georgia was detected only in whites, and two smaller clusters (0-32 km radii) were detected in Southwest Georgia only in black men. Clusters of high-grade and late-stage tumors were identified primarily in the northern portion of the state among men of both races. This study revealed a pattern of higher incidence and more advanced disease in northern and northwest central Georgia, highlighting geographic patterns that need more research and investigation of possible environmental determinants.

Human population, urban settlement patterns and their impact on Plasmodium falciparum malaria endemicity.

PubMed

Tatem, Andrew J; Guerra, Carlos A; Kabaria, Caroline W; Noor, Abdisalan M; Hay, Simon I

2008-10-27

The efficient allocation of financial resources for malaria control and the optimal distribution of appropriate interventions require accurate information on the geographic distribution of malaria risk and of the human populations it affects. Low population densities in rural areas and high population densities in urban areas can influence malaria transmission substantially. Here, the Malaria Atlas Project (MAP) global database of Plasmodium falciparum parasite rate (PfPR) surveys, medical intelligence and contemporary population surfaces are utilized to explore these relationships and other issues involved in combining malaria risk maps with those of human population distribution in order to define populations at risk more accurately. First, an existing population surface was examined to determine if it was sufficiently detailed to be used reliably as a mask to identify areas of very low and very high population density as malaria free regions. Second, the potential of international travel and health guidelines (ITHGs) for identifying malaria free cities was examined. Third, the differences in PfPR values between surveys conducted in author-defined rural and urban areas were examined. Fourth, the ability of various global urban extent maps to reliably discriminate these author-based classifications of urban and rural in the PfPR database was investigated. Finally, the urban map that most accurately replicated the author-based classifications was analysed to examine the effects of urban classifications on PfPR values across the entire MAP database. Masks of zero population density excluded many non-zero PfPR surveys, indicating that the population surface was not detailed enough to define areas of zero transmission resulting from low population densities. In contrast, the ITHGs enabled the identification and mapping of 53 malaria free urban areas within endemic countries. Comparison of PfPR survey results showed significant differences between author-defined 'urban' and 'rural' designations in Africa, but not for the remainder of the malaria endemic world. The Global Rural Urban Mapping Project (GRUMP) urban extent mask proved most accurate for mapping these author-defined rural and urban locations, and further sub-divisions of urban extents into urban and peri-urban classes enabled the effects of high population densities on malaria transmission to be mapped and quantified. The availability of detailed, contemporary census and urban extent data for the construction of coherent and accurate global spatial population databases is often poor. These known sources of uncertainty in population surfaces and urban maps have the potential to be incorporated into future malaria burden estimates. Currently, insufficient spatial information exists globally to identify areas accurately where population density is low enough to impact upon transmission. Medical intelligence does however exist to reliably identify malaria free cities. Moreover, in Africa, urban areas that have a significant effect on malaria transmission can be mapped.

Effect of Baseline Anxiety and Depression Symptoms on Selected Outcomes Following Pulmonary Rehabilitation.

PubMed

Cullen, Kate; Talbot, Daniel; Gillmor, Julie; McGrath, Colin; OʼDonnell, Rory; Baily-Scanlan, Maria; Broderick, Julie

2017-07-01

Anxiety and depression are prevalent comorbidities in people with chronic respiratory diseases (CRDs). This study sought to quantify the influence of varying degrees of anxiety and depression on functional performance and disease impact in a population with CRDs following pulmonary rehabilitation (PR) intervention. The Hospital Anxiety and Depression Scale (HADS), the 6-Minute Walk Test (6MWT), and the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) were assessed pre- and post-PR. Participants were categorized into 3 groups (None, Probable, and Present) based on their level of anxiety and depression. Functional performance and disease impact outcomes were compared pre- and post-PR. Patients consisted of a total of 134 program completers (72 males, 62 females; mean age = 67.8 years). Significant improvements in functional performance with regard to 6MWT scores were observed across all groups postintervention (P < .05). The Present group, in both the anxiety and depression domains, failed to reach a minimally clinically important difference postintervention. The Probable and Present groups achieved a significant improvement in CAT scores postintervention (P < .05). This study showed that symptoms of anxiety and depression in people with CRDs were significantly related to lower exercise tolerance levels and higher levels of disease impact. People with increased levels of anxiety and depression have the potential to significantly improve disease impact outcomes post-PR. The results demonstrated that the detection and treatment of anxiety and depression symptoms in people with CRDs are likely to be clinically important.

A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias.

PubMed

Wang, Hong-Gang; Zhu, Wandi; Kanter, Ronald J; Silva, Jonathan R; Honeywell, Christina; Gow, Robert M; Pitt, Geoffrey S

2016-03-01

Inherited autosomal dominant mutations in cardiac sodium channels (NaV1.5) cause various arrhythmias, such as long QT syndrome and Brugada syndrome. Although dozens of mutations throughout the protein have been reported, there are few reported mutations within a voltage sensor S4 transmembrane segment and few that are homozygous. Here we report analysis of a novel lidocaine-sensitive recessive mutation, p.R1309H, in the NaV1.5 DIII/S4 voltage sensor in a patient with a complex arrhythmia syndrome. We expressed the wild type or mutant NaV1.5 heterologously for analysis with the patch-clamp and voltage clamp fluorometry (VCF) techniques. p.R1309H depolarized the voltage-dependence of activation, hyperpolarized the voltage-dependence of inactivation, and slowed recovery from inactivation, thereby reducing the channel availability at physiologic membrane potentials. Additionally, p.R1309H increased the "late" Na(+) current. The location of the mutation in DIIIS4 prompted testing for a gating pore current. We observed an inward current at hyperpolarizing voltages that likely exacerbates the loss-of-function defects at resting membrane potentials. Lidocaine reduced the gating pore current. The p.R1309H homozygous NaV1.5 mutation conferred both gain-of-function and loss-of-function effects on NaV1.5 channel activity. Reduction of a mutation-induced gating pore current by lidocaine suggested a therapeutic mechanism. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

Lebron, S; Kahler, D; Liu, C

Purpose: To predict photon percentage depth dose (PDD) from profile due to a change in flattened (FF) and flattening-filter-free (FFF) beam quality. Methods: 6MV photon beam PDDs and profiles in a 3D water tank (3DW) and profiles in an ionization chamber array (ICP) were collected for different field sizes and depths with FF and FFF beams in a Versa HD (Elekta Ltd.). The energy was adjusted by changing the bending magnet current (BMC) ±15% from the clinical beam (6MV) in 5% increments. For baseline establishment, PDDs(depth≥3cm) were parameterized with bi-exponential functions and the PDD 20 to 10cm ratios (PDD{sub 20,10})more » were calculated. Then, the FF profile at 10cm from the central axis (Pr{sub 10}) and the slope of the FFF central linear region (SFFF) were calculated. Calibration curves were established: (1) change in Pr{sub 10} and SFFF as functions of the change in PDD{sub 20,10} and (2) change in PDD(depth=3, 15 and 30cm) as function of the change in PDD{sub 20,10}. The differences between Pr{sub 10} and SFFF from baseline were calculated and, from calibration curves, changes in PDD{sub 20,10} and PDD(depth=3, 15 and 30cm) were obtained. Then, absolute PDD(depth=3, 15 and 30cm) values were input into a least-square-optimization algorithm to calculate the bi-exponential function’s optimal coefficients and generate the PDD(depths≥3cm). Results: The change in PDD{sub 20,10} relative to baseline increased (<±4%) with BMC. Pr{sub 10} increased (±6%) and SFFF decreased (±11%) with BMC. Relative differences between measured and calculated (i.e. PDD calculation from Pr{sub 10} and SFFF) PDDs were less than 1%. Results apply to FF and FFF beams measured in 3DW and ICP. Conclusion: Pr{sub 10} and SFFF are more sensitive than PDD to changes in beam energy and PDD information can be accurately generated from them. With known 3DW and ICP profile relationship, ICP can be used to obtain PDD for current photon beam.« less

The effects of short-term and long-term pulmonary rehabilitation on functional capacity, perceived dyspnea, and quality of life.

PubMed

Verrill, David; Barton, Cole; Beasley, Will; Lippard, W Michael

2005-08-01

The purposes of this study were as follows: (1) to determine whether physical performance, quality of life, and dyspnea with activities of daily living improved following both short-term and long-term pulmonary rehabilitation (PR) across multiple hospital outpatient programs; (2) to examine the differences in these parameters between men and women; and (3) to determine what relationships existed between the psychosocial parameters and the results of the 6-min walk (6MW) test performance across programs. Non-experimental, prospective, and comparative. Seven outpatient hospital PR programs from urban and rural settings across North Carolina. Three hundred nine women and 281 men who were 20 to 93 years of age (mean [+/- SD] age, 66.7 +/- 11.1 years) with chronic lung disease. All 6MW tests and health surveys were administered prior to and immediately following 12 and 24 weeks of supervised PR participation. Scores from the 6MW tests, the Ferrans and Powers quality of life index-pulmonary version III (QLI), the Medical Outcomes Study 36-item short form (SF-36), and the University of California at San Diego shortness of breath questionnaire (SOBQ) were compared at PR entry, at 12 weeks, and at 24 weeks for differences by gender with repeated-measures analysis of variance. The study entry and follow-up SF-36 physical and mental component summary scores, the QLI health/function and overall scores, and the SOBQ scores were also compared to the 6MW test scores with Pearson correlation coefficient analysis. The mean summary scores on the SF-36 and the QLI increased after 12 weeks of PR (p < 0.05), and improvements were maintained by 24 weeks of PR participation (p < 0.05). Scores on the SOBQ improved after 12 weeks (p < 0.001) among the short-term participants, but not until after 24 weeks among the long-term participants (p = 0.009). The 6MW test performance improved after 12 weeks (p < 0.001) and again from 12 to 24 weeks (p = 0.002) in the long-term participants. No relevant correlational relationships were found between 6MW scores and the summary scores of the administered surveys (r = -0.43 to 0.36). Physical performance, as measured by the 6MW test, continued to improve with up to 24 weeks of PR participation. Quality-of-life measures and the perception of dyspnea improved after 12 weeks of PR participation, with improvements maintained by 24 weeks of PR participation. It is recommended that PR patients participate in supervised PR for at least 24 weeks to gain and maintain optimal health benefits.

A Novel WRKY transcription factor is required for induction of PR-1a gene expression by salicylic acid and bacterial elicitors.

PubMed

van Verk, Marcel C; Pappaioannou, Dimitri; Neeleman, Lyda; Bol, John F; Linthorst, Huub J M

2008-04-01

PR-1a is a salicylic acid-inducible defense gene of tobacco (Nicotiana tabacum). One-hybrid screens identified a novel tobacco WRKY transcription factor (NtWRKY12) with specific binding sites in the PR-1a promoter at positions -564 (box WK(1)) and -859 (box WK(2)). NtWRKY12 belongs to the class of transcription factors in which the WRKY sequence is followed by a GKK rather than a GQK sequence. The binding sequence of NtWRKY12 (WK box TTTTCCAC) deviated significantly from the consensus sequence (W box TTGAC[C/T]) shown to be recognized by WRKY factors with the GQK sequence. Mutation of the GKK sequence in NtWRKY12 into GQK or GEK abolished binding to the WK box. The WK(1) box is in close proximity to binding sites in the PR-1a promoter for transcription factors TGA1a (as-1 box) and Myb1 (MBSII box). Expression studies with PR-1a promoterbeta-glucuronidase (GUS) genes in stably and transiently transformed tobacco indicated that NtWRKY12 and TGA1a act synergistically in PR-1a expression induced by salicylic acid and bacterial elicitors. Cotransfection of Arabidopsis thaliana protoplasts with 35SNtWRKY12 and PR-1aGUS promoter fusions showed that overexpression of NtWRKY12 resulted in a strong increase in GUS expression, which required functional WK boxes in the PR-1a promoter.

Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease

PubMed Central

Kaufman, Adam C.; Herber, Charlotte S.; Haas, Laura T.; Robinson, Sophie; Lee, Michael K.

2017-01-01

Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrPC) prevents development of memory deficits in APPswe/PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset. SIGNIFICANCE STATEMENT The study presented here further elucidates our understanding of the soluble oligomeric amyloid-β–Aβo-binding cellular prion protein (PrPC) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrPC as a potential therapeutic target for AD. In particular, genetic deletion of Prnp rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrPC deletion given that patients already present symptoms at the time of diagnosis. PMID:28842420

The protective effect of LRRK2 p.R1398H on risk of Parkinson’s disease is independent of MAPT and SNCA variants

PubMed Central

Heckman, Michael G.; Elbaz, Alexis; Soto-Ortolaza, Alexandra I.; Serie, Daniel J.; Aasly, Jan O.; Annesi, Grazia; Auburger, Georg; Bacon, Justin A.; Boczarska-Jedynak, Magdalena; Bozi, Maria; Brighina, Laura; Chartier-Harlin, Marie-Christine; Dardiotis, Efthimios; Destée, Alain; Ferrarese, Carlo; Ferraris, Alessandro; Fiske, Brian; Gispert, Suzana; Hadjigeorgiou, Georgios M.; Hattori, Nobutaka; Ioannidis, John P. A.; Jasinska-Myga, Barbara; Jeon, Beom S.; Kim, Yun Joong; Klein, Christine; Kruger, Rejko; Kyratzi, Elli; Lin, Chin-Hsien; Lohmann, Katja; Loriot, Marie-Anne; Lynch, Timothy; Mellick, George D.; Mutez, Eugénie; Opala, Grzegorz; Park, Sung Sup; Petrucci, Simona; Quattrone, Aldo; Sharma, Manu; Silburn, Peter A.; Sohn, Young Ho; Stefanis, Leonidas; Tadic, Vera; Tomiyama, Hiroyuki; Uitti, Ryan J.; Valente, Enza Maria; Vassilatis, Demetrios K.; Vilariño-Güell, Carles; White, Linda R.; Wirdefeldt, Karin; Wszolek, Zbigniew K.; Wu, Ruey-Meei; Xiromerisiou, Georgia; Maraganore, Demetrius M.; Farrer, Matthew J.; Ross, Owen A.

2013-01-01

The best validated susceptibility variants for Parkinson’s disease (PD) are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined four SNCA variants (rs181489, rs356219, rs11931074, rs2583988), the MAPT H1-haplotype defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (N=10,322) and Asian (N=2,289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all P≥0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with PD is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations. PMID:23962496

The pathogenesis-related protein PR-4b from Theobroma cacao presents RNase activity, Ca2+ and Mg2+ dependent-DNase activity and antifungal action on Moniliophthora perniciosa

PubMed Central

2014-01-01

Background The production and accumulation of pathogenesis-related proteins (PR proteins) in plants in response to biotic or abiotic stresses is well known and is considered as a crucial mechanism for plant defense. A pathogenesis-related protein 4 cDNA was identified from a cacao-Moniliophthora perniciosa interaction cDNA library and named TcPR-4b. Results TcPR-4b presents a Barwin domain with six conserved cysteine residues, but lacks the chitin-binding site. Molecular modeling of TcPR-4b confirmed the importance of the cysteine residues to maintain the protein structure, and of several conserved amino acids for the catalytic activity. In the cacao genome, TcPR-4b belonged to a small multigene family organized mainly on chromosome 5. TcPR-4b RT-qPCR analysis in resistant and susceptible cacao plants infected by M. perniciosa showed an increase of expression at 48 hours after infection (hai) in both cacao genotypes. After the initial stage (24-72 hai), the TcPR-4b expression was observed at all times in the resistant genotypes, while in the susceptible one the expression was concentrated at the final stages of infection (45-90 days after infection). The recombinant TcPR-4b protein showed RNase, and bivalent ions dependent-DNase activity, but no chitinase activity. Moreover, TcPR-4b presented antifungal action against M. perniciosa, and the reduction of M. perniciosa survival was related to ROS production in fungal hyphae. Conclusion To our knowledge, this is the first report of a PR-4 showing simultaneously RNase, DNase and antifungal properties, but no chitinase activity. Moreover, we showed that the antifungal activity of TcPR-4b is directly related to RNase function. In cacao, TcPR-4b nuclease activities may be related to the establishment and maintenance of resistance, and to the PCD mechanism, in resistant and susceptible cacao genotypes, respectively. PMID:24920373

A New Method for the Characterization of Strain-Specific Conformational Stability of Protease-Sensitive and Protease-Resistant PrPSc

PubMed Central

Pirisinu, Laura; Di Bari, Michele; Marcon, Stefano; Vaccari, Gabriele; D'Agostino, Claudia; Fazzi, Paola; Esposito, Elena; Galeno, Roberta; Langeveld, Jan; Agrimi, Umberto; Nonno, Romolo

2010-01-01

Although proteinacious in nature, prions exist as strains with specific self-perpetuating biological properties. Prion strains are thought to be associated with different conformers of PrPSc, a disease-associated isoform of the host-encoded cellular protein (PrPC). Molecular strain typing approaches have been developed which rely on the characterization of protease-resistant PrPSc. However, PrPSc is composed not only of protease-resistant but also of protease-sensitive isoforms. The aim of this work was to develop a protocol for the molecular characterization of both, protease-resistant and protease-sensitive PrPSc aggregates. We first set up experimental conditions which allowed the most advantageous separation of PrPC and PrPSc by means of differential centrifugation. The conformational solubility and stability assay (CSSA) was then developed by measuring PrPSc solubility as a function of increased exposure to GdnHCl. Brain homogenates from voles infected with human and sheep prion isolates were analysed by CSSA and showed strain-specific conformational stabilities, with mean [GdnHCl]1/2 values ranging from 1.6 M for MM2 sCJD to 2.1 for scrapie and to 2.8 M for MM1/MV1 sCJD and E200K gCJD. Interestingly, the rank order of [GdnHCl]1/2 values observed in the human and sheep isolates used as inocula closely matched those found following transmission in voles, being MM1 sCJD the most resistant (3.3 M), followed by sheep scrapie (2.2 M) and by MM2 sCJD (1.6 M). In order to test the ability of CSSA to characterise protease-sensitive PrPSc, we analysed sheep isolates of Nor98 and compared them to classical scrapie isolates. In Nor98, insoluble PrPSc aggregates were mainly protease-sensitive and showed a conformational stability much lower than in classical scrapie. Our results show that CSSA is able to reveal strain-specified PrPSc conformational stabilities of protease-resistant and protease-sensitive PrPSc and that it is a valuable tool for strain typing in natural hosts, such as humans and sheep. PMID:20856860

A proteorhodopsin-based biohybrid light-powering pH sensor.

PubMed

Rao, Siyuan; Guo, Zhibin; Liang, Dawei; Chen, Deliang; Wei, Yen; Xiang, Yan

2013-10-14

The biohybrid sensor is an emerging technique for multi-functional detection that utilizes the instinctive responses or interactions of biomolecules. We develop a biohybrid pH sensor by taking advantage of the pH-dependent photoelectric characteristics of proteorhodopsin (pR). The transient absorption kinetics study indicates that the photoelectric behavior of pR is attributed to the varying lifetime of the M intermediate at different environmental pH values. This pR-based biohybrid light-powering sensor with microfluidic design can achieve real-time pH detection with quick response and high sensitivity. The results of this work would shed light on pR and its potential applications.

The Reduction of Advanced Military Aircraft Noise

DTIC Science & Technology

2011-12-01

omplexity of t he m ilitary e ngine’s noz zle, the j et i s almost ne ver i deally e xpanded. T hat i s, t he pr essure a t t he j et e xit doe s not...sound pr essure l evel ( SPL) t o c ompute t he l ossless SPL as ex plained i n Kuo, V eltin a nd McLaughlin6. The co rrections, al l p receded b y...spectra expressed as a function of Strouhal number. Correction i s m ost us eful a t pol ar a ngles f or which t he s ound pr essure level shows l

ABO and Rh blood groups frequency in women with HER2 positive breast cancer.

PubMed

Urun, Y; Utkan, G; Altundag, K; Arslan, O; Onur, H; Arslan, U Y; Kocer, M; Dogan, I; Senler, F C; Yalcin, B; Demirkazik, A; Akbulut, H; Icli, F

2012-01-01

The role of genetic factors in the development of cancer is widely accepted. Data on the role of ABO blood group and Rh factor in breast cancer is inconclusive. The aim of this study was to investigate the presence of a possible association between HER2 (+) breast cancer in Turkish women and ABO blood groups and Rh factor. In 294 female patients with HER2 (+) breast cancer, ABO blood groups and Rh factor were examined. The relationship of blood groups with age, menopausal status, and family history of cancer, estrogen receptor (ER), progesterone receptor (PR) and HER2 status of these patients was evaluated. Blood groups distribution of 22,821 healthy blood donors was also assessed and compared with the patients' blood groups distribution. The median patient age was 47 years (range 20-80) and 56% of the patients were premenopausal. ER and PR were positive in 50 and 60% of the patients, respectively. Overall, the ABO blood group distribution of the 294 HER2 (+) breast cancer patients was similar to that of the healthy blood donors (p=0.36). Likewise there was no correlation between blood type and ER, PR and menopausal status. Rh (-) patients had more frequent family cancer history and this difference was significant for patients with blood group B Rh (-) and O Rh (-) (p = 0.04). In the present study we didn't find any relationship between HER2 status and ABO blood group and Rh factor. However, further studies with larger number of patients are needed to establish the role (if any) of blood groups in patients with breast cancer.

Assessment of the potential pathogenicity of missense mutations identified in the GTPase-activating protein (GAP)-related domain of the neurofibromatosis type-1 (NF1) gene.

PubMed

Thomas, Laura; Richards, Mark; Mort, Matthew; Dunlop, Elaine; Cooper, David N; Upadhyaya, Meena

2012-12-01

Neurofibromatosis type-1 (NF1) is caused by constitutional mutations of the NF1 tumor-suppressor gene. Although ∼85% of inherited NF1 microlesions constitute truncating mutations, the remaining ∼15% are missense mutations whose pathological relevance is often unclear. The GTPase-activating protein-related domain (GRD) of the NF1-encoded protein, neurofibromin, serves to define its major function as a negative regulator of the Ras-MAPK (mitogen-activated protein kinase) signaling pathway. We have established a functional assay to assess the potential pathogenicity of 15 constitutional nonsynonymous NF1 missense mutations (11 novel and 4 previously reported but not functionally characterized) identified in the NF1-GRD (p.R1204G, p.R1204W, p.R1276Q, p.L1301R, p.I1307V, p.T1324N, p.E1327G, p.Q1336R, p.E1356G, p.R1391G, p.V1398D, p.K1409E, p.P1412R, p.K1436Q, p.S1463F). Individual mutations were introduced into an NF1-GRD expression vector and activated Ras was assayed by an enzyme-linked immunosorbent assay (ELISA). Ten NF1-GRD variants were deemed to be potentially pathogenic by virtue of significantly elevated levels of activated GTP-bound Ras in comparison to wild-type NF1 protein. The remaining five NF1-GRD variants were deemed less likely to be of pathological significance as they exhibited similar levels of activated Ras to the wild-type protein. These conclusions received broad support from both bioinformatic analysis and molecular modeling and serve to improve our understanding of NF1-GRD structure and function. © 2012 Wiley Periodicals, Inc.

PR Toxin – Biosynthesis, Genetic Regulation, Toxicological Potential, Prevention and Control Measures: Overview and Challenges

PubMed Central

Dubey, Manish K.; Aamir, Mohd; Kaushik, Manish S.; Khare, Saumya; Meena, Mukesh; Singh, Surendra; Upadhyay, Ram S.

2018-01-01

Out of the various mycotoxigenic food and feed contaminant, the fungal species belonging to Penicillium genera, particularly Penicillium roqueforti is of great economic importance, and well known for its crucial role in the manufacturing of Roquefort and Gorgonzola cheese. The mycotoxicosis effect of this mold is due to secretion of several metabolites, of which PR toxin is of considerable importance, with regard to food quality and safety challenges issues. The food products and silages enriched with PR toxin could lead into damage to vital internal organs, gastrointestinal perturbations, carcinogenicity, immunotoxicity, necrosis, and enzyme inhibition. Moreover, it also has the significant mutagenic potential to disrupt/alter the crucial processes like DNA replication, transcription, and translation at the molecular level. The high genetic diversities in between the various strains of P. roqueforti persuaded their nominations with Protected Geographical Indication (PGI), accordingly to the cheese type, they have been employed. Recently, the biosynthetic mechanism and toxicogenetic studies unraveled the role of ari1 and prx gene clusters that cross-talk with the synthesis of other metabolites or involve other cross-regulatory pathways to negatively regulate/inhibit the other biosynthetic route targeted for production of a strain-specific metabolites. Interestingly, the chemical conversion that imparts toxic properties to PR toxin is the substitution/oxidation of functional hydroxyl group (-OH) to aldehyde group (-CHO). The rapid conversion of PR toxin to the other derivatives such as PR imine, PR amide, and PR acid, based on conditions available reflects their unstability and degradative aspects. Since the PR toxin-induced toxicity could not be eliminated safely, the assessment of dose-response and other pharmacological aspects for its safe consumption is indispensable. The present review describes the natural occurrences, diversity, biosynthesis, genetics, toxicological aspects, control and prevention strategies, and other management aspects of PR toxin with paying special attention on economic impacts with intended legislations for avoiding PR toxin contamination with respect to food security and other biosafety purposes. PMID:29651243

The roles of the conserved tyrosine in the β2-α2 loop of the prion protein.

PubMed

Huang, Danzhi; Caflisch, Amedeo

2015-01-01

Prions cause neurodegenerative diseases for which no cure exists. Despite decades of research activities the function of the prion protein (PrP) in mammalians is not known. Moreover, little is known on the molecular mechanisms of the self-assembly of the PrP from its monomeric state (cellular PrP, PrP(C)) to the multimeric state. The latter state includes the toxic species (scrapie PrP, PrP(Sc)) knowledge of which would facilitate the development of drugs against prion diseases. Here we analyze the role of a tyrosine residue (Y169) which is strictly conserved in mammalian PrPs. Nuclear magnetic resonance (NMR) spectroscopy studies of many mammalian PrP(C) proteins have provided evidence of a conformational equilibrium between a 3(10)-helical turn and a type I β turn conformation in the β2-α2 loop (residues 165-175). In vitro cell-free experiments of the seeded conversion of PrP(C) indicate that non-aromatic residues at position 169 reduce the formation of proteinase K-resistant PrP. Recent molecular dynamics (MD) simulations of monomeric PrP and several single-point mutants show that Y169 stabilizes the 3(10)-helical turn conformation more than single-point mutants at position 169 or residues in contact with it. In the 3(10)-helical turn conformation the hydrophobic and aggregation-prone segment 169-YSNQNNF-175 is buried and thus not-available for self-assembly. From the combined analysis of simulation and experimental results it emerges that Y169 is an aggregation gatekeeper with a twofold role. Mutations related to 3 human prion diseases are interpreted on the basis of the gatekeeper role in the monomeric state. Another potential role of the Y169 side chain is the stabilization of the ordered aggregates, i.e., reduction of frangibility of filamentous protofibrils and fibrils, which is likely to reduce the generation of toxic species.

Electronic structure and magnetic properties of Pr-Co intermetallics: ab initio FP-LAPW calculations and correlation with experiments

NASA Astrophysics Data System (ADS)

Bakkari, Karim; Fersi, Riadh; Kebir Hlil, El; Bessais, Lotfi; Thabet Mliki, Najeh

2018-03-01

First-principle calculations combining density functional theory and the full-potential linearized augmented plane wave (FP-LAPW) method are performed to investigate the electronic and magnetic structure of Pr2Co7 in its two polymorphic forms, (2:7 H) and (2:7 R), for the first time. This type of calculation was also performed for PrCo5 and PrCo2 intermetallics. We have computed the valence density of states separately for spin-up and spin-down states in order to investigate the electronic band structure. This is governed by the strong contribution of the partial DOS of 3d-Co bands compared to the partial DOS of the 4f-Pr bands. Such a high ferromagnetic state is discussed in terms of the strong spin polarization observed in the total DOS. The magnetic moments carried by the Co and Pr atoms located in several sites for all compounds are computed. These results mainly indicate that cobalt atoms make a dominant contribution to the magnetic moments. The notable difference in the atomic moments of Pr and Co atoms between different structural slabs is explained in terms of the magnetic characteristics of the PrCo2 and PrCo5 compounds and the local chemical environments of the Pr and Co atoms in different structural slabs of Pr2Co7. From spin-polarized calculations we have simulated the 3d and 4f band population to estimate the local magnetic moments. These results are in accordance with the magnetic moments calculated using the FP-LAPW method. In addition, the exchange interactions J ij are calculated and used as input for M(T) simulations. Involving the data obtained from the electronic structure calculations, the appropriate Padé Table is applied to simulate the magnetization M(T) and to estimate the mean-field Curie temperature. We report a fairly good agreement between the ab initio calculation of magnetization and Curie temperature with the experimental data.

PR Toxin - Biosynthesis, Genetic Regulation, Toxicological Potential, Prevention and Control Measures: Overview and Challenges.

PubMed

Dubey, Manish K; Aamir, Mohd; Kaushik, Manish S; Khare, Saumya; Meena, Mukesh; Singh, Surendra; Upadhyay, Ram S

2018-01-01

Out of the various mycotoxigenic food and feed contaminant, the fungal species belonging to Penicillium genera, particularly Penicillium roqueforti is of great economic importance, and well known for its crucial role in the manufacturing of Roquefort and Gorgonzola cheese. The mycotoxicosis effect of this mold is due to secretion of several metabolites, of which PR toxin is of considerable importance, with regard to food quality and safety challenges issues. The food products and silages enriched with PR toxin could lead into damage to vital internal organs, gastrointestinal perturbations, carcinogenicity, immunotoxicity, necrosis, and enzyme inhibition. Moreover, it also has the significant mutagenic potential to disrupt/alter the crucial processes like DNA replication, transcription, and translation at the molecular level. The high genetic diversities in between the various strains of P. roqueforti persuaded their nominations with Protected Geographical Indication (PGI), accordingly to the cheese type, they have been employed. Recently, the biosynthetic mechanism and toxicogenetic studies unraveled the role of ari1 and prx gene clusters that cross-talk with the synthesis of other metabolites or involve other cross-regulatory pathways to negatively regulate/inhibit the other biosynthetic route targeted for production of a strain-specific metabolites. Interestingly, the chemical conversion that imparts toxic properties to PR toxin is the substitution/oxidation of functional hydroxyl group (-OH) to aldehyde group (-CHO). The rapid conversion of PR toxin to the other derivatives such as PR imine, PR amide, and PR acid, based on conditions available reflects their unstability and degradative aspects. Since the PR toxin-induced toxicity could not be eliminated safely, the assessment of dose-response and other pharmacological aspects for its safe consumption is indispensable. The present review describes the natural occurrences, diversity, biosynthesis, genetics, toxicological aspects, control and prevention strategies, and other management aspects of PR toxin with paying special attention on economic impacts with intended legislations for avoiding PR toxin contamination with respect to food security and other biosafety purposes.

Palladium(II) complexes with highly basic imidazolin-2-imines and their reactivity toward small bio-molecules.

PubMed

Bogojeski, Jovana; Volbeda, Jeroen; Freytag, Matthias; Tamm, Matthias; Bugarčić, Živadin D

2015-10-21

A series of novel Pd(ii) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands were synthesized. The crystal structures of [Pd(DMEAIm(iPr))Cl2] and [Pd(DPENIm(iPr))Cl2] were determined by X-ray diffraction analysis. The reactivity of the six Pd(ii) complexes, namely, [Pd(en)Cl2], [Pd(EAIm(iPr))Cl2], [Pd(DMEAIm(iPr))Cl2], [Pd(DPENIm(iPr))Cl2], [Pd(BL(iPr))Cl2] and [Pd(DACH(Im(iPr))2)Cl2], were investigated. Spectrophotometric acid-base titrations were performed to determine the pKa values of the coordinated water molecules in [Pd(en)(H2O)2](2+), [Pd(EAIm(iPr))(H2O)2](2+), [Pd(DMEAIm(iPr))(H2O)2](2+), [Pd(DPENIm(iPr))(H2O)2](2+), [Pd(BL(iPr))(H2O)2](2+) and [Pd(DACH(Im(iPr))2)(H2O)2](2+). The substitution of the chloride ligands in these complexes by TU, l-Met, l-His and Gly was studied under pseudo-first-order conditions as a function of the nucleophile concentration and temperature using stopped-flow techniques; the sulfur-donor nucleophiles have shown better reactivity than nitrogen-donor nucleophiles. The obtained results indicate that there is a clear correlation between the nature of the imidazolin-2-imine ligands and the acid-base characteristics and reactivity of the resulting Pd(ii) complexes; the order of reactivity of the investigated Pd(ii) complexes is: [Pd(en)Cl2] > [Pd(EAIm(iPr))Cl2] > [Pd(DMEAIm(iPr))Cl2] > [Pd(DPENIm(iPr))Cl2] > [Pd(BL(iPr))Cl2] > [Pd(DACH(Im(iPr))2)Cl2]. The solubility measurements revealed good solubility of the studied imidazolin-2-imine complexes in water, despite the fact that these Pd(ii) complexes are neutral complexes. Based on the performed studies, three unusual features of the novel imidazolin-2-imine Pd(ii) complexes are observed, that is, good solubility in water, very low reactivity and high pKa values. The coordination geometries around the palladium atoms are distorted square-planar; the [Pd(DMEAIm(iPr))Cl2] complex displays Pd-N distances of 2.013(2) and 2.076(2) Å, while the [Pd(DPENIm(iPr))Cl2] complex displays similar Pd-N distances of 2.034(4) and 2.038(3) Å. The studied systems are of interest because little is known about the substitution behavior of imidazolin-2-imine Pd(ii) complexes with bio-molecules under physiological conditions.

Pathways of Prion Spread during Early Chronic Wasting Disease in Deer.

PubMed

Hoover, Clare E; Davenport, Kristen A; Henderson, Davin M; Denkers, Nathaniel D; Mathiason, Candace K; Soto, Claudio; Zabel, Mark D; Hoover, Edward A

2017-05-15

Among prion infections, two scenarios of prion spread are generally observed: (i) early lymphoid tissue replication or (ii) direct neuroinvasion without substantial antecedent lymphoid amplification. In nature, cervids are infected with chronic wasting disease (CWD) prions by oral and nasal mucosal exposure, and studies of early CWD pathogenesis have implicated pharyngeal lymphoid tissue as the earliest sites of prion accumulation. However, knowledge of chronological events in prion spread during early infection remains incomplete. To investigate this knowledge gap in early CWD pathogenesis, we exposed white-tailed deer to CWD prions by mucosal routes and performed serial necropsies to assess PrP CWD tissue distribution by real-time quaking-induced conversion (RT-QuIC) and tyramide signal amplification immunohistochemistry (TSA-IHC). Although PrP CWD was not detected by either method in the initial days (1 and 3) postexposure, we observed PrP CWD seeding activity and follicular immunoreactivity in oropharyngeal lymphoid tissues at 1 and 2 months postexposure (MPE). At 3 MPE, PrP CWD replication had expanded to all systemic lymphoid tissues. By 4 MPE, the PrP CWD burden in all lymphoid tissues had increased and approached levels observed in terminal disease, yet there was no evidence of nervous system invasion. These results indicate the first site of CWD prion entry is in the oropharynx, and the initial phase of prion amplification occurs in the oropharyngeal lymphoid tissues followed by rapid dissemination to systemic lymphoid tissues. This lymphoid replication phase appears to precede neuroinvasion. IMPORTANCE Chronic wasting disease (CWD) is a universally fatal transmissible spongiform encephalopathy affecting cervids, and natural infection occurs through oral and nasal mucosal exposure to infectious prions. Terminal disease is characterized by PrP CWD accumulation in the brain and lymphoid tissues of affected animals. However, the initial sites of prion accumulation and pathways of prion spread during early CWD infection remain unknown. To investigate the chronological events of early prion pathogenesis, we exposed deer to CWD prions and monitored the tissue distribution of PrP CWD over the first 4 months of infection. We show CWD uptake occurs in the oropharynx with initial prion replication in the draining oropharyngeal lymphoid tissues, rapidly followed by dissemination to systemic lymphoid tissues without evidence of neuroinvasion. These data highlight the two phases of CWD infection: a robust prion amplification in systemic lymphoid tissues prior to neuroinvasion and establishment of a carrier state. Copyright © 2017 American Society for Microbiology.

Evaluating the distributional effects of regional transportation plans and projects : final report.

DOT National Transportation Integrated Search

2017-05-01

Metropolitan planning organizations (MPOs) have long been required to consider the equity implications of their regional transportation plans and processes. Funded by the National Institute for Transportation and Communities, this research aims to pr...

Ab initio calculation of electronic structure and magnetic properties of R2Fe14BNx (R = Pr,Nd)

NASA Astrophysics Data System (ADS)

Tian, Guang; Zha, Liang; Yang, Wenyun; Qiao, Guanyi; Wang, Changsheng; Yang, Yingchang; Yang, Jinbo

2018-05-01

The site preference of N atom for R2Fe14BNx (R= Pr, Nd) and the interstitial nitrogen effect on the magnetic properties have been studied by the first-principles method. It was found that the nitrogen is more likely to occupy the 4e site for Pr2Fe14BNx compound, while 4f site for Nd2Fe14BNx. When N atoms entering some specific crystal sites (such as 2a and 4f), the total magnetic moments of these compounds are not reduced, but slightly increased. Although the doping of N may reduce the total magnetic moments of some R2Fe14B compounds in the cases of optimal occupancy, the volumetric effect caused by N doping can still change the electron density distributions of Fe near the Fermi level, improving the magnetic ordering temperature of such compounds.

[What do pediatricians and pediatric residents think of the rotation into Primary Health Care].

PubMed

García Puga, J M; Villazán Pérez, C; Domínguez Aurrecoechea, B; Ugarte Líbano, R

2009-05-01

Since 2007, on a mandatory, pediatric residents (PR) have been obliged to rotate into primary health care centers for 3 months. On disagreeing with the type of rotation proposed, the teaching group of the Spanish Primary Care Pediatrics Association (AEPap) was raised to find out the views of Hospital Pediatricians (PH), Pediatrics Health Care (PHC) and PR in terms of need, length, year in which it should take place and rotation expectations. Cross-sectional study using a 13 question validated questionnaire, which was distributed to the various AEPap associations, and completed via the website. The data was processed with SPSS 12.0 and analysed using the Chi(2) test. A total of 323 surveys from 13 Autonomous Regions were analysed, of which 56% were answered by PHC, 38.7% by PR and 5.3% by PH, 67.5% of which were women, with two age groups; one under 30 years old and the other between 41-50 years. Of the participants, 99% believed it was necessary to rotate, with a duration of 6 months proposed by the PHC (73.3%) while PR considered 1 or 2 months (56.9%), (P<0001), preferably performed in two periods (65.1% of PHC). Of the PHC, 75.5% believed that the PR who were going to work in Primary Care should work 6 months more in their last year of residency (P<0001). Of the PR, 63,9% hoped to improve their training in the rotation into Primary Health Care. The need to rotate into Primary Health Care was almost unanimous and three months are insufficient for the majority of respondents and PHC believe it should be 6 months. There appears to be two preferences for rotation: in a period in any year of residence or in two periods. Those PR who are thinking of working in a Primary Health Care should rotate 6 months during the fourth year of residency. The PR expect rotation to improve their training.

High-Mobility Group Chromatin Proteins 1 and 2 Functionally Interact with Steroid Hormone Receptors To Enhance Their DNA Binding In Vitro and Transcriptional Activity in Mammalian Cells

PubMed Central

Boonyaratanakornkit, Viroj; Melvin, Vida; Prendergast, Paul; Altmann, Magda; Ronfani, Lorenza; Bianchi, Marco E.; Taraseviciene, Laima; Nordeen, Steven K.; Allegretto, Elizabeth A.; Edwards, Dean P.

1998-01-01

We previously reported that the chromatin high-mobility group protein 1 (HMG-1) enhances the sequence-specific DNA binding activity of progesterone receptor (PR) in vitro, thus providing the first evidence that HMG-1 may have a coregulatory role in steroid receptor-mediated gene transcription. Here we show that HMG-1 and the highly related HMG-2 stimulate DNA binding by other steroid receptors, including estrogen, androgen, and glucocorticoid receptors, but have no effect on DNA binding by several nonsteroid nuclear receptors, including retinoid acid receptor (RAR), retinoic X receptor (RXR), and vitamin D receptor (VDR). As highly purified recombinant full-length proteins, all steroid receptors tested exhibited weak binding affinity for their optimal palindromic hormone response elements (HREs), and the addition of purified HMG-1 or -2 substantially increased their affinity for HREs. Purified RAR, RXR, and VDR also exhibited little to no detectable binding to their cognate direct repeat HREs but, in contrast to results with steroid receptors, the addition of HMG-1 or HMG-2 had no stimulatory effect. Instead, the addition of purified RXR enhanced RAR and VDR DNA binding through a heterodimerization mechanism and HMG-1 or HMG-2 had no further effect on DNA binding by RXR-RAR or RXR-VDR heterodimers. HMG-1 and HMG-2 (HMG-1/-2) themselves do not bind to progesterone response elements, but in the presence of PR they were detected as part of an HMG-PR-DNA ternary complex. HMG-1/-2 can also interact transiently in vitro with PR in the absence of DNA; however, no direct protein interaction was detected with VDR. These results, taken together with the fact that PR can bend its target DNA and that HMG-1/-2 are non-sequence-specific DNA binding proteins that recognize DNA structure, suggest that HMG-1/-2 are recruited to the PR-DNA complex by the combined effect of transient protein interaction and DNA bending. In transient-transfection assays, coexpression of HMG-1 or HMG-2 increased PR-mediated transcription in mammalian cells by as much as 7- to 10-fold without altering the basal promoter activity of target reporter genes. This increase in PR-mediated gene activation by coexpression of HMG-1/-2 was observed in different cell types and with different target promoters, suggesting a generality to the functional interaction between HMG-1/-2 and PR in vivo. Cotransfection of HMG-1 also increased reporter gene activation mediated by other steroid receptors, including glucocorticoid and androgen receptors, but it had a minimal influence on VDR-dependent transcription in vivo. These results support the conclusion that HMG-1/-2 are coregulatory proteins that increase the DNA binding and transcriptional activity of the steroid hormone class of receptors but that do not functionally interact with certain nonsteroid classes of nuclear receptors. PMID:9671457

Unraveling HIV protease flaps dynamics by Constant pH Molecular Dynamics simulations.

PubMed

Soares, Rosemberg O; Torres, Pedro H M; da Silva, Manuela L; Pascutti, Pedro G

2016-08-01

The active site of HIV protease (HIV-PR) is covered by two flaps. These flaps are known to be essential for the catalytic activity of the HIV-PR, but their exact conformations at the different stages of the enzymatic pathway remain subject to debate. Understanding the correct functional dynamics of the flaps might aid the development of new HIV-PR inhibitors. It is known that, the HIV-PR catalytic efficiency is pH-dependent, likely due to the influence of processes such as charge transfer and protonation/deprotonation of ionizable residues. Several Molecular Dynamics (MD) simulations have reported information about the HIV-PR flaps. However, in MD simulations the protonation of a residue is fixed and thus it is not possible to study the correlation between conformation and protonation state. To address this shortcoming, this work attempts to capture, through Constant pH Molecular Dynamics (CpHMD), the conformations of the apo, substrate-bound and inhibitor-bound HIV-PR, which differ drastically in their flap arrangements. The results show that the HIV-PR flaps conformations are defined by the protonation of the catalytic residues Asp25/Asp25' and that these residues are sensitive to pH changes. This study suggests that the catalytic aspartates can modulate the opening of the active site and substrate binding. Copyright © 2016 Elsevier Inc. All rights reserved.

Magnetic, thermodynamic and optical properties of Sb-substituted Ba2PrBiO6 double perovskite oxides

NASA Astrophysics Data System (ADS)

Onodera, K.; Kogawa, T.; Matsukawa, M.; Taniguchi, H.; Nishidate, K.; Matsushita, A.; Shimoda, M.

2018-03-01

We demonstrated crystal structures, magnetic, thermodynamic and optical properties of the B-site substituted perovskite oxides Ba2Pr(Bi1 ‑ x,Sbx ) O6 (x=0, 0.1 and 0.2). Polycrystalline samples of Sb-substituted Ba2PrBiO6 were prepared with the conventional solid-state reaction technique. The X-ray diffraction data revealed that the polycrystalline samples are an almost single phase with a monoclinic structure (C2 /m). Substitution of smaller Sb ion at Bi site causes a monotonic decrease in both the lattice parameters and volume. Magnetization measurements at high temperatures above 200 K show that the effective magnetic moment is estimated to be around 3.15 µB , which is close to that for Pr3+ion. The X-ray photoemission spectroscopy analysis revealed that a prominent peak of Pr3+ is dominant with a smaller shoulder structure of Pr4+. A Schottky-like anomaly observed in the low-temperature specific heat measurement is explained by low-lying splitting of Pr ions under the crystal field effect. Optical spectra were measured using a diffuse-reflectance method. The band gaps were estimated from the optical data to be 0.977 eV and 1.073 eV, at x = 0 and 0.2, respectively. The effect of band gap opening due to Sb substitution is examined by using the density functional theory.

Interspecific Sex in Grass Smuts and the Genetic Diversity of Their Pheromone-Receptor System

PubMed Central

Kellner, Ronny; Vollmeister, Evelyn; Feldbrügge, Michael; Begerow, Dominik

2011-01-01

The grass smuts comprise a speciose group of biotrophic plant parasites, so-called Ustilaginaceae, which are specifically adapted to hosts of sweet grasses, the Poaceae family. Mating takes a central role in their life cycle, as it initiates parasitism by a morphological and physiological transition from saprobic yeast cells to pathogenic filaments. As in other fungi, sexual identity is determined by specific genomic regions encoding allelic variants of a pheromone-receptor (PR) system and heterodimerising transcription factors. Both operate in a biphasic mating process that starts with PR–triggered recognition, directed growth of conjugation hyphae, and plasmogamy of compatible mating partners. So far, studies on the PR system of grass smuts revealed diverse interspecific compatibility and mating type determination. However, many questions concerning the specificity and evolutionary origin of the PR system remain unanswered. Combining comparative genetics and biological approaches, we report on the specificity of the PR system and its genetic diversity in 10 species spanning about 100 million years of mating type evolution. We show that three highly syntenic PR alleles are prevalent among members of the Ustilaginaceae, favouring a triallelic determination as the plesiomorphic characteristic of this group. Furthermore, the analysis of PR loci revealed increased genetic diversity of single PR locus genes compared to genes of flanking regions. Performing interspecies sex tests, we detected a high potential for hybridisation that is directly linked to pheromone signalling as known from intraspecies sex. Although the PR system seems to be optimised for intraspecific compatibility, the observed functional plasticity of the PR system increases the potential for interspecific sex, which might allow the hybrid-based genesis of newly combined host specificities. PMID:22242007

Sympatry influence in the interaction of Trypanosoma cruzi with triatomine.

PubMed

Dworak, Elaine Schultz; Araújo, Silvana Marques de; Gomes, Mônica Lúcia; Massago, Miyoko; Ferreira, Érika Cristina; Toledo, Max Jean de Ornelas

2017-01-01

Trypanosoma cruzi, the etiologic agent of Chagas disease, is widely distributed in nature, circulating between triatomine bugs and sylvatic mammals, and has large genetic diversity. Both the vector species and the genetic lineages of T. cruzi present a varied geographical distribution. This study aimed to verify the influence of sympatry in the interaction of T. cruzi with triatomines. Methods: The behavior of the strains PR2256 (T. cruzi II) and AM14 (T. cruzi IV) was studied in Triatoma sordida (TS) and Rhodnius robustus (RR). Eleven fifth-stage nymphs were fed by artificial xenodiagnosis with 5.6 × 103 blood trypomastigotes/0.1mL of each T. cruzi strain. Every 20 days, their excreta were examined for up to 100 days, and every 30 days, the intestinal content was examined for up to 120 days, by parasitological (fresh examination and differential count with Giemsa-stained smears) and molecular (PCR) methods. Rates of infectivity, metacyclogenesis and mortality, and mean number of parasites per insect and of excreted parasites were determined. Sympatric groups RR+AM14 and TS+PR2256 showed higher values of the four parameters, except for mortality rate, which was higher (27.3%) in the TS+AM14 group. General infectivity was 72.7%, which was mainly proven by PCR, showing the following decreasing order: RR+AM14 (100%), TS+PR2256 (81.8%), RR+PR2256 (72.7%) and TS+AM14 (36.4%). Our working hypothesis was confirmed once higher infectivity and vector capacity (flagellate production and elimination of infective metacyclic forms) were recorded in the groups that contained sympatric T. cruzi lineages and triatomine species.

Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland

PubMed Central

Hernández-Ramírez, Laura C.; Morgan, Rhodri M.L.; Barry, Sayka; D’Acquisto, Fulvio; Prodromou, Chrisostomos; Korbonits, Márta

2018-01-01

Despite the well-recognized role of loss-of-function mutations of the aryl hydrocarbon receptor interacting protein gene (AIP) predisposing to pituitary adenomas, the pituitary-specific function of this tumor suppressor remains an enigma. To determine the repertoire of interacting partners for the AIP protein in somatotroph cells, wild-type and variant AIP proteins were used for pull-down/quantitative mass spectrometry experiments against lysates of rat somatotropinoma-derived cells; relevant findings were validated by co-immunoprecipitation and co-localization. Global gene expression was studied in AIP mutation positive and negative pituitary adenomas via RNA microarrays. Direct interaction with AIP was confirmed for three known and six novel partner proteins. Novel interactions with HSPA5 and HSPA9, together with known interactions with HSP90AA1, HSP90AB1 and HSPA8, indicate that the function/stability of multiple chaperone client proteins could be perturbed by a deficient AIP co-chaperone function. Interactions with TUBB, TUBB2A, NME1 and SOD1 were also identified. The AIP variants p.R304* and p.R304Q showed impaired interactions with HSPA8, HSP90AB1, NME1 and SOD1; p.R304* also displayed reduced binding to TUBB and TUBB2A, and AIP-mutated tumors showed reduced TUBB2A expression. Our findings suggest that cytoskeletal organization, cell motility/adhesion, as well as oxidative stress responses, are functions that are likely to be involved in the tumor suppressor activity of AIP. PMID:29507682

RAPID RESCUE: BREAKING THE MOLD OF ROUTINE CONTINGENCY RESPONSE FOR PERSONNEL RECOVERY

DTIC Science & Technology

2016-10-23

ultimately lead to timelier response and greater economy of force for an already critically strained Air Force core function. 1 INTRODUCTION...achieve economy of force. When an OPLAN calls for PR, a capability is requested rather than individual unit. The existing UTCs are too rigid and...the combatant commander and operational planners to achieve unity and economy of force without exceeding PR capacity.61 Tactical Employment

A Preliminary Analysis of Wind Retrieval, Based on GF-3 Wave Mode Data.

PubMed

Wang, Lei; Han, Bing; Yuan, Xinzhe; Lei, Bin; Ding, Chibiao; Yao, Yulin; Chen, Qi

2018-05-17

This paper presents an analysis of measurements of the normalized radar cross-(NRCS) in Wave Mode for Chinese C-band Gaofen-3(GF-3) synthetic aperture radar (SAR). Based on 2779 images from GF-3 quad-polarization SAR in Wave Mode and collocated wind vectors from ERA-Interim, this experiment verifies the feasibility of using ocean surface wind fields and VV-polarized NRCS to perform normalized calibration. The method uses well-validated empirical C-band geophysical model function (CMOD4) to estimate the calibration constant for each beam. In addition, the relationship between cross-pol NRCS and wind vectors is discussed. The cross-pol NRCS increases linearly with wind speed and it is obviously modulated by the wind direction when the wind speed is greater than 8 m/s. Furthermore, the properties of the polarization ratio, denoted PR, are also investigated. The PR is dependent on incidence angle and azimuth angle. Two empirical models of the PR are fitted, one as a function of incidence angle only, the other with additional dependence on azimuth angle. Assessments show that the σ VV 0 retrieved from new PR models as well as σ HH 0 is in good agreement with σ VV 0 extracted from SAR images directly.

Red hair is the null phenotype of MC1R.

PubMed

Beaumont, Kimberley A; Shekar, Sri N; Cook, Anthony L; Duffy, David L; Sturm, Richard A

2008-08-01

The Melanocortin-1 Receptor (MC1R) is a G-protein coupled receptor, which is responsible for production of the darker eumelanin pigment and the tanning response. The MC1R gene has many polymorphisms, some of which have been linked to variation in pigmentation phenotypes within human populations. In particular, the p.D84E, p.R151C, p.R160W and p.D294 H alleles have been strongly associated with red hair, fair skin and increased skin cancer risk. These red hair colour (RHC) variants are relatively well described and are thought to result in altered receptor function, while still retaining varying levels of signaling ability in vitro. The mouse Mc1r null phenotype is yellow fur colour, the p.R151C, p.R160W and p.D294 H alleles were able to partially rescue this phenotype, leading to the question of what the true null phenotype of MC1R would be in humans. Due to the rarity of MC1R null alleles in human populations, they have only been found in the heterozygous state until now. We report here the first case of a homozygous MC1R null individual, phenotypic analysis indicates that red hair and fair skin is found in the absence of MC1R function.

The Strawberry Pathogenesis-related 10 (PR-10) Fra a Proteins Control Flavonoid Biosynthesis by Binding to Metabolic Intermediates*

PubMed Central

Casañal, Ana; Zander, Ulrich; Muñoz, Cristina; Dupeux, Florine; Luque, Irene; Botella, Miguel Angel; Schwab, Wilfried; Valpuesta, Victoriano; Marquez, José A.

2013-01-01

Pathogenesis-related 10 (PR-10) proteins are involved in many aspects of plant biology but their molecular function is still unclear. They are related by sequence and structural homology to mammalian lipid transport and plant abscisic acid receptor proteins and are predicted to have cavities for ligand binding. Recently, three new members of the PR-10 family, the Fra a proteins, have been identified in strawberry, where they are required for the activity of the flavonoid biosynthesis pathway, which is essential for the development of color and flavor in fruits. Here, we show that Fra a proteins bind natural flavonoids with different selectivity and affinities in the low μm range. The structural analysis of Fra a 1 E and a Fra a 3-catechin complex indicates that loops L3, L5, and L7 surrounding the ligand-binding cavity show significant flexibility in the apo forms but close over the ligand in the Fra a 3-catechin complex. Our findings provide mechanistic insight on the function of Fra a proteins and suggest that PR-10 proteins, which are widespread in plants, may play a role in the control of secondary metabolic pathways by binding to metabolic intermediates. PMID:24133217

A Preliminary Analysis of Wind Retrieval, Based on GF-3 Wave Mode Data

PubMed Central

Wang, Lei; Han, Bing; Yuan, Xinzhe; Lei, Bin; Ding, Chibiao; Yao, Yulin; Chen, Qi

2018-01-01

This paper presents an analysis of measurements of the normalized radar cross-(NRCS) in Wave Mode for Chinese C-band Gaofen-3(GF-3) synthetic aperture radar (SAR). Based on 2779 images from GF-3 quad-polarization SAR in Wave Mode and collocated wind vectors from ERA-Interim, this experiment verifies the feasibility of using ocean surface wind fields and VV-polarized NRCS to perform normalized calibration. The method uses well-validated empirical C-band geophysical model function (CMOD4) to estimate the calibration constant for each beam. In addition, the relationship between cross-pol NRCS and wind vectors is discussed. The cross-pol NRCS increases linearly with wind speed and it is obviously modulated by the wind direction when the wind speed is greater than 8 m/s. Furthermore, the properties of the polarization ratio, denoted PR, are also investigated. The PR is dependent on incidence angle and azimuth angle. Two empirical models of the PR are fitted, one as a function of incidence angle only, the other with additional dependence on azimuth angle. Assessments show that the σVV0 retrieved from new PR models as well as σHH0 is in good agreement with σVV0 extracted from SAR images directly. PMID:29772821

Unexpected magnetism, and transport properties in mixed lanthanide compound

NASA Astrophysics Data System (ADS)

Pathak, Arjun; Gschneidner, Karl, Jr.; Pecharsky, Vitalij; Ames Laboratory Team

For intelligent materials design it is desirable to have compounds which have multiple functionalities such as a large magnetoresistance, ferromagnetic and ferrimagnetic states, and field-induced first-order metamagnetic transitions. Here, we discuss one such example where we have combined two lanthanide elements Pr and Er in Pr0.6Er0.4Al2. This compound exhibits multiple functionalities in magnetic fields between 1 and 40 kOe. It undergoes only a trivial ferrimagnetism to paramagnetism transition in a zero magnetic field, but Pr0.6Er0.4Al2 exhibits a large positive magnetoresistance (MR) for H >=40 kOe, a small but non negligible negative MR for H <=30 kOe, and a clear Griffiths-like phase behavior at <1 kOe. The compound also exhibits an asymmetry of hysteresis loop, or exchange bias (EB) effect after field cooling from the paramagnetic state. These phenomena are attributed to the competition between single-ion anisotropies of Pr and Er ions coupled with the opposite nearest-neighbor and next-nearest-neighbor exchange interactions. This work was supported by the US Department of Energy, Office of Basic Energy Science, Division of Material Sciences and Engineering. The research was performed at the Ames Laboratory. The Ames Laboratory is operated by Iowa State University for the US D.

Gene replacement in Penicillium roqueforti.

PubMed

Goarin, Anne; Silar, Philippe; Malagnac, Fabienne

2015-05-01

Most cheese-making filamentous fungi lack suitable molecular tools to improve their biotechnology potential. Penicillium roqueforti, a species of high industrial importance, would benefit from functional data yielded by molecular genetic approaches. This work provides the first example of gene replacement by homologous recombination in P. roqueforti, demonstrating that knockout experiments can be performed in this fungus. To do so, we improved the existing transformation method to integrate transgenes into P. roqueforti genome. In the meantime, we cloned the PrNiaD gene, which encodes a NADPH-dependent nitrate reductase that reduces nitrate to nitrite. Then, we performed a deletion of the PrNiaD gene from P. roqueforti strain AGO. The ΔPrNiaD mutant strain is more resistant to chlorate-containing medium than the wild-type strain, but did not grow on nitrate-containing medium. Because genomic data are now available, we believe that generating selective deletions of candidate genes will be a key step to open the way for a comprehensive exploration of gene function in P. roqueforti.

Mechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate

PubMed Central

Lee, Young Kwang; Low-Nam, Shalini T.; Chung, Jean K.; Hansen, Scott D.; Lam, Hiu Yue Monatrice; Alvarez, Steven; Groves, Jay T.

2017-01-01

The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition. This inhibitory role of the PR domain limits Grb2-independent recruitment of SOS to the membrane through binding of Ras·GTP in the SOS allosteric binding site. More generally, this assay strategy enables characterization of the functional behaviour of GEFs with single-molecule precision but without the need for purification. PMID:28452363

Mechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate.

PubMed

Lee, Young Kwang; Low-Nam, Shalini T; Chung, Jean K; Hansen, Scott D; Lam, Hiu Yue Monatrice; Alvarez, Steven; Groves, Jay T

2017-04-28

The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition. This inhibitory role of the PR domain limits Grb2-independent recruitment of SOS to the membrane through binding of Ras·GTP in the SOS allosteric binding site. More generally, this assay strategy enables characterization of the functional behaviour of GEFs with single-molecule precision but without the need for purification.

A Scoping Review of Physical Rehabilitation in Long-Term Care: Interventions, Outcomes, Tools.

PubMed

McArthur, Caitlin; Gibbs, Jenna C; Patel, Ruchit; Papaioannou, Alexandra; Neves, Paula; Killingbeck, Jaimie; Hirdes, John; Milligan, James; Berg, Katherine; Giangregorio, Lora

2017-12-01

Residents in long-term care (LTC) often require physical rehabilitation (PR) to maintain/improve physical function. This scoping review described the breadth of literature regarding PR in LTC to date, synthesizing PR interventions that have been evaluated, outcomes used, and tools for determining service eligibility. A structured search, conducted in six licensed databases and grey literature, identified 381 articles for inclusion. Most interventions were delivered and evaluated at the resident level and typically were multicomponent exercise programs. Performance-based measures, activities of daily living, and mood were the most frequently reported outcomes. A key knowledge gap was PR in relation to goals, such as quality of life. Future studies should reflect medically complex residents who live in LTC, and length of residents' stay should be differentiated. Intervention studies should also explore realistic delivery methods; moreover, tool development for determining service eligibility is necessary to ensure equality in rehabilitative care across the LTC sector.

Patterns of exchange of forensic DNA data in the European Union through the Prüm system.

PubMed

Santos, Filipe; Machado, Helena

2017-07-01

This paper presents a study of the 5-year operation (2011-2015) of the transnational exchange of forensic DNA data between Member States of the European Union (EU) for the purpose of combating cross-border crime and terrorism within the so-called Prüm system. This first systematisation of the full official statistical dataset provides an overall assessment of the match figures and patterns of operation of the Prüm system for DNA exchange. These figures and patterns are analysed in terms of the differentiated contributions by participating EU Member States. The data suggest a trend for West and Central European countries to concentrate the majority of Prüm matches, while DNA databases of Eastern European countries tend to contribute with profiles of people that match stains in other countries. In view of the necessary transparency and accountability of the Prüm system, more extensive and informative statistics would be an important contribution to the assessment of its functioning and societal benefits. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Evolution in Action: N and C Termini of Subunits in Related T=4 Viruses Exchange Roles as Molecular Switches

PubMed Central

Speir, Jeffrey A.; Taylor, Derek J.; Natarajan, Padmaja; Pringle, Fiona M.; Ball, L. Andrew; Johnson, John E.

2010-01-01

Summary The T=4 tetravirus and T=3 nodavirus capsid proteins undergo closely similar autoproteolysis to produce the N-terminal ß and C-terminal, lipophilic γ polypeptides. The γ peptides and N-termini of ß also act as molecular switches that determine their quasi-equivalent capsid structures. The crystal structure of Providence virus (PrV), only the second of a tetravirus (the first was NωV), reveals conserved folds and cleavage sites, but the protein termini have completely different structures and the opposite functions of those in N⌉V. N-termini of ß form the molecular switch in PrV, while γ peptides have this role in N⌉V. PrV γ peptides instead interact with packaged RNA at the particle 2-folds using a repeating sequence pattern found in only four other RNA or membrane binding proteins. The disposition of peptide termini in PrV is closely related to those in nodaviruses suggesting that PrV may be closer to the primordial T=4 particle than NωV. PMID:20541507

Polymyalgia rheumatica and giant cell arteritis: a 5-year epidemiologic and clinical study in Reggio Emilia, Italy.

PubMed

Salvarani, C; Macchioni, P L; Tartoni, P L; Rossi, F; Baricchi, R; Castri, C; Chiaravalloti, F; Portioli, I

1987-01-01

Among the population of Reggio Emilia, Italy, 56 patients with polymyalgia rheumatica (PR) and giant cell arteritis (GCA) were identified during the 5-year period 1981-85. The average annual incidence rates of PR and GCA were 12.8 and 8.8 respectively per 100,000 population aged 50 years or older. Forty-nine patients were followed up and the mean duration of follow-up was 32 months. All the patients received steroid therapy. We have evaluated the cumulative probability of requiring continued steroid therapy between patients with PR only, GCA only, and PR associated with GCA using life-table methods with permanent discontinuation of therapy as an end point. The different duration of steroid therapy between these 3 groups did not achieve statistical significance by the method of Lee and Desu. We identified a 5 variable discriminant function that correctly predicted whether the duration of therapy would be longer or shorter than 16 months (median duration of therapy) in 80% of our patients followed up for at least 24 months. The presence of synovitis in PR is also discussed.

Superionic Conductivity of Sm3+, Pr3+, and Nd3+ Triple-Doped Ceria through Bulk and Surface Two-Step Doping Approach.

PubMed

Liu, Yanyan; Fan, Liangdong; Cai, Yixiao; Zhang, Wei; Wang, Baoyuan; Zhu, Bin

2017-07-19

Sufficiently high oxygen ion conductivity of electrolyte is critical for good performance of low-temperature solid oxide fuel cells (LT-SOFCs). Notably, material conductivity, reliability, and manufacturing cost are the major barriers hindering LT-SOFC commercialization. Generally, surface properties control the physical and chemical functionalities of materials. Hereby, we report a Sm 3+ , Pr 3+ , and Nd 3+ triple-doped ceria, exhibiting the highest ionic conductivity among reported doped-ceria oxides, 0.125 S cm -1 at 600 °C. It was designed using a two-step wet-chemical coprecipitation method to realize a desired doping for Sm 3+ at the bulk and Pr 3+ /Nd 3+ at surface domains (abbreviated as PNSDC). The redox couple Pr 3+ /Pr 4+ contributes to the extraordinary ionic conductivity. Moreover, the mechanism for ionic conductivity enhancement is demonstrated. The above findings reveal that a joint bulk and surface doping methodology for ceria is a feasible approach to develop new oxide-ion conductors with high impacts on advanced LT-SOFCs.

A Highly Toxic Cellular Prion Protein Induces a Novel, Nonapoptotic Form of Neuronal Death

PubMed Central

Christensen, Heather M.; Dikranian, Krikor; Li, Aimin; Baysac, Kathleen C.; Walls, Ken C.; Olney, John W.; Roth, Kevin A.; Harris, David A.

2010-01-01

Several different deletions within the N-terminal tail of the prion protein (PrP) induce massive neuronal death when expressed in transgenic mice. This toxicity is dose-dependently suppressed by coexpression of full-length PrP, suggesting that it results from subversion of a normal physiological activity of cellular PrP. We performed a combined biochemical and morphological analysis of Tg(ΔCR) mice, which express PrP carrying a 21-aa deletion (residues 105-125) within a highly conserved region of the protein. Death of cerebellar granule neurons in Tg(ΔCR) mice is not accompanied by activation of either caspase-3 or caspase-8 or by increased levels of the autophagy marker, LC3-II. In electron micrographs, degenerating granule neurons displayed a unique morphology characterized by heterogeneous condensation of the nuclear matrix without formation of discrete chromatin masses typical of neuronal apoptosis. Our data demonstrate that perturbations in PrP functional activity induce a novel, nonapoptotic, nonautophagic form of neuronal death whose morphological features are reminiscent of those associated with excitotoxic stress. PMID:20472884

A multimedia Electronic Patient Record (ePR) system for Image-Assisted Minimally Invasive Spinal Surgery

PubMed Central

Documet, Jorge; Le, Anh; Liu, Brent; Chiu, John; Huang, HK

2009-01-01

Purpose This paper presents the concept of bridging the gap between diagnostic images and image-assisted surgical treatment through the development of a one-stop multimedia electronic patient record (ePR) system that manages and distributes the real-time multimodality imaging and informatics data that assists the surgeon during all clinical phases of the operation from planning Intra-Op to post-care follow-up. We present the concept of this multimedia ePR for surgery by first focusing on Image-Assisted Minimally Invasive Spinal Surgery as a clinical application. Methods Three clinical Phases of Minimally Invasive Spinal Surgery workflow in Pre-Op, Intra-Op, and Post Op are discussed. The ePR architecture was developed based on the three-phased workflow, which includes the Pre-Op, Intra-Op, and Post-Op modules and four components comprising of the input integration unit, fault-tolerant gateway server, fault-tolerant ePR server, and the visualization and display. A prototype was built and deployed to a Minimally Invasive Spinal Surgery clinical site with user training and support for daily use. Summary A step-by step approach was introduced to develop a multi-media ePR system for Imaging-Assisted Minimally Invasive Spinal Surgery that includes images, clinical forms, waveforms, and textual data for planning the surgery, two real-time imaging techniques (digital fluoroscopic, DF) and endoscope video images (Endo), and more than half a dozen live vital signs of the patient during surgery. Clinical implementation experiences and challenges were also discussed. PMID:20033507

The HIV-1 late domain-2 S40A polymorphism in antiretroviral (or ART)-exposed individuals influences protease inhibitor susceptibility.

PubMed

Watanabe, Susan M; Simon, Viviana; Durham, Natasha D; Kemp, Brittney R; Machihara, Satoshi; Kemal, Kimdar Sherefa; Shi, Binshan; Foley, Brian; Li, Hongru; Chen, Benjamin K; Weiser, Barbara; Burger, Harold; Anastos, Kathryn; Chen, Chaoping; Carter, Carol A

2016-09-06

The p6 region of the HIV-1 structural precursor polyprotein, Gag, contains two motifs, P7TAP11 and L35YPLXSL41, designated as late (L) domain-1 and -2, respectively. These motifs bind the ESCRT-I factor Tsg101 and the ESCRT adaptor Alix, respectively, and are critical for efficient budding of virus particles from the plasma membrane. L domain-2 is thought to be functionally redundant to PTAP. To identify possible other functions of L domain-2, we examined this motif in dominant viruses that emerged in a group of 14 women who had detectable levels of HIV-1 in both plasma and genital tract despite a history of current or previous antiretroviral therapy. Remarkably, variants possessing mutations or rare polymorphisms in the highly conserved L domain-2 were identified in seven of these women. A mutation in a conserved residue (S40A) that does not reduce Gag interaction with Alix and therefore did not reduce budding efficiency was further investigated. This mutation causes a simultaneous change in the Pol reading frame but exhibits little deficiency in Gag processing and virion maturation. Whether introduced into the HIV-1 NL4-3 strain genome or a model protease (PR) precursor, S40A reduced production of mature PR. This same mutation also led to high level detection of two extended forms of PR that were fairly stable compared to the WT in the presence of IDV at various concentrations; one of the extended forms was effective in trans processing even at micromolar IDV. Our results indicate that L domain-2, considered redundant in vitro, can undergo mutations in vivo that significantly alter PR function. These may contribute fitness benefits in both the absence and presence of PR inhibitor.

Enhanced Mixed Electronic-Ionic Conductors through Cation Ordering

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

Jacobson, Allan J.; Morgan, Dane; Grey, Clare

2014-08-31

The performance of many energy conversion and storage devices depend on the properties of mixed ionic-electronic conducting (miec) materials. Mixed or ambipolar conductors simultaneously transport ions and electrons and provide the critical interface between chemical and electrical energy in devices such as fuel cells, ion transport membranes, and batteries. Enhancements in storage capacity, reversibility, power density and device lifetime all require new materials and a better understanding of the fundamentals of ambipolar conductivity and surface reactivity.The high temperature properties of the ordered perovksites AA’B 2O 5+x, where A = rare earth ion, Y and B = Ba, Sr were studied.more » The work was motivated by the high oxygen transport and surface exchange rates observed for members of this class of mixed ionic and electronic conductors. A combined experimental and computational approach, including structural, electrochemical, and transport characterization and modeling was used. The approach attacks the problem simultaneously at global (e.g., neutron diffraction and impedance spectroscopy), local (e.g., pair distribution function, nuclear magnetic resonance) and molecular (ab initio thermokinetic modeling) length scales. The objectives of the work were to understand how the cation and associated anion order lead to exceptional ionic and electronic transport properties and surface reactivity in AA’B2O5+x perovskites. A variety of compounds were studied by X-ray and neutron diffraction, measurements of thermodynamics and transport and theoretically. These included PrBaCo 2O 5+x and NdBaCo 2O 5+x, PrBaCo 2-xFexO 6- δ (x = 0, 0.5, 1.0, 1.5 and 2) and LnBaCoFeO 6- δ (Ln = La, Pr, Nd, Sm, Eu and Gd), Sr 3YCo 4O 10.5, YBaMn 2O 5+x. A 0.5A’ 0.5BO 3 (where A=Y, Sc, La, Ce, Pr, Nd, Pm, Sm; A’= Sr, Ba; and B= Fe, Co, Mn, Ni), Ba 2In 2O 5, and La 1 xSr xCoO 3-δ /(La 1-ySry) 2CoO 4±δ interfaces.« less

New examples of ternary rare-earth metal boride carbides containing finite boron carbon chains: The crystal and electronic structure of RE15B6C20 (RE=Pr, Nd)

NASA Astrophysics Data System (ADS)

Babizhetskyy, Volodymyr; Mattausch, Hansjürgen; Simon, Arndt; Hiebl, Kurt; Ben Yahia, Mouna; Gautier, Régis; Halet, Jean-François

2008-08-01

The ternary rare-earth metal boride carbides RE15B6C20 (RE=Pr, Nd) were synthesized by co-melting the elements. They exist above 1270 K. Their crystal structures were determined from single-crystal X-ray diffraction data. Both crystallize in the space group P1¯, Z=1, a=8.3431(8) Å, b=9.2492(9) Å, c=8.3581(8) Å, α=84.72(1)°, β=89.68(1)°, γ =84.23(1)° (R1=0.041 (wR2=0.10) for 3291 reflections with Io>2σ(Io)) for Pr15B6C20, and a=8.284(1) Å, b=9.228(1) Å, c=8.309(1) Å, α=84.74(1)°, β=89.68(1)°, γ=84.17(2)° (R1=0.033 (wR2=0.049) for 2970 reflections with Io>2σ(Io)) for Nd15B6C20. Their structure consists of a three-dimensional framework of rare-earth metal atoms resulting from the stacking of slightly corrugated and distorted square nets, leading to cavities filled with unprecedented B2C4 finite chains, disordered C3 entities and isolated carbon atoms, respectively. Structural and theoretical analyses suggest the ionic formulation (RE3+)15([B2C4]6-)3([C3]4-)2(C4-)2·11ē. Accordingly, density functional theory calculations indicate that the compounds are metallic. Both structural arguments as well as energy calculations on different boron vs. carbon distributions in the B2C4 chains support the presence of a CBCCBC unit. Pr15B6C18 exhibits antiferromagnetic order at TN=7.9 K, followed by a meta-magnetic transition above a critical external field B>0.03 T. On the other hand, Nd15B6C18 is a ferromagnet below TC≈40 K.

Cellular prion protein modulates defensive attention and innate fear-induced behaviour evoked in transgenic mice submitted to an agonistic encounter with the tropical coral snake Oxyrhopus guibei.

PubMed

Lobão-Soares, Bruno; Walz, Roger; Prediger, Rui Daniel Schröder; Freitas, Renato Leonardo; Calvo, Fabrício; Bianchin, Marino Muxfeldt; Leite, João Pereira; Landemberger, Michele Christine; Coimbra, Norberto Cysne

2008-12-12

The cellular prion protein (PrP(C)) is a neuronal anchored glycoprotein that has been associated with distinct functions in the CNS, such as cellular adhesion and differentiation, synaptic plasticity and cognition. Here we investigated the putative involvement of the PrP(C) in the innate fear-induced behavioural reactions in wild-type (WT), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice evoked in a prey versus predator paradigm. The behavioural performance of these mouse strains in olfactory discrimination tasks was also investigated. When confronted with coral snakes, mice from both Prnp(0/0) and Tg-20 strains presented a significant decrease in frequency and duration of defensive attention and risk assessment, compared to WT mice. Tg-20 mice presented decreased frequency of escape responses, increased exploratory behaviour, and enhancement of interaction with the snake, suggesting a robust fearlessness caused by PrP(C) overexpression. Interestingly, there was also a discrete decrease in the attentional defensive response (decreased frequency of defensive alertness) in Prnp(0/0) mice in the presence of coral snakes. Moreover, Tg-20 mice presented an increased exploration of novel environment and odors. The present findings indicate that the PrP(C) overexpression causes hyperactivity, fearlessness, and increased preference for visual, tactile and olfactory stimuli-associated novelty, and that the PrP(c) deficiency might lead to attention deficits. These results suggest that PrP(c) exerts an important role in the modulation of innate fear and novelty-induced exploration.

Benefits of pulmonary rehabilitation in patients with COPD and normal exercise capacity.

PubMed

Lan, Chou-Chin; Chu, Wen-Hua; Yang, Mei-Chen; Lee, Chih-Hsin; Wu, Yao-Kuang; Wu, Chin-Pyng

2013-09-01

Pulmonary rehabilitation (PR) is beneficial for patients with COPD, with improvement in exercise capacity and health-related quality of life. Despite these overall benefits, the responses to PR vary significantly among different individuals. It is not clear if PR is beneficial for patients with COPD and normal exercise capacity. We aimed to investigate the effects of PR in patients with normal exercise capacity on health-related quality of life and exercise capacity. Twenty-six subjects with COPD and normal exercise capacity were studied. All subjects participated in 12-week, 2 sessions per week, hospital-based, out-patient PR. Baseline and post-PR status were evaluated by spirometry, the St George's Respiratory Questionnaire, cardiopulmonary exercise test, respiratory muscle strength, and dyspnea scores. The mean FEV1 in the subjects was 1.29 ± 0.47 L/min, 64.8 ± 23.0% of predicted. After PR there was significant improvement in maximal oxygen uptake and work rate. Improvements in St George's Respiratory Questionnaire scores of total, symptoms, activity, and impact were accompanied by improvements of exercise capacity, respiratory muscle strength, maximum oxygen pulse, and exertional dyspnea scores (all P < .05). There were no significant changes in pulmonary function test results (FEV1, FVC, and FEV1/FVC), minute ventilation, breathing frequency, or tidal volume at rest or exercise after PR. Exercise training can result in significant improvement in health-related quality of life, exercise capacity, respiratory muscle strength, and exertional dyspnea in subjects with COPD and normal exercise capacity. Exercise training is still indicated for patients with normal exercise capacity.

An Ethylene-Induced Regulatory Module Delays Flower Senescence by Regulating Cytokinin Content.

PubMed

Wu, Lin; Ma, Nan; Jia, Yangchao; Zhang, Yi; Feng, Ming; Jiang, Cai-Zhong; Ma, Chao; Gao, Junping

2017-01-01

In many plant species, including rose (Rosa hybrida), flower senescence is promoted by the gaseous hormone ethylene and inhibited by the cytokinin (CTK) class of hormones. However, the molecular mechanisms underlying these antagonistic effects are not well understood. In this study, we characterized the association between a pathogenesis-related PR-10 family gene from rose (RhPR10.1) and the hormonal regulation of flower senescence. Quantitative reverse transcription PCR analysis showed that RhPR10.1 was expressed at high levels during senescence in different floral organs, including petal, sepal, receptacle, stamen, and pistil, and that expression was induced by ethylene treatment. Silencing of RhPR10.1 expression in rose plants by virus-induced gene silencing accelerated flower senescence, which was accompanied by a higher ion leakage rate in the petals, as well as increased expression of the senescence marker gene RhSAG12 CTK content and the expression of three CTK signaling pathway genes were reduced in RhPR10.1-silenced plants, and the accelerated rate of petal senescence that was apparent in the RhPR10.1-silenced plants was restored to normal levels by CTK treatment. Finally, RhHB6, a homeodomain-Leu zipper I transcription factor, was observed to bind to the RhPR10.1 promoter, and silencing of its expression also promoted flower senescence. Our results reveal an ethylene-induced RhHB6-RhPR10.1 regulatory module that functions as a brake of ethylene-promoted senescence through increasing the CTK content. © 2017 American Society of Plant Biologists. All Rights Reserved.

Conserved Epigenetic Mechanisms Could Play a Key Role in Regulation of Photosynthesis and Development-Related Genes during Needle Development of Pinus radiata.

PubMed

Valledor, Luis; Pascual, Jesús; Meijón, Mónica; Escandón, Mónica; Cañal, María Jesús

2015-01-01

Needle maturation is a complex process that involves cell growth, differentiation and tissue remodelling towards the acquisition of full physiological competence. Leaf induction mechanisms are well known; however, those underlying the acquisition of physiological competence are still poorly understood, especially in conifers. We studied the specific epigenetic regulation of genes defining organ function (PrRBCS and PrRBCA) and competence and stress response (PrCSDP2 and PrSHMT4) during three stages of needle development and one de-differentiated control. Gene-specific changes in DNA methylation and histone were analysed by bisulfite sequencing and chromatin immunoprecipitation (ChIP). The expression of PrRBCA and PrRBCS increased during needle maturation and was associated with the progressive loss of H3K9me3, H3K27me3 and the increase in AcH4. The maturation-related silencing of PrSHMT4 was correlated with increased H3K9me3 levels, and the repression of PrCSDP2, to the interplay between AcH4, H3K27me3, H3K9me3 and specific DNA methylation. The employ of HAT and HDAC inhibitors led to a further determination of the role of histone acetylation in the regulation of our target genes. The integration of these results with high-throughput analyses in Arabidopsis thaliana and Populus trichocarpa suggests that the specific epigenetic mechanisms that regulate photosynthetic genes are conserved between the analysed species.

Conserved Epigenetic Mechanisms Could Play a Key Role in Regulation of Photosynthesis and Development-Related Genes during Needle Development of Pinus radiata

PubMed Central

Meijón, Mónica; Escandón, Mónica; Cañal, María Jesús

2015-01-01

Needle maturation is a complex process that involves cell growth, differentiation and tissue remodelling towards the acquisition of full physiological competence. Leaf induction mechanisms are well known; however, those underlying the acquisition of physiological competence are still poorly understood, especially in conifers. We studied the specific epigenetic regulation of genes defining organ function (PrRBCS and PrRBCA) and competence and stress response (PrCSDP2 and PrSHMT4) during three stages of needle development and one de-differentiated control. Gene-specific changes in DNA methylation and histone were analysed by bisulfite sequencing and chromatin immunoprecipitation (ChIP). The expression of PrRBCA and PrRBCS increased during needle maturation and was associated with the progressive loss of H3K9me3, H3K27me3 and the increase in AcH4. The maturation-related silencing of PrSHMT4 was correlated with increased H3K9me3 levels, and the repression of PrCSDP2, to the interplay between AcH4, H3K27me3, H3K9me3 and specific DNA methylation. The employ of HAT and HDAC inhibitors led to a further determination of the role of histone acetylation in the regulation of our target genes. The integration of these results with high-throughput analyses in Arabidopsis thaliana and Populus trichocarpa suggests that the specific epigenetic mechanisms that regulate photosynthetic genes are conserved between the analysed species. PMID:25965766

Methods and Protocols for Developing Prion Vaccines.

PubMed

Marciniuk, Kristen; Taschuk, Ryan; Napper, Scott

2016-01-01

Prion diseases denote a distinct form of infectivity that is based in the misfolding of a self-protein (PrP(C)) into a pathological, infectious conformation (PrP(Sc)). Efforts to develop vaccines for prion diseases have been complicated by the potential dangers that are associated with induction of immune responses against a self-protein. As a consequence, there is considerable appeal for vaccines that specifically target the misfolded prion conformation. Such conformation-specific immunotherapy is made possible through the identification of vaccine targets (epitopes) that are exclusively presented as a consequence of misfolding. An immune response directed against these targets, termed disease-specific epitopes (DSEs), has the potential to spare the function of the native form of the protein while clearing, or neutralizing, the infectious isomer. Although identification of DSEs represents a critical first step in the induction of conformation-specific immune responses, substantial efforts are required to translate these targets into functional vaccines. Due to the poor immunogenicity that is inherent to self-proteins, and that is often associated with short peptides, substantial efforts are required to overcome tolerance-to-self and maximize the resultant immune response following DSE-based immunization. This often includes optimization of target sequences in terms of immunogenicity and development of effective formulation and delivery strategies for the associated peptides. Further, these vaccines must satisfy additional criteria from perspectives of specificity (PrP(C) vs. PrP(Sc)) and safety (antibody-induced template-driven misfolding of PrP(C)). The emphasis of this report is on the steps required to translate DSEs into prion vaccines and subsequent evaluation of the resulting immune responses.

Effects of quantum interference between radiative and dielectronic recombination on photorecombination cross-section profiles for the He-like ions Ar{sup 16+} and Fe{sup 24+}

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

Behar, Ehud; Jacobs, Verne L.; Oreg, Joseph

Total cross sections for electron-ion photorecombination (PR) processes are calculated using a projection-operator and resolvent-operator approach. This approach provides a unified quantum-mechanical description of the combined electron-ion PR process, including radiative and dielectronic recombination as coherent, interfering components. An especially adapted version of the Hebrew-University Lawrence-Livermore Atomic Code HULLAC is developed and employed for the calculations. In particular, PR cross sections for He-like argon and iron ions are calculated for incident-electron energies in the vicinity of the 1s2l2l{sup '} and 1s2l3l{sup '} doubly-excited, autoionizing levels of the Li-like ions. Significant effects of quantum interference between radiative and dielectronic recombination, inmore » the form of asymmetric PR cross-section profiles, are predicted, especially for weak transitions. The general behavior of the interference effect, as a function of the ion charge q and as a function of the principal quantum number n{sup '} of the outer electron in the autoionizing state, is investigated using a hydrogenic-scaling analysis. It is found that the degree of asymmetry in the PR cross-section profile can be substantial for close-to-neutral ions and also for very highly-charged ions. In the intermediate-charge regime, on the other hand, the asymmetry is anticipated to be less prominent. The dependence of the quantum-interference effect on n{sup '} is predicted to be much weaker.« less

Reciprocal peer review for quality improvement: an ethnographic case study of the Improving Lung Cancer Outcomes Project.

PubMed

Aveling, Emma-Louise; Martin, Graham; Jiménez García, Senai; Martin, Lisa; Herbert, Georgia; Armstrong, Natalie; Dixon-Woods, Mary; Woolhouse, Ian

2012-12-01

Peer review offers a promising way of promoting improvement in health systems, but the optimal model is not yet clear. We aimed to describe a specific peer review model-reciprocal peer-to-peer review (RP2PR)-to identify the features that appeared to support optimal functioning. We conducted an ethnographic study involving observations, interviews and documentary analysis of the Improving Lung Cancer Outcomes Project, which involved 30 paired multidisciplinary lung cancer teams participating in facilitated reciprocal site visits. Analysis was based on the constant comparative method. Fundamental features of the model include multidisciplinary participation, a focus on discussion and observation of teams in action, rather than paperwork; facilitated reflection and discussion on data and observations; support to develop focused improvement plans. Five key features were identified as important in optimising this model: peers and pairing methods; minimising logistic burden; structure of visits; independent facilitation; and credibility of the process. Facilitated RP2PR was generally a positive experience for participants, but implementing improvement plans was challenging and required substantial support. RP2PR appears to be optimised when it is well organised; a safe environment for learning is created; credibility is maximised; implementation and impact are supported. RP2PR is seen as credible and legitimate by lung cancer teams and can act as a powerful stimulus to produce focused quality improvement plans and to support implementation. Our findings have identified how RP2PR functioned and may be optimised to provide a constructive, open space for identifying opportunities for improvement and solutions.

Executive function associated with sexual risk in young South African women: Findings from the HPTN 068 cohort

PubMed Central

Pettifor, Audrey; Duta, Mihaela; Demeyere, Nele; Wagner, Ryan G.; Selin, Amanda; MacPhail, Catherine; Laeyendecker, Oliver; Hughes, James P.; Stein, Alan; Tollman, Stephen; Kahn, Kathleen

2018-01-01

Purpose Heightened sexual risk in adolescence and young adulthood may be partially explained by deficits in executive functioning, the set of cognitive processes used to make reasoned decisions. However, the association between executive function and sexual risk is understudied among adolescent girls and young women, particularly in low- and middle-income countries. Methods In a cohort of 853 young women age 18–25 in rural Mpumalanga province, South Africa, we evaluated executive function with three non-verbal cognitive tests: I. a rule-finding test, II. a trail-making test, and III. a figure drawing test. Using log-binomial regression models, we estimated the association between lower executive function test scores and indicators of sexual risk (unprotected sex acts, concurrent partnerships, transactional sex, and recent HSV-2 infection). Results In general, young women with lower executive function scores reported higher frequencies of sexual risk outcomes, though associations tended to be small with wide confidence intervals. Testing in the lowest quintile of Test I was associated with more unprotected sex [aPR (95% CI): 1.4 (1.0, 1.8)]. Testing in the lowest quintile of Test II was associated with more concurrent relationships and transactional sex [aPR (95% CI): 1.6 (1.1, 2.5) and 1.7 (1.3, 2.4), respectively], and testing in the lowest four quintiles of Test III was associated with more concurrent relationships [aPR (95% CI): 1.7 (1.0, 2.7)]. Conclusions These results demonstrate an association between low executive function and sexual risk in South African young women. Future work should seek to understand the nature of this association and whether there is promise in developing interventions to enhance executive function to reduce sexual risk. PMID:29608615

A 2.5-Kilobase Deletion Containing a Cluster of Nine MicroRNAs in the Latency-Associated-Transcript Locus of the Pseudorabies Virus Affects the Host Response of Porcine Trigeminal Ganglia during Established Latency

PubMed Central

Mahjoub, Nada; Dhorne-Pollet, Sophie; Fuchs, Walter; Endale Ahanda, Marie-Laure; Lange, Elke; Klupp, Barbara; Arya, Anoop; Loveland, Jane E.; Lefevre, François; Mettenleiter, Thomas C.

2014-01-01

ABSTRACT The alphaherpesvirus pseudorabies virus (PrV) establishes latency primarily in neurons of trigeminal ganglia when only the transcription of the latency-associated transcript (LAT) locus is detected. Eleven microRNAs (miRNAs) cluster within the LAT, suggesting a role in establishment and/or maintenance of latency. We generated a mutant (M) PrV deleted of nine miRNA genes which displayed properties that were almost identical to those of the parental PrV wild type (WT) during propagation in vitro. Fifteen pigs were experimentally infected with either WT or M virus or were mock infected. Similar levels of virus excretion and host antibody response were observed in all infected animals. At 62 days postinfection, trigeminal ganglia were excised and profiled by deep sequencing and quantitative RT-PCR. Latency was established in all infected animals without evidence of viral reactivation, demonstrating that miRNAs are not essential for this process. Lower levels of the large latency transcript (LLT) were found in ganglia infected by M PrV than in those infected by WT PrV. All PrV miRNAs were expressed, with highest expression observed for prv-miR-LLT1, prv-miR-LLT2 (in WT ganglia), and prv-miR-LLT10 (in both WT and M ganglia). No evidence of differentially expressed porcine miRNAs was found. Fifty-four porcine genes were differentially expressed between WT, M, and control ganglia. Both viruses triggered a strong host immune response, but in M ganglia gene upregulation was prevalent. Pathway analyses indicated that several biofunctions, including those related to cell-mediated immune response and the migration of dendritic cells, were impaired in M ganglia. These findings are consistent with a function of the LAT locus in the modulation of host response for maintaining a latent state. IMPORTANCE This study provides a thorough reference on the establishment of latency by PrV in its natural host, the pig. Our results corroborate the evidence obtained from the study of several LAT mutants of other alphaherpesviruses encoding miRNAs from their LAT regions. Neither PrV miRNA expression nor high LLT expression levels are essential to achieve latency in trigeminal ganglia. Once latency is established by PrV, the only remarkable differences are found in the pattern of host response. This indicates that, as in herpes simplex virus, LAT functions as an immune evasion locus. PMID:25320324

PageRank and rank-reversal dependence on the damping factor

NASA Astrophysics Data System (ADS)

Son, S.-W.; Christensen, C.; Grassberger, P.; Paczuski, M.

2012-12-01

PageRank (PR) is an algorithm originally developed by Google to evaluate the importance of web pages. Considering how deeply rooted Google's PR algorithm is to gathering relevant information or to the success of modern businesses, the question of rank stability and choice of the damping factor (a parameter in the algorithm) is clearly important. We investigate PR as a function of the damping factor d on a network obtained from a domain of the World Wide Web, finding that rank reversal happens frequently over a broad range of PR (and of d). We use three different correlation measures, Pearson, Spearman, and Kendall, to study rank reversal as d changes, and we show that the correlation of PR vectors drops rapidly as d changes from its frequently cited value, d0=0.85. Rank reversal is also observed by measuring the Spearman and Kendall rank correlation, which evaluate relative ranks rather than absolute PR. Rank reversal happens not only in directed networks containing rank sinks but also in a single strongly connected component, which by definition does not contain any sinks. We relate rank reversals to rank pockets and bottlenecks in the directed network structure. For the network studied, the relative rank is more stable by our measures around d=0.65 than at d=d0.

Dissociation of recombinant prion autocatalysis from infectivity.

PubMed

Noble, Geoffrey P; Supattapone, Surachai

2015-01-01

Within the mammalian prion field, the existence of recombinant prion protein (PrP) conformers with self-replicating (ie. autocatalytic) activity in vitro but little to no infectious activity in vivo challenges a key prediction of the protein-only hypothesis of prion replication--that autocatalytic PrP conformers should be infectious. To understand this dissociation of autocatalysis from infectivity, we recently performed a structural and functional comparison between a highly infectious and non-infectious pair of autocatalytic recombinant PrP conformers derived from the same initial prion strain. (1) We identified restricted, C-terminal structural differences between these 2 conformers and provided evidence that these relatively subtle differences prevent the non-infectious conformer from templating the conversion of native PrP(C) substrates containing a glycosylphosphatidylinositol (GPI) anchor. (1) In this article we discuss a model, consistent with these findings, in which recombinant PrP, lacking post-translational modifications and associated folding constraints, is capable of adopting a wide variety of autocatalytic conformations. Only a subset of these recombinant conformers can be adopted by post-translationally modified native PrP(C), and this subset represents the recombinant conformers with high specific infectivity. We examine this model's implications for the generation of highly infectious recombinant prions and the protein-only hypothesis of prion replication.

Mapping PrBn and Other Quantitative Trait Loci Responsible for the Control of Homeologous Chromosome Pairing in Oilseed Rape (Brassica napus L.) Haploids

PubMed Central

Liu, Zhiqian; Adamczyk, Katarzyna; Manzanares-Dauleux, Maria; Eber, Frédérique; Lucas, Marie-Odile; Delourme, Régine; Chèvre, Anne Marie; Jenczewski, Eric

2006-01-01

In allopolyploid species, fair meiosis could be challenged by homeologous chromosome pairing and is usually achieved by the action of homeologous pairing suppressor genes. Oilseed rape (Brassica napus) haploids (AC, n = 19) represent an attractive model for studying the mechanisms used by allopolyploids to ensure the diploid-like meiotic pairing pattern. In oilseed rape haploids, homeologous chromosome pairing at metaphase I was found to be genetically based and controlled by a major gene, PrBn, segregating in a background of polygenic variation. In this study, we have mapped PrBn within a 10-cM interval on the C genome linkage group DY15 and shown that PrBn displays incomplete penetrance or variable expressivity. We have identified three to six minor QTL/BTL that have slight additive effects on the amount of pairing at metaphase I but do not interact with PrBn. We have also detected a number of other loci that interact epistatically, notably with PrBn. Our results support the idea that, as in other polyploid species, metaphase I homeologous pairing in oilseed rape haploids is controlled by an integrated system of several genes, which function in a complex manner. PMID:16951054

Subepidermal moisture detection of heel pressure injury: The pressure ulcer detection study outcomes.

PubMed

Bates-Jensen, Barbara M; McCreath, Heather E; Nakagami, Gojiro; Patlan, Anabel

2018-04-01

We examined subepidermal moisture (SEM) and visual skin assessment of heel pressure injury (PrI) among 417 nursing home residents in 19 facilities over 16 weeks. Participants were older (mean age 77 years), 58% were female, over half were ethnic minorities (29% African American, 12% Asian American, 21% Hispanic), and at risk for PrI (mean Braden Scale Risk score = 15.6). Blinded concurrent visual assessments and SEM measurements were obtained at heels weekly. Visual skin damage was categorised as normal, erythema, stage 1 PrI, deep tissue injury (DTI) or stage 2 or greater PrI. PrI incidence was 76%. Off-loading occurred with pillows (76% of residents) rather than heel boots (21%) and often for those with DTI (91%). Subepidermal moisture was measured with a device where higher readings indicate greater moisture (range: 0-70 tissue dielectric constant), with normal skin values significantly different from values in the presence of skin damage. Subepidermal moisture was associated with concurrent damage and damage 1 week later in generalised multinomial logistic models adjusting for age, diabetes and function. Subepidermal moisture detected DTI and differentiated those that resolved, remained and deteriorated over 16 weeks. Subepidermal moisture may be an objective method for detecting PrI. © 2017 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

DLRS: gene tree evolution in light of a species tree.

PubMed

Sjöstrand, Joel; Sennblad, Bengt; Arvestad, Lars; Lagergren, Jens

2012-11-15

PrIME-DLRS (or colloquially: 'Delirious') is a phylogenetic software tool to simultaneously infer and reconcile a gene tree given a species tree. It accounts for duplication and loss events, a relaxed molecular clock and is intended for the study of homologous gene families, for example in a comparative genomics setting involving multiple species. PrIME-DLRS uses a Bayesian MCMC framework, where the input is a known species tree with divergence times and a multiple sequence alignment, and the output is a posterior distribution over gene trees and model parameters. PrIME-DLRS is available for Java SE 6+ under the New BSD License, and JAR files and source code can be downloaded from http://code.google.com/p/jprime/. There is also a slightly older C++ version available as a binary package for Ubuntu, with download instructions at http://prime.sbc.su.se. The C++ source code is available upon request. joel.sjostrand@scilifelab.se or jens.lagergren@scilifelab.se. PrIME-DLRS is based on a sound probabilistic model (Åkerborg et al., 2009) and has been thoroughly validated on synthetic and biological datasets (Supplementary Material online).

Diagnostic value of progesterone receptor, p16, p53 and pHH3 expression in uterine atypical leiomyoma.

PubMed

Liang, Yun; Zhang, Xiaofei; Chen, Xiaoduan; Lü, Weiguo

2015-01-01

The differential diagnosis between atypical leiomyoma and leiomyosarcoma may be hard based on morphological criterion at times. It would be helpful to find out biomarkers that can be used to distinguish them. The aim of the study was to investigate the diagnostic value of progesterone receptor (PR), p16, p53 and pHH3 expression in a series of uterine smooth muscle tumors. Immunohistochemical expression of PR, p16, p53 and pHH3 was investigated on 32 atypical leiomyomas, 15 leiomyosarcomas and 15 usual leomyomas. The difference in expression was compared between atypical leiomyoma and other groups. The expression of PR, p16, and pHH3 was found significantly different between atypical leiomyomas and leiomyosarcomas, but lack of significant difference between atypical leiomyomas and usual leiomyomas. There was no significant difference with regard to p53 distribution among these uterine smooth muscle tumors. High p16, pHH3 expression and low PR expression preferred the diagnosis of leiomyosarcoma. The panel of antibodies used in this study is a useful complementary analysis in the assessment of problematic uterine smooth muscle tumors.

Diagnostic value of progesterone receptor, p16, p53 and pHH3 expression in uterine atypical leiomyoma

PubMed Central

Liang, Yun; Zhang, Xiaofei; Chen, Xiaoduan; Lü, Weiguo

2015-01-01

The differential diagnosis between atypical leiomyoma and leiomyosarcoma may be hard based on morphological criterion at times. It would be helpful to find out biomarkers that can be used to distinguish them. The aim of the study was to investigate the diagnostic value of progesterone receptor (PR), p16, p53 and pHH3 expression in a series of uterine smooth muscle tumors. Immunohistochemical expression of PR, p16, p53 and pHH3 was investigated on 32 atypical leiomyomas, 15 leiomyosarcomas and 15 usual leomyomas. The difference in expression was compared between atypical leiomyoma and other groups. The expression of PR, p16, and pHH3 was found significantly different between atypical leiomyomas and leiomyosarcomas, but lack of significant difference between atypical leiomyomas and usual leiomyomas. There was no significant difference with regard to p53 distribution among these uterine smooth muscle tumors. High p16, pHH3 expression and low PR expression preferred the diagnosis of leiomyosarcoma. The panel of antibodies used in this study is a useful complementary analysis in the assessment of problematic uterine smooth muscle tumors. PMID:26261614

Stoneflies of the genus Zwicknia Murányi, 2014 (Plecoptera: Capniidae) from western Switzerland.

PubMed

Reding, Jean-Paul G

2018-02-21

Le genre Zwicknia Murányi, de la famille des Capniidae, a récemment été proposé pour inclure Capnia bifrons (Newman), ce qui a rendu nécessaire la révision du matériel collecté en Suisse occidentale et identifié précédemment comme correspondant à cette espèce. Cette révision, qui a depuis abouti à la description d'une espèce nouvelle pour la science, Zwicknia ledoarei Reding et al., est maintenant complétée, permettant de signaler la présence de deux espèces supplémentaires, Z. bifrons et Z. westermanni Boumans Murányi, la dernière nouvelle pour la Suisse. Des informations sur la distribution, les préférences écologiques, la zoogéographie et le statut de conservation de ces espèces en Suisse occidentale sont également apportées. Finalement, une clé d'identification pour les larves et les adultes mâles des espèces précitées est proposée.

Proteolytic Processing and Assembly of gag and gag-pol Proteins of TED, a Baculovirus-Associated Retrotransposon of the Gypsy Family

PubMed Central

Hajek, Kathryn L.; Friesen, Paul D.

1998-01-01

TED (transposable element D) is an env-containing member of the gypsy family of retrotransposons that represents a possible retrovirus of invertebrates. This lepidopteran (moth) retroelement contains gag and pol genes that encode proteins capable of forming viruslike particles (VLP) with reverse transcriptase. Since VLP are likely intermediates in TED transposition, we investigated the roles of gag and pol in TED capsid assembly and maturation. By using constructed baculovirus vectors and TED Gag-specific antiserum, we show that the principal translation product of gag (Pr55gag) is cleaved to produce a single VLP structural protein, p37gag. Replacement of Asp436 within the retrovirus-like active site of the pol-encoded protease (PR) abolished Pr55gag cleavage and demonstrated the requirement for PR in capsid processing. As shown by expression of an in-frame fusion of TED gag and pol, PR is derived from the Gag-Pol polyprotein Pr195gag-pol. The PR cleavage site within Pr55gag was mapped to a position near the junction of a basic, nucleocapsid-like domain and a C-terminal acidic domain. Once released by cleavage, the C-terminal fragment was not detected. This acidic fragment was dispensable for VLP assembly, as demonstrated by the formation of VLP by C-terminal Pr55gag truncation proteins and replacement of the acidic domain with a heterologous protein. In contrast, C-terminal deletions that extended into the adjacent nucleocapsid-like domain of Pr55gag abolished VLP recovery and demonstrated that this central region contributes to VLP assembly or stability, or both. Collectively, these data suggest that the single TED protein p37gag provides both capsid and nucleocapsid functions. TED may therefore use a simple processing strategy for VLP assembly and genome packaging. PMID:9765414

Proteolytic processing and assembly of gag and gag-pol proteins of TED, a baculovirus-associated retrotransposon of the gypsy family.

PubMed

Hajek, K L; Friesen, P D

1998-11-01

TED (transposable element D) is an env-containing member of the gypsy family of retrotransposons that represents a possible retrovirus of invertebrates. This lepidopteran (moth) retroelement contains gag and pol genes that encode proteins capable of forming viruslike particles (VLP) with reverse transcriptase. Since VLP are likely intermediates in TED transposition, we investigated the roles of gag and pol in TED capsid assembly and maturation. By using constructed baculovirus vectors and TED Gag-specific antiserum, we show that the principal translation product of gag (Pr55(gag)) is cleaved to produce a single VLP structural protein, p37(gag). Replacement of Asp436 within the retrovirus-like active site of the pol-encoded protease (PR) abolished Pr55(gag) cleavage and demonstrated the requirement for PR in capsid processing. As shown by expression of an in-frame fusion of TED gag and pol, PR is derived from the Gag-Pol polyprotein Pr195(gag-pol). The PR cleavage site within Pr55(gag) was mapped to a position near the junction of a basic, nucleocapsid-like domain and a C-terminal acidic domain. Once released by cleavage, the C-terminal fragment was not detected. This acidic fragment was dispensable for VLP assembly, as demonstrated by the formation of VLP by C-terminal Pr55(gag) truncation proteins and replacement of the acidic domain with a heterologous protein. In contrast, C-terminal deletions that extended into the adjacent nucleocapsid-like domain of Pr55(gag) abolished VLP recovery and demonstrated that this central region contributes to VLP assembly or stability, or both. Collectively, these data suggest that the single TED protein p37(gag) provides both capsid and nucleocapsid functions. TED may therefore use a simple processing strategy for VLP assembly and genome packaging.

Optimal costs of HIV pre-exposure prophylaxis for men who have sex with men

PubMed Central

Chen, Anders; Hoover, Karen W.; Kelly, Jane; Dowdy, David; Sharifi, Parastu; Sullivan, Patrick S.; Rosenberg, Eli S.

2017-01-01

Introduction Men who have sex with men (MSM) are disproportionately affected by HIV due to their increased risk of infection. Oral pre-exposure prophylaxis (PrEP) is a highly effictive HIV-prevention strategy for MSM. Despite evidence of its effectiveness, PrEP uptake in the United States has been slow, in part due to its cost. As jurisdictions and health organizations begin to think about PrEP scale-up, the high cost to society needs to be understood. Methods We modified a previously-described decision-analysis model to estimate the cost per quality-adjusted life-year (QALY) gained, over a 1-year duration of PrEP intervention and lifetime time horizon. Using updated parameter estimates, we calculated: 1) the cost per QALY gained, stratified over 4 strata of PrEP cost (a function of both drug cost and provider costs); and 2) PrEP drug cost per year required to fall at or under 4 cost per QALY gained thresholds. Results When PrEP drug costs were reduced by 60% (with no sexual disinhibition) to 80% (assuming 25% sexual disinhibition), PrEP was cost-effective (at <$100,000 per QALY averted) in all scenarios of base-case or better adherence, as long as the background HIV prevalence was greater than 10%. For PrEP to be cost saving at base-case adherence/efficacy levels and at a background prevalence of 20%, drug cost would need to be reduced to $8,021 per year with no disinhibition, and to $2,548 with disinhibition. Conclusion Results from our analysis suggest that PrEP drug costs need to be reduced in order to be cost-effective across a range of background HIV prevalence. Moreover, our results provide guidance on the pricing of generic emtricitabine/tenofovir disoproxil fumarate, in order to provide those at high risk for HIV an affordable prevention option without financial burden on individuals or jurisdictions scaling-up coverage. PMID:28570572

Electronic structure of Pr{sub 1{minus}x}Y{sub x}Ba{sub 2}Cu{sub 3}O{sub y} (x=0, 0.5, and 1.0)

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

Kakinuma, K.; Fueki, K.

1997-08-01

In order to elucidate the reason why PrBa{sub 2}Cu{sub 3}O{sub y}is not a superconductor, we examined the Pr valence and measured the oxygen nonstoichiometry and the conductivity at temperatures up to 1200 K for three kinds of oxides, PrBa{sub 2}Cu{sub 3}O{sub y}, (Pr{sub 0.5}Y{sub 0.5})Ba{sub 2}Cu{sub 3}O{sub y}, and YBa{sub 2}Cu{sub 3}O{sub y}. The valence of Pr was found to be +3. Any difference was not found in oxygen nonstoichiometry and conductivity among three kinds of oxides. We analyzed the data of oxygen nonstoichiometry on the basis of defect thermodynamics and calculated the numbers of Cu{sup +}, Cu{sup 2+}, andmore » Cu{sup 3+} ions in the unit cell as a function of y. The number of Cu{sup 3+} ions (the amount of holes) was found to be proportional to ({Delta}y){sup 1.6}({Delta}y=y{minus}6.0), whereas the conductivity was found to be proportional to ({Delta}y){sup 3.2} in these oxides. We interpreted the remarkable increase of {sigma} with {Delta}y as an evidence of the increase of both mobility and hole concentration with {Delta}y. At high temperatures, we detected the conductivity minimum {sigma}{sub min} which was found in the log{sub 10}{sigma}{minus}log{sub 10}P{sub O{sub 2}} plot at constant temperatures. From the slope of the Arrhenius plot for {sigma}{sub min}, the band gap was determined to be 1.21, 1.32, and 1.37 eV for PrBa{sub 2}Cu{sub 3}O{sub y}, (Pr{sub 0.5}Y{sub 0.5})Ba{sub 2}Cu{sub 3}O{sub y} and YBa{sub 2}Cu{sub 3}O{sub y}, respectively. We determined the conductivity of the same oxygen content as a function of temperature from 4.2 to 1200 K. The energy gap {Delta}E between the acceptor level and the top of the valence band was calculated from the slope of the Arrhenius plot for conductivity. {Delta}E for superconducting YBa{sub 2}Cu{sub 3}O{sub y} and (Pr{sub 0.5}Y{sub 0.5})Ba{sub 2}Cu{sub 3}O{sub y} were zero at 300 K but that for nonsuperconducting PrBa{sub 2}Cu{sub 3}O{sub y} was 20 meV at 100 K even for y=6.93. (Abstract Truncated)« less

Stress-controlled Poisson ratio of a crystalline membrane: Application to graphene

NASA Astrophysics Data System (ADS)

Burmistrov, I. Â. S.; Gornyi, I. Â. V.; Kachorovskii, V. Â. Yu.; Katsnelson, M. Â. I.; Los, J. Â. H.; Mirlin, A. Â. D.

2018-03-01

We demonstrate that a key elastic parameter of a suspended crystalline membrane—the Poisson ratio (PR) ν —is a nontrivial function of the applied stress σ and of the system size L , i.e., ν =νL(σ ) . We consider a generic two-dimensional membrane embedded into space of dimensionality 2 +dc . (The physical situation corresponds to dc=1 .) A particularly important application of our results is to freestanding graphene. We find that at a very low stress, when the membrane exhibits linear response, the PR νL(0 ) decreases with increasing system size L and saturates for L →∞ at a value which depends on the boundary conditions and is essentially different from the value ν =-1 /3 previously predicted by the membrane theory within a self-consistent scaling analysis. By increasing σ , one drives a sufficiently large membrane (with the length L much larger than the Ginzburg length) into a nonlinear regime characterized by a universal value of PR that depends solely on dc, in close connection with the critical index η controlling the renormalization of bending rigidity. This universal nonlinear PR acquires its minimum value νmin=-1 in the limit dc→∞ , when η →0 . With the further increase of σ , the PR changes sign and finally saturates at a positive nonuniversal value prescribed by the conventional elasticity theory. We also show that one should distinguish between the absolute and differential PR (ν and νdiff, respectively). While coinciding in the limits of very low and very high stress, they differ in general: ν ≠νdiff . In particular, in the nonlinear universal regime, νdiff takes a universal value which, similarly to the absolute PR, is a function solely of dc (or, equivalently, of η ) but is different from the universal value of ν . In the limit of infinite dimensionality of the embedding space, dc→∞ (i.e., η →0 ), the universal value of νdiff tends to -1 /3 , at variance with the limiting value -1 of ν . Finally, we briefly discuss generalization of these results to a disordered membrane.

Transcriptional analysis of four family 4 P450s in a Puerto Rico strain of Aedes aegypti (Diptera: Culicidae) compared with an Orlando strain and their possible functional roles in permethrin resistance

USDA-ARS?s Scientific Manuscript database

A field strain of Aedes aegypti was collected from Puerto Rico (PR) in October 2008. Based on LD50 values by topical application, the PR strain was 73-fold resistant to permethrin compared to a susceptible Orlando strain. In the presence of piperonyl butoxide (PBO), the resistance of Puerto Rico str...

A Latent Class Analysis of Pathological-Gambling Criteria Among High School Students: Associations With Gambling, Risk and Health/Functioning Characteristics

PubMed Central

Kong, Grace; Tsai, Jack; Krishnan-Sarin, Suchitra; Cavallo, Dana A.; Hoff, Rani A.; Steinberg, Marvin A.; Rugle, Loreen; Potenza, Marc N.

2015-01-01

Objectives To identify subtypes of adolescent gamblers based on the 10 Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for pathological gambling and the 9 Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for gambling disorder and to examine associations between identified subtypes with gambling, other risk behaviors, and health/functioning characteristics. Methods Using cross-sectional survey data from 10 high schools in Connecticut (N = 3901), we conducted latent class analysis to classify adolescents who reported past-year gambling into gambling groups on the basis of items from the Massachusetts Gambling Screen. Adolescents also completed questions assessing demographic information, substance use (cigarette, marijuana, alcohol, and other drugs), gambling behaviors (relating to gambling formats, locations, motivations, and urges), and health/functioning characteristics (eg, extracurricular activities, mood, aggression, and body mass index). Results The optimal solution consisted of 4 classes that we termed low-risk gambling (86.4%), at-risk chasing gambling (7.6%), at-risk negative consequences gambling (3.7%), and problem gambling (PrG) (2.3%). At-risk and PrG classes were associated with greater negative functioning and more gambling behaviors. Different patterns of associations between at-risk and PrG classes were also identified. Conclusions Adolescent gambling classifies into 4 classes, which are differentially associated with demographic, gambling patterns, risk behaviors, and health/functioning characteristics. Early identification and interventions for adolescent gamblers should be sensitive to the heterogeneity of gambling subtypes. PMID:25275877

[Effects of Tillage on Distribution of Heavy Metals and Organic Matter Within Purple Paddy Soil Aggregates].

PubMed

Shi, Qiong-bin; Zhao, Xiu-lan; Chang, Tong-ju; Lu, Ji-wen

2016-05-15

A long-term experiment was utilized to study the effects of tillage methods on the contents and distribution characteristics of organic matter and heavy metals (Cu, Zn, Pb, Cd, Fe and Mn) in aggregates with different sizes (including 1-2, 0.25-1, 0.05-0.25 mm and < 0.05 mm) in a purple paddy soil under two tillage methods including flooded paddy field (FPF) and paddy-upland rotation (PR). The relationship between heavy metals and organic matter in soil aggregates was also analyzed. The results showed that the aggregates of two tillage methods were dominated by 0.05-0.25 mm and < 0.05 mm particle size, respectively. The contents of organic matter in each aggregate decreased with the decrease of aggregate sizes, however, compared to PR, FPF could significantly increase the contents of organic matter in soils and aggregates. The tillage methods did not significantly affect the contents of heavy metals in soils, but FPF could enhance the accumulation and distribution of aggregate, organic matter and heavy metals in aggregates with diameters of 1-2 mm and 0.25-1 mm. Correlation analysis found that there was a negative correlation between the contents of heavy metals and organic matter in soil aggregates, but a positive correlation between the amounts of heavy metal and organic matter accumulated in soil aggregates. From the slope of the correlation analysis equations, we could found that the sensitivities of heavy metals to the changes of soil organic matters followed the order of Mn > Zn > Pb > Cu > Fe > Cd under the same tillage. When it came to the same heavy metal, it was more sensitive in PR than in FPF.

Factors effecting impact of Aspergillus fumigatus sensitization in cystic fibrosis.

PubMed

Kanthan, Senthooran Kathirgama; Bush, Andrew; Kemp, Michael; Buchdahl, Roger

2007-09-01

The clinical impact of Aspergillus fumigatus (Af) sensitization in cystic fibrosis (CF) is controversial. We examined the effect of Af sensitization (Afs) on pulmonary function and growth using a retrospective cohort analysis over two 5-year study periods: 1996-2000 (19 Afs cases and 19 controls) and 2001-2005 (24 Afs cases and 23 controls). Sensitization was defined as Af specific radioallergosorbent test (RAST) >or= 17.5 iu/ml and total serum IgE level >or=150 iu/ml. We examined the impact of changing treatment schedules over these periods. Afs cases had lower median FEV(1) %predicted (%PR) compared to matched controls 1996: 67 versus 80, P < 0.01; 2001: 78 versus 93, P < 0.01. Afs cases in the 2001 cohort had a higher FEV(1) %PR compared to Afs cases in the 1996 cohort: 78 versus 67, P < 0.01. For the 1996 Afs cohort FEV(1) %PR fell significantly over 5 years but not for the 2001 Afs cohort. Af RAST and total IgE reflected the changes in pulmonary function. Children in the 2001 Afs cohort were prescribed significantly more oral antifungal treatment (odds ratio 4.3, 95%CI 1.2-15.7, P = 0.03). Afs children continue to have poorer lung function compared to controls but this observational, hypothesis generating study, suggests that the use of antifungal treatment is associated with better lung function. (c) 2007 Wiley-Liss, Inc.

Overcoming Etch Challenges on a 6″ Hg1- x Cd x Te MBE on Si Wafer

NASA Astrophysics Data System (ADS)

Apte, Palash; Norton, Elyse; Robinson, Solomon

2017-10-01

The effect of increasing photoresist (PR) thickness on the inductively coupled plasma (ICP) dry etched characteristics of a 6″ (c.15 cm) molecular beam epitaxy Hg1- x Cd x Te/Si wafer is investigated. It is determined that the Hg1- x Cd x Te etch rate (ER) does not vary significantly with a change in the PR thickness. Also, the vertical ER of the PR is seen to be independent of the PR thickness, but the lateral ER is seen to reduce significantly with increased PR thickness. Indeed, very little reduction in the pixel mesa area post-dry etch is seen for the thicker PR. Consequently, the trench sidewall angle is also seen to vary as a function of the PR thickness. Since ICP is the more attractive choice for dry etching Hg1- x Cd x Te, this simple, cost-effective way to extend the capabilities of dry etching (larger mesa top area post-dry etch, ability to create tailor-made trench sidewall angles for optimal conformal passivation deposition, and potential for reduced dry etch damage) described here would allow for the fabrication of next generation infrared detectors with increased yield and reduced cost. Although similar results have been presented using the electron cyclotron resonance system to dry etch Hg1- x Cd x Te, to the best of our knowledge, this is the first time that such results have been presented using an ICP system.

High cocoa polyphenol rich chocolate may reduce the burden of the symptoms in chronic fatigue syndrome

PubMed Central

2010-01-01

Background Chocolate is rich in flavonoids that have been shown to be of benefit in disparate conditions including cardiovascular disease and cancer. The effect of polyphenol rich chocolate in subjects with chronic fatigue syndrome (CFS) has not been studied previously. Methods We conducted a double blinded, randomised, clinical pilot crossover study comparing high cocoa liquor/polyphenol rich chocolate (HCL/PR) in comparison to simulated iso-calorific chocolate (cocoa liquor free/low polyphenols(CLF/LP)) on fatigue and residual function in subjects with chronic fatigue syndrome. Subjects with CFS having severe fatigue of at least 10 out of 11 on the Chalder Fatigue Scale were enrolled. Subjects had either 8 weeks of intervention in the form of HCL/PR or CLF/LP, with a 2 week wash out period followed by 8 weeks of intervention with the other chocolate. Results Ten subjects were enrolled in the study. The Chalder Fatigue Scale score improved significantly after 8 weeks of the HCL/PR chocolate arm [median (range) Exact Sig. (2-tailed)] [33 (25 - 38) vs. 21.5 (6 - 35) 0.01], but that deteriorated significantly when subjects were given simulated iso-calorific chocolate (CLF/CP) [ 28.5 (17 - 20) vs. 34.5 (13-26) 0.03]. The residual function, as assessed by the London Handicap scale, also improved significantly after the HCL/PR arm [0.49 (0.33 - 0.62) vs. 0.64 (0.44 - 0.83) 0.01] and deteriorated after iso-calorific chocolate [00.44 (0.43 - 0.68) vs. 0.36 (0.33 - 0.62)0.03]. Likewise the Hospital Anxiety and Depression score also improved after the HCL/PR arm, but deteriorated after CLF/CP. Mean weight remained unchanged throughout the trial. Conclusion This study suggests that HCL/PR chocolate may improve symptoms in subjects with chronic fatigue syndrome. PMID:21092175

High cocoa polyphenol rich chocolate may reduce the burden of the symptoms in chronic fatigue syndrome.

PubMed

Sathyapalan, Thozhukat; Beckett, Stephen; Rigby, Alan S; Mellor, Duane D; Atkin, Stephen L

2010-11-22

Chocolate is rich in flavonoids that have been shown to be of benefit in disparate conditions including cardiovascular disease and cancer. The effect of polyphenol rich chocolate in subjects with chronic fatigue syndrome (CFS) has not been studied previously. We conducted a double blinded, randomised, clinical pilot crossover study comparing high cocoa liquor/polyphenol rich chocolate (HCL/PR) in comparison to simulated iso-calorific chocolate (cocoa liquor free/low polyphenols(CLF/LP)) on fatigue and residual function in subjects with chronic fatigue syndrome. Subjects with CFS having severe fatigue of at least 10 out of 11 on the Chalder Fatigue Scale were enrolled. Subjects had either 8 weeks of intervention in the form of HCL/PR or CLF/LP, with a 2 week wash out period followed by 8 weeks of intervention with the other chocolate. Ten subjects were enrolled in the study. The Chalder Fatigue Scale score improved significantly after 8 weeks of the HCL/PR chocolate arm [median (range) Exact Sig. (2-tailed)] [33 (25 - 38) vs. 21.5 (6 - 35) 0.01], but that deteriorated significantly when subjects were given simulated iso-calorific chocolate (CLF/CP) [ 28.5 (17 - 20) vs. 34.5 (13-26) 0.03]. The residual function, as assessed by the London Handicap scale, also improved significantly after the HCL/PR arm [0.49 (0.33 - 0.62) vs. 0.64 (0.44 - 0.83) 0.01] and deteriorated after iso-calorific chocolate [00.44 (0.43 - 0.68) vs. 0.36 (0.33 - 0.62)0.03]. Likewise the Hospital Anxiety and Depression score also improved after the HCL/PR arm, but deteriorated after CLF/CP. Mean weight remained unchanged throughout the trial. This study suggests that HCL/PR chocolate may improve symptoms in subjects with chronic fatigue syndrome.

Metal-Assisted Oxo Atom Addition to an Fe(III) Thiolate.

PubMed

Villar-Acevedo, Gloria; Lugo-Mas, Priscilla; Blakely, Maike N; Rees, Julian A; Ganas, Abbie S; Hanada, Erin M; Kaminsky, Werner; Kovacs, Julie A

2017-01-11

Cysteinate oxygenation is intimately tied to the function of both cysteine dioxygenases (CDOs) and nitrile hydratases (NHases), and yet the mechanisms by which sulfurs are oxidized by these enzymes are unknown, in part because intermediates have yet to be observed. Herein, we report a five-coordinate bis-thiolate ligated Fe(III) complex, [Fe III (S 2 Me2 N 3 (Pr,Pr))] + (2), that reacts with oxo atom donors (PhIO, IBX-ester, and H 2 O 2 ) to afford a rare example of a singly oxygenated sulfenate, [Fe III (η 2 -S Me2 O)(S Me2 )N 3 (Pr,Pr)] + (5), resembling both a proposed intermediate in the CDO catalytic cycle and the essential NHase Fe-S(O) Cys114 proposed to be intimately involved in nitrile hydrolysis. Comparison of the reactivity of 2 with that of a more electron-rich, crystallographically characterized derivative, [Fe III S 2 Me2 N Me N 2 amide (Pr,Pr)] - (8), shows that oxo atom donor reactivity correlates with the metal ion's ability to bind exogenous ligands. Density functional theory calculations suggest that the mechanism of S-oxygenation does not proceed via direct attack at the thiolate sulfurs; the average spin-density on the thiolate sulfurs is approximately the same for 2 and 8, and Mulliken charges on the sulfurs of 8 are roughly twice those of 2, implying that 8 should be more susceptible to sulfur oxidation. Carboxamide-ligated 8 is shown to be unreactive towards oxo atom donors, in contrast to imine-ligated 2. Azide (N 3 - ) is shown to inhibit sulfur oxidation with 2, and a green intermediate is observed, which then slowly converts to sulfenate-ligated 5. This suggests that the mechanism of sulfur oxidation involves initial coordination of the oxo atom donor to the metal ion. Whether the green intermediate is an oxo atom donor adduct, Fe-O═I-Ph, or an Fe(V)═O remains to be determined.

Molecular cloning and characterization of a novel salt-inducible gene encoding an acidic isoform of PR-5 protein in soybean (Glycine max [L.] Merr.).

PubMed

Onishi, M; Tachi, H; Kojima, T; Shiraiwa, M; Takahara, H

2006-10-01

We identified a novel salt-inducible soybean gene encoding an acidic-isoform of pathogenesis-related protein group 5 (PR-5 protein). The soybean PR-5-homologous gene, designated as Glycine max osmotin-like protein, acidic isoform (GmOLPa)), encodes a putative polypeptide having an N-terminal signal peptide. The mature GmOLPa protein without the signal peptide has a calculated molecular mass of 21.5 kDa and a pI value of 4.4, and was distinguishable from a known PR-5-homologous gene of soybean (namely P21 protein) through examination of the structural features. A comparison with two intracellular salt-inducible PR-5 proteins, tobacco osmotin and tomato NP24, revealed that GmOLPa did not have a C-terminal extension sequence functioning as a vacuole-targeting motif. The GmOLPa gene was transcribed constitutively in the soybean root and was induced almost exclusively in the root during 24 h of high-salt stress (300 mM NaCl). Interestingly, GmOLPa gene expression in the stem and leaf, not observed until 24 h, was markedly induced at 48 and 72 h after commencement of the high-salt stress. Abscisic acid (ABA) and dehydration also induced expression of the GmOLPa gene in the root; additionally, dehydration slightly induced expression in the stem and leaf. In fact, the 5'-upstream sequence of the GmOLPa gene contained several putative cis-elements known to be involved in responsiveness to ABA and dehydration, e.g. ABA-responsive element (ABRE), MYB/MYC, and low temperature-responsive element (LTRE). These results suggested that GmOLPa may function as a protective PR-5 protein in the extracellular space of the soybean root in response to high-salt stress and dehydration.

A comparison between Peng-Robinson and Soave-Redlich-Kwong cubic equations of state from modification perspective

NASA Astrophysics Data System (ADS)

Ghanbari, Mehdi; Ahmadi, Mahdi; Lashanizadegan, Asghar

2017-06-01

The Cubic Equations of State (CEOSs) are the most important tools in PVT calculations due to their simplicity in use and their extrapolative abilities to condition well outside their correlation ranges. Peng-Robinson (PR) and Soave-Redlich-Kwong (SRK) are most successful in the CEOSs which have repeatedly been modified in order to improve their accuracy in wider ranges of temperature and pressure. Unfortunately, most of modifications carried out on these EOSs have no adequate justification for selecting either of these as the basic starting point for the modifications. In this paper, PR and SRK EOSs were critically compared with each other using some new features of their subcritical and supercritical results. For this purpose, the CEOSs were assessed using comprehensive tests of the PVT calculations in the vapor-liquid equilibrium (for pure hydrocarbons over a wide range of acentric factor values: Methane, Ethane Propane, Butane, Heptane and Nonane) and Joule-Thomson Inversion Curves' (JTICs) predictions (for compounds which have reliable JTICs data: Methane, Ethane, Ethylene, Nitrogen, Oxygen, Argon and Carbon dioxide) in subcritical and supercritical regions, respectively. The results indicated that the PR EOS by using any of realistic α-function forms will never be able to accurately predict the JTICs in full span. On the other hand, the subcritical results revealed that the great success of the PR CEOS in predicting liquid phase density is only due to its function in shifting the results of the SRK CEOS to the lower values with the same curve trend. In addition, the Patel and Teja's (PT) EOS, has been reevaluated and the results showed that most of the defects of PR EOS still remain. This article suggests that in order to develop CEOSs, the original SRK EOS is a better candidate than original and alternative forms of PR EOS.

Phosphorylated recombinant HSP27 protects the brain and attenuates blood-brain barrier disruption following stroke in mice receiving intravenous tissue-plasminogen activator.

PubMed

Shimada, Yoshiaki; Shimura, Hideki; Tanaka, Ryota; Yamashiro, Kazuo; Koike, Masato; Uchiyama, Yasuo; Urabe, Takao; Hattori, Nobutaka

2018-01-01

Loss of integrity of the blood-brain barrier (BBB) in ischemic stroke victims initiates a devastating cascade of events causing brain damage. Maintaining the BBB is important to preserve brain function in ischemic stroke. Unfortunately, recombinant tissue plasminogen activator (tPA), the only effective fibrinolytic treatment at the acute stage of ischemic stroke, also injures the BBB and increases the risk of brain edema and secondary hemorrhagic transformation. Thus, it is important to identify compounds that maintain BBB integrity in the face of ischemic injury in patients with stroke. We previously demonstrated that intravenously injected phosphorylated recombinant heat shock protein 27 (prHSP27) protects the brains of mice with transient middle cerebral artery occlusion (tMCAO), an animal stroke-model. Here, we determined whether prHSP27, in addition to attenuating brain injury, also decreases BBB damage in hyperglycemic tMCAO mice that had received tPA. After induction of hyperglycemia and tMCAO, we examined 4 treatment groups: 1) bovine serum albumin (BSA), 2) prHSP27, 3) tPA, 4) tPA plus prHSP27. We examined the effects of prHSP27 by comparing the BSA and prHSP27 groups and the tPA and tPA plus prHSP27 groups. Twenty-four hours after injection, prHSP27 reduced infarct volume, brain swelling, neurological deficits, the loss of microvessel proteins and endothelial cell walls, and mortality. It also reduced the rates of hemorrhagic transformation, extravasation of endogenous IgG, and MMP-9 activity, signs of BBB damage. Therefore, prHSP27 injection attenuated brain damage and preserved the BBB in tPA-injected, hyperglycemic tMCAO experimental stroke-model mice, in which the BBB is even more severely damaged than in simple tMCAO mice. The attenuation of brain damage and BBB disruption in the presence of tPA suggests the effectiveness of prHSP27 and tPA as a combination therapy. prHSP27 may be a novel therapeutic agent for ischemic stroke patients whose BBBs are injured following tPA injections.

Magnetic interactions in praseodymium ruthenate Pr{sub 3}RuO{sub 7} with fluorite-related structure

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

Inabayashi, Masaki; Doi, Yoshihiro; Wakeshima, Makoto

2017-06-15

Solid solutions Pr{sub 3}(Ru{sub 1-x}Ta{sub x})O{sub 7} (0≤x≤1.0) and (Pr{sub 1-x}Y{sub x}){sub 3}RuO{sub 7} (0≤x≤0.7) were obtained as a single phase compound. They crystallize in an orthorhombic superstructure derived from that of the cubic fluorite with space group Cmcm. The results of the Rietveld analysis for X-ray diffraction profiles of Pr{sub 3}(Ru{sub 1-x}Ta{sub x})O{sub 7} showed that Ru and Ta atoms are randomly situated at the six-coordinate 4b site. For (Pr{sub 1-x}Y{sub x}){sub 3}RuO{sub 7}, with increasing the concentration of Y ions (x value), the smaller Y ions occupy selectively the seven-coordinate 8g site rather than the eight-coordinate 4a site.more » Through magnetic susceptibility measurements for Pr{sub 3}(Ru{sub 1-x}Ta{sub x})O{sub 7}, the antiferromagnetic transition temperatures decrease linearly with increasing x value, and at x=0.75 no magnetic ordering was found down to 1.8 K, indicating the magnetic interaction is not one-dimensional, but three-dimensional. On the other hand, the antiferromagnetic transition temperature for (Pr{sub 1-x}Y{sub x}){sub 3}RuO{sub 7} decreases with increasing x value, but above x≥0.50 it becomes constant (~12 K). This result indicates that Pr{sup 3+} ions at the seven-coordinate site greatly contribute to the antiferromagnetic interactions observed in (Pr{sub 1-x}Y{sub x}){sub 3}RuO{sub 7}. Density functional calculations of Pr{sub 3}RuO{sub 7} demonstrate that the electronic structure gives insulating character and that oxygen 2p orbitals hybridize strongly with Ru 4d orbitals in the valence band (VB). Near the top of VB, the Pr 4 f orbitals at the seven-coordinated site also show a weak hybridization with the O(1) 2p orbitals. The Ru-O(1)-Pr superexchange pathway take part in three-dimensional magnetic interaction and play an important role in an enhancement of long-range magnetic ordering. - Graphical abstract: The spin densities and the spin polarization of Pr{sub 3}RuO{sub 7} are shown. Significant spin polarization is seen on the magnetic Pr and Ru ions, but there is also some on the O(1), (3) ligands of Ru. - Highlights: • New fluorite-related quaternary praseodymium ruthenates were prepared. • Pr{sub 3}RuO{sub 7} shows an antiferromagnetic transition at 55 K. • The Ru-O-Pr superexchange interactions are three-dimensional.« less

Experimental transmission of U.S. scrapie agent to neonatal sheep by oral route

USDA-ARS?s Scientific Manuscript database

Scrapie, a transmissible spongiform encephalopathy (TSE), is a naturally occurring fatal neurodegenerative disease of sheep and goats. This study documents incubation periods, pathological findings and distribution of abnormal prion proteins (PrP**Sc) by immunohistochemistry and Western blot in tiss...

Diversity in a Hidden Community: Tardiagrades in Lichens.

ERIC Educational Resources Information Center

Shofner, Marcia; Vodopich, Darrell

1993-01-01

Describes an interesting field experiment examining the distribution and diversity of a single community using lichens and the animals living in them. Combining field experience and laboratory work reveals not only the biology of some unusual organisms, but also community ecology and diversity. (PR)

IRIS Toxicological Review of Pentachlorophenol (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Pentachlorophenol, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Pr...

STAR - Copperhead Interface.

DTIC Science & Technology

1981-03-01

elements which fall outside the original box initiate new clusters. 65 ELL. CH ECK This routine provides the calculation which determines if a target...US Air Force Project Rand Report 3-152b-PR, March 197 88 INITIAL DISTRIBUTION LIST 1o. Copies 1. Defense Technical Information Center 2 Cameron

NMR study of xenotropic murine leukemia virus-related virus protease in a complex with amprenavir

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

Furukawa, Ayako; Okamura, Hideyasu; Morishita, Ryo

2012-08-24

Highlights: Black-Right-Pointing-Pointer Protease (PR) of XMR virus (XMRV) was successfully synthesized with cell-free system. Black-Right-Pointing-Pointer Interface of XMRV PR with an inhibitor, amprenavir (APV), was identified with NMR. Black-Right-Pointing-Pointer Structural heterogeneity is induced for two PR protomers in the APV:PR = 1:2 complex. Black-Right-Pointing-Pointer Structural heterogeneity is transmitted even to distant regions from the interface. Black-Right-Pointing-Pointer Long-range transmission of structural change may be utilized for drug discovery. -- Abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a virus created through recombination of two murine leukemia proviruses under artificial conditions during the passage of human prostate cancer cells in athymic nudemore » mice. The homodimeric protease (PR) of XMRV plays a critical role in the production of functional viral proteins and is a prerequisite for viral replication. We synthesized XMRV PR using the wheat germ cell-free expression system and carried out structural analysis of XMRV PR in a complex with an inhibitor, amprenavir (APV), by means of NMR. Five different combinatorially {sup 15}N-labeled samples were prepared and backbone resonance assignments were made by applying Otting's method, with which the amino acid types of the [{sup 1}H, {sup 15}N] HSQC resonances were automatically identified using the five samples (Wu et al., 2006) . A titration experiment involving APV revealed that one APV molecule binds to one XMRV PR dimer. For many residues, two distinct resonances were observed, which is thought to be due to the structural heterogeneity between the two protomers in the APV:XMRV PR = 1:2 complex. PR residues at the interface with APV have been identified on the basis of chemical shift perturbation and identification of the intermolecular NOEs by means of filtered NOE experiments. Interestingly, chemical shift heterogeneity between the two protomers of XMRV PR has been observed not only at the interface with APV but also in regions apart from the interface. This indicates that the structural heterogeneity induced by the asymmetry of the binding of APV to the XMRV PR dimer is transmitted to distant regions. This is in contrast to the case of the APV:HIV-1 PR complex, in which the structural heterogeneity is only localized at the interface. Long-range transmission of the structural change identified for the XMRV PR complex might be utilized for the discovery of a new type of drug.« less

Pregnancy-related Acute Kidney Injury and a Review of the Literature in China.

PubMed

Liu, Yu-mei; Bao, Hong-da; Jiang, Zhen-zhen; Huang, Ya-juan; Wang, Nian-song

2015-01-01

To determine the incidence, causes and prognosis of pregnancy-related acute kidney injury (PR-AKI) in Chinese women. From July 2004 to February 2013, 18,589 women of Han ethnicity who attended the Obstetrics and Nephrology Department of our tertiary hospital were investigated, and individuals meeting the PR-AKI criteria were included in the analysis. The WanFang, Chinese Science Journal, Chinese Knowledge, MEDLINE, EMBASE and Cochrane library databases were searched, and literature describing PR-AKI diagnoses with Chinese women as study subjects and a sample size of ≥5 were included. The incidence of PR-AKI was 0.1183% (22/18,589). Hemorrhagic shock (31.8%) and pre-eclampsia (severe, 18.2%) were the two most common causes of PR-AKI. Twelve women recovered completely, six women displayed persistent proteinuria and four women had an increased serum creatinine level at discharge. There were no cases of death. Twenty women demonstrated adverse pregnancy outcomes (90.9%), including eight cases of stillbirth (36.4%). In our literature review, 29 of 4,076 articles were included, and the incidence of PR-AKI in China was found to range from 0.02% to 1.84%. Pregnancy hypertension (49.2%) and postpartum hemorrhage (13.8%) were found to be the most common causes of PR-AKI in China. The prognosis improved in 81.9% of the patients, the renal function deteriorated in 4.5% of the patients and 13.6% of the patients died. The rate of stillbirth was 27.0%. The maternal condition after active treatment was good, whereas the pregnancy outcomes were generally poor. Although the incidence of PR-AKI was relatively low, this finding is noteworthy. Further studies are thus warranted to improve maternal-fetal outcomes.

Weather-Corrected Performance Ratio

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

Dierauf, T.; Growitz, A.; Kurtz, S.

Photovoltaic (PV) system performance depends on both the quality of the system and the weather. One simple way to communicate the system performance is to use the performance ratio (PR): the ratio of the electricity generated to the electricity that would have been generated if the plant consistently converted sunlight to electricity at the level expected from the DC nameplate rating. The annual system yield for flat-plate PV systems is estimated by the product of the annual insolation in the plane of the array, the nameplate rating of the system, and the PR, which provides an attractive way to estimatemore » expected annual system yield. Unfortunately, the PR is, again, a function of both the PV system efficiency and the weather. If the PR is measured during the winter or during the summer, substantially different values may be obtained, making this metric insufficient to use as the basis for a performance guarantee when precise confidence intervals are required. This technical report defines a way to modify the PR calculation to neutralize biases that may be introduced by variations in the weather, while still reporting a PR that reflects the annual PR at that site given the project design and the project weather file. This resulting weather-corrected PR gives more consistent results throughout the year, enabling its use as a metric for performance guarantees while still retaining the familiarity this metric brings to the industry and the value of its use in predicting actual annual system yield. A testing protocol is also presented to illustrate the use of this new metric with the intent of providing a reference starting point for contractual content.« less

Paradoxical Lung Function Response to Beta2-agonists: Radiologic Correlates and Clinical Implications

PubMed Central

Bhatt, Surya P.; Wells, James M.; Kim, Victor; Criner, Gerard J.; Hersh, Craig P.; Hardin, Megan; Bailey, William C.; Nath, Hrudaya; il-Kim, Young; Foreman, Marilyn G.; Stinson, Douglas S.; Wilson, Carla G.; Rennard, Stephen I.; Silverman, Edwin K.; Make, Barry J.; Dransfield, Mark T.

2014-01-01

Background Bronchodilator response is seen in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response (PR) to beta2-agonists, resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely far more common but there has been no systematic study of this phenomenon.We assessed theprevalence of PR in current and former smokers with and without COPD, and its radiologic correlates and clinical implications. Methods Subjects from a large multicenter study (COPDGene) were categorized into two groups based on PR defined as at least a 12% and 200mLreduction in FEV1 and/or FVC after administration of a short-acting beta2-agonist (180ucg albuterol). Predictors of PR and associations with respiratory morbidity and computed tomographic measures of emphysema and airway disease were assessed. Findings 9986 subjects were included. PR was seen in 4.54% and the frequency was similar in those with COPD and smokers without airflow obstruction. Compared to Caucasians, PR was twice as common in African-Americans (6.9% vs. 3.4%;p <0.001). On multivariate analyses, African- American race (adjusted OR 1.89, 95%CI 1.50 to 2.39), lesspercent emphysema (OR 0.96, 95%CI 0.92 to 0.99) and increased wall-area% of segmental airways (OR 1.04,95%CI 1.01 to 1.08) were independently associated with PR.PR was independently associated with worse dyspnea, lower six-minute-walk distance, higher BODE index, and a greater frequency of exacerbations(increased by a factor of 1.35, 95%CI 1.003 to 1.81). Interpretation Paradoxical response to beta2-agonists is associated with respiratory morbidity and is more common in African Americans. PMID:25217076

The calculation of rare-earth levels in layered cobaltates Rx/3CoO2 (x ≦ 1)

NASA Astrophysics Data System (ADS)

Novák, P.; Knížek, K.; Jirák, Z.; Buršík, J.

2015-05-01

We studied theoretically the crystal field and Zeeman split electronic levels of trivalent rare earths that are distributed over trigonal prismatic sites of the layered Rx/3CoO2 system (closely related to sodium cobaltate NaxCoO2). The calculations were done in the whole basis of 4fn configurations (up to 3000 many-electron determinantal functions) for the ideal trigonal symmetry D3h, as well as for the reduced symmetry C2v that takes into account a more distant neighborhood of the R-sites. Detailed data on the doublet and singlet states for Pr, Nd, Sm, Tb and Dy are presented. The obtained g-factor and the van Vleck susceptibility tensor components are used for calculations of anisotropic magnetic susceptibilities and their temperature dependencies.

Reversal magnetization, spin reorientation, and exchange bias in YCr O3 doped with praseodymium

NASA Astrophysics Data System (ADS)

Durán, A.; Escamilla, R.; Escudero, R.; Morales, F.; Verdín, E.

2018-01-01

Crystal structure, thermal properties, and magnetic properties were studied systematically in Y1 -xP rxCr O3 with 0.0 ≤x ≤0.3 compositions. Magnetic susceptibility and specific-heat measurements show an increase in the antiferromagnetic transition temperature (TN) as Pr is substituted in the Y sites and notable magnetic features are observed below TN. Strong coupling between magnetic and crystalline parameters is observed in a small range of Pr compositions. A small perturbation in the lattice parameters by a Pr ion is sufficient to induce a spin-reorientation transition followed by magnetization reversal to finally induce the exchange-bias effect. The spin-reorientation temperature (TSR) is increased from 35 to 149 K for 0.025 ≤x ≤0.1 compositions. It is found that the Cr spin sublattice rotates continuously from TSR to a new spin configuration at lower temperature. In addition, magnetization reversal is observed at T*˜35 K for x =0.05 up to T*˜63 K for x =0.20 composition. The M -H curves show a negative exchange-bias effect induced by Pr ions, which are observed below 100 K and are more intense at 5 K. At 10 K, the magnetic contribution of the specific heat as well as the ZFC magnetization show the rise of a peak with increasing Pr content. The magnetic anomaly could be associated with the freezing of the Pr magnetic moment randomly distributed at the 4 c crystallographic site. A clear correspondence between spin reorientation, magnetization reversal, and exchange-bias anisotropy with the tilting and octahedral distortion is also discussed.

Optimizing pattern recognition-based control for partial-hand prosthesis application.

PubMed

Earley, Eric J; Adewuyi, Adenike A; Hargrove, Levi J

2014-01-01

Partial-hand amputees often retain good residual wrist motion, which is essential for functional activities involving use of the hand. Thus, a crucial design criterion for a myoelectric, partial-hand prosthesis control scheme is that it allows the user to retain residual wrist motion. Pattern recognition (PR) of electromyographic (EMG) signals is a well-studied method of controlling myoelectric prostheses. However, wrist motion degrades a PR system's ability to correctly predict hand-grasp patterns. We studied the effects of (1) window length and number of hand-grasps, (2) static and dynamic wrist motion, and (3) EMG muscle source on the ability of a PR-based control scheme to classify functional hand-grasp patterns. Our results show that training PR classifiers with both extrinsic and intrinsic muscle EMG yields a lower error rate than training with either group by itself (p<0.001); and that training in only variable wrist positions, with only dynamic wrist movements, or with both variable wrist positions and movements results in lower error rates than training in only the neutral wrist position (p<0.001). Finally, our results show that both an increase in window length and a decrease in the number of grasps available to the classifier significantly decrease classification error (p<0.001). These results remained consistent whether the classifier selected or maintained a hand-grasp.

On-treatment platelet reactivity: State of the art and perspectives.

PubMed

Marcucci, Rossella; Grifoni, Elisa; Giusti, Betti

2016-02-01

High on-clopidogrel platelet reactivity (HcPR) during dual-antiplatelet therapy is a marker of vascular risk, in particular stent thrombosis, in patients with acute coronary syndromes (ACS). Genetic determinants (CYP2C19*2 polymorphism), advanced age, female gender, diabetes and reduced ventricular function are related to a higher risk to develop HcPR. In addition, inflammation and increased platelet turnover, as revealed by the elevated percentage of reticulated platelets in patients' blood, that characterize the acute phase of acute coronary syndromes, are associated with HcPR. To overcome the limitation of clopidogrel, new antiplatelet agents (prasugrel and ticagrelor) were developed and the demonstration of their superiority over clopidogrel was obtained in the two randomized trials, TRITON TIMI 38 and PLATO. Emerging evidence is accumulating on the role of high-on aspirin platelet reactivity (HaPR), especially in the clinical context of diabetes. Finally, the presence of new, potent antiplatelet drugs has shifted the focus from thrombotic to bleeding risk. Recent data document that low on-treatment platelet reactivity (LPR) is associated with a significantly higher bleeding risk. Due to the current possibility to choose between multiple antiplatelet strategies, the future perspective is to include in the management of ACS, in addition to clinical data and classical risk factors, the definition of platelet function during treatment in order to set a tailored therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

TREM2 R47H variant and risk of essential tremor: A cross-sectional international multicenter study

PubMed Central

Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Lorenzo, Elena; Agúndez, José A.G.; Jiménez-Jiménez, Félix J.; Ross, Owen A.; Wurster, Isabel; Mielke, Carina; Lin, Juei-Jueng; Coria, Francisco; Clarimon, Jordi; Ezquerra, Mario; Brighina, Laura; Annesi, Grazia; Alonso-Navarro, Hortensia; García-Martin, Elena; Gironell, Alex; Marti, Maria J.; Yueh, Kuo-Chu; Wszolek, Zbigniew K.; Sharma, Manu; Berg, Daniela; Krüger, Rejko; Pastor, Maria A.; Pastor, Pau

2015-01-01

Introduction Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. Methods This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. Results There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203–29.626; p = 0.042), but it was not replicated in other populations. Conclusions These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed. PMID:25585992

TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study.

PubMed

Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Lorenzo, Elena; Agúndez, José A G; Jiménez-Jiménez, Félix J; Ross, Owen A; Wurster, Isabel; Mielke, Carina; Lin, Juei-Jueng; Coria, Francisco; Clarimon, Jordi; Ezquerra, Mario; Brighina, Laura; Annesi, Grazia; Alonso-Navarro, Hortensia; García-Martin, Elena; Gironell, Alex; Marti, Maria J; Yueh, Kuo-Chu; Wszolek, Zbigniew K; Sharma, Manu; Berg, Daniela; Krüger, Rejko; Pastor, Maria A; Pastor, Pau

2015-03-01

Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations. These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Expanded HIV pre-exposure prophylaxis (PrEP) implementation in communities in New South Wales, Australia (EPIC-NSW): design of an open label, single arm implementation trial.

PubMed

Zablotska, Iryna B; Selvey, Christine; Guy, Rebecca; Price, Karen; Holden, Jo; Schmidt, Heather-Marie; McNulty, Anna; Smith, David; Jin, Fengyi; Amin, Janaki; Cooper, David A; Grulich, Andrew E

2018-02-02

The New South Wales (NSW) HIV Strategy 2016-2020 aims for the virtual elimination of HIV transmission in NSW, Australia, by 2020. Despite high and increasing levels of HIV testing and treatment since 2012, the annual number of HIV diagnoses in NSW has remained generally unchanged. Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV infection among gay and bisexual men (GBM) when taken appropriately. However, there have been no population-level studies that evaluate the impact of rapid PrEP scale-up in high-risk GBM. Expanded PrEP Implementation in Communities in NSW (EPIC-NSW) is a population-level evaluation of the rapid, targeted roll-out of PrEP to high-risk individuals. EPIC-NSW, is an open-label, single-arm, multi-centre prospective observational study of PrEP implementation and impact. Over 20 public and private clinics across urban and regional areas in NSW have participated in the rapid roll-out of PrEP, supported by strong community mobilization and PrEP promotion. The study began on 1 March 2016, aiming to enroll at least 3700 HIV negative people at high risk of HIV. This estimate took into consideration criteria for PrEP prescription in people at high risk for acquiring HIV as defined in the NSW PrEP guidelines. Study participants receive once daily co-formulated tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) and are followed for up to 24 months. Follow-up includes: testing for HIV at 1 month, HIV and other sexually transmissible infections three-monthly, HCV annually and monitoring of renal function six-monthly. Optional online behavioural surveys are conducted quarterly. The co-primary endpoints are (i) HIV diagnoses and incidence in the cohort and (ii) HIV diagnoses in NSW. EPIC-NSW is a population-based PrEP implementation trial which targets the entire estimated population of GBM at high risk for HIV infection in NSW. It will provide a unique opportunity to evaluate the population impact of PrEP on a concentrated HIV epidemic. https://clinicaltrials.gov/ (identifying number NCT02870790 ; registration date 14 August 2016), pre-results stage.

Population structure of microbial communities associated with two deep, anaerobic, alkaline aquifers.

PubMed Central

Fry, N K; Fredrickson, J K; Fishbain, S; Wagner, M; Stahl, D A

1997-01-01

Microbial communities of two deep (1,270 and 316 m) alkaline (pH 9.94 and 8.05), anaerobic (Eh, -137 and -27 mV) aquifers were characterized by rRNA-based analyses. Both aquifers, the Grande Ronde (GR) and Priest rapids (PR) formations, are located within the Columbia River Basalt Group in south-central Washington, and sulfidogenesis and methanogenesis characterize the GR and PR formations, respectively. RNA was extracted from microorganisms collected from groundwater by ultrafiltration through hollow-fiber membranes and hybridized to taxon-specific oligonucleotide probes. Of the three domains, Bacteria dominated both communities, making up to 92.0 and 64.4% of the total rRNA from the GR and PR formations, respectively. Eucarya comprised 5.7 and 14.4%, and Archaea comprised 1.8% and 2.5%, respectively. The gram-positive target group was found in both aquifers, 11.7% in GR and 7.6% in PR. Two probes were used to target sulfate- and/or metal-reducing bacteria within the delta subclass of Proteobacteria. The Desulfobacter groups was present (0.3%) only in the high-sulfate groundwater (GR). However, comparable hybridization to a probe selective for the desulfovibrios and some metal-reducing bacteria was found in both aquifers, 2.5 and 2.9% from the GR and PR formations, respectively. Selective PCR amplification and sequencing of the desulfovibrio/metal-reducing group revealed a predominance of desulfovibrios in both systems (17 of 20 clones), suggesting that their environmental distribution is not restricted by sulfate availability. PMID:9097447

Population structure of microbial communities associated with two deep, anaerobic, alkaline aquifers.

PubMed

Fry, N K; Fredrickson, J K; Fishbain, S; Wagner, M; Stahl, D A

1997-04-01

Microbial communities of two deep (1,270 and 316 m) alkaline (pH 9.94 and 8.05), anaerobic (Eh, -137 and -27 mV) aquifers were characterized by rRNA-based analyses. Both aquifers, the Grande Ronde (GR) and Priest rapids (PR) formations, are located within the Columbia River Basalt Group in south-central Washington, and sulfidogenesis and methanogenesis characterize the GR and PR formations, respectively. RNA was extracted from microorganisms collected from groundwater by ultrafiltration through hollow-fiber membranes and hybridized to taxon-specific oligonucleotide probes. Of the three domains, Bacteria dominated both communities, making up to 92.0 and 64.4% of the total rRNA from the GR and PR formations, respectively. Eucarya comprised 5.7 and 14.4%, and Archaea comprised 1.8% and 2.5%, respectively. The gram-positive target group was found in both aquifers, 11.7% in GR and 7.6% in PR. Two probes were used to target sulfate- and/or metal-reducing bacteria within the delta subclass of Proteobacteria. The Desulfobacter groups was present (0.3%) only in the high-sulfate groundwater (GR). However, comparable hybridization to a probe selective for the desulfovibrios and some metal-reducing bacteria was found in both aquifers, 2.5 and 2.9% from the GR and PR formations, respectively. Selective PCR amplification and sequencing of the desulfovibrio/metal-reducing group revealed a predominance of desulfovibrios in both systems (17 of 20 clones), suggesting that their environmental distribution is not restricted by sulfate availability.

Similarities and differences between three coexisting spaceborne radars in global rainfall and snowfall estimation

NASA Astrophysics Data System (ADS)

Tang, Guoqiang; Wen, Yixin; Gao, Jinyu; Long, Di; Ma, Yingzhao; Wan, Wei; Hong, Yang

2017-05-01

Precipitation is one of the most important components in the water and energy cycles. Radars are considered the best available technology for observing the spatial distribution of precipitation either from the ground since the 1980s or from space since 1998. This study, for the first time ever, compares and evaluates the only three existing spaceborne precipitation radars, i.e., the Ku-band precipitation radar (PR), the W-band Cloud Profiling Radar (CPR), and the Ku/Ka-band Dual-frequency Precipitation Radar (DPR). The three radars are matched up globally and intercompared in the only period which they coexist: 2014-2015. In addition, for the first time ever, TRMM PR and GPM DPR are evaluated against hourly rain gauge data in Mainland China. Results show that DPR and PR agree with each other and correlate very well with gauges in Mainland China. However, both show limited performance in the Tibetan Plateau (TP) known as the Earth's third pole. DPR improves light precipitation detectability, when compared with PR, whereas CPR performs best for light precipitation and snowfall. DPR snowfall has the advantage of higher sampling rates than CPR; however, its accuracy needs to be improved further. The future development of spaceborne radars is also discussed in two complementary categories: (1) multifrequency radar instruments on a single platform and (2) constellations of many small cube radar satellites, for improving global precipitation estimation. This comprehensive intercomparison of PR, CPR, and DPR sheds light on spaceborne radar precipitation retrieval and future radar design.

Localization of estrogen receptor α and progesterone receptor B in bovine cervix and vagina during the follicular and luteal phases of the sexual cycle.

PubMed

Sağsöz, H; Akbalik, M E; Saruhan, B G; Ketani, M A

2011-08-01

The localization and distribution of estrogen receptors (ERα) and progesterone receptors (PR-B) in the cervix and vagina of sexually mature bovines during the follicular and luteal phases of the sexual cycle were studied using immunohistochemistry. The estrous cycle stage of 23 Holstein bovines was assessed by gross and histological appearance of ovaries and blood steroid hormone values. Tissue samples from cervix and vagina were fixed in 10% formaldehyde for routine histological processing. Nuclear staining for ERα and PR-B was observed in the epithelial cells of the surface epithelium, stromal cells and smooth muscle cells. Generally, in the cervix, ERα immunoreactivity was more intense in the epithelial and smooth muscle cells during the follicular phase and in the epithelial cells during the luteal phase (p < 0.05). PR-B immunoreactivity was more intense in the epithelial and smooth muscle cells than in the superficial and deep stromal cells during the follicular and luteal phases (p < 0.05). In the vagina, ERα and PR-B immunoreactivities were more intense in the epithelial cells than in the connective tissue cells and smooth muscle cells during the follicular and luteal phases (p < 0.05). These results indicated that the frequency and intensity of ERα and PR-B immunoreactivity in the cervix and vagina of bovines varied according to the cervical and vaginal cell types and the phases of the sexual cycle.

Molecular insights of protein contour recognition with ligand pharmacophoric sites through combinatorial library design and MD simulation in validating HTLV-1 PR inhibitors.

PubMed

Selvaraj, Chandrabose; Omer, Ankur; Singh, Poonam; Singh, Sanjeev Kumar

2015-01-01

Retroviruses HIV-1 and HTLV-1 are chiefly considered to be the most dangerous pathogens in Homo sapiens. These two viruses have structurally unique protease (PR) enzymes, which are having common function of its replication mechanism. Though HIV PR drugs failed to inhibit HTLV-1 infections, they emphatically emphasise the need for designing new lead compounds against HTLV-1 PR. Therefore, we tried to understand the binding level interactions through the charge environment present in both ligand and protein active sites. The domino effect illustrates that libraries of purvalanol-A are attuned to fill allosteric binding site of HTLV-1 PR through molecular recognition and shows proper binding of ligand pharmacophoric features in receptor contours. Our screening evaluates seven compounds from purvalanol-A libraries, and these compounds' pharmacophore searches for an appropriate place in the binding site and it places well according to respective receptor contour surfaces. Thus our result provides a platform for the progress of more effective compounds, which are better in free energy calculation, molecular docking, ADME and molecular dynamics studies. Finally, this research provided novel chemical scaffolds for HTLV-1 drug discovery.

Mahogunin regulates fusion between amphisomes/MVBs and lysosomes via ubiquitination of TSG101

PubMed Central

Majumder, P; Chakrabarti, O

2015-01-01

Aberrant metabolic forms of the prion protein (PrP), membrane-associated CtmPrP and cytosolic (cyPrP) interact with the cytosolic ubiquitin E3 ligase, Mahogunin Ring Finger-1 (MGRN1) and affect lysosomes. MGRN1 also interacts with and ubiquitinates TSG101, an ESCRT-I protein, involved in endocytosis. We report that MGRN1 modulates macroautophagy. In cultured cells, functional depletion of MGRN1 or overexpression of CtmPrP and cyPrP blocks autophagosome–lysosome fusion, alleviates the autophagic flux and its degradative competence. Concurrently, the degradation of cargo from the endo-lysosomal pathway is also affected. This is significant because catalytic inactivation of MGRN1 alleviates fusion of lysosomes with either autophagosomes (via amphisomes) or late endosomes (either direct or mediated through amphisomes), without drastically perturbing maturation of late endosomes, generation of amphisomes or lysosomal proteolytic activity. The compromised lysosomal fusion events are rescued by overexpression of TSG101 and/or its monoubiquitination in the presence of MGRN1. Thus, for the first time we elucidate that MGRN1 simultaneously modulates both autophagy and heterophagy via ubiquitin-mediated post-translational modification of TSG101. PMID:26539917