bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitric oxide positively regulates Ag (I)-induced Ca2+ influx and mast cell activation: role of a nitric oxide synthase-independent pathway
Authors: Inoue Toshio , Suzuki Yoshihiro , Yoshimaru Tetsuro , Ra Chisei
Published: August 2009

NOS-independent NO mediates Ag (I)-induced mast cell activation.

NO is generated by NOS activity and known to act as a negative regulator of mast cell activation. We reported previously that Ag (I) directly evokes mast cell degranulation and LTC4 release via Ca2+ influx through thiol-sensitive, store-independent channels. Here, we report that NO generated independently of NOS activity mediates the store-independent Ca2+ influx. Exposure of mast cells to Ag (I) resulted in increased intracellular NO levels and NO2–/NO3– contents in the extracellular fluid. The NO increase was blocked by NO scavenger Hb and DTT but not by NOS inhibitors such as amino-BH4 and l-NAME. This NO production occurred independently of the Src family kinase and PI3K activities, both of which were necessary for antigen-induced, NOS-dependent NO production. Hb and DTT reduced Ag (I)-induced β-hexosaminidase release and LTC4 release, whereas the NO scavengers and NOS inhibitors augmented antigen-induced mediator release. Moreover, Hb and DTT, but not the NOS inhibitors, abolished the Ag (I)-induced Ca2+ influx, and none of the drugs blocked CRAC channel activity. Finally, Ag (I)-induced Ca2+ influx was distinct from LTCC activity in terms of its sensitivities to wortmannin and LTCC antagonists and the effects of Cav1.2 LTCC gene silencing. These data show that NOS-independent NO regulates mast cell activation positively via a unique store-independent Ca2+ influx pathway. The present findings suggest multiple sources and functions of NO in mast cell biology.
A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer
Authors: Smith Vicki E. , Read Martin L. , Turnell Andrew S. , Watkins Rachel J. , Watkinson John C. , Lewy Greg D. , Fong Jim C. W. , James Sally R. , Eggo Margaret C. , Boelaert Kristien , Franklyn Jayne A. , McCabe Christopher J.
Published: August 2009

Differentiated thyroid cancers and their metastases frequently exhibit reduced iodide uptake, impacting on the efficacy of radioiodine ablation therapy. PTTG binding factor (PBF) is a proto-oncogene implicated in the pathogenesis of thyroid cancer. We recently reported that PBF inhibits iodide uptake, and have now elucidated a mechanism by which PBF directly modulates sodium iodide symporter (NIS) activity in vitro. In subcellular localisation studies, PBF overexpression resulted in the redistribution of NIS from the plasma membrane into intracellular vesicles, where it colocalised with the tetraspanin CD63. Cell-surface biotinylation assays confirmed a reduction in plasma membrane NIS expression following PBF transfection compared with vector-only treatment. Coimmunoprecipitation and GST-pull-down experiments demonstrated a direct interaction between NIS and PBF, the functional consequence of which was assessed using iodide-uptake studies in rat thyroid FRTL-5 cells. PBF repressed iodide uptake, whereas three deletion mutants, which did not localise within intracellular vesicles, lost the ability to inhibit NIS activity. In summary, we present an entirely novel mechanism by which the proto-oncogene PBF binds NIS and alters its subcellular localisation, thereby regulating its ability to uptake iodide. Given that PBF is overexpressed in thyroid cancer, these findings have profound implications for thyroid cancer ablation using radioiodine.
PDZ-domain-directed basolateral targeting of the peripheral membrane protein FRMPD2 in epithelial cells
Authors: Stenzel Nina , Fetzer Christian P. , Heumann Rolf , Erdmann Kai S.
Published: August 2009

Multi-PDZ (PSD-95/Discs large/Zonula-occludens-1) domain proteins play a crucial role in the establishment and maintenance of cell polarization. The novel multi-PDZ domain protein FRMPD2 is a potential scaffolding protein consisting of an N-terminal KIND domain, a FERM domain and three PDZ domains. Here we show that FRMPD2 is localized in a polarized fashion in epithelial cells at the basolateral membrane and partially colocalizes with the tight-junction marker protein Zonula-occludens-1. Downregulation of FRMPD2 protein in Caco-2 cells is associated with an impairment of tight junction formation. We find that the FERM domain of FRMPD2 binds phosphatidylinositols and is sufficient for membrane localization. Moreover, we demonstrate that recruitment of FRMPD2 to cell-cell junctions is strictly E-cadherin-dependent, which is in line with our identification of catenin family proteins as binding partners for FRMPD2. We demonstrate that the FERM domain and binding of the PDZ2 domain to the armadillo protein p0071 are required for basolateral restriction of FRMPD2. Moreover, the PDZ2 domain of FRMPD2 is sufficient to partially redirect an apically localized protein to the basolateral membrane. Our results provide novel insights into the molecular function of FRMPD2 and into the targeting mechanism of peripheral membrane proteins in polarized epithelial cells.
Nap1-mediated actin remodeling is essential for mammalian myoblast fusion
Authors: Nowak Scott J. , Nahirney Patrick C. , Hadjantonakis Anna-Katerina , Baylies Mary K.
Published: August 2009

Myoblast fusion is crucial for the formation, growth, maintenance and regeneration of healthy skeletal muscle. Unfortunately, the molecular machinery, cell behaviors, and membrane and cytoskeletal remodeling events that govern fusion and myofiber formation remain poorly understood. Using time-lapse imaging approaches on mouse C2C12 myoblasts, we identify discrete and specific molecular events at myoblast membranes during fusion and myotube formation. These events include rearrangement of cell shape from fibroblast to spindle-like morphologies, changes in lamellipodial and filopodial extensions during different periods of differentiation, and changes in membrane alignment and organization during fusion. We find that actin-cytoskeleton remodeling is crucial for these events: pharmacological inhibition of F-actin polymerization leads to decreased lamellipodial and filopodial extensions and to reduced myoblast fusion. Additionally, shRNA-mediated inhibition of Nap1, a member of the WAVE actin-remodeling complex, results in accumulations of F-actin structures at the plasma membrane that are concomitant with a decrease in myoblast fusion. Our data highlight distinct and essential roles for actin cytoskeleton remodeling during mammalian myoblast fusion, provide a platform for cellular and molecular dissection of the fusion process, and suggest a functional conservation of Nap1-regulated actin-cytoskeleton remodeling during myoblast fusion between mammals and Drosophila.
Epidermal-growth-factor-induced proliferation of astrocytes requires Egr transcription factors
Authors: Mayer Sabine I. , Rössler Oliver G. , Endo Takeshi , Charnay Patrick , Thiel Gerald
Published: August 2009

Stimulation of astrocytes with epidermal growth factor (EGF) induced proliferation and triggered the biosynthesis of the transcription factor Egr-1, involving the activation of the extracellular signal-regulated protein kinase (ERK) signaling pathway. No differences in the proliferation rate of astrocytes prepared from wild-type or Egr-1-deficient mice were detected. However, expression of a dominant-negative mutant of Egr-1 that interfered with DNA-binding of all Egr proteins prevented EGF-induced proliferation of astrocytes. Site-directed mutagenesis of two crucial cysteine residues within the zinc finger DNA-binding domain revealed that DNA-binding of the Egr-1 mutant was essential to inhibit proliferation of EGF-stimulated astrocytes. Expression of NAB2 (a negative co-regulator of Egr-1, Egr-2 and Egr-3) or a dominant-negative mutant of Elk-1 (a key regulator of Egr-1 biosynthesis) abolished EGF-induced proliferation of astrocytes. Chromatin immunoprecipitation experiments showed that Egr-1, Egr-2 and Egr-3 bound to the gene expressing basic fibroblast growth factor (bFGF) in EGF-stimulated astrocytes. Egr-2 and Egr-3 also interacted with the bFGF gene in EGF-stimulated astrocytes prepared from Egr-1-deficient mice, indicating that loss of Egr-1 is compensated by other Egr proteins. Together, these data show that Egr transcription factors are essential for conversion of the mitogenic signal of EGF into a proliferative response.
An intrinsic quality-control mechanism ensures unconventional secretion of fibroblast growth factor 2 in a folded conformation
Authors: Torrado Lucía Cespón , Temmerman Koen , Müller Hans-Michael , Mayer Matthias P. , Seelenmeyer Claudia , Backhaus Rafael , Nickel Walter
Published: August 2009

Fibroblast growth factor 2 (FGF2) is a proangiogenic mitogen that is secreted by an unconventional mechanism, which does not depend on a functional ER-Golgi system. FGF2 is first recruited to the inner leaflet of plasma membranes, in a process that is mediated by the phosphoinositide PtdIns(4,5)P2. On the extracellular side, membrane-proximal FGF2-binding sites provided by heparan-sulfate proteoglycans are essential for trapping and accumulating FGF2 in the extracellular space. Here we demonstrate that FGF2 membrane translocation can occur in a folded conformation, i.e. unfolded molecules are not obligatory intermediates in FGF2 secretion. Furthermore, we find that initial sorting into its export pathway requires FGF2 to be folded, because the interaction with PtdIns(4,5)P2 is lost upon unfolding of FGF2. Our combined findings suggest an intrinsic quality-control mechanism that ensures extracellular accumulation of FGF2 in a biologically active form.
Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells
Authors: Pan Mei-Ren , Chang Tsung-Ming , Chang Hui-Chiu , Su Jen-Liang , Wang Hsei-Wei , Hung Wen-Chun
Published: August 2009

Prox1 is a master regulator for the development of lymphatic vasculature and the induction of lymphangiogenesis. In this study, we identified Prox1 as a new target for small ubiquitin-like modifier 1 (SUMO-1). Lysine 556 (K556) was found to be the major sumoylation site for Prox1 in vitro and in vivo. Mutation of this site (from lysine to arginine K556R) reduced DNA binding and the transcriptional activity of Prox1. Overexpression of Prox1 in EA.hy926 endothelial cells induced expression of lymphatic endothelial cell-specific genes including vascular endothelial growth factor receptor 3 (VEGFR3), fibroblast growth factor receptor 3 (FGFR3) and p57 while expression of K556R mutant Prox1 had little effect. The induction of VEGFR3 by Prox1 in EA.hy926 endothelial cells was an indication of their response to VEGF-C-induced lymphangiogenic signals, including the enhancement of proliferation, sprouting and tube formation and the inhibition of apoptosis. This effect is SUMO-dependent because ectopic expression of SUMO-specific protease 2 (SENP2) effectively reduced Prox1 sumoylation and Prox1-induced VEGFR3 expression. In addition, K556R mutant Prox1 could not induce lymphatic phenotypes. Taken together, our results indicate that Prox1 is a target for SUMO-1 and suggest that sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells.
SUMO-dependent regulation of centrin-2
Authors: Klein Ulf R. , Nigg Erich A.
Published: August 2009

Centrins are multifunctional Ca2+-binding proteins that are highly conserved from yeast to humans. Centrin-2 is a core component of the centrosome of higher eukaryotes. In addition, it is present within the nucleus, in which it is part of the xeroderma pigmentosum group C (XPC) complex, which controls nucleotide excision repair (NER). Regulation of the subcellular distribution of centrin-2 has so far remained elusive. Here we show that centrin-2 is a substrate of SUMOylation in vitro and in vivo, and that it is preferentially modified by SUMO2/3. Moreover, we identify the SUMO E3-like ligase human polycomb protein 2 (PC2; also known as hPC2) as essential for centrin-2 modification. Interference with the SUMOylation pathway leads to a striking defect in nuclear localization of centrin-2 and accumulation in the cytoplasm, whereas centrosomal recruitment of centrin-2 is unaffected. Depletion of the XPC protein mimics this situation and we provide evidence that SUMO conjugation of centrin-2 enhances its binding to the XPC protein. These data show that the nucleocytoplasmic shuttling of centrin-2 depends on the SUMO system and indicates that localization of centrin-2 within the nucleus depends on its ability to bind to the XPC protein.
The response owing to inclined forces at an interface of a viscous fluid and a generalized thermoelastic micropolar honeycomb medium
Authors: Kumar R , Gupta R R
Published: August 2009

The present investigation deals with the study of effect of change in angle of inclined forces at an interface of a viscous fluid/generalized thermoelastic micropolar honeycomb medium. The inclined load is assumed to be a linear combination of normal load and tangential load. The method of potential function, together with the application of integral transforms, has been applied to obtain the expressions of stresses and temperature distribution in the transformed domain. A particular type of boundary condition has been taken to illustrate the utility of the approach in three different cases, namely, time domain, frequency domain, and steady state, with the appropriate change of variables. A numerical inversion technique to invert the integral transforms is used on the transformed solution. The effect of micropolarity and change in angle of inclination is shown graphically owing to the response of different forces. Some particular cases of interest are also discussed.
Strain measurements on porous concrete samples for triaxial compression and extension tests under very high confinement
Authors: Vu X H , Malecot Y , Daudeville L
Published: August 2009

This article presents the production of strain measurements on porous concrete samples for use in triaxial compression and extension tests with a very high lateral confining pressure. When a massive concrete structure is subjected to severe loadings (e.g. rock falls, near-field detonations, and ballistic impacts), the material undergoes triaxial loading at a high confining pressure. To reproduce high levels of stress with well-controlled loading paths, static tests are carried out on concrete using a high-capacity triaxial press, called GIGA. This press allows the testing of concrete specimens (7 cm in diameter and 14 or 15.5 cm long) for levels of confining pressure ranging up to 850 MPa and axial stresses of up to 2.35 GPa. The porous characteristic of the material together with the high confining pressure require both developing a material protection device and building strain gauge-based instrumentation of unprecedented design for such confining pressures. In addition, the effect of pressure and other sources of error on strain and stress measurements are identified herein thanks to tests performed on model materials. This study shows that the effect of pressure on strain gauge measurements is negligible, whereas this same effect proves significant in the axial displacement measurement by means of a linear variable differential transformer (LVDT) sensor and must be taken into account therefore during the data processing phase. This article will present the initial results of triaxial compression tests conducted at high confining pressure on both dry and saturated concrete samples instrumented with gauges. It will also provide results of a triaxial extension test conducted at high confinement on dry concrete: a unique step in characterizing the triaxial behaviour of concrete. Moreover, it will be demonstrated that simultaneous axial strain measurements using gauges and the LVDT sensor serve to evaluate strain homogeneity of the sample tested at high confinement.
The Ritz formulation applied to the study of the vibration frequency characteristics of functionally graded circular cylindrical shells
Authors: Naeem M N , Arshad S H , Sharma C B
Published: August 2009

In this article vibration frequencies of functionally graded circular cylindrical shells are analysed and studied using the Ritz formulation. Since closed-form solutions are limited to simple cases, an approximate method is employed to solve the shell problem, and numerical evaluation is carried out using a direct variational method. Axial modal dependence is chosen in terms of Ritz polynomials to ascertain a rapid convergence of the method. Sanders and Budiansky's thin shell theory is utilized for strain—displacement and curvature—displacement relations. Functionally graded material characteristics for the constituent materials are distributed in accordance with a volume fraction law. Influence of boundary conditions and volume fraction exponents on the vibration frequency spectra is analysed. The present results are compared with some previous works and excellent agreement is found.
Theoretical approximations to analyse the onset of self-excited oscillations in flow through collapsible tubes
Authors: Oruç V , Çarpınlıoğlu M Ö
Published: August 2009

In this study, flow through collapsible tubes is analysed theoretically for the case of the onset of collapse which induces self-excited oscillations. The basic tools in the theoretical calculations are the linear stability theory and the tube law. The experimental data in the form of measured oscillation frequency at the onset of collapse of an elastic tube is supplied as a base input parameter for the theoretical approximations. The calculations offer a possibility for estimating the unmeasured parameters such as critical oscillation speed, speed index, and tube cross-sectional area at the onset of collapse. It was seen by referring to the obtained results that theoretical predictions agreed with the experimental measurements.
Optimum design of 3-RRR planar parallel manipulators
Authors: Dou Runliang
Published: August 2009

This article deals with the optimum design of 3-RRR planar parallel manipulators. Based on the kinematic model and Jacobian matrix, the global conditioning index, global velocity index and global stiffness index of 3-RRR parallel manipulators are investigated. The corresponding atlases are represented graphically in the established design space, and the geometrical parameters without dimension are determined. An example is presented to achieve the optimum dimensional parameter based on the optimum non-dimensional result. The result of this article is not only useful for the development of 3-RRR planar parallel manipulators, but also helpful for the optimum design of other parallel manipulators.
Dynamic analysis of three-dimensional flow in the opening process of a single-disc butterfly valve
Authors: Wang L , Song X G , Park Y C
Published: August 2009

A numerical dynamic analysis is carried out to simulate a three-dimensional flow and to study the performance of a single-disc butterfly valve with a diameter of 1.35 m in the opening process. The unsteady fluid flow during the opening process is studied by using the moving grid technique. The turbulent separated flow is also studied to understand the unsteady flow better through velocity distributions and pressure distributions on the mid-symmetric plane. The formation of vortexes is also discussed. Then the characteristics of butterfly valves such as the flow coefficient, the dynamic torque coefficient, and the drag coefficient are studied. The curves of these characteristics corresponding with the variational valve opening angle are obtained to investigate the performance of the single-disc butterfly valve.
Shape-memory coaxial bimorphs
Authors: Jähne R , Campanile L F
Published: August 2009

The thermal shape recovery shown by shape memory alloys is a property that makes these materials very attractive for applications in the field of smart structures, e.g. bending actuators. This article shows a design method for coaxial bimorphs that are composed of a linear-elastic and shape memory alloy component, properly coupled. A simple and effective method is proposed to solve for the component designs in order to achieve given bimorph configurations. Analytical examples and finite-element simulations are shown for the case of assigned bimorph's warm shape.
The effect of fin spacing and material on the performance of a heat sink with circular pin fins
Authors: Dewan A , Patro P , Khan I , Mahanta P
Published: August 2009

This article presents a computational study of the steady-state thermal and air-flow resistance characteristics and performance analysis through a rectangular channel with circular pin fins attached to a flat surface. The pin fins are arranged in staggered manner and the heat transfer is assumed to be conjugated in nature. The body forces and radiation effects are assumed to be negligible. The hydrodynamic and thermal behaviours are studied in detail for the Reynolds numbers varying from 200 to 1000. The heat transfer increases with an increase of the fin density along the streamwise direction. For the same surface area and pumping power, the fin materials with large thermal conductivity provide high heat transfer rate with no increase in the pressure drop. The emphasis of the present research work is not only to look into the traditional objective of maximum heat transfer in a heat exchanger, but also to obtain it with minimum pressure drop.
Herpes simplex virus type 2 and HIV infection among US military personnel: implications for health prevention programmes
Authors: Bautista C T , Singer D E , O'Connell R J , Crum-Cianflone N , Agan B K , Malia J A , Sanchez J L , Peel S A , Michael N L , Scott P T
Published: August 2009

US military personnel are routinely screened for HIV infection. Herpes simplex virus type 2 (HSV-2) is a risk factor for HIV acquisition. To determine the association between HSV-2 and HIV, a matched case-control study was conducted among US Army and Air Force servicemembers with incident HIV infections (cases) randomly matched with two HIV-uninfected servicemembers (controls) between 2000 and 2004. HSV-2 prevalence was significantly higher among cases (30.3%, 138/456) than among controls (9.7%, 88/912, P < 0.001). HSV-2 was strongly associated with HIV in univariate (odds ratio [OR] = 4.2, 95% confidence interval [CI] = 3.1–5.8) and multiple analyses (adjusted [OR] = 3.9, 95% CI = 2.8–5.6). The population attributable risk percentage of HIV infection due to HSV-2 was 23%. Identifying HSV-2 infections may afford the opportunity to provide targeted behavioural interventions that could decrease the incidence of HIV infections in the US military population; further studies are needed.
Enterococcus pneumonia complicated with empyema and lung abscess in an HIV-positive patient. Case report and review of the literature
Authors: Vanschooneveld T , Mindru C , Madariaga M G , Kalil A C , Florescu D F
Published: August 2009

This report describes the first case of vancomycin-resistant Enterococcus pneumonia complicated with empyema and lung abscess in an HIV patient and reviews previously published cases of Enterococcus pleuro-pulmonary infection. Our case highlights the rarity of this entity and reviews the risk factors for Enterococcus pleuro-pulmonary infections.
Successful treatment of profuse recalcitrant extra-genital warts in an HIV-positive patient using 5% imiquimod cream
Authors: Walzman M
Published: August 2009

Common warts, particularly plantar warts, are difficult to treat at the best of times and are likely to be even more difficult to treat when the patient is HIV positive. This case report highlights the successful treatment of profuse common warts of both hands and both feet in an HIV-positive patient using imiquimod 5% cream, following unsuccessful regular cryocautery therapy.
Dysfunctional ideas (‘male myths’) are a result of, rather than the cause of, psychogenic erectile dysfunction in heterosexual men
Authors: Beckwith A C E , Green J , Goldmeier D , Hetherton J
Published: August 2009

A variety of aetiological factors have been suggested as predisposing men to psychogenic erectile dysfunction (ED). One issue that has been repeatedly identified is holding dysfunctional beliefs about normal male sexual functioning (‘male myths’ – MMs). Past research found that those with a sexual dysfunction are more likely to believe in MMs. However, there was no distinction between whether these beliefs were the cause or result of having a sexual dysfunction. We sought to establish whether holding dysfunctional beliefs is a psychological predisposing factor for those with psychogenic ED. A total of 91 men (40 – organic ED, 24 – psychogenic ED and 27 controls) completed measures to establish their sexual functioning and beliefs in a number of suggested MM. Individuals with organic and psychogenic ED did not differ in their level of belief in MM but both groups differed significantly from controls. The results suggest that subscribing to MMs is a result, not the cause, of psychogenic ED.
Acceptance of genitourinary medicine clinic appointments within 48 hours is influenced by patient perception of risk but not by symptoms
Authors: Steedman N M , Worsnop V , Fernie R
Published: August 2009

The Department of Health has addressed access to genitourinary medicine services by setting targets that 100% of patients should be offered an appointment within 48 hours of contact and 95% should be seen within 48 hours. Such rapid access appointments are often declined by patients. We wished to ascertain whether patient perception of health risk or the presence of symptoms suggestive of a sexually transmitted infection (STI) might influence how quickly patients accept an appointment. We designed a two-armed study which demonstrated that up to 37% of patients offered an appointment within 48 hours declined it, with work commitments offered by 84% of these patients as the reason for deferring attendance. The presence of symptoms did not influence whether patients accepted an early appointment, however the patient's perception of health risk associated with an untreated STI was statistically significantly associated with earlier attendance ( P < 0.0001). Increased public education regarding the consequences of untreated STI may therefore improve the acceptance by patients of appointments within 48 hours.
Predictors of mortality among women with AIDS in Illinois, USA
Authors: Borchardt S M , Haufle V , Whitaker E E , Dworkin M S
Published: August 2009

Population-based surveillance data can help guide research priorities and plan programmes to prevent death among women with AIDS. We describe the predictors of mortality among women diagnosed with AIDS in Illinois, USA. Using the HIV/AIDS Reporting System), we identified 1944 adult women who were diagnosed with AIDS during January 1999–December 2004. The proportion of women who died within one year of diagnosis of AIDS declined from 97% in 1999 to 12% in 2005. Multivariate analysis indicated that age ≥45 years, intravenous drug use, diagnosis of clinical AIDS and hospitalization at the time of AIDS diagnosis were significant predictors of death among women with AIDS. The number of women who died soon after diagnosis with AIDS declined substantially. Nevertheless, prevention programmes designed to improve survival among women with AIDS should emphasize early diagnosis and referral for care in an effort to prevent first diagnosis with clinical AIDS during hospitalization.
Is accelerated partner therapy a feasible and acceptable strategy for rapid partner notification in the UK?: a qualitative study of genitourinary medicine clinic attenders
Authors: Sutcliffe L , Brook M G , Chapman J L , Cassell J M , Estcourt C S
Published: August 2009

Partner notification (PN) in the UK is of limited effectiveness. Expedited partner therapy improves PN outcomes but does not comply with existing UK professional guidance. We developed two new strategies, known as accelerated partner therapy (APT), based on elements of PN practice for which there is evidence of efficacy, and which conform to UK prescribing guidance. We explored the acceptability and feasibility of these models qualitatively in genitourinary medicine clinic attenders. Both strategies were viewed favourably. Preference was influenced by age, relationship type, whether participants were delivering or receiving APT and whether the sex partner was aware of the participant's clinic visit. APT provides a new approach to PN, which has strong patient support and complies with existing UK regulations. The complex factors that influence patients' choice of PN method suggest that provision of a range of PN options including APT may be central to improving the effectiveness of PN in the UK.
Aetiology of genital ulcer disease in female partners of male participants in a circumcision trial in Uganda
Authors: Brankin A E , Tobian A A R , Laeyendecker O , Suntoke T R , Kizza A , Mpoza B , Kigozi G , Nalugoda F , Iga B , Chen M Z , Gray R H , Wawer M J , Quinn T C , Reynolds S J
Published: August 2009

HIV acquisition is associated with herpes simplex virus type 2 (HSV-2) infection and genital ulcer disease (GUD). Three randomized control trials demonstrated that male circumcision significantly decreases HIV, HSV-2, human papillomavirus and self-reported GUD among men. GUD is also decreased among female partners of circumcised men, but it is unknown whether male circumcision status affects GUD pathogens in female partners. For the evaluation of GUD aetiology, two separate multiplex assays were performed to detect Haemophilus ducreyi, Treponema pallidum, HSV-1 and HSV-2. Of all the female GUD swabs evaluated, 67.5% had an aetiology identified, and HSV-2 was the primary pathogen detected (96.3%). However, there was no difference in the proportion of ulcers due to HSV-2 or other pathogens between female partners of circumcised men (11/15, 73.3%) compared with uncircumcised men (15/25, 60.0%, P = 0.39). The seroprevalence of HSV-2 is high in this population and therefore most of the detected HSV-2 infections represent reactivation. Since GUD is associated with HIV acquisition and one-third of GUD in this study did not have an aetiological agent identified, further research is needed to better understand the aetiology of GUD in Africa, and its relationship to circumcision and HIV infection.
Control of Flexible Software Development Under Uncertainty
Authors: Harris Michael L. , Collins Rosann Webb , Hevner Alan R.
Published: August 2009

When should software development teams have the flexibility to modify their directions and how do we balance that flexibility with controls essential to produce acceptable outcomes? We use dynamic capabilities theory and an extension of control theory to understand these questions. This work is examined in a case study. Our results demonstrate that flexibility may be needed when the starting conditions are uncertain and that effective control in these situations requires use of traditional controls plus a new type of control we term emergent outcome control.
Applying test operating characteristics to measures of exercise motivation: A primer
Authors: Brickell Tracey A. , Lange Rael T. , Chatzisarantis Nikos L. D.
Published: August 2009

Physical activity programmes that include a motivational counselling component can be effective at increasing exercise participation. Reliable screening procedures could provide a cost effective method of identifying and channelling those ‘at risk’ for non‐participation into a motivational counselling intervention and increase participation and long‐term adherence. Traditional statistical methods have played an important step in developing measures that are good predictors of future exercise behaviour. Test operating characteristics (TOCs), a set of clinical outcome statistics, could be used to evaluate the accuracy of these measures as screening tools in identifying those ‘at risk’ for non‐participation and those ‘not at risk’ for use in applied settings, such as physical activity programmes. This paper will provide a primer on the use of TOCs, particularly as they apply to the evaluation of measures of exercise motivation. Also provided is an example application using eight measures of exercise motivation previously used in research.
Errata: Atomic weights of the elements (Technical Report). Pure Appl. Chem. 71(8), 1593-1607 (1999)
Authors: Vocke R. D.
Published: August 2009

Errata: Atomic weights of the elements: (Technical Report). (R. D. Vocke, Jr.). Pure Appl. Chem. 71, 1593-1607 (1999); doi:10.1351/pac199971081593.
The p75 Neurotrophin Receptor Promotes Amyloid-β(1-42)-Induced Neuritic DystrophyIn VitroandIn Vivo
Authors: Knowles Juliet K. , Rajadas Jayakumar , Nguyen Thuy-Vi V. , Yang Tao , LeMieux Melburne C. , Vander Griend Lilith , Ishikawa Chihiro , Massa Stephen M. , Wyss-Coray Tony , Longo Frank M.
Published: August 2009

Oligomeric forms of amyloid-β (Aβ) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75NTR) has been implicated in Aβ-induced neurodegeneration. To further define the functions of p75NTRin AD, we examined the interaction of oligomeric Aβ(1-42) with p75NTR, and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Aβ, and fluorescence resonance energy transfer analysis revealed that Aβ oligomers interact with the extracellular domain of p75NTR.In vitrostudies of Aβ-induced death in neuron cultures isolated from wild-type and p75NTR−/−mice, in which the p75NTRextracellular domain is deleted, showed reduced sensitivity of mutant cells to Aβ-induced cell death. Interestingly, Aβ-induced neuritic dystrophy and activation of c-Jun, a known mediator of Aβ-induced deleterious signaling, were completely prevented in p75NTR−/−neuron cultures. Thy1-hAPPLond/Swe× p75NTR−/−mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75NTR. Aβ levels were not affected, suggesting that removal of p75NTRextracellular domain reduced the ability of excess Aβ to promote neuritic degeneration. These findings indicate that although p75NTRlikely does not mediate all Aβ effects, it does play a significant role in enabling Aβ-induced neurodegenerationin vitroandin vivo, establishing p75NTRas an important therapeutic target for AD.
Age-Dependent Impairment of Cognitive and Synaptic Function in the htau Mouse Model of Tau Pathology
Authors: Polydoro Manuela , Acker Christopher M. , Duff Karen , Castillo Pablo E. , Davies Peter
Published: August 2009

A hallmark feature of Alzheimer's disease pathology is the presence of neurofibrillary tangles (NFTs), which are intracellular aggregates of conformationally abnormal and hyperphosphorylated tau. The presence of NFTs in the forebrain is associated with impairments of cognitive function, supporting a central role for tau in dementia. The significance of the accumulation of NFTs for neuronal and cognitive function is still obscure. It is possible that NFTs disrupt synaptic transmission and plasticity, leading to memory deficits and cognitive malfunction. To elucidate the relationship between the development of tau pathology and synaptic and cognitive functions, we performed behavioral tests and electrophysiological experiments in the htau mouse. Here we report age-dependent cognitive and physiological impairments in htau mice that preceded neurodegeneration. Twelve-month-old htau mice with moderate tau pathology, but not 4-month-old mice with early-stage tau pathology, presented cognitive deficits in an object recognition memory task in which the visual recognition memory of a novel object was disrupted. Moreover, only 12-month-old htau mice exhibit spatial memory deficits, as indicated by the impaired performance in the Morris water maze. In addition, we report that basal synaptic transmission and induction of long-term potentiation with high-frequency stimulation, but not theta burst stimulation, is perturbed in hippocampal CA1 region of old but not young htau mice. Our results suggest that tau pathology may underlie an age-dependent learning impairment through disruption of synaptic function.
Search for a Threatening Target Triggers Limbic Guidance of Spatial Attention
Authors: Mohanty Aprajita , Egner Tobias , Monti Jim M. , Mesulam M.-Marsel
Published: August 2009

The ability to actively locate potential threats in our environment is highly adaptive. To investigate mediating neural mechanisms, we designed a visual search task in which central cues signaled future location and emotional expression (angry or neutral) of a target face. Cues predicting angry targets accelerated subsequent attention shifts, indicating that endogenous signals predicting threatening events can prime the spatial attention network. Functional imaging showed that spatially informative cues activated the fusiform gyrus (FG) as well as frontoparietal components of the spatial attention network, including intraparietal sulcus (IPS) and frontal eye field (FEF), whereas cues predicting angry faces also activated limbic areas, including the amygdala. Anatomically overlapping, additive effects of spatial and emotional cuing were identified in the IPS, FEFs, and FG, regions that also displayed augmented connectivity with the amygdala after cues predicting angry faces. These data highlight a key role for the frontoparietal spatial attention network in the compilation of a salience map that combines the spatial coordinates of an event with its motivational relevance. Furthermore, they suggest that active search for a threatening stimulus elicits amygdala input to the spatial attention network and inferotemporal visual areas, facilitating the rapid detection of upcoming motivationally significant events.
The Ca2+Channel Subunit β2 Regulates Ca2+Channel Abundance and Function in Inner Hair Cells and Is Required for Hearing
Authors: Neef Jakob , Gehrt Anna , Bulankina Anna V. , Meyer Alexander C. , Riedel Dietmar , Gregg Ronald G. , Strenzke Nicola , Moser Tobias
Published: August 2009

Hearing relies on Ca2+influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of the Ca2+channel subunit CaVβ2in hearing. Of the CaVβ1–4mRNAs, IHCs predominantly contained CaVβ2. Hearing was severely impaired in mice lacking CaVβ2in extracardiac tissues (CaVβ2−/−). This involved deficits in cochlear amplification and sound encoding. Otoacoustic emissions were reduced or absent inCaVβ2−/−mice, which showed strongly elevated auditory thresholds in single neuron recordings and auditory brainstem response measurements.CaVβ2−/−IHCs showed greatly reduced exocytosis (by 68%). This was mostly attributable to a decreased number of membrane-standing CaV1.3 channels. Confocal Ca2+imaging revealed presynaptic Ca2+microdomains albeit with much lower amplitudes, indicating synaptic clustering of fewer CaV1.3 channels. The coupling of the remaining Ca2+influx to IHC exocytosis appeared unaffected. Extracellular recordings of sound-evoked spiking in the cochlear nucleus and auditory nerve revealed reduced spike rates in theCaVβ2−/−mice. Still, sizable onset and adapted spike rates were found during suprathreshold stimulation inCaVβ2−/−mice. This indicated that residual synaptic sound encoding occurred, although the number of presynaptic CaV1.3 channels and exocytosis were reduced to one-third. The normal developmental upregulation, clustering, and gating of large-conductance Ca2+activated potassium channels in IHCs were impaired in the absence of CaVβ2. Moreover, we found the developmental efferent innervation to persist in CaVβ2-deficient IHCs. In summary, CaVβ2has an essential role in regulating the abundance and properties of CaV1.3 channels in IHCs and, thereby, is critical for IHC development and synaptic encoding of sound.
Long-Term Potentiation in the Rat Medial Vestibular Nuclei Depends on Locally Synthesized 17β-Estradiol
Authors: Grassi Silvarosa , Frondaroli Adele , Dieni Cristina , Scarduzio Mariangela , Pettorossi Vito E.
Published: August 2009

In male rat brainstem slices, we investigated the involvement of locally synthesized 17β-estradiol (E2) in the induction in the medial vestibular nucleus (MVN) of long-term potentiation (LTP) by high-frequency stimulation (HFS) of the primary vestibular afferents. We demonstrated that the blockade of aromatase by letrozole or of E2receptors (ERα and ERβ) by ICI 182,780 prevented the HFS-induced LTP of the N1 wave of the evoked field potential (FP) without affecting baseline responses. Only prolonged afferent activation could induce low LTP. In contrast, HFS applied under a combined blockade of GABAAreceptors and aromatase or ERs was still able to induce LTP, but it was significantly lower and slower. These findings demonstrate that E2does not have a tonic influence on the activity of the MVN neurons and provide the first evidence of the crucial role played by local synthesis of E2in inducing LTP. We suggest that the synthesis of E2occurs after aromatase activation during HFS and facilitates the development of vestibular synaptic plasticity by influencing glutamate and GABA transmission.
Multimodal Integration in Rostral Fastigial Nucleus Provides an Estimate of Body Movement
Authors: Brooks Jessica X. , Cullen Kathleen E.
Published: August 2009

The ability to accurately control posture and perceive self-motion and spatial orientation requires knowledge of the motion of both the head and body. However, whereas the vestibular sensors and nuclei directly encode head motion, no sensors directly encode body motion. Instead, the convergence of vestibular and neck proprioceptive inputs during self-motion is generally believed to underlie the ability to compute body motion. Here, we provide evidence that the brain explicitly computes an internal estimate of body motion at the level of single cerebellar neurons. Neuronal responses were recorded from the rostral fastigial nucleus, the most medial of the deep cerebellar nuclei, during whole-body, body-under-head, and head-on-body rotations. We found that approximately half of the neurons encoded the motion of the body in space, whereas the other half encoded the motion of the head in space in a manner similar to neurons in the vestibular nuclei. Notably, neurons encoding body motion responded to both vestibular and proprioceptive stimulation (accordingly termed bimodal neurons). In contrast, neurons encoding head motion were sensitive only to vestibular inputs (accordingly termed unimodal neurons). Comparison of the proprioceptive and vestibular responses of bimodal neurons further revealed similar tuning in response to changes in head-on-body position. We propose that the similarity in nonlinear processing of vestibular and proprioceptive signals underlies the accurate computation of body motion. Furthermore, the same neurons that encode body motion (i.e., bimodal neurons) most likely encode vestibular signals in a body-referenced coordinate frame, since the integration of proprioceptive and vestibular information is required for both computations.
A Simple Model of Cortical Dynamics Explains Variability and State Dependence of Sensory Responses in Urethane-Anesthetized Auditory Cortex
Authors: Curto Carina , Sakata Shuzo , Marguet Stephan , Itskov Vladimir , Harris Kenneth D.
Published: August 2009

The responses of neocortical cells to sensory stimuli are variable and state dependent. It has been hypothesized that intrinsic cortical dynamics play an important role in trial-to-trial variability; the precise nature of this dependence, however, is poorly understood. We show here that in auditory cortex of urethane-anesthetized rats, population responses to click stimuli can be quantitatively predicted on a trial-by-trial basis by a simple dynamical system model estimated from spontaneous activity immediately preceding stimulus presentation. Changes in cortical state correspond consistently to changes in model dynamics, reflecting a nonlinear, self-exciting system in synchronized states and an approximately linear system in desynchronized states. We propose that the complex and state-dependent pattern of trial-to-trial variability can be explained by a simple principle: sensory responses are shaped by the same intrinsic dynamics that govern ongoing spontaneous activity.
Cortical Inhibitory Cell Types Differentially Form Intralaminar and Interlaminar Subnetworks withExcitatory Neurons
Authors: Otsuka Takeshi , Kawaguchi Yasuo
Published: August 2009

The neocortical circuit is composed of excitatory principal neurons and inhibitory interneurons. Recent advances have established that multiple subnetworks of synaptically coupled excitatory neurons provide distinct pathways for information flow through the cortical circuit. Here we have investigated how inhibitory interneurons are incorporated into these excitatory subnetworks in the rat frontal cortex. In layer 5 (L5), the probability of reciprocal synaptic connections between pyramidal cells and fast-spiking (FS) interneurons was significantly higher than the probability of reciprocal connections between pyramidal cells and non-FS interneurons. Further, the amplitude of synaptic currents in reciprocally connected FS/pyramidal cell pairs was larger than that in pairs connected only in one direction. To examine interlaminar connection specificity, we stimulated layer 2/3 (L2/3) pyramidal cells, using focal glutamate puff stimulation, and recorded evoked EPSCs in L5 cells. Stimulation of L2/3 cells evoked EPSCs in L5 non-FS cells more frequently than in L5 FS cells. Dual recordings from L5 interneurons and neighboring pyramidal cells revealed that connected non-FS/pyramidal cell pairs were more likely to share excitatory inputs from L2/3 cells than were unconnected cell pairs. On the other hand, the connectivity between L5 FS and pyramidal cell pairs did not affect the common input probability from L2/3. Our results suggest that L5 inhibitory interneurons form distinct intralaminar and interlaminar subnetworks with pyramidal cells, depending on inhibitory cell types.
Astrocytic Dysfunction in Epileptogenesis: Consequence of Altered Potassium and Glutamate Homeostasis?
Authors: David Yaron , Cacheaux Luisa P. , Ivens Sebastian , Lapilover Ezequiel , Heinemann Uwe , Kaufer Daniela , Friedman Alon
Published: August 2009

Focal epilepsy often develops following traumatic, ischemic, or infectious brain injury. While the electrical activity of the epileptic brain is well characterized, the mechanisms underlying epileptogenesis are poorly understood. We have recently shown that in the rat neocortex, long-lasting breakdown of the blood–brain barrier (BBB) or direct exposure of the neocortex to serum-derived albumin leads to rapid upregulation of the astrocytic marker GFAP (glial fibrillary acidic protein), followed by delayed (within 4–7 d) development of an epileptic focus. We investigated the role of astrocytes in epileptogenesis in the BBB-breakdown and albumin models of epileptogenesis. We found similar, robust changes in astrocytic gene expression in the neocortex within hours following treatment with deoxycholic acid (BBB breakdown) or albumin. These changes predict reduced clearance capacity for both extracellular glutamate and potassium. Electrophysiological recordingsin vitroconfirmed the reduced clearance of activity-dependent accumulation of both potassium and glutamate 24 h following exposure to albumin. We used a NEURON model to simulate the consequences of reduced astrocytic uptake of potassium and glutamate on EPSPs. The model predicted that the accumulation of glutamate is associated with frequency-dependent (>100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependent (10–50 Hz) and NMDA-dependent synaptic facilitation.In vitroelectrophysiological recordings during epileptogenesis confirmed frequency-dependent synaptic facilitation leading to seizure-like activity. Our data indicate a transcription-mediated astrocytic transformation early during epileptogenesis. We suggest that the resulting reduction in the clearance of extracellular potassium underlies frequency-dependent neuronal hyperexcitability and network synchronization.