bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune regulation of canine tumour and macrophage PD‐L1 expression
Authors: Hartley G. , Faulhaber E. , Caldwell A. , Coy J. , Kurihara J. , Guth A. , Regan D. , Dow S.
Published: February 2016

Expression of programmed cell death receptor ligand 1 (PD‐L1) on tumor cells has been associated with immune escape in human and murine cancers, but little is known regarding the immune regulation of PD‐L1 expression by tumor cells and tumor‐infiltrating macrophages in dogs. Therefore, 14 canine tumor cell lines, as well as primary cultures of canine monocytes and macrophages, were evaluated for constitutive PD‐L1 expression and for responsiveness to immune stimuli. We found that PD‐L1 was expressed constitutively on all canine tumor cell lines evaluated, although the levels of basal expression were very variable. Significant upregulation of PD‐L1 expression by all tumor cell lines was observed following IFN‐γ exposure and by exposure to a TLR3 ligand. Canine monocytes and monocyte‐derived macrophages did not express PD‐L1 constitutively, but did significantly upregulate expression following treatment with IFN‐γ. These findings suggest that most canine tumors express PD‐L1 constitutively and that both innate and adaptive immune stimuli can further upregulate PD‐L1 expression. Therefore the upregulation of PD‐L1 expression by tumor cells and by tumor‐infiltrating macrophages in response to cytokines such as IFN‐γ may represent an important mechanism of tumor‐mediated T‐cell suppression in dogs as well as in humans.
Unlocking neural complexity with a robotic key
Authors: Stratton Peter , Hasselmo Michael , Milford Michael
Published: February 2016

Complex brains evolved in order to comprehend and interact with complex environments in the real world. Despite significant progress in our understanding of perceptual representations in the brain, our understanding of how the brain carries out higher level processing remains largely superficial. This disconnect is understandable, since the direct mapping of sensory inputs to perceptual states is readily observed, while mappings between (unknown) stages of processing and intermediate neural states is not. We argue that testing theories of higher level neural processing on robots in the real world offers a clear path forward, since (1) the complexity of the neural robotic controllers can be staged as necessary, avoiding the almost intractable complexity apparent in even the simplest current living nervous systems; (2) robotic controller states are fully observable, avoiding the enormous technical challenge of recording from complete intact brains; and (3) unlike computational modelling, the real world can stand for itself when using robots, avoiding the computational intractability of simulating the world at an arbitrary level of detail. We suggest that embracing the complex and often unpredictable closed‐loop interactions between robotic neuro‐controllers and the physical world will bring about deeper understanding of the role of complex brain function in the high‐level processing of information and the control of behaviour.

image
Primary visual cortex shows laminar‐specific and balanced circuit organization of excitatory and inhibitory synaptic connectivity
Authors: Xu Xiangmin , Olivas Nicholas D. , Ikrar Taruna , Peng Tao , Holmes Todd C. , Nie Qing , Shi Yulin
Published: February 2016

Key points

Using functional mapping assays, we conducted a quantitative assessment of both excitatory and inhibitory synaptic laminar connections to excitatory neurons in layers 2/3–6 of the mouse visual cortex (V1).

Laminar‐specific synaptic wiring diagrams of excitatory neurons were constructed on the basis of circuit mapping.

The present study reveals that that excitatory and inhibitory synaptic connectivity is spatially balanced across excitatory neuronal networks in V1.

In the mammalian neocortex, excitatory neurons provide excitation in both columnar and laminar dimensions, which is modulated further by inhibitory neurons. However, our understanding of intracortical excitatory and inhibitory synaptic inputs in relation to principal excitatory neurons remains incomplete, and it is unclear how local excitatory and inhibitory synaptic connections to excitatory neurons are spatially organized on a layer‐by‐layer basis. In the present study, we combined whole cell recordings with laser scanning photostimulation via glutamate uncaging to map excitatory and inhibitory synaptic inputs to single excitatory neurons throughout cortical layers 2/3–6 in the mouse primary visual cortex (V1). We find that synaptic input sources of excitatory neurons span the radial columns of laminar microcircuits, and excitatory neurons in different V1 laminae exhibit distinct patterns of layer‐specific organization of excitatory inputs. Remarkably, the spatial extent of inhibitory inputs of excitatory neurons for a given layer closely mirrors that of their excitatory input sources, indicating that excitatory and inhibitory synaptic connectivity is spatially balanced across excitatory neuronal networks. Strong interlaminar inhibitory inputs are found, particularly for excitatory neurons in layers 2/3 and 5. This differs from earlier studies reporting that inhibitory cortical connections to excitatory neurons are generally localized within the same cortical layer. On the basis of the functional mapping assays, we conducted a quantitative assessment of both excitatory and inhibitory synaptic laminar connections to excitatory cells at single cell resolution, establishing precise layer‐by‐layer synaptic wiring diagrams of excitatory neurons in the visual cortex.
Vibration Modeling and Experimental Results of Two-Phase Twin-Screw Pump
Authors: Muhammed Ameen , Childs Dara W.
Published: February 2016

In turbomachines, the transfer of energy between the rotor and the fluid does not—in theory—result in lateral forces on the rotor. In positive displacement machines, on the other hand, the transfer of energy between the moving components and the working fluid usually results in unbalanced pressure fields and forces. Muhammed and Childs (2013, “Rotordynamics of a Two-Phase Flow Twin Screw Pump,” ASME J. Eng. Gas Turbines Power, 135(6), p. 062502) developed a model to predict the dynamic forces in twin-screw pumps, showing that the helical screw shape generates hydraulic forces that oscillate at multiples of running speed. The work presented here attempts to validate the model of Muhammed and Childs (2013, “Rotordynamics of a Two-Phase Flow Twin Screw Pump,” ASME J. Eng. Gas Turbines Power, 135(6), p. 062502) using a clear-casing twin-screw pump. The pump runs in both single and multiphase conditions with exit pressure up to 300 kPa and a flow rate 0.6 l/s. The pump was instrumented with dynamic pressure probes across the axial length of the screw in two perpendicular directions to validate the dynamic model. Two proximity probes measured the dynamic rotor displacement at the outlet to validate the rotordynamics model and the hydrodynamic cyclic forces predicted by Muhammed and Childs (2013, “Rotordynamics of a Two-Phase Flow Twin Screw Pump,” ASME J. Eng. Gas Turbines Power, 135(6), p. 062502). The predictions were found to be in good agreement with the measurements. The amplitude of the dynamic pressure measurements in two perpendicular plans supported the main assumptions of the model (constant pressure inside the chambers and linear pressure drop across the screw lands). The predicted rotor orbits at the pump outlet in the middle of the rotor matched the experimental orbits closely. The spectrum of the response showed harmonics of the running speed as predicted by the model. The pump rotor's calculated critical speed was at 24.8 krpm, roughly 14 times the rotor's running speed of 1750 rpm. The measured and observed excitation frequencies extended out to nine times running speed, still well below the first critical speed. However, for longer twin-screw pumps running at higher speed, the coincidence of a higher-harmonic excitation frequency with the lightly damped first critical speed should be considered.
Wind Turbine Design Optimization Under Environmental Uncertainty
Authors: Caboni Marco , Sergio Campobasso M. , Minisci Edmondo
Published: February 2016

Wind turbine design optimization is typically performed considering a given wind distribution. However, turbines so designed often end up being used at sites characterized by different wind distributions, resulting in significant performance penalties. This paper presents a probabilistic integrated multidisciplinary approach to the design optimization of multimegawatt wind turbines accounting for the stochastic variability of the mean wind speed. The presented technology is applied to the design of a 5 MW rotor for use at sites of wind power class from 3 to 7, where the mean wind speed at 50 m above the ground ranges from 6.4 to 11.9 m/s. Assuming the mean wind speed to vary stochastically in such range, the rotor design is optimized by minimizing mean and standard deviation of the levelized cost of energy (LCOE). Airfoil shapes, spanwise distributions of blade chord and twist, blade internal structural layup, and rotor speed are optimized concurrently, subject to structural and aeroelastic constraints. The probabilistically designed turbine achieves a more favorable probabilistic performance than the initial baseline turbine. The presented probabilistic design framework is portable and modular in that any of its analysis modules can be replaced with counterparts of user-selected fidelity.
Generalized Three-Dimensional Mathematical Models for Force and Stiffness in Axially, Radially, and Perpendicularly Magnetized Passive Magnetic Bearings With “n” Number of Ring Pairs
Authors: Bekinal Siddappa I. , Jana Soumendu
Published: February 2016

This work deals with generalized three-dimensional (3D) mathematical model to estimate the force and stiffness in axially, radially, and perpendicularly polarized passive magnetic bearings with “n” number of permanent magnet (PM) ring pairs. Coulombian model and vector approach are used to derive generalized equations for force and stiffness. Bearing characteristics (in three possible standard configurations) of permanent magnet bearings (PMBs) are evaluated using matlab codes. Further, results of the model are validated with finite element analysis (FEA) results for five ring pairs. Developed matlab codes are further utilized to determine only the axial force and axial stiffness in three stacked PMB configurations by varying the number of rings. Finally, the correlation between the bearing characteristics (PMB with only one and multiple ring pairs) is proposed and discussed in detail. The proposed mathematical model might be useful for the selection of suitable configuration of PMB as well as its optimization for geometrical parameters for high-speed applications.
High-mass heterogeneous cluster formation by ion bombardment of the ternary alloy Au7Cu5Al4
Authors: Zinovev Alexander V. , King Bruce V. , Veryovkin Igor V. , Pellin Michael J.
Published: February 2016

The ternary alloy Au7Cu5Al4 was irradiated with 0.1–10 keV Ar+ and the surface composition analyzed using laser sputter neutral mass spectrometry. Ejected clusters containing up to seven atoms, with masses up to 2000 amu, were observed. By monitoring the signals from sputtered clusters, the surface composition of the alloy was seen to change with 100 eV Ar+ dose, reaching equilibrium after 10 nm of the surface was eroded, in agreement with TRIDYN simulation and indicating that the changes were due to preferential sputtering of Al and Cu. Ejected gold containing clusters were found to increase markedly in intensity while aluminum containing clusters decreased in intensity as a result of Ar sputtering. Such an effect was most pronounced for low energy (<1 keV) Ar+ sputtering and was consistent with TRIDYN simulations of the depth profiling. The component sputter yields from the ternary alloy were consistent with previous binary alloy measurements but showed greater Cu surface concentrations than expected from TRIDYN simulations.
Influence of RF excitation during pulsed laser deposition in oxygen atmosphere on the structural properties and luminescence of nanocrystalline ZnO:Al thin films
Authors: Meljanac Daniel , Juraić Krunoslav , Plodinec Milivoj , Siketić Zdravko , Gracin Davor , Krstulović Nikša , Salamon Krešimir , Skenderović Hrvoje , Kregar Zlatko , Rakić Iva Šrut , Bernstorff Sigrid
Published: February 2016

Thin ZnO:Al layers were deposited by pulsed laser deposition in vacuum and in oxygen atmosphere at gas pressures between 10 and 70 Pa and by applying radio-frequency (RF) plasma. Grazing incidence small angle x-ray scattering and grazing incidence x-ray diffraction (GIXRD) data showed that an increase in the oxygen pressure leads to an increase in the roughness, a decrease in the sample density, and changes in the size distribution of nanovoids. The nanocrystal sizes estimated from GIXRD were around 20 nm, while the sizes of the nanovoids increased from 1 to 2 nm with the oxygen pressure. The RF plasma mainly influenced the nanostructural properties and point defects dynamics. The photoluminescence consisted of three contributions, ultraviolet (UV), blue emission due to Zn vacancies, and red emission, which are related to an excess of oxygen. The RF excitation lowered the defect level related to blue emission and narrowed the UV luminescence peak, which indicates an improvement of the structural ordering. The observed influence of the deposition conditions on the film properties is discussed as a consequence of two main effects: the variation of the energy transfer from the laser plume to the growing film and changes in the growth chemistry.
Thermal transport and thermal stress in a molybdenum film–glass substrate system
Authors: Miao Tingting , Ma Weigang , Yan Shen , Zhang Xing , Kohno Masamichi , Takata Yasuyuki , Ikoma Yoshifumi
Published: February 2016

Three-dimensional integration with through-silicon vias is emerging as an approach for improving the performance of integrated circuits. Thermal transport and thermal stress in such designs currently limit their performance and reliability. In this study, the thermal dissipation and thermal stress in a 95.3-nm-thick molybdenum (Mo) film–glass substrate system were investigated using a picosecond laser pump–probe method with four different configurations. This allowed the thermal transport and the generation and propagation of coherent acoustic phonon waves in a Mo film–glass substrate system to be comprehensively studied for the first time. The universality of the superposition model previously proposed for a platinum film on a glass substrate was verified using the present Mo film–glass substrate system from the close agreement between experimental data and theoretical predictions. The thermal transport in the Mo film and the coherent acoustic phonon wave propagation in the Mo film and glass substrate, i.e., thermal diffusivity and longitudinal sound velocity, respectively, were also studied.
In situ baking method for degassing of a kicker magnet in accelerator beam line
Authors: Kamiya Junichiro , Ogiwara Norio , Yanagibashi Toru , Kinsho Michikazu , Yasuda Yuichi
Published: February 2016

In this study, the authors propose a new in situ degassing method by which only kicker magnets in the accelerator beam line are baked out without raising the temperature of the vacuum chamber to prevent unwanted thermal expansion of the chamber. By simply installing the heater and thermal radiation shield plates between the kicker magnet and the chamber wall, most of the heat flux from the heater directs toward the kicker magnet. The result of the verification test showed that each part of the kicker magnet was heated to above the target temperature with a small rise in the vacuum chamber temperature. A graphite heater was selected in this application to bake-out the kicker magnet in the beam line to ensure reliability and easy maintainability of the heater. The vacuum characteristics of graphite were suitable for heater operation in the beam line. A preliminary heat-up test conducted in the accelerator beam line also showed that each part of the kicker magnet was successfully heated and that thermal expansion of the chamber was negligibly small.
Finding an ethical path forward for mitochondrial replacement
Authors: Claiborne Anne B. , English Rebecca A. , Kahn Jeffrey P.
Published: February 2016

It is ethically permissible to initiate clinical investigations of mitochondrial replacement techniques in humans so long as significant conditions and restrictions are in place
Draft Genome Sequence of Oceanobacillus picturae Heshi-B3, Isolated from Fermented Rice Bran in a Traditional Japanese Seafood Dish
Authors: Akuzawa Sayuri , Nagaoka Junko , Kanekatsu Motoki , Kanesaki Yu , Suzuki Tomonori
Published: February 2016

Oceanobacillus picturae
strain Heshi-B3 was isolated from rice bran in a traditional fermented seafood dish named Heshiko, which was produced in Fukui Prefecture in Japan. Here, we report the draft genome sequence of
O. picturae
strain Heshi B-3.
Evaluation of Performance Characteristics of the Aptima HIV-1 Quant Dx Assay for Detection and Quantitation of Human Immunodeficiency Virus Type 1 in Plasma and Cervicovaginal Lavage Samples
Authors: Sam Soya S. , Kurpewski Jaclynn R. , Cu-Uvin Susan , Caliendo Angela M.
Published: February 2016

Quantification of HIV-1 RNA has become the standard of care in the clinical management of HIV-1-infected individuals. The objective of this study was to evaluate performance characteristics and relative workflow of the Aptima HIV-1 Quant Dx assay in comparison with the Abbott RealTime HIV-1 assay using plasma and cervicovaginal lavage (CVL) specimens. Assay performance was evaluated by using an AcroMetrix HIV-1 panel, AcroMetrix positive controls, Qnostics and SeraCare HIV-1 evaluation panels, 208 clinical plasma samples, and 205 matched CVL specimens on the Panther and m2000 platforms. The Aptima assay demonstrated good linearity over the quantification range tested (2 to 5 log
10
copies/ml), and there was strong linear correlation between the assays (
R
2
= 0.99), with a comparable coefficient of variance of <5.5%. For the plasma samples, Deming regression analyses and Bland-Altman plots showed excellent agreement between the assays, with an interassay concordance of 91.35% (kappa = 0.75; 95% confidence interval [CI], 0.65 to 0.85), and on average, the viral loads determined by the Aptima assay were 0.21 log
10
copies/ml higher than those determined by the RealTime assay. The assays differed in their sensitivity for quantifying HIV-1 RNA loads in CVL samples, with the Aptima and RealTime assays detecting 30% and 20%, respectively. Aptima had fewer invalid results, and on average, the viral loads in CVL samples quantified by the Aptima assay were 0.072 log
10
copies/ml higher than those of the RealTime assay. Our results demonstrate that the Aptima assay is sensitive and accurate in quantifying viral loads in both plasma and CVL specimens and that the fully automated Panther system has all the necessary features suitable for clinical laboratories demanding high-throughput sample processing.
Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection
Authors: Gianella Sara , Anderson Christy M. , Var Susanna R. , Oliveira Michelli F. , Lada Steven M. , Vargas Milenka V. , Massanella Marta , Little Susan J. , Richman Douglas D. , Strain Matthew C. , Pérez-Santiago Josué , Smith Davey M.
Published: February 2016

Asymptomatic replication of human herpesviruses (HHV) is frequent in HIV-infected men and is associated with increased T-cell activation and HIV disease progression. We hypothesized that the presence of replication of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) (the most frequently detected HHV) might influence HIV DNA decay during antiretroviral therapy (ART). We investigated 607 peripheral blood mononuclear cell (PBMC) samples from 107 CMV-seropositive, HIV-infected men who have sex with men, who started ART within a median of 3 months from their estimated date of infection (EDI) and were monitored for a median of 19 months thereafter. Levels of HIV, CMV, and EBV DNA and cellular HIV RNA were measured by droplet digital PCR (ddPCR) for each time point. Using a general linear mixed-effect regression model, we evaluated associations between the presence of detectable CMV DNA and EBV DNA levels and HIV DNA decay and cellular HIV RNA levels, while adjusting for peak HIV RNA, nadir CD4
+
count, CD4/CD8 ratio, CMV IgG levels, time from EDI to ART initiation, time from ART initiation to virologic suppression, detectable CMV DNA pre-ART, and age. The presence of intermittent CMV DNA in PBMC during ART was significantly associated with slower decay of HIV DNA (
P
= 0.011) but not with increased cellular HIV RNA transcription or more detectable 2-long terminal repeat circles. Higher levels of EBV DNA were also associated with higher levels of HIV DNA (
P
< 0.001) and increased unspliced cellular HIV RNA transcription (
P
= 0.010). These observations suggest that replication of HHV may help maintain a larger HIV DNA reservoir, but the underlying mechanisms remain unclear.

IMPORTANCE
Over three-fourths of HIV-infected men have at least one actively replicating human herpesvirus (HHV) in their mucosal secretions at any one time. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the most common, and although it is often asymptomatic, such CMV and EBV replication is associated with higher levels of immune activation and HIV disease progression. We hypothesized that HHV-associated activation of HIV-infected CD4
+
T cells might lead to increased HIV DNA. This study found that detectable CMV in blood cells of HIV-infected men was associated with slower decay of HIV DNA even during antiretroviral therapy (ART) that was started during early HIV infection. Similarly, levels of EBV DNA were associated with higher levels of HIV DNA during ART. If this observation points to a causal pathway, interventions that control CMV and EBV replication may be able to reduce the HIV reservoir, which might be relevant to current HIV cure efforts.
Expansion of Inefficient HIV-Specific CD8 T Cells during Acute Infection
Authors: Eller Michael A. , Goonetilleke Nilu , Tassaneetrithep Boonrat , Eller Leigh Anne , Costanzo Margaret C. , Johnson Susan , Betts Michael R. , Krebs Shelly J. , Slike Bonnie M. , Nitayaphan Sorachai , Rono Kathleen , Tovanabutra Sodsai , Maganga Lucas , Kibuuka Hannah , Jagodzinski Linda , Peel Sheila , Rolland Morgane , Marovich Mary A. , Kim Jerome H. , Michael Nelson L. , Robb Merlin L. , Streeck Hendrik
Published: February 2016

Attrition within the CD4
+
T cell compartment, high viremia, and a cytokine storm characterize the early days after HIV infection. When the first emerging HIV-specific CD8
+
T cell responses gain control over viral replication it is incomplete, and clearance of HIV infection is not achieved even in the rare cases of individuals who spontaneously control viral replication to nearly immeasurably low levels. Thus, despite their partial ability to control viremia, HIV-specific CD8
+
T cell responses are insufficient to clear HIV infection. Studying individuals in the first few days of acute HIV infection, we detected the emergence of a unique population of CD38
+
CD27
−
CD8
+
T cells characterized by the low expression of the CD8 receptor (CD8
dim
). Interestingly, while high frequencies of HIV-specific CD8
+
T cell responses occur within the CD38
+
CD27
−
CD8
dim
T cell population, the minority populations of CD8
bright
T cells are significantly more effective in inhibiting HIV replication. Furthermore, the frequency of CD8
dim
T cells directly correlates with viral load and clinical predictors of more rapid disease progression. We found that a canonical burst of proliferative cytokines coincides with the emergence of CD8
dim
T cells, and the size of this population inversely correlates with the acute loss of CD4
+
T cells. These data indicate, for the first time, that early CD4
+
T cell loss coincides with the expansion of a functionally impaired HIV-specific CD8
dim
T cell population less efficient in controlling HIV viremia.

IMPORTANCE
A distinct population of activated CD8
+
T cells appears during acute HIV infection with diminished capacity to inhibit HIV replication and is predictive of viral set point, offering the first immunologic evidence of CD8
+
T cell dysfunction during acute infection.
Development of Broadly Neutralizing Antibodies and Their Mapping by Monomeric gp120 in Human Immunodeficiency Virus Type 1-Infected Humans and Simian-Human Immunodeficiency Virus SHIV
SF162P3N
-Infected Macaques
Authors: Jia Manxue , Lu Hong , Markowitz Martin , Cheng-Mayer Cecilia , Wu Xueling
Published: February 2016

To improve our understanding of the similarities and differences between neutralizing antibodies elicited by simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and human immunodeficiency virus type 1 (HIV-1)-infected humans, we examined the plasma of 13 viremic macaques infected with SHIV
SF162P3N
and 85 HIV-1-infected humans with known times of infection. We identified 5 macaques (38%) from 1 to 2 years postinfection (p.i.) with broadly neutralizing antibodies (bnAbs) against tier 2 HIV-1. In comparison, only 2 out of 42 (5%) human plasma samples collected in a similar time frame of 1 to 3 years p.i. exhibited comparable neutralizing breadths and potencies, with the number increasing to 7 out of 21 (30%) after 3 years p.i. Plasma mapping with monomeric gp120 identified only 2 out of 9 humans and 2 out of 4 macaques that contained gp120-reactive neutralizing antibodies, indicating distinct specificities in these plasma samples, with most of them recognizing the envelope trimer (including gp41) rather than the gp120 monomer. Indeed, a total of 20 gp120-directed monoclonal antibodies (MAbs) isolated from a human subject (AD358) and a Chinese rhesus macaque (GB40) displayed no or limited neutralizing activity against tier 2 strains. These isolated MAbs, mapped to the CD4-binding site, the V3 loop, the inner domain, and the C5 region of gp120, revealed genetic similarity between the human and macaque immunoglobulin genes used to encode some V3-directed MAbs. These results also support the use of envelope trimer probes for efficient isolation of HIV-1 bnAbs.

IMPORTANCE
HIV-1 vaccine research can benefit from understanding the development of broadly neutralizing antibodies (bnAbs) in rhesus macaques, commonly used to assess vaccine immunogenicity and efficacy. Here, we examined 85 HIV-1-infected humans and 13 SHIV
SF162P3N
-infected macaques for bnAbs and found that, similar to HIV-1-infected humans, bnAbs in SHIV-infected macaques are also rare, but their development might have been faster in some of the studied macaques. Plasma mapping with monomeric gp120 indicated that most bnAbs bind to the envelope trimer rather than the gp120 monomer. In support of this, none of the isolated gp120-reactive monoclonal antibodies (MAbs) displayed the neutralization breadth observed in the corresponding plasma. However, the MAb sequences revealed similarity between human and macaque genes used to encode some V3-directed MAbs. Our study sheds light on the timing and development of bnAbs in SHIV-infected macaques in comparison to HIV-1-infected humans and highlights the use of envelope trimer probes for efficient recovery of bnAbs.
Nuclear Translocation Sequence and Region in Autographa californica Multiple Nucleopolyhedrovirus ME53 That Are Important for Optimal Baculovirus Production
Authors: Liu Yang , de Jong Jondavid , Nagy Éva , Theilmann David A. , Krell Peter J.
Published: February 2016

Autographa californica
multiple nucleopolyhedrovirus (AcMNPV) is in the family
Baculoviridae
, genus
Alphabaculovirus
. AcMNPV
me53
is a highly conserved immediate early gene in all lepidopteran baculoviruses that have been sequenced and is transcribed up to late times postinfection. Although
me53
is not essential for viral DNA synthesis, infectious budded virus (BV) production is greatly attenuated when it is deleted. ME53 associates with the nucleocapsid on both budded virus and occlusion-derived virus, but not with the virus envelope. ME53 colocalizes in plasma membrane foci with the envelope glycoprotein GP64 in a GP64-dependent manner. ME53 localizes in the cytoplasm early postinfection, and despite the lack of a reported nuclear localization signal (NLS), ME53 translocates to the nucleus at late times postinfection. To map determinants of ME53 that facilitate its nuclear translocation, recombinant AcMNPV bacmids containing a series of ME53 truncations, internal deletions, and peptides fused with hemagglutinin (HA) or green fluorescent protein (GFP) tags were constructed. Intracellular-localization studies identified residues within amino acids 109 to 137 at the N terminus of ME53 that acted as the nuclear translocation sequence (NTS), facilitating its nuclear transport at late times postinfection. The first 100 N-terminal amino acids and the last 50 C-terminal amino acids of ME53 are dispensable for high levels of budded virus production. The region within amino acids 101 to 398, which also contains the NTS, is critical for optimal levels of budded virus production.

IMPORTANCE
Baculovirus
me53
is a conserved immediate early gene found in all sequenced lepidopteran alpha- and betabaculoviruses. We first identified residues within amino acids 109 to 137 at the N terminus that act as the ME53 nuclear translocation sequence (NTS) to facilitate its nuclear translocation and defined an internal region within amino acids 101 to 398, which includes the NTS, as being necessary for optimal budded virus production. Altogether, these results indicate a previously unidentified nuclear role that ME53 plays in virus replication.
Promoter-Targeted Histone Acetylation of Chromatinized Parvoviral Genome Is Essential for the Progress of Infection
Authors: Mäntylä Elina , Salokas Kari , Oittinen Mikko , Aho Vesa , Mäntysaari Pekka , Palmujoki Lassi , Kalliolinna Olli , Ihalainen Teemu O. , Niskanen Einari A. , Timonen Jussi , Viiri Keijo , Vihinen-Ranta Maija
Published: February 2016

The association of host histones with parvoviral DNA is poorly understood. We analyzed the chromatinization and histone acetylation of canine parvovirus DNA during infection by confocal imaging and
in situ
proximity ligation assay combined with chromatin immunoprecipitation and high-throughput sequencing. We found that during late infection, parvovirus replication bodies were rich in histones bearing modifications characteristic of transcriptionally active chromatin, i.e., histone H3 lysine 27 acetylation (H3K27ac). H3K27ac, in particular, was located in close proximity to the viral DNA-binding protein NS1. Importantly, our results show for the first time that in the chromatinized parvoviral genome, the two viral promoters in particular were rich in H3K27ac. Histone acetyltransferase (HAT) inhibitors efficiently interfered with the expression of viral proteins and infection progress. Altogether, our data suggest that the acetylation of histones on parvoviral DNA is essential for viral gene expression and the completion of the viral life cycle.

IMPORTANCE
Viral DNA introduced into cell nuclei is exposed to cellular responses to foreign DNA, including chromatinization and epigenetic silencing, both of which determine the outcome of infection. How the incoming parvovirus resists cellular epigenetic downregulation of its genes is not understood. Here, the critical role of epigenetic modifications in the regulation of parvovirus infection was demonstrated. We showed for the first time that a successful parvovirus infection is characterized by the deposition of nucleosomes with active histone acetylation on the viral promoter areas. The results provide new insights into the regulation of parvoviral gene expression, which is an important aspect of the development of parvovirus-based virotherapy.
Recurrent cerebral ischaemic events in the setting of paroxysmal nocturnal haemoglobinuria
Authors: Azevedo Luísa , Costa Mariana Reis , Fonseca Ana Catarina , Pinho e Melo Teresa
Published: February 2016

The authors present a case of a 28-year-old man with a known history of paroxysmal nocturnal haemoglobinuria (PNH), under platelet antiaggregation, admitted following recurrent transitory arterial ischaemic attacks. Concomitant thrombosis of the superior mesenteric artery and bilateral renal infarction was found. Cardioembolism, namely patent foramen ovale, was excluded and anticoagulation added, with no further events on 10-month follow-up. PNH is a rare acquired disorder of haematopoietic stem cells, characterised by haemolytic anaemia, pancytopenia and thrombotic events classically involving the venous system. Reports of cerebral artery stroke and accompanying intra-abdominal arterial thrombosis are especially rare. Complementary investigation and treatment options in these patients are discussed.
Effects of aerobic and muscle strengthening exercise in adults with rheumatoid arthritis: a narrative review summarising a chapter inPhysical activity in the prevention and treatment of disease(FYSS 2016)
Authors: Swärdh E , Brodin N
Published: February 2016

Background

Besides pharmacological treatment, regular exercise is one of the cornerstones of care in rheumatoid arthritis (RA). In many of the earlier studies of exercise in RA, the intensity of the exercise did not reach the current recommendations or is not described in satisfactory detail. This narrative review is based on randomised controlled trials with a detailed description of the exercise type, frequency, duration and intensity.

Results

There is moderate-quality evidence that short-term land-based aerobic exercise of moderate to high intensity augments oxygen uptake but does not improve muscle strength. Short-term water-based aerobic exercise of moderate to high intensity augments oxygen uptake; short term land-based aerobic and muscle strengthening exercise of moderate to high intensity augments oxygen uptake and muscle strength. Long-term land-based aerobic and muscle strengthening exercise of moderate to high intensity reduces activity limitations and improves both oxygen uptake and muscle strength.

Conclusions

Clinicians should recommend that patients with RA participate in various types of exercise.
Using Lean management to leverage innovation in healthcare projects: case study of a public hospital in the UAE
Authors: Abuhejleh Ala'a , Dulaimi Mohammed , Ellahham Samer
Published: February 2016

This paper demonstrates that Lean management serves as a foundation to leverage innovation throughout the healthcare projects. An organisation that successfully accommodates both Lean and innovation will gain higher competitive advantage and reach long-term sustainability. Innovation in the healthcare sector in the United Arab Emirates (UAE) is encouraged through responses to the challenges of patient needs and government pressure on the organisations towards innovation and sustainability concerns. The objective of the paper is to investigate critical success factors (CSFs) for effective diffusion of Lean innovation in healthcare projects in the UAE. A conceptual model is developed to explain the CSFs for diffusion of Lean innovation in the healthcare projects. A public hospital that implemented Lean innovation projects in the UAE was selected as a case study and the data provided through the interviews were reviewed and analysed. It is concluded that the successful implementation of Lean innovation had outstanding implications: It has markedly and sustainably decreased patient access and waiting time, improved safety and patient satisfaction and supported the hospital culture of empowering front-line caregivers. The championing role of leadership commitment and management support, and employee involvement across all levels is required for successful implementation.
The alcohol tracker application: an initial evaluation of user preferences
Authors: Zhang Melvyn W B , Ward John , Ying John J B , Pan Fang , Ho Roger C M
Published: February 2016

Background

The prevalence of at-risk drinking and alcohol use disorders is increasing. Advances in technology have resulted in numerous smartphone applications for this disorder. However, there are still concerns about the evidence base of previously developed alcohol applications.

Objective

The following study aims to illustrate how the authors have made use of innovative methodologies to overcome the issues relating to the accuracy of tracking the amount of alcohol one has consumed; it also aims to determine user perceptions about the innovative tracker and various other features of an alcohol self-management application among a group of individuals from the general population of a developed country (Canada).

Methodology

A native alcohol self-management application was developed. In order to determine user perspectives towards this new innovative application, the authors took advantage and made use of crowdsourcing to acquire user perspectives.

Results

Our results showed that smartphone ownership is highest among the age group of 35–44 years (91%) and lowest for those aged between 55 and 64 (58%). Our analysis also showed that 25–34-year-olds and 35–44-year-olds drink more frequently than the other groups. Results suggest that notification and information were the two most useful functions, with psychotherapy expected to be the least useful. Females indicated that notification service was the most useful function, while males preferred the information component.

Conclusions

This study has demonstrated how the authors have made use of innovative technologies to overcome the existing concerns pertaining to the utilisation of the blood alcohol concentration levels as a tracker. In addition, the authors have managed to highlight user preferences with regard to an alcohol application.
Effect of telehealth on hospital utilisation and mortality in routine clinical practice: a matched control cohort study in an early adopter site
Authors: Steventon Adam , Ariti Cono , Fisher Elizabeth , Bardsley Martin
Published: February 2016

Objectives

To assess the effects of a home-based telehealth intervention on the use of secondary healthcare and mortality.

Design

Observational study of a mainstream telehealth service, using person-level administrative data. Time to event analysis (Cox regression) was performed comparing telehealth patients with controls who were matched using a machine-learning algorithm.

Setting

A predominantly rural region of England (North Yorkshire).

Participants

716 telehealth patients were recruited from community, general practice and specialist acute care, between June 2010 and March 2013. Patients had chronic obstructive pulmonary disease, congestive heart failure or diabetes, and a history of associated inpatient admission. Patients were matched 1:1 to control patients, also selected from North Yorkshire, with respect to demographics, diagnoses of health conditions, previous hospital use and predictive risk score.

Interventions

Telehealth involved the remote exchange of medical data between patients and healthcare professionals as part of the ongoing management of the patient's health condition. Monitoring centre staff alerted healthcare professionals if the telemonitored data exceeded preset thresholds. Control patients received usual care, without telehealth.

Primary and secondary outcome measures

Time to the first emergency (unplanned) hospital admission or death. Secondary metrics included time to death and time to first admission, outpatient attendance and emergency department visit.

Results

Matched controls and telehealth patients were similar at baseline. Following enrolment, telehealth patients were more likely than matched controls to experience emergency admission or death (adjusted HR 1.34, 95% CI 1.16 to 1.56, p<0.001). They were also more likely to have outpatient attendances (adjusted HR=1.25, 1.11 to 1.40, p<0.001), but mortality rates were similar between groups. Sensitivity analyses showed that we were unlikely to have missed reductions in the likelihood of an emergency admission or death because of unobserved baseline differences between patient groups.

Conclusions

Telehealth was not associated with a reduction in secondary care utilisation.
Genetics of Glucose regulation in Gestation and Growth (Gen3G): a prospective prebirth cohort of mother–child pairs in Sherbrooke, Canada
Authors: Guillemette Laetitia , Allard Catherine , Lacroix Marilyn , Patenaude Julie , Battista Marie-Claude , Doyon Myriam , Moreau Julie , Ménard Julie , Bouchard Luigi , Ardilouze Jean-Luc , Perron Patrice , Hivert Marie-France
Published: February 2016

Purpose

We initiated the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort to increase our understanding of biological, environmental and genetic determinants of glucose regulation during pregnancy and their impact on fetal development.

Participants

Between January 2010 and June 2013, we invited pregnant women aged ≥18 years old who visited the blood sampling in pregnancy clinic in Sherbrooke for their first trimester clinical blood samples: 1034 women accepted to participate in our cohort study.

Findings to date

At first and second trimester, we collected demographics and lifestyle questionnaires, anthropometry measures (including fat and lean mass estimated using bioimpedance), blood pressure, and blood samples. At second trimester, women completed a full 75 g oral glucose tolerance test and we collected additional blood samples. At delivery, we collected cord blood and placenta samples; obstetrical and neonatal clinical data were abstracted from electronic medical records. We also collected buffy coats and extracted DNA from maternal and/or offspring samples (placenta and blood cells) to pursue genetic and epigenetic hypotheses. So far, we have found that low adiponectin and low vitamin D maternal levels in first trimester predict higher risk of developing gestational diabetes.

Future plans

We are now in the phase of prospective follow-up of mothers and offspring 3 and 5 years postdelivery to investigate the consequences of maternal dysglycaemia during pregnancy on offspring adiposity and metabolic profile.

Trial registration number

NCT01623934.
Role of gender, family, lifestyle and psychological factors in self-rated health among urban adolescents in Peru: a school-based cross-sectional survey
Authors: Sharma Bimala , Nam Eun Woo , Kim Dohyeong , Yoon Young Min , Kim Yeunju , Kim Ha Yun
Published: February 2016

Objective

We examined the role of gender, family, lifestyle and psychological factors in self-rated health.

Design

Cross-sectional study.

Setting

A total of 970 randomly selected students from 11 secondary schools in Lima and Callao, Peru, participated in 2014.

Main outcome measure

Self-rated health was measured with a single item: ‘In general, how would you rate your health?’ Responses were arranged along a five-point Likert-type scale: ‘excellent’, ‘very good’, ‘good’, ‘fair’ and ‘poor’. The outcome variable was dichotomised as ‘good’ (excellent, very good or good) or ‘poor/fair’ (poor or fair).

Methods

We calculated adjusted ORs (AORs) and 95% CIs for poor/fair self-rated health using multivariate logistic regression analyses at 3-graded levels.

Results

32.5% of the respondents had fair/poor self-rated health, 23.7% of the total males and 40.0% of the total female samples. Males were less likely to have poor/fair self-rated health (AOR 0.61; CI 0.41 to 0.91). Poor family support strongly increased the likelihood of having poor/fair self-rated health (no support, (AOR 3.15; CI 1.63 to 6.09); low support, (AOR 2.50; CI 1.29 to 4.85)). The other associated variables were missed meals due to a shortage of food (AOR 1.97; CI 1.15 to 3.36), television watching during leisure time (AOR 1.70; CI 1.09 to 2.67), low physical activity (AOR 1.49; CI 1.03 to 2.15), school absenteeism (AOR 1.54; CI 1.03 to 2.31) and perceived life satisfaction (AOR 0.28; CI 0.15 to 0.25).

Conclusions

Gender, missing meals due to a shortage of food, family support, physical activity and life satisfaction influenced self-rated health among adolescents in Peru. Interventions that focus on promoting physical activity for at least 1 h each day for 3 or more days per week, food security and strengthening supportive family roles may improve self-rated health during adolescence.
The usefulness of cardiopulmonary exercise testing in assessment of patients with suspected coronary artery disease
Authors: Mazaheri Reza , Shakerian Farshad , Vasheghani-Farahani Ali , Halabchi Farzin , Mirshahi Maryam , Mansournia Mohammad Ali
Published: February 2016

Objective

The aim of this study is to assess different parameters of cardiopulmonary exercise testing that can predict the development of myocardial ischaemia in patients with suspected coronary artery disease (CAD) and to identify the parameters which have more correlation with myocardial ischaemia.

Study design

Cross-sectional study.

Methods

In this study, a total of 31 men (mean age 57.23±11.09 years) with suggestive symptoms of CAD underwent an exercise stress test with breath-by-breath gas exchange analysis, followed by coronary angiography as the gold standard for diagnosing CAD.

Results

The ventilation versus CO2 output (VE/VCO2) peak was significantly different between patients with negative and positive angiography results. Receiver operator characteristic analysis showed an area under the curve of 0.73 for VE/VCO2 peak with diagnostic threshold equal to 35 (95% CI 0.54 to 0.9; p=0.05). Exercise stress testing had sensitivity and specificity of 75% and 40%, respectively.

Conclusions

A change in ventilatory efficiency assessed using the VE/VCO2 peak has the predictive ability to identify exercise-induced myocardial ischaemia. The present study has provided additional evidence of the potential clinical value of cardiopulmonary exercise testing in the diagnosis of CAD.
Evaluation of abnormal liver function tests
Authors: Agrawal Swastik , Dhiman Radha K , Limdi Jimmy K
Published: February 2016

Incidentally detected abnormality in liver function tests is a common situation encountered by physicians across all disciplines. Many of these patients do not have primary liver disease as most of the commonly performed markers are not specific for the liver and are affected by myriad factors unrelated to liver disease. Also, many of these tests like liver enzyme levels do not measure the function of the liver, but are markers of liver injury, which is broadly of two types: hepatocellular and cholestatic. A combination of a careful history and clinical examination along with interpretation of pattern of liver test abnormalities can often identify type and aetiology of liver disease, allowing for a targeted investigation approach. Severity of liver injury is best assessed by composite scores like the Model for End Stage Liver Disease rather than any single parameter. In this review, we discuss the interpretation of the routinely performed liver tests along with the indications and utility of quantitative tests.