bluuebunny/crossref_metadata_2025 huggingface dataset:
Origin of external quantum efficiency degradation in organic light-emitting diodes with a DC magnetron sputtered cathode
Authors: Fujimoto Hiroshi , Miyayama Takuya , Sanada Noriaki , Adachi Chihaya
Published: October 2014

This paper characterizes changes in organic light-emitting diodes to better understand the origin of the decrease in external quantum efficiency (ηext) when switching the cathode deposition method from evaporation to DC magnetron sputtering. An increase of driving voltage and a hole-barrier-dependent decrease of ηext when the Al cathode is sputtered suggest that disruption of carrier balance and penetration of holes from the emissive layer (EML) into the electron transport layer (ETL) are significant sources of the device degradation. When the ETL was doped with Li, degradation was suppressed and the increase in driving voltage was drastically reduced although ηext still decreased by 5%–7%. Analysis of the films by time-of-flight secondary ion mass spectrometry indicates that Li diffuses into the EML when Al is sputtered, and Li is shown to act as an exciton quencher that can decrease ηext. Doping of the ETL is also used to significantly suppress the performance reduction with sputtered cathodes even when using a phosphorescent emitter having high ηext.
Electrical characteristics of flexible ZnO thin-film transistors annealed by microwave irradiation
Authors: Park Sukhyung , Cho Kyoungah , Yang Kyungwhan , Kim Sangsig
Published: October 2014

This study examines the effect of microwave annealing upon the electrical characteristics of a representative ZnO thin-film transistor (TFT) deposited on a flexible plastic substrate. After microwave irradiation, the mobility of the TFT is increased from 0.2 to 1.5 cm2/(V s) and its on/off ratio increases from 36.5 to 6.9 × 106. The photoluminescence study reveals that the concentration of oxygen vacancies increases remarkably when the ZnO thin films are exposed to microwave radiation. In this paper, in addition to the results mentioned above, the correlation between the photoluminescence and electrical characteristics is discussed and the electrical characteristics of the ZnO TFT under strain are analyzed.
Respiratory motion management using audio‐visual biofeedback for respiratory‐gated radiotherapy of synchrotron‐based pulsed heavy‐ion beam delivery
Authors: He Pengbo , Li Qiang , Liu Xinguo , Dai Zhongying , Zhao Ting , Fu Tingyan , Shen Guosheng , Ma Yuanyuan , Huang Qiyan , Yan Yuanlin
Published: October 2014

Purpose:

To efficiently deliver respiratory‐gated radiation during synchrotron‐based pulsed heavy‐ion radiotherapy, a novel respiratory guidance method combining a personalized audio‐visual biofeedback (BFB) system, breath hold (BH), and synchrotron‐based gating was designed to help patients synchronize their respiratory patterns with synchrotron pulses and to overcome typical limitations such as low efficiency, residual motion, and discomfort.

Methods:

In‐house software was developed to acquire body surface marker positions and display BFB, gating signals, and real‐time beam profiles on a LED screen. Patients were prompted to perform short BHs or short deep breath holds (SDBH) with the aid of BFB following a personalized standard BH/SDBH (stBH/stSDBH) guiding curve or their own representative BH/SDBH (reBH/reSDBH) guiding curve. A practical simulation was performed for a group of 15 volunteers to evaluate the feasibility and effectiveness of this method. Effective dose rates (EDRs), mean absolute errors between the guiding curves and the measured curves, and mean absolute deviations of the measured curves were obtained within 10%–50% duty cycles (DCs) that were synchronized with the synchrotron's flat‐top phase.

Results:

All maneuvers for an individual volunteer took approximately half an hour, and no one experienced discomfort during the maneuvers. Using the respiratory guidance methods, the magnitude of residual motion was almost ten times less than during nongated irradiation, and increases in the average effective dose rate by factors of 2.39–4.65, 2.39–4.59, 1.73–3.50, and 1.73–3.55 for the stBH, reBH, stSDBH, and reSDBH guiding maneuvers, respectively, were observed in contrast with conventional free breathing‐based gated irradiation, depending on the respiratory‐gated duty cycle settings.

Conclusions:

The proposed respiratory guidance method with personalized BFB was confirmed to be feasible in a group of volunteers. Increased effective dose rate and improved overall treatment precision were observed compared to conventional free breathing‐based, respiratory‐gated irradiation. Because breathing guidance curves could be established based on the respective average respiratory period and amplitude for each patient, it may be easier for patients to cooperate using this technique.
Constraints on Mimas’ interior from Cassini ISS libration measurements
Authors: Tajeddine R. , Rambaux N. , Lainey V. , Charnoz S. , Richard A. , Rivoldini A. , Noyelles B.
Published: October 2014

Like our Moon, the majority of the solar system’s satellites are locked in a 1:1 spin-orbit resonance; on average, these satellites show the same face toward the planet at a constant rotation rate equal to the satellite’s orbital rate. In addition to the uniform rotational motion, physical librations (oscillations about an equilibrium) also occur. The librations may contain signatures of the satellite’s internal properties. Using stereophotogrammetry on Cassini Image Science Subsystem (ISS) images, we measured longitudinal physical forced librations of Saturn’s moon Mimas. Our measurements confirm all the libration amplitudes calculated from the orbital dynamics, with one exception. This amplitude depends mainly on Mimas’ internal structure and has an observed value of twice the predicted one, assuming hydrostatic equilibrium. After considering various possible interior models of Mimas, we argue that the satellite has either a large nonhydrostatic interior, or a hydrostatic one with an internal ocean beneath a thick icy shell.
Evidence of nonthermal particles in coronal loops heated impulsively by nanoflares
Authors: Testa P. , De Pontieu B. , Allred J. , Carlsson M. , Reale F. , Daw A. , Hansteen V. , Martinez-Sykora J. , Liu W. , DeLuca E. E. , Golub L. , McKillop S. , Reeves K. , Saar S. , Tian H. , Lemen J. , Title A. , Boerner P. , Hurlburt N. , Tarbell T. D. , Wuelser J. P. , Kleint L. , Kankelborg C. , Jaeggli S.
Published: October 2014

The physical processes causing energy exchange between the Sun’s hot corona and its cool lower atmosphere remain poorly understood. The chromosphere and transition region (TR) form an interface region between the surface and the corona that is highly sensitive to the coronal heating mechanism. High-resolution observations with the Interface Region Imaging Spectrograph (IRIS) reveal rapid variability (~20 to 60 seconds) of intensity and velocity on small spatial scales (≲500 kilometers) at the footpoints of hot and dynamic coronal loops. The observations are consistent with numerical simulations of heating by beams of nonthermal electrons, which are generated in small impulsive (≲30 seconds) heating events called “coronal nanoflares.” The accelerated electrons deposit a sizable fraction of their energy (≲10
25
erg) in the chromosphere and TR. Our analysis provides tight constraints on the properties of such electron beams and new diagnostics for their presence in the nonflaring corona.
Hot explosions in the cool atmosphere of the Sun
Authors: Peter H. , Tian H. , Curdt W. , Schmit D. , Innes D. , De Pontieu B. , Lemen J. , Title A. , Boerner P. , Hurlburt N. , Tarbell T. D. , Wuelser J. P. , Martínez-Sykora Juan , Kleint L. , Golub L. , McKillop S. , Reeves K. K. , Saar S. , Testa P. , Kankelborg C. , Jaeggli S. , Carlsson M. , Hansteen V.
Published: October 2014

The solar atmosphere was traditionally represented with a simple one-dimensional model. Over the past few decades, this paradigm shifted for the chromosphere and corona that constitute the outer atmosphere, which is now considered a dynamic structured envelope. Recent observations by the Interface Region Imaging Spectrograph (IRIS) reveal that it is difficult to determine what is up and down, even in the cool 6000-kelvin photosphere just above the solar surface: This region hosts pockets of hot plasma transiently heated to almost 100,000 kelvin. The energy to heat and accelerate the plasma requires a considerable fraction of the energy from flares, the largest solar disruptions. These IRIS observations not only confirm that the photosphere is more complex than conventionally thought, but also provide insight into the energy conversion in the process of magnetic reconnection.
Sensing biodiversity
Authors: Turner Woody
Published: October 2014

Sophisticated networks are required to make the best use of biodiversity data from satellites and in situ sensors
Changes on the horizon for consumer genomics in the EU
Authors: Kalokairinou Louiza , Howard Heidi Carmen , Borry Pascal
Published: October 2014

Test results may no longer be available directly to consumers
Perception of root-derived peptides by shoot LRR-RKs mediates systemic N-demand signaling
Authors: Tabata Ryo , Sumida Kumiko , Yoshii Tomoaki , Ohyama Kentaro , Shinohara Hidefumi , Matsubayashi Yoshikatsu
Published: October 2014

Nitrogen (N) is a critical nutrient for plants but is often distributed unevenly in the soil. Plants therefore have evolved a systemic mechanism by which N starvation on one side of the root system leads to a compensatory and increased nitrate uptake on the other side. Here, we study the molecular systems that support perception of N and the long-distance signaling needed to alter root development. Rootlets starved of N secrete small peptides that are translocated to the shoot and received by two leucine-rich repeat receptor kinases (LRR-RKs).
Arabidopsis
plants deficient in this pathway show growth retardation accompanied with N-deficiency symptoms. Thus, signaling from the root to the shoot helps the plant adapt to fluctuations in local N availability.
Detection of T cell responses to a ubiquitous cellular protein in autoimmune disease
Authors: Ito Yoshinaga , Hashimoto Motomu , Hirota Keiji , Ohkura Naganari , Morikawa Hiromasa , Nishikawa Hiroyoshi , Tanaka Atsushi , Furu Moritoshi , Ito Hiromu , Fujii Takao , Nomura Takashi , Yamazaki Sayuri , Morita Akimichi , Vignali Dario A. A. , Kappler John W. , Matsuda Shuichi , Mimori Tsuneyo , Sakaguchi Noriko , Sakaguchi Shimon
Published: October 2014

T cells that mediate autoimmune diseases such as rheumatoid arthritis (RA) are difficult to characterize because they are likely to be deleted or inactivated in the thymus if the self antigens they recognize are ubiquitously expressed. One way to obtain and analyze these autoimmune T cells is to alter T cell receptor (TCR) signaling in developing T cells to change their sensitivity to thymic negative selection, thereby allowing their thymic production. From mice thus engineered to generate T cells mediating autoimmune arthritis, we isolated arthritogenic TCRs and characterized the self antigens they recognized. One of them was the ubiquitously expressed 60
S
ribosomal protein L23a (RPL23A), with which T cells and autoantibodies from RA patients reacted. This strategy may improve our understanding of the underlying drivers of autoimmunity.
To learn is to myelinate
Authors: Long Patrick , Corfas Gabriel
Published: October 2014

The adult mammalian brain requires the production of new glial cells and myelin for learning
Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy
Authors: Villalta S. Armando , Rosenthal Wendy , Martinez Leonel , Kaur Amanjot , Sparwasser Tim , Tidball James G. , Margeta Marta , Spencer Melissa J. , Bluestone Jeffrey A.
Published: October 2014

Regulatory T cells ameliorate symptoms of muscular dystrophy by suppressing type 1 inflammatory responses in muscle.
Performance of Rapid Influenza Diagnostic Testing in Outbreak Settings
Authors: Peci Adriana , Winter Anne-Luise , King Eddie-Chong , Blair Joanne , Gubbay Jonathan B.
Published: October 2014

Rapid influenza diagnostic tests (RIDTs) may be useful during institutional respiratory disease outbreaks to identify influenza and enable antivirals to be rapidly administered to patients and for the prophylactic treatment of those exposed to the virus but not yet symptomatic. The performance of RIDTs at the outbreak level is not well documented in the literature. This study aimed to evaluate the performance of RIDTs in comparison with that of real-time reverse transcription (rRT)-PCR in the context of institutional respiratory disease outbreaks. This study included outbreak-related respiratory specimens tested for influenza virus at Public Health Ontario Laboratories by both RIDT and rRT-PCR, from 1 September 2010 to 30 April 2013. At the outbreak level, performance testing of RIDTs compared to rRT-PCR for the detection of any influenza virus type demonstrated an overall sensitivity of 76.5%, a specificity of 99.7%, a positive predictive value (PPV) of 99.5%, and a negative predictive value of 85.3%. Because of their high specificity and PPV, even outside of the influenza season, RIDTs can play a role in screening for influenza virus in outbreaks and instituting antiviral therapy in a timely manner when positive. RIDTs can also be useful in remote settings where molecular virology testing is not easily accessible. Suboptimal sensitivity of RIDTs can be addressed by the use of molecular testing.
Autographa californica Multiple Nucleopolyhedrovirus ORF11 Is Essential for Budded-Virus Production and Occlusion-Derived-Virus Envelopment
Authors: Tao Xue Ying , Choi Jae Young , Kim Woo Jin , An Saes Byeol , Liu Qin , Kim Song Eun , Lee Seok Hee , Kim Jong Hoon , Woo Soo Dong , Jin Byung Rae , Je Yeon Ho
Published: October 2014

ORF11 (
ac11
) of
Autographa californica
multiple nucleopolyhedrovirus (AcMNPV) is a highly conserved gene with unknown function. To determine the role of
ac11
in the baculovirus life cycle, an
ac11
knockout mutant of AcMNPV, Ac11KO, was constructed. Northern blot and 5′ rapid amplification of cDNA ends (RACE) analyses revealed that
ac11
is an early gene in the life cycle. Microscopy, titration assays, and Western blot analysis revealed that budded viruses (BVs) were not produced in Ac11KO-transfected Sf9 cells. However, quantitative PCR (qPCR) analysis demonstrated that the deletion of
ac11
did not affect viral DNA replication. Furthermore, electron microscopy revealed that there was no nucleocapsid in the cytoplasm or plasma membrane of Ac11KO-transfected cells, which demonstrates that the defect in BV production in Ac11KO-transfected cells is due to the inefficient egress of nucleocapsids from the nucleus to the cytoplasm. In addition, electron microscopy observations showed that the nucleocapsids in the nucleus were not enveloped to form occlusion-derived viruses (ODVs) and that their subsequent embedding into occlusion bodies (OBs) was also blocked in Ac11KO-transfected cells, demonstrating that
ac11
is required for ODV envelopment. These results therefore demonstrate that
ac11
is an early gene that is essential for BV production and ODV envelopment.

IMPORTANCE
Baculoviruses have been extensively used not only as specific, environmentally benign insecticides but also as helper-independent protein expression vectors. Although the function of baculovirus genes in viral replication has been studied by using gene knockout technology, the functions of more than one-third of viral genes, which include some highly conserved genes, are still unknown. In this study,
ac11
was proven to play a crucial role in BV production and ODV envelopment. These results will lead to a better understanding of baculovirus infection cycles.
Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses
Authors: Fu Bishi , Kuang Ersheng , Li Wenwei , Avey Denis , Li Xiaojuan , Turpin Zachary , Valdes Ahmed , Brulois Kevin , Myoung Jinjong , Zhu Fanxiu
Published: October 2014

We have previously shown that ORF45, an immediate-early and tegument protein of Kaposi's sarcoma-associated herpesvirus (KSHV), causes sustained activation of p90 ribosomal S6 kinases (RSKs) and extracellular regulated kinase (ERK) (E. Kuang, Q. Tang, G. G. Maul, and F. Zhu, J Virol 82:1838–1850, 2008,
http://dx.doi.org/10.1128/JVI.02119-07
). We now have identified the critical region of ORF45 that is involved in RSK interaction and activation. Alanine scanning mutagenesis of this region revealed that a single F66A point mutation abolished binding of ORF45 to RSK or ERK and, consequently, its ability to activate the kinases. We introduced the F66A mutation into BAC16 (a bacterial artificial chromosome clone containing the entire infectious KSHV genome), producing BAC16-45F66A. In parallel, we also repaired the mutation and obtained a revertant, BAC16-45A66F. The reconstitution of these mutants in iSLK cells demonstrated that the ORF45-F66A mutant failed to cause sustained ERK and RSK activation during lytic reactivation, resulting in dramatic differences in the phosphoproteomic profile between the wild-type virus-infected cells and the mutant virus-infected cells. ORF45 mutation or deletion also was accompanied by a noticeable decreased in viral gene expression during lytic reactivation. Consequently, the ORF45-F66A mutant produced significantly fewer infectious progeny virions than the wild type or the revertant. These results suggest a critical role for ORF45-mediated RSK activation in KSHV lytic replication.

IMPORTANCE
KSHV is the causative agent of three human malignancies. KSHV pathogenesis is intimately linked to its ability to modulate the host cell microenvironment and to facilitate efficient production of progeny viral particles. We previously described the mechanism by which the KSHV lytic protein ORF45 activates the cellular kinases ERK and RSK. We now have mapped the critical region of ORF45 responsible for binding and activation of ERK/RSK to a single residue, F66. We mutated this amino acid of ORF45 (F66A) and introduced the mutation into a newly developed bacterial artificial chromosome containing the KSHV genome (BAC16). This system has provided us with a useful tool to characterize the functions of ORF45-activated RSK upon KSHV lytic reactivation. We show that viral gene expression and virion production are significantly reduced by F66A mutation, indicating a critical role for ORF45-activated RSK during KSHV lytic replication.
Perturbation in the Conserved Methyltransferase-Polymerase Interface of Flavivirus NS5 Differentially Affects Polymerase Initiation and Elongation
Authors: Wu Jiqin , Lu Guoliang , Zhang Bo , Gong Peng
Published: October 2014

The flavivirus NS5 is a natural fusion of a methyltransferase (MTase) and an RNA-dependent RNA polymerase (RdRP). Analogous to DNA-dependent RNA polymerases, the NS5 polymerase initiates RNA synthesis through a
de novo
mechanism and then makes a transition to a processive elongation phase. However, whether and how the MTase affects polymerase activities through intramolecular interactions remain elusive. By solving the crystal structure of the Japanese encephalitis virus (JEV) NS5, we recently identified an MTase-RdRP interface containing a set of six hydrophobic residues highly conserved among flaviviruses. To dissect the functional relevance of this interface, we made a series of JEV NS5 constructs with mutations of these hydrophobic residues and/or with the N-terminal first 261 residues and other residues up to the first 303 residues deleted. Compared to the wild-type (WT) NS5, full-length NS5 variants exhibited consistent up- or downregulation of the initiation activities in two types of polymerase assays. Five representative full-length NS5 constructs were then tested in an elongation assay, from which the apparent single-nucleotide incorporation rate constant was estimated. Interestingly, two constructs exhibited different elongation kinetics from the WT NS5, with an effect rather opposite to what was observed at initiation. Moreover, constructs with MTase and/or the linker region (residues 266 to 275) removed still retained polymerase activities, albeit at overall lower levels. However, further removal of the N-terminal extension (residues 276 to 303) abolished regular template-directed synthesis. Together, our data showed that the MTase-RdRP interface is relevant in both polymerase initiation and elongation, likely with different regulation mechanisms in these two major phases of RNA synthesis.

IMPORTANCE
The flavivirus NS5 is very unique in having a methyltransferase (MTase) placed on the immediate N terminus of its RNA-dependent RNA polymerase (RdRP). We recently solved the crystal structure of the full-length NS5, which revealed a conserved interface between MTase and RdRP. Building on this discovery, here we carried out
in vitro
polymerase assays to address the functional relevance of the interface interactions. By explicitly probing polymerase initiation and elongation activities, we found that perturbation in the MTase-RdRP interface had different impacts on different phases of synthesis, suggesting that the roles and contribution of the interface interactions may change upon phase transitions. By comparing the N-terminal-truncated enzymes with the full-length NS5, we collected data to indicate the indispensability to regular polymerase activities of a region that was functionally unclarified previously. Taken together, we provide biochemical evidence and mechanistic insights for the cross talk between the two enzyme modules of flavivirus NS5.
A 2.5-Kilobase Deletion Containing a Cluster of Nine MicroRNAs in the Latency-Associated-Transcript Locus of the Pseudorabies Virus Affects the Host Response of Porcine Trigeminal Ganglia during Established Latency
Authors: Mahjoub Nada , Dhorne-Pollet Sophie , Fuchs Walter , Endale Ahanda Marie-Laure , Lange Elke , Klupp Barbara , Arya Anoop , Loveland Jane E. , Lefevre François , Mettenleiter Thomas C. , Giuffra Elisabetta
Published: October 2014

The alphaherpesvirus pseudorabies virus (PrV) establishes latency primarily in neurons of trigeminal ganglia when only the transcription of the latency-associated transcript (LAT) locus is detected. Eleven microRNAs (miRNAs) cluster within the LAT, suggesting a role in establishment and/or maintenance of latency. We generated a mutant (M) PrV deleted of nine miRNA genes which displayed properties that were almost identical to those of the parental PrV wild type (WT) during propagation
in vitro
. Fifteen pigs were experimentally infected with either WT or M virus or were mock infected. Similar levels of virus excretion and host antibody response were observed in all infected animals. At 62 days postinfection, trigeminal ganglia were excised and profiled by deep sequencing and quantitative RT-PCR. Latency was established in all infected animals without evidence of viral reactivation, demonstrating that miRNAs are not essential for this process. Lower levels of the large latency transcript (LLT) were found in ganglia infected by M PrV than in those infected by WT PrV. All PrV miRNAs were expressed, with highest expression observed for prv-miR-LLT1, prv-miR-LLT2 (in WT ganglia), and prv-miR-LLT10 (in both WT and M ganglia). No evidence of differentially expressed porcine miRNAs was found. Fifty-four porcine genes were differentially expressed between WT, M, and control ganglia. Both viruses triggered a strong host immune response, but in M ganglia gene upregulation was prevalent. Pathway analyses indicated that several biofunctions, including those related to cell-mediated immune response and the migration of dendritic cells, were impaired in M ganglia. These findings are consistent with a function of the LAT locus in the modulation of host response for maintaining a latent state.

IMPORTANCE
This study provides a thorough reference on the establishment of latency by PrV in its natural host, the pig. Our results corroborate the evidence obtained from the study of several LAT mutants of other alphaherpesviruses encoding miRNAs from their LAT regions. Neither PrV miRNA expression nor high LLT expression levels are essential to achieve latency in trigeminal ganglia. Once latency is established by PrV, the only remarkable differences are found in the pattern of host response. This indicates that, as in herpes simplex virus, LAT functions as an immune evasion locus.
Venezuelan Equine Encephalitis Virus Variants Lacking Transcription Inhibitory Functions Demonstrate Highly Attenuated Phenotype
Authors: Atasheva Svetlana , Kim Dal Young , Frolova Elena I. , Frolov Ilya
Published: October 2014

Alphaviruses represent a significant public health threat worldwide. They are transmitted by mosquitoes and cause a variety of human diseases ranging from severe meningoencephalitis to polyarthritis. To date, no efficient and safe vaccines have been developed against any alphavirus infection. However, in recent years, significant progress has been made in understanding the mechanism of alphavirus replication and virus-host interactions. These data have provided the possibility for the development of new rationally designed alphavirus vaccine candidates that combine efficient immunogenicity, high safety, and inability to revert to pathogenic phenotype. New attenuated variants of Venezuelan equine encephalitis virus (VEEV) designed in this study combine a variety of characteristics that independently contribute to a reduction in virulence. These constructs encode a noncytopathic VEEV capsid protein that is incapable of interfering with the innate immune response. The capsid-specific mutations strongly affect neurovirulence of the virus. In other constructs, they were combined with changes in control of capsid translation and an extensively mutated packaging signal. These modifications also affected the residual neurovirulence of the virus, but it remained immunogenic, and a single immunization protected mice against subsequent infection with epizootic VEEV. Similar approaches of attenuation can be applied to other encephalitogenic New World alphaviruses.

IMPORTANCE
Venezuelan equine encephalitis virus (VEEV) is an important human and animal pathogen, which causes periodic outbreaks of highly debilitating disease. Despite a continuous public health threat, no safe and efficient vaccine candidates have been developed to date. In this study, we applied accumulated knowledge about the mechanism of VEEV replication, RNA packaging, and interaction with the host to design new VEEV vaccine candidates that demonstrate exceptionally high levels of safety due to a combination of extensive modifications in the viral genome. The introduced mutations did not affect RNA replication or structural protein synthesis but had deleterious effects on VEEV neuroinvasion and virulence. In spite of dramatically reduced virulence, the designed mutants remained highly immunogenic and protected mice against subsequent infection with epizootic VEEV. Similar methodologies can be applied for attenuation of other encephalitogenic New World alphaviruses.
G
2
/M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex
Authors: Berger Gregory , Lawrence Madeleine , Hué Stephane , Neil Stuart J. D.
Published: October 2014

The accessory gene
vpr
, common to all primate lentiviruses, induces potent G
2
/M arrest in cycling cells. A recent study showed that human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) mediates this through activation of the SLX4/MUS81/EME1 exonuclease complex that forms part of the Fanconi anemia DNA repair pathway. To confirm these observations, we have examined the G
2
/M arrest phenotypes of a panel of simian immunodeficiency virus (SIV) Vpr proteins. We show that SIV Vpr proteins differ in their ability to promote cell cycle arrest in human cells. While this is dependent on the DCAF1/DDB1/CUL4 ubiquitin ligase complex, interaction with human DCAF1 does not predict G
2
/M arrest activity of SIV Vpr in human cells. In all cases, SIV Vpr-mediated cell cycle arrest in human cells correlated with interaction with human SLX4 (huSLX4) and could be abolished by small interfering RNA (siRNA) depletion of any member of the SLX4 complex. In contrast, all but one of the HIV/SIV Vpr proteins tested, including those that lacked activity in human cells, were competent for G
2
/M arrest in grivet cells. Correspondingly, here cell cycle arrest correlated with interaction with the grivet orthologues of the SLX4 complex, suggesting a level of host adaptation in these interactions. Phylogenetic analyses strongly suggest that G
2
/M arrest/SLX4 interactions are ancestral activities of primate lentiviral Vpr proteins and that the ability to dysregulate the Fanconi anemia DNA repair pathway is an essential function of Vpr
in vivo
.

IMPORTANCE
The Vpr protein of HIV-1 and related viruses is essential for the virus
in vivo
. The ability of Vpr to block the cell cycle at mitotic entry is well known, but the importance of this function for viral replication is unclear. Recent data have shown that HIV-1 Vpr targets the Fanconi anemia DNA repair pathway by interacting with and activating an endonuclease complex, SLX4/MUS81/EME1, that processes interstrand DNA cross-links. Here we show that the ability of a panel of SIV Vpr proteins to mediate cell cycle arrest correlates with species-specific interactions with the SLX4 complex in human and primate cells. The results of these studies suggest that the SLX4 complex is a conserved target of primate lentiviral Vpr proteins and that the ability to dysregulate members of the Fanconi anemia DNA repair pathway is essential for HIV/SIV replication
in vivo
.
Malawi Polyomavirus Is a Prevalent Human Virus That Interacts with Known Tumor Suppressors
Authors: Berrios Christian , Jung Joonil , Primi Blake , Wang Michael , Pedamallu Chandrasekhar , Duke Fujiko , Marcelus Christina , Cheng Jingwei , Garcea Robert L. , Meyerson Matthew , DeCaprio James A.
Published: October 2014

Malawi polyomavirus (MWPyV) is a recently identified human polyomavirus. Serology for MWPyV VP1 indicates that infection frequently occurs in childhood and reaches a prevalence of 75% in adults. The MWPyV small T antigen (ST) binds protein phosphatase 2A (PP2A), and the large T antigen (LT) binds pRb, p107, p130, and p53. However, the MWPyV LT was less stable than the simian virus 40 (SV40) LT and was unable to promote the growth of normal cells. This report confirms that MWPyV is a widespread human virus expressing T antigens with low transforming potential.
Identification of TRIM27 as a Novel Degradation Target of Herpes Simplex Virus 1 ICP0
Authors: Conwell Sara E. , White Anne E. , Harper J. Wade , Knipe David M.
Published: October 2014

The herpes simplex virus 1 (HSV-1) immediate early protein ICP0 performs many functions during infection, including transactivation of viral gene expression, suppression of innate immune responses, and modification and eviction of histones from viral chromatin. Although these functions of ICP0 have been characterized, the detailed mechanisms underlying ICP0's complex role during infection warrant further investigation. We thus undertook an unbiased proteomic approach to identifying viral and cellular proteins that interact with ICP0 in the infected cell. Cellular candidates resulting from our analysis included the ubiquitin-specific protease USP7, the transcriptional repressor TRIM27, DNA repair proteins NBN and MRE11A, regulators of apoptosis, including BIRC6, and the proteasome. We also identified two HSV-1 early proteins involved in nucleotide metabolism, U
L
39 and U
L
50, as novel candidate interactors of ICP0. Because TRIM27 was the most statistically significant cellular candidate, we investigated the relationship between TRIM27 and ICP0. We observed rapid, ICP0-dependent loss of TRIM27 during HSV-1 infection. TRIM27 protein levels were restored by disrupting the RING domain of ICP0 or by inhibiting the proteasome, arguing that TRIM27 is a novel degradation target of ICP0. A mutant ICP0 lacking E3 ligase activity interacted with endogenous TRIM27 during infection as demonstrated by reciprocal coimmunoprecipitation and supported by immunofluorescence data. Surprisingly, ICP0-null mutant virus yields decreased upon TRIM27 depletion, arguing that TRIM27 has a positive effect on infection despite being targeted for degradation. These results illustrate a complex interaction between TRIM27 and viral infection with potential positive or negative effects of TRIM27 on HSV under different infection conditions.

IMPORTANCE
During productive infection, a virus must simultaneously redirect multiple cellular pathways to replicate itself while evading detection by the host's defenses. To orchestrate such complex regulation, viruses, including herpes simplex virus 1 (HSV-1), rely on multifunctional proteins such as the E3 ubiquitin ligase ICP0. This protein regulates various cellular pathways concurrently by targeting a diverse set of cellular factors for degradation. While some of these targets have been previously identified and characterized, we undertook a proteomic screen to identify additional targets of this activity to further characterize ICP0's role during infection. We describe a set of candidate interacting proteins of ICP0 identified through this approach and our characterization of the most statistically significant result, the cellular transcriptional repressor TRIM27. We present TRIM27 as a novel degradation target of ICP0 and describe the relationship of these two proteins during infection.
Granulomatous tubulointerstitial nephritis secondary to omeprazole
Authors: Nadri Quaid , Althaf Mohammed Mahdi
Published: October 2014

Drug-induced interstitial nephritis is a common cause of acute kidney injury indicated by elevated serum creatinine. We report a case of omeprazole-induced acute granulomatous interstitial nephritis (GIN). Our patient developed acute GIN secondary to omeprazole ingestion requiring haemodialysis. Treatment with steroids and withdrawal of omperazole was successful allowing the patient to discontinue haemodialysis in 3 months. She remains dialysis free with chronic kidney disease stage IV, reflected by a serum creatine of 191 μmol/L and estimated glomerular filtration rate of 23 mL/min/1.73 m2at 5 years on follow-up.
Colonic gallstone ileus: the rolling stones
Authors: Heaney Roisin Mary
Published: October 2014

Gallstone ileus is a rare complication of cholelithiasis accounting for 1–4% of cases of intestinal obstruction with a predominance in the elderly population. Unfortunately, it has an insipid presentation and is associated with significant rates of morbidity and mortality. Controversy arises over the management of gallstone ileus, and while surgery remains the mainstay of treatment, the main point of contention surrounds the extent of surgery. We describe the case of an 85-year-old woman who presented with symptoms and signs of large bowel obstruction. Radiological evaluation revealed a 5 cm×3.5 cm gallstone impacted in the sigmoid colon. A laparoscopic-assisted enterolithotomy alone relieved the obstruction with minimal surgical insult and allowed for a swift and uneventful recovery. Our case emphasises the need for a high index of suspicion for the condition as well as highlighting the advantages of the use of laparoscopic surgery in an emergency setting.
Isolated oculomotor nerve palsy: a rare manifestation of internal carotid artery dissection
Authors: Santos Telma , Morais Hugo , Oliveira Gustavo , Barros Pedro
Published: October 2014

A 58-year-old man reported sudden-onset binocular double vision that appeared 3 days earlier. He denied history of headache/cervical pain or trauma. He had a medical history of well-controlled diabetes, hypertension and dyslipidaemia. Neurological examination revealed a left-sided ptosis and binocular horizontal diplopia in dextroversion without apparent extraocular-muscle paresis or pupillary involvement. Other cranial nerves were spared as well as motor, sensory and coordination systems. There were no signs of ocular erythema, proptosis or palpable orbital mass. Brain MR angiography revealed a crescent-shaped mural hyperintensity in left internal carotid artery (ICA) at skull base, extending to intrapetrous segment, with reduced calibre and flow, suggesting a left ICA dissection. The patient was started on antiaggregation therapy. A year later he was asymptomatic and CT angiography confirmed ICA recanalisation.
Axillary intranodal palisaded myofibroblastoma: report of a case associated with chronic mastitis
Authors: D'Antonio Antonio , Addesso Maria , Amico Paolo , Fragetta Filippo
Published: October 2014

Intranodal palisaded myofibroblastoma is a rare tumour of the lymph node that may be derived from myofibroblasts. The most usual area of presentation is the inguinal lymph nodes, but occurrence within other areas has also been reported. It is characterised by spindle cells, amianthoid-like fibres, and by the proliferation of hemosiderin-containing histiocytes in the lymph node. Although intranodal palisaded myofibroblastoma is benign, it is frequently confused with metastatic lesions, especially when it occurs in atypical sites. We herein report the second case of axillary intranodal palisaded myofibroblastoma occurring in a woman with a granulomatous chronic mastitis. The salient clinicopathological features of this unusual tumour are presented with emphasis to the pathogenesis of the tumour as well as to its histological and immunohistochemical characteristics. Clinicians and pathologists must be aware of this rare tumour to avoid a misdiagnosis of malignancy and assure patient a correct therapeutic management.
Cross-cultural adaptation, evaluation and validation of the Spouse Response Inventory: a study protocol
Authors: Kaiser Ulrike , Steinmetz Dorit , Scharnagel Rüdiger , Jensen Mark P , Balck Friedrich , Sabatowski Rainer
Published: October 2014

Introduction

Since the response of spouses has been proven to be an important reinforcement of pain behaviour and disability it has been addressed in research and therapy. Fordyce suggestedpain behaviourandwell behaviourbe considered in explaining suffering in chronic pain patients. Among existing instruments concerning spouse's responses the aspect of well behaviour has not been examined so far. The SRI (Spouse Response Inventory) tries to consider pain behaviour and well behaviour and appears to be acceptable because of its brevity and close proximity to daily language. Theaim of the studyis the translation into German, followed by evaluation and validation, of the SRI on a German sample of patients with chronic pain.

Methods and analyses

The study is comprehensively designed: initially, the focus will lie on thetranslationof the instrument following the guidelines for cross-cultural translation and adaptation andevaluationof the German version according to the source study. Subsequently, avalidationreferring to predictive, incremental and construct validation will be conducted using instruments based on similar or close but different constructs. Evaluation of the resulting SRI-G (SRI-German) will be conducted on a sample of at least 30 patients with chronic pain attending a comprehensive pain centre. For validation at least 120 patients with chronic headache, back pain, cancer related pain and somatoform pain disorder shall be included, for a total of 480 patients. Separate analyses according to specific pain diagnoses will be performed to ensure psychometric property, interpretability and control of diagnosis of specific limitations. Analyses will include comprehensive investigation of psychometric property of the scale by hierarchical regression analyses, correlation analyses, multivariate analysis of variance and exploratory factor analyses (SPSS).

Ethics

The study protocol was approved by the Ethics Committee of the University of Dresden (EK 335 122008) based on the Helsinki declaration.
Job demand and control in mid-life and physical and mental functioning in early old age: do childhood factors explain these associations in a British birth cohort?
Authors: von Bonsdorff Mikaela B , Cooper Rachel , Kuh Diana
Published: October 2014

Objectives

Adverse work-related exposures have been linked with decreased physical and mental functioning in later life, however, whether childhood factors explain the associations between work exposures and functioning is unknown. Our aim was to investigate if job demand and control in mid-life were related to self-reported physical and mental functioning in early old age and whether childhood factors explained these associations.

Design

Prospective cohort study.

Setting

England, Scotland and Wales.

Participants and outcome measures

Data come from the UK Medical Research Council National Survey of Health and Development, a cohort with follow-up since birth in 1946. 1485 occupationally active study members had data available on job demand and control in mid-life and on physical and mental functioning assessed using the Short Form-36 questionnaire at 60–64 years.

Results

Those with higher job control in mid-life had better physical functioning than those who reported lower job control (β 0.51, 95% CI 0.02 to 1.01, p=0.04 adjusted for adult confounders). Those with higher job demand in mid-life had poorer mental functioning (β −0.82, 95% CI −1.14 to −0.51, p<0.001). Associations between job control and mental functioning were similar but less pronounced. Adjustment for childhood factors (father's and mother's educational attainment, parents’ interest in school at age 7 and cognitive ability at age 8) partially explained the association between job control and physical functioning, but did not explain the association between job demand and mental functioning.

Conclusions

Job demand and control in mid-life are differentially associated with mental and physical functioning in early old age and some of these associations may be partially explained by childhood factors.
The use of parental occupation in adolescent health surveys. An application of ISCO-based measures of occupational status
Authors: Pförtner Timo-Kolja , Günther Sebastian , Levin Kate A , Torsheim Torbjørn , Richter Matthias
Published: October 2014

Background

Recent research has emphasised that the challenge in researching socioeconomic differences in adolescent health cross-nationally lies in providing valid and comparable measures of socioeconomic position (SEP) across regions. This study aims to examine measures of occupational status derived from the International Standard Classiﬁcation of Occupations (ISCO), alongside commonly used affluence measures in association with adolescent self-rated health (SRH).

Methods

Data were from the 2005/2006 ‘Health Behaviour in School-aged Children study’ (HBSC); 27 649 individuals aged 11, 13 and 15 years from Germany, Macedonia, Norway, Turkey, Wales and Scotland. Three occupational scales were compared: the International Socioeconomic Index of Occupational Status (ISEI), the Standard International Occupational Prestige Scale (SIOPS) and the Erikson–Goldthorpe–Portocarero class categories (EGP). Correlation analyses compared these occupational scales with the family affluence scale (FAS) and a family well-off measure, while logistic regression assessed the association between occupational scales and poor SRH. Multiple imputation techniques investigated possible bias arising from parental occupation missingness.

Results

Moderate correlations existed between occupational scales and FAS and family well-off. Socioeconomic inequalities in poor SRH were found for ISEI, SIOPS and EGP in all regions, independent of FAS and family well-off. Models of imputed data sets did not alter the results. The relationship between SEP and SRH was therefore not biased by high levels of missing values for ISCO.

Conclusions

ISCO-based indicators of occupational status in cross-national self-administered adolescent health surveys were found to be robust measures of SEP in adolescence. These measure different aspects of SEP independent of FAS and family well-off.
Omentalisation in the treatment of sublumbar abscessation: long‐term outcome in 10 dogs
Authors: Woodbridge N. , Martinoli S. , Cherubini G. B. , Caine A. , Nelissen P. , White R.
Published: October 2014

The objectives of this study were to report the technique of omentalisation for the management of sublumbar abscessation associated with suspected migrating plant material, the intraoperative and postoperative complications that occurred and the long‐term outcome of the cases. A retrospective case series of dogs (n=10) with sublumbar abscessation managed by exploration and drainage combined with omentalisation of the abscess cavity is reported in this study. The sublumbar area was approached through a ventral midline coeliotomy, the abscess was explored, drained, debrided and subsequently packed with omentum. One dog sustained an aortic rupture during exploration of the abscess, the aorta was repaired; there were no postoperative complications. There was long‐term (>12 months) resolution of clinical signs in all dogs. Drainage and omentalisation of sublumbar abscesses resulted in complete resolution of signs in all dogs and was associated with a low incidence of complications. Omentalisation is an effective treatment for dogs presenting with sublumbar abscesses associated with suspected migrating plant material.
Climate change and vulnerability of bull trout (Salvelinus confluentus) in a fire-prone landscape
Authors: Falke Jeffrey A. , Flitcroft Rebecca L. , Dunham Jason B. , McNyset Kristina M. , Hessburg Paul F. , Reeves Gordon H.
Published: October 2014

Linked atmospheric and wildfire changes will complicate future management of native coldwater fishes in fire-prone landscapes, and new approaches to management that incorporate uncertainty are needed to address this challenge. We used a Bayesian network (BN) approach to evaluate population vulnerability of bull trout (Salvelinus confluentus) in the Wenatchee River basin, Washington, USA, under current and future climate and fire scenarios. The BN was based on modeled estimates of wildfire, water temperature, and physical habitat prior to, and following, simulated fires throughout the basin. We found that bull trout population vulnerability depended on the extent to which climate effects can be at least partially offset by managing factors such as habitat connectivity and fire size. Moreover, our analysis showed that local management can significantly reduce the vulnerability of bull trout to climate change given appropriate management actions. Tools such as our BN that explicitly integrate the linked nature of climate and wildfire, and incorporate uncertainty in both input data and vulnerability estimates, will be vital in effective future management to conserve native coldwater fishes.
Pyrosequencing analysis of free-living and attached bacterial communities in Meiliang Bay, Lake Taihu, a large eutrophic shallow lake in China
Authors: Tang Xiangming , Li Linlin , Shao Keqiang , Wang Boweng , Cai Xianlei , Zhang Lei , Chao Jianying , Gao Guang
Published: October 2014

To elucidate the relationship between particle-attached (PA, ≥5.0 μm) and free-living (FL, 0.2–5.0 μm) bacterial communities, samplings were collected seasonally from November 2011 to August 2012 in Meiliang Bay, Lake Taihu, China. We used 454 pyrosequencing of 16S rRNA genes to study bacterial diversity and structure of PA and FL communities. The analysis rendered 37 985 highly qualified reads, subsequently assigned to 1755 operational taxonomic units (97% similarity) for the 8 samples. Although 27 high-level taxonomic groups were obtained, the 3 dominant phyla (Proteobacteria, Actinobacteria, and Bacteroidetes) comprised about 75.9% and 82.4% of the PA and FL fractions, respectively. Overall, we found no significant differences between community types, as indicated by ANOSIM R statistics (R = 0.063, P > 0.05) and the Parsimony test (P = 0.222). Dynamics of bacterial communities were correlated with changes in concentrations of total suspended solids (TSS) and total phosphorus (TP). In summer, a significant taxonomic overlap in the 2 size fractions was observed when Cyanobacteria, a major contributor of TSS and TP, dominated in the water, highlighting the potential rapid exchange between PA and FL bacterial populations in large shallow eutrophic lakes.