bluuebunny/crossref_metadata_2025 huggingface dataset:
Output-Only Modal Identification of a Nonuniform Beam by Using Decomposition Methods
Authors: Caldwell Rickey A. , Feeny Brian F.
Published: March 2014

Reduced-order mass weighted proper orthogonal decomposition (RMPOD), smooth orthogonal decomposition (SOD), and state variable modal decomposition (SVMD) are used to extract modal parameters from a nonuniform experimental beam. The beam was sensed by accelerometers. Accelerometer signals were integrated and passed through a high-pass filter to obtain velocities and displacements, all of which were used to build the necessary ensembles for the decomposition matrices. Each of these decomposition methods was used to extract mode shapes and modal coordinates. RMPOD can directly quantify modal energy, while SOD and SVMD directly produce estimates of modal frequencies. The extracted mode shapes and modal frequencies were compared to an analytical approximation of these quantities, and to frequencies estimated by applying the fast Fourier transform to accelerometer data. SVMD is also applied to estimate modal damping, which was compared to the estimate by logarithmic decrement applied to modal coordinate signals, with varying degrees of success. This paper shows that these decomposition methods are capable of extracting lower modal parameters of an actual experimental beam.
Buckling of Cylinders With Imperfect Length
Authors: Błachut J.
Published: March 2014

Eighteen mild steel cylinders with the length-to-radius ratio, L/R ≈ 2.4 and with the radius-to-wall thickness ratio, R/t ≈ 185 were collapsed by axial compression. Cylinders had variable length at one end of sinusoidal profile. The magnitude of axial imperfection-to-wall thickness ratio, 2A/t, was varied between 0.05 and 1.0. Experimental results show that buckling strength strongly depends on the axial amplitude of imperfection. On average imperfect cylinders, with 2A/t = 1.0, are able to support 49% of experimental buckling load obtained for geometrically perfect model. The largest sensitivity of buckling strength was associated with small amplitude of imperfection in axial length. For example, for axial length imperfection amounting to 25% of wall thickness the buckling strength was reduced by 40%. It appears that the number of sinusoidal waves in the imperfection profile plays a secondary role, i.e., its role in reducing the buckling strength is not a dominant factor. The paper provides experimental details and comparisons with numerical results.
Design of a Surgical Device for Office-Based Myringotomy and Grommet Insertion for Patients With Otitis Media With Effusion
Authors: Kiong Tan Kok , Liang Wenyu , Phuong Pham Le , Huang Sunan , Wee Gan Chee , Yee Lim Hsueh
Published: March 2014

Otitis media with effusion (OME) is a very common ear disease occurring in adults and children alike when the middle ear is infected or the eustachian tube becomes dysfunctional, resulting in accumulation of fluid in the middle ear space. When medication as the first treatment fails, a grommet is commonly surgically inserted on the tympanic membrane (TM) of the patient to discharge the fluid. In this paper, a novel “all-in-one” device allowing office-based grommet insertion in an awake patient with OME is proposed, designed, fabricated, and tested. It utilizes a highly integrated structure encompassing key components of a mechanical system, a sensing system and a motion control system, all are synergized to enable the surgery to be completed in a short time automatically, precisely, effectively, and safely. The experimental results obtained with the device working on a mock membrane with characteristics representative of the TM are duly furnished, showing a success rate of up to 98%.
Experimental Investigation of Temperature Separation in a Counter-Flow Vortex Tube
Authors: Ramakrishna P. A. , Ramakrishna M. , Manimaran R.
Published: March 2014

An experimental study of a counter-flow Ranque–Hilsch vortex tube is reported here. Literature has been divided over the mechanism of energy transfer responsible for the temperature separation in the vortex tube. A black box approach is used to design experiments to infer the relative roles of heat transfer and shear work transfer in the counter-flow vortex tube. To this end, the stagnation temperature and the mass flow rates are measured at the inlet and the two outlets. In addition, pressure measurements at the stagnation condition and at the inlet section to the vortex tube were made. Based on these experiments, it is reasoned that the predominant mode of energy transfer responsible for temperature separation in a counter-flow vortex is the shear work transfer between the core and the periphery.
Thoracic cavity segmentation algorithm using multiorgan extraction and surface fitting in volumetric CT
Authors: Bae JangPyo , Kim Namkug , Lee Sang Min , Seo Joon Beom , Kim Hee Chan
Published: March 2014

Purpose:

To develop and validate a semiautomatic segmentation method for thoracic cavity volumetry and mediastinum fat quantification of patients with chronic obstructive pulmonary disease.

Methods:

The thoracic cavity region was separated by segmenting multiorgans, namely, the rib, lung, heart, and diaphragm. To encompass various lung disease‐induced variations, the inner thoracic wall and diaphragm were modeled by using a three‐dimensional surface‐fitting method. To improve the accuracy of the diaphragm surface model, the heart and its surrounding tissue were segmented by a two‐stage level set method using a shape prior. To assess the accuracy of the proposed algorithm, the algorithm results of 50 patients were compared to the manual segmentation results of two experts with more than 5 years of experience (these manual results were confirmed by an expert thoracic radiologist). The proposed method was also compared to three state‐of‐the‐art segmentation methods. The metrics used to evaluate segmentation accuracy were volumetric overlap ratio (VOR), false positive ratio on VOR (FPRV), false negative ratio on VOR (FNRV), average symmetric absolute surface distance (ASASD), average symmetric squared surface distance (ASSSD), and maximum symmetric surface distance (MSSD).

Results:

In terms of thoracic cavity volumetry, the mean ± SD VOR, FPRV, and FNRV of the proposed method were (98.17 ± 0.84)%, (0.49 ± 0.23)%, and (1.34 ± 0.83)%, respectively. The ASASD, ASSSD, and MSSD for the thoracic wall were 0.28 ± 0.12, 1.28 ± 0.53, and 23.91 ± 7.64 mm, respectively. The ASASD, ASSSD, and MSSD for the diaphragm surface were 1.73 ± 0.91, 3.92 ± 1.68, and 27.80 ± 10.63 mm, respectively. The proposed method performed significantly better than the other three methods in terms of VOR, ASASD, and ASSSD.

Conclusions:

The proposed semiautomatic thoracic cavity segmentation method, which extracts multiple organs (namely, the rib, thoracic wall, diaphragm, and heart), performed with high accuracy and may be useful for clinical purposes.
Low‐complexity atlas‐based prostate segmentation by combining global, regional, and local metrics
Authors: Xie Qiuliang , Ruan Dan
Published: March 2014

Purpose:

To improve the efficiency of atlas‐based segmentation without compromising accuracy, and to demonstrate the validity of the proposed method on MRI‐based prostate segmentation application.

Methods:

Accurate and efficient automatic structure segmentation is an important task in medical image processing. Atlas‐based methods, as the state‐of‐the‐art, provide good segmentation at the cost of a large number of computationally intensive nonrigid registrations, for anatomical sites/structures that are subject to deformation. In this study, the authors propose to utilize a combination of global, regional, and local metrics to improve the accuracy yet significantly reduce the number of required nonrigid registrations. The authors first perform an affine registration to minimize the global mean squared error (gMSE) to coarsely align each atlas image to the target. Subsequently, atarget‐specific regional MSE (rMSE), demonstrated to be a good surrogate for dice similarity coefficient (DSC), is used to select a relevant subset from the training atlas. Only within this subset are nonrigid registrations performed between the training images and the target image, to minimize a weighted combination of gMSE and rMSE. Finally, structure labels are propagated from the selected training samples to the target via the estimated deformation fields, and label fusion is performed based on a weighted combination of rMSE and local MSE (lMSE) discrepancy, with proper total‐variation‐based spatial regularization.

Results:

The proposed method was applied to a public database of 30 prostate MR images with expert‐segmented structures. The authors’ method, utilizing only eight nonrigid registrations, achieved a performance with a median/mean DSC of over 0.87/0.86, outperforming the state‐of‐the‐art full‐fledged atlas‐based segmentation approach of which the median/mean DSC was 0.84/0.82 when applying to their data set.

Conclusions:

The proposed method requires a fixed number of nonrigid registrations, independent of atlas size, providing desirable scalability especially important for a large or growing atlas. When applied to prostate segmentation, the method achieved better performance to the state‐of‐the‐art atlas‐based approaches, with significant improvement in computation efficiency. The proposed rationale of utilizing jointly global, regional, and local metrics, based on the information characteristic and surrogate behavior for registration and fusion subtasks, can be extended naturally to similarity metrics beyond MSE, such as correlation or mutual information types.
Humans Can Discriminate More than 1 Trillion Olfactory Stimuli
Authors: Bushdid C. , Magnasco M. O. , Vosshall L. B. , Keller A.
Published: March 2014

All the Smells of the World

How many odorant stimuli can a normal human being discriminate? During psychophysical tests of odor mixture discrimination,

Bushdid
et al.

(p.
1370
) were surprised to find that humans can discriminate among more than a trillion different smells. Because the authors reduced the complexity by investigating only mixtures of 10, 20, or 30 components drawn from a collection of 128 odorous molecules, this astonishingly large number is probably the lower limit of the potential number of olfactory stimuli that humans can distinguish.
Nanoframe Catalysts
Authors: Greer Julia R.
Published: March 2014

Nanoframe electrocatalysts containing only small amounts of precious metal show very high activities.

[Also see Report by

Chen
et al.

]
Epstein-Barr Virus Turns 50
Authors: Lieberman Paul M.
Published: March 2014

Fifty years after the discovery of Epstein-Barr virus and its association with cancer, a vaccine or therapy for the virus remains elusive.
Exxon Valdez
: 25 Years Later
Authors: McNutt Marcia
Published: March 2014

After I was called upon in 2010, as director of the U.S. Geological Survey, to help with well control and flow estimation for the
Deepwater Horizon
(
DWH
) oil spill, I reviewed what had been learned from the
Exxon Valdez
(
EV
) oil spill. Although
EV
and
DWH
differed in their spill characteristics and impacts, I suspected that insight gained in the decades since
EV
could help guide how to best invest research funds targeted for
DWH
recovery and future oil spill prevention
First Wrinkles in Spacetime Confirm Cosmic Inflation
Authors: Cho Adrian , Bhattacharjee Yudhijit
Published: March 2014

Signs of gravitational waves shaking the newborn universe bolster the mind-boggling theory of cosmic inflation and electrify scientists the world over.
Irreproducibility Dogs New Reprogramming Method
Authors: Normile Dennis , Vogel Gretchen
Published: March 2014

As scientists around the world attempt to reproduce a new way to make stem cells—so far without success—
Science
has learned that several co-authors on the feted papers have not yet made the cells either.
Deriving Group A Streptococcus Typing Information from Short-Read Whole-Genome Sequencing Data
Authors: Athey Taryn B. T. , Teatero Sarah , Li Aimin , Marchand-Austin Alex , Beall Bernard W. , Fittipaldi Nahuel
Published: March 2014

Typing of group AStreptococcus (GAS) is crucial for infection control and epidemiology. While whole-genome sequencing (WGS) is revolutionizing the way that bacterial organisms are typed, it is necessary to provide backward compatibility with currently used typing schemas to facilitate comparisons and understanding of epidemiological trends. Here, we sequenced the genomes of 191 GAS isolates representing 42 differentemmtypes and used bioinformatics tools to derive commonly used GAS typing information directly from the short-read WGS data. We show thatemmtyping and multilocus sequence typing can be achieved rapidly and efficiently using this approach, which also permits the determination of the presence or absence of genes associated with GAS tissue tropism. We also report on how the WGS data analysis was instrumental in identifying ambiguities present in the commonly usedemmtype database hosted by the U.S. Centers for Disease Control and Prevention.
Rapid Genome Detection of Schmallenberg Virus and Bovine Viral Diarrhea Virus by Use of Isothermal Amplification Methods and High-Speed Real-Time Reverse Transcriptase PCR
Authors: Aebischer Andrea , Wernike Kerstin , Hoffmann Bernd , Beer Martin
Published: March 2014

Over the past few years, there has been an increasing demand for rapid and simple diagnostic tools that can be applied outside centralized laboratories by using transportable devices. In veterinary medicine, such mobile test systems would circumvent barriers associated with the transportation of samples and significantly reduce the time to diagnose important infectious animal diseases. Among a wide range of available technologies, high-speed real-time reverse transcriptase quantitative PCR (RT-qPCR) and the two isothermal amplification techniques loop-mediated isothermal amplification (LAMP) and recombinase polymerase amplification (RPA) represent three promising candidates for integration into mobile pen-side tests. The aim of this study was to investigate the performance of these amplification strategies and to evaluate their suitability for field application. In order to enable a valid comparison, novel pathogen-specific assays have been developed for the detection of Schmallenberg virus and bovine viral diarrhea virus. The newly developed assays were evaluated in comparison with established standard RT-qPCR using samples from experimentally or field-infected animals. Even though all assays allowed detection of the target virus in less than 30 min, major differences were revealed concerning sensitivity, specificity, robustness, testing time, and complexity of assay design. These findings indicated that the success of an assay will depend on the integrated amplification technology. Therefore, the application-specific pros and cons of each method that were identified during this study provide very valuable insights for future development and optimization of pen-side tests.
Polymicrobial Ventriculitis Involving Pseudomonas fulva
Authors: Rebolledo Paulina A. , Vu Catphuong Cathy L. , Carlson Renee Donahue , Kraft Colleen S. , Anderson Evan J. , Burd Eileen M.
Published: March 2014

Infections due to
Pseudomonas fulva
remain a rare but emerging concern. A case of ventriculitis due to
Enterobacter cloacae
and
Pseudomonas fulva
following placement of an external ventricular drain is described. Similar to other reports, the organism was initially misidentified as
Pseudomonas putida
. The infection was successfully treated with levofloxacin.
Efficient Reovirus- and Measles Virus-Mediated Pore Expansion during Syncytium Formation Is Dependent on Annexin A1 and Intracellular Calcium
Authors: Ciechonska Marta , Key Tim , Duncan Roy
Published: March 2014

Orthoreovirus fusion-associated small transmembrane (FAST) proteins are dedicated cell-cell fusogens responsible for multinucleated syncytium formation and are virulence determinants of the fusogenic reoviruses. While numerous studies on the FAST proteins and enveloped-virus fusogens have delineated steps involved in membrane fusion and pore formation, little is known about the mechanics of pore expansion needed for syncytiogenesis. We now report that RNA interference (RNAi) knockdown of annexin A1 (AX1) expression dramatically reduced both reptilian reovirus p14 and measles virus F and H protein-mediated pore expansion during syncytiogenesis but had no effect on pore formation. A similar effect was obtained by chelating intracellular calcium, which dramatically decreased syncytiogenesis in the absence of detectable effects on p14-induced pore formation. Coimmunoprecipitation revealed calcium-dependent interaction between AX1 and p14 or measles virus F and H proteins, and fluorescence resonance energy transfer (FRET) demonstrated calcium-dependent p14-AX1 interactions
in cellulo
. Furthermore, antibody inhibition of extracellular AX1 had no effect on p14-induced syncytium formation but did impair cell-cell fusion mediated by the endogenous muscle cell fusion machinery in C2C12 mouse myoblasts. AX1 can therefore exert diverse, fusogen-specific effects on cell-cell fusion, functioning as an extracellular mediator of differentiation-dependent membrane fusion or as an intracellular promoter of postfusion pore expansion and syncytium formation following virus-mediated cell-cell fusion.

IMPORTANCE
Numerous enveloped viruses and nonenveloped fusogenic orthoreoviruses encode membrane fusion proteins that induce syncytium formation, which has been linked to viral pathogenicity. Considerable insights into the mechanisms of membrane fusion have been obtained, but processes that drive postfusion expansion of fusion pores to generate syncytia are poorly understood. This study identifies intracellular calcium and annexin A1 (AX1) as key factors required for efficient pore expansion during syncytium formation mediated by the reptilian reovirus p14 and measles virus F and H fusion protein complexes. Involvement of intracellular AX1 in syncytiogenesis directly correlates with a requirement for intracellular calcium in p14-AX1 interactions and pore expansion but not membrane fusion and pore formation. This is the first demonstration that intracellular AX1 is involved in pore expansion, which suggests that the AX1 pathway may be a common host cell response needed to resolve virus-induced cell-cell fusion pores.
Structural Analysis of Determinants of Histo-Blood Group Antigen Binding Specificity in Genogroup I Noroviruses
Authors: Shanker Sreejesh , Czako Rita , Sankaran Banumathi , Atmar Robert L. , Estes Mary K. , Prasad B. V. Venkataram
Published: March 2014

Human noroviruses (NoVs) cause acute epidemic gastroenteritis. Susceptibility to the majority of NoV infections is determined by genetically controlled secretor-dependent expression of histo-blood group antigens (HBGAs), which are also critical for NoV attachment to host cells. Human NoVs are classified into two major genogroups (genogroup I [GI] and GII), with each genogroup further divided into several genotypes. GII NoVs are more prevalent and exhibit periodic emergence of new variants, suggested to be driven by altered HBGA binding specificities and antigenic drift. Recent epidemiological studies show increased activity among GI NoVs, with some members showing the ability to bind nonsecretor HBGAs. NoVs bind HBGAs through the protruding (P) domain of the major capsid protein VP1. GI NoVs, similar to GII, exhibit significant sequence variations in the P domain; it is unclear how these variations affect HBGA binding specificities. To understand the determinants of possible strain-specific HBGA binding among GI NoVs, we determined the structure of the P domain of a GI.7 clinical isolate and compared it to the previously determined P domain structures of GI.1 and GI.2 strains. Our crystallographic studies revealed significant structural differences, particularly in the loop regions of the GI.7 P domain, altering its surface topography and electrostatic landscape and potentially indicating antigenic variation. The GI.7 strain bound to H- and A-type, Lewis secretor, and Lewis nonsecretor families of HBGAs, allowing us to further elucidate the structural determinants of nonsecretor HBGA binding among GI NoVs and to infer several contrasting and generalizable features of HBGA binding in the GI NoVs.

IMPORTANCE
Human noroviruses (NoVs) cause acute epidemic gastroenteritis. Recent epidemiological studies have shown increased prevalence of genogroup I (GI) NoVs. Although secretor-positive status is strongly correlated with NoV infection, cases of NoV infection associated with secretor-negative individuals are reported. Biochemical studies have shown that GI NoVs exhibit genotype-dependent binding to nonsecretor histo-blood group antigens (HBGAs). From our crystallographic studies of a GI.7 NoV, in comparison with previous studies on GI.1 and GI.2 NoVs, we show that genotypic differences translate to extensive structural changes in the loop regions that significantly alter the surface topography and electrostatic landscape of the P domain; these features may be indicative of antigenic variations contributing to serotypic differentiation in GI NoVs and also differential modulation of the HBGA binding characteristics. A significant finding is that the threshold length and the structure of one of the loops are critical determinants in the binding of GI NoVs to nonsecretor HBGAs.
Augmented Replicative Capacity of the Boosting Antigen Improves the Protective Efficacy of Heterologous Prime-Boost Vaccine Regimens
Authors: Penaloza-MacMaster Pablo , Teigler Jeffrey E. , Obeng Rebecca C. , Kang Zi H. , Provine Nicholas M. , Parenteau Lily , Blackmore Stephen , Ra Joshua , Borducchi Erica N. , Barouch Dan H.
Published: March 2014

Prime-boost immunization regimens have proven efficacious at generating robust immune responses. However, whether the level of replication of the boosting antigen impacts the magnitude and protective efficacy of vaccine-elicited immune responses remains unclear. To evaluate this, we primed mice with replication-defective adenovirus vectors expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP), followed by boosting with either LCMV Armstrong, which is rapidly controlled, or LCMV CL-13, which leads to a more prolonged exposure to the boosting antigen. Although priming of naive mice with LCMV CL-13 normally results in T cell exhaustion and establishment of chronic infection, boosting with CL-13 resulted in potent recall CD8 T cell responses that were greater than those following boosting with LCMV Armstrong. Furthermore, following the CL-13 boost, a greater number of anamnestic CD8 T cells localized to the lymph nodes, exhibited granzyme B expression, and conferred improved protection againstListeriaand vaccinia virus challenges compared with the Armstrong boost. Overall, our findings suggest that the replicative capacity of the boosting antigen influences the protective efficacy afforded by prime-boost vaccine regimens. These findings are relevant for optimizing vaccine candidates and suggest a benefit of robustly replicating vaccine vectors.

IMPORTANCEThe development of optimal prime-boost vaccine regimens is a high priority for the vaccine development field. In this study, we compared two boosting antigens with different replicative capacities. Boosting with a more highly replicative vector resulted in augmented immune responses and improved protective efficacy.
Identification of Conserved Amino Acids in pUL34 Which Are Critical for Function of the Pseudorabies Virus Nuclear Egress Complex
Authors: Paßvogel Lars , Janke Una , Klupp Barbara G. , Granzow Harald , Mettenleiter Thomas C.
Published: March 2014

Nuclear egress of herpesvirus capsids is mediated by a conserved heterodimeric complex of two viral proteins, designated pUL34 and pUL31 in herpes simplex virus and pseudorabies virus (PrV). pUL34, a tail-anchored membrane protein, is targeted to the nuclear envelope and recruits pUL31 to the inner nuclear membrane (INM) to provide the docking and envelopment machinery for the nascent capsid. While the less conserved C-terminal part of pUL34 is required for correct positioning of the nuclear egress complex (NEC) at the INM, the conserved N-terminal part functions as a docking site for pUL31. Since no crystal structure of NEC is available yet, structure-function studies depend on mutational analyses, with several approaches already being performed for different herpesvirus NECs. Here, we extended our studies on PrV pUL34 and identified two asparagine residues (N75, N103) and a dileucine motif (LL166/167), adjacent to an endoplasmic reticulum retention signal, which are absolutely required for NEC function. While the pUL34–N75A substitution mutant is unable to interact with pUL31, the pUL34–N103A mutant is nonfunctional, despite continuing complex formation. Surprisingly, mutant pUL34–G77A, which does not efficiently recruit pUL31 to the nuclear rim after cotransfection, nonetheless complements a UL34 deletion mutant, indicating that the NEC may be stabilized by additional viral factors during infection.

IMPORTANCE
In the absence of a crystal structure of the nuclear egress complex (NEC) required for herpesvirus maturation, site-directed mutagenesis studies provide important information on critical amino acid residues. Here, we identify conserved amino acid residues in the membrane-bound component of the NEC which are relevant for its function.
Limits of Structural Plasticity in a Picornavirus Capsid Revealed by a Massively Expanded Equine Rhinitis A Virus Particle
Authors: Bakker Saskia E. , Groppelli Elisabetta , Pearson Arwen R. , Stockley Peter G. , Rowlands David J. , Ranson Neil A.
Published: March 2014

The
Picornaviridae
family of small, nonenveloped viruses includes major pathogens of humans and animals. They have positive-sense, single-stranded RNA genomes, and the mechanism(s) by which these genomes are introduced into cells to initiate infection remains poorly understood. The structures of presumed uncoating intermediate particles of several picornaviruses show limited expansion and some increased porosity compared to the mature virions. Here, we present the cryo-electron microscopy structure of native equine rhinitis A virus (ERAV), together with the structure of a massively expanded ERAV particle, each at ∼17–Å resolution. The expanded structure has large pores on the particle 3-fold axes and has lost the RNA genome and the capsid protein VP4. The expanded structure thus illustrates both the limits of structural plasticity in such capsids and a plausible route by which genomic RNA might exit.

IMPORTANCE
Picornaviruses are important animal and human pathogens that protect their genomic RNAs within a protective protein capsid. Upon infection, this genomic RNA must be able to leave the capsid to initiate a new round of infection. We describe here the structure of a unique, massively expanded state of equine rhinitis A virus that provides insight into how this exit might occur.
Single-Cell Analysis Uncovers Extensive Biological Noise in Poliovirus Replication
Authors: Schulte Michael B. , Andino Raul
Published: March 2014

Viral infections often begin with a very small number of initiating particles. Accordingly, the outcome of an infection is likely to be affected by variability in the initial molecular interactions between virus and host. In this study, we investigated the range of outcomes upon infection of single cells. We isolated individual cells infected with poliovirus at low or high multiplicities of infection (MOI) and measured viral genomic replication and infectious viral progeny in each cell. We first determined that at 7 h postinfection, the ratio of positive to negative strands in individual cells varies from 5:1 to more than 190:1, with and average of 20:1, suggesting a significant variability in RNA synthesis. We further found that while virus genome production is higher in cells infected at a high multiplicity, the production of infectious particles is largely independent of the number of viruses infecting each cell. Strikingly, by correlating RNA and particle production within individual infections, we uncovered a significant contribution of stochastic noise to the outcome of infection. At low MOI, stochastic influences appear as kinetic effects which are most critical at the initial steps in infection. At high MOI, stochastic influences appear to dictate the virus's ability to harness cellular resources. We conclude that biological noise is a critical determinant of the overall productivity of viral infections. The distinct nature of stochasticity in the outcome of infection by low and high numbers of viral particles may have important implications for our understanding of the determinants of successful viral infections.

IMPORTANCE
By correlating genome and particle production in single-cell infections, we elucidated sources of noise in viral infections. When a cell was infected by only a single infectious particle, variation in the kinetics of the initial steps of replication contributed significantly to the overall productivity of the infection. Additionally, variation in the distribution of subcellular resources impacted infections initiated by one or many infectious particles. We also observed that when a cell was infected with multiple particles, more genomes were produced, while particle production was hindered by an apparent cellular resource limit. Understanding variations in viral infections may illuminate the dynamics of infection and pathogenesis and has implications for virus adaptation and evolution.
Beta Human Papillomavirus E6 Expression Inhibits Stabilization of p53 and Increases Tolerance of Genomic Instability
Authors: Wallace Nicholas A. , Robinson Kristin , Galloway Denise A.
Published: March 2014

Infections with the beta genus of human papillomaviruses (β-HPVs) may contribute to the development of nonmelanoma skin cancers. However, β-HPV genomes are found at too low a copy number in tumors for the virus to be necessary for tumor maintenance. Instead, they are hypothesized to destabilize the host genome by allowing the persistence of mutations that can drive tumorigenesis independently of the viral genome. Supporting this premise is our previous finding that the expression of some β-HPV E6 proteins can attenuate p53 signaling in response to DNA damage. We show that β-HPV E6 proteins can prevent the stabilization of p53 in response to two types of genome-destabilizing events, aberrant mitosis and dysregulated centrosome duplication. The inability to stabilize p53 in response to these stimuli allows cells expressing HPV5, HPV8, or HPV38 E6 to remain proliferatively active, leading to further genome deterioration in a proportion of these cells. These phenotypes are lost by the introduction of a mutation into the p300 binding domain of HPV8 E6 or by the transfection of mutated p300 that is resistant to the degradation mediated by HPV5 or HPV8 E6. These findings expand the understanding of the role played by p300 in promoting the faithful resolution of mitotic figures as well as proper centrosome duplication. Finally, we describe a phenomenon by which binucleated cells are resolved via cytokinesis into two cells, each with one nucleus. These data support the hypothesis that β-HPV infections may promote tumorigenesis via genome destabilization.

IMPORTANCE
The work described in this report provides support for the hypothesis that β-HPV infections may contribute to nonmelanoma skin cancer by increasing the likelihood that tumorigenic mutations are introduced into the host cell's genome. We demonstrate that expression of the E6 proteins from some of these viruses increases the tolerance of two genome-destabilizing events, aberrant cell division and dysregulated centrosome duplication. Typically, these mutagenic occurrences elicit the stabilization of the tumor suppressor p53, which prevents further propagation of cells containing these errors. We show that the expression of β-HPV E6 restricts this stabilization of p53, leading not only to continued cellular proliferation but also to further accumulation of similar mutagenic events. Finally, in addition to supporting a role for β-HPV infections in certain skin cancers, we present studies with a mutated β-HPV E6 protein suggesting that the histone acetyltransferase p300 plays a role in promoting genome stability during replication.
Characterizing the Molecular Basis of Attenuation of Marek's Disease Virus via
In Vitro
Serial Passage Identifies
De Novo
Mutations in the Helicase-Primase Subunit Gene UL5 and Other Candidates Associated with Reduced Virulence
Authors: Hildebrandt Evin , Dunn John R. , Perumbakkam Sudeep , Niikura Masahiro , Cheng Hans H.
Published: March 2014

Marek's disease (MD) is a lymphoproliferative disease of chickens caused by the oncogenic Gallid herpesvirus 2, commonly known as Marek's disease virus (MDV). MD vaccines, the primary control method, are often generated by repeated
in vitro
serial passage of this highly cell-associated virus to attenuate virulent MDV strains. To understand the genetic basis of attenuation, we used experimental evolution by serially passing three virulent MDV replicates generated from an infectious bacterial artificial chromosome (BAC) clone. All replicates became completely or highly attenuated, indicating that
de novo
mutation, and not selection among quasispecies existing in a strain, is the primary driving force for the reduction in virulence. Sequence analysis of the attenuated replicates revealed 41 to 95 single-nucleotide variants (SNVs) at 2% or higher frequency in each population and several candidate genes containing high-frequency, nonsynonymous mutations. Five candidate mutations were incorporated into recombinant viruses to determine their
in vivo
effect. SNVs within UL42 (DNA polymerase auxiliary subunit) and UL46 (tegument) had no measurable influence, while two independent mutations in LORF2 (a gene of unknown function) improved survival time of birds but did not alter disease incidence. A fifth SNV located within UL5 (helicase-primase subunit) greatly reduced
in vivo
viral replication, increased survival time of birds, and resulted in only 0 to 11% disease incidence. This study shows that multiple genes, often within pathways involving DNA replication and transcriptional regulation, are involved in
de novo
attenuation of MDV and provides targets for the rational design of future MD vaccines.

IMPORTANCE
Marek's disease virus (MDV) is a very important pathogen in chickens that costs the worldwide poultry industry $1 billion to $2 billion annually. Marek's disease (MD) vaccines, the primary control method, are often produced by passing virulent strains in cell culture until attenuated. To understand this process, we identified all the changes in the viral genome that occurred during repeated cell passage. We find that a single mutation in the UL5 gene, which encodes a viral protein necessary for DNA replication, reduces disease incidence by 90% or more. In addition, other candidate genes were identified. This information should lead to the development of more effective and rationally designed MD vaccines leading to improved animal health and welfare and lower costs to consumers.
Miliary tuberculosis with atypical presentation in an immunocompetent young African man
Authors: Albrecht Nicole , Cottagnoud Philippe , Chatterjee Bidisha
Published: March 2014

We present an atypical case of tuberculosis in an immunocompetent man from west Africa living in Europe. The patient entered the hospital with a painful lump of 3 cm on his right clavicule which he noticed 2 weeks before and back pain. During the examinations for further evaluation his condition deteriorated within short time. Tuberculosis was diagnosed, treatment started but he needed mechanical ventilation at the intensive care unit and had kidney failure. The further evolvement was favourable in the end but needed intensive treatment for over 4 weeks. Tuberculosis cases with such severe evolution are rather known with immunodeficient patients. Extrapulmonary tuberculosis, especially skeletal tuberculosis is seen more frequent in young immunocompetent migrants. The migrating persons seem to be more at risk to get sick than the ones staying in their origin country. We suppose the course of our patient's disease is miliary or septic, of which both are rather rare entities.
Successful flexible bronchoscopic management of a large-sized aspirated partial denture
Authors: Jamshed Nayer , Madan Karan , Ekka Meera , Guleria Randeep
Published: March 2014

A 48-year-old male patient presented to the emergency room with a history of chest pain and breathlessness. Chest X-ray demonstrated a large radio-opaque foreign body in relation to the proximal right bronchial tree. The patient subsequently revealed a history of a misplaced denture 4 months previously. Urgent flexible bronchoscopy (FB) examination demonstrated a large partial denture impacted in the right intermediate bronchus, which was removed successfully using a flexible bronchoscope. Although rigid bronchoscopy (RB) is the procedure of choice for large-sized and impacted airway foreign bodies, the present case highlights the utility of FB in airway foreign body removal. In clinically stable patients with foreign body inhalation, FB can be employed initially as it is an outpatient and cost-effective procedure which can obviate the need for administration of general anaesthesia.
Dilated cardiomyopathy and progressive familial intrahepatic cholestasis
Authors: James Stephanie , Waterhouse Deirdre , McDonald Kenneth , O'Hanlon Rory
Published: March 2014

This case is of a 29-year-old man with progressive familial intrahepatic cholestasis type 1 also known as Byler's disease. At the age of 21, our patient developed non-ischaemic dilated cardiomyopathy. Cardiac MRI demonstrated global wall thinning, with significant areas of myocardial fibrosis in the mid and epicardial walls from base to apex on postgadolinium late contrast enhanced images. No shared genetic loci between dilated cardiomyopathy and Byler's or cholestatic liver disease have yet been found. This presents the first documented case of non-ischaemic dilated cardiomyopathy, with evidence of mid wall fibrosis, in association with an established diagnosis of progressive familial intrahepatic cholestasis type 1 since childhood.
Life-threatening angioedema of the tongue: the detection of the RNA ofB henselaein the saliva of a male patient and his dog as well as of the DNA of threeBartonellaspecies in the blood of the patient
Authors: Lösch Barbara , Wank Rudolf
Published: March 2014

Non-hereditary angioedema is a common disease with a prevalence between 5% and 19% and approximately half of the patients experience a swelling of the tongue. We report a case of a 49-year-old Caucasian man with a gross life-threatening angioedema of the tongue, whose attacks occurred every 4 weeks. The most frequent causes of angioedema were excluded. We detected DNA and RNA fromBartonella henselaein the blood and saliva of the patient and in the saliva of the patient’s hunting dog. Treatment with azithromycin plus minocycline cleared the blood and saliva of RNA and DNA ofBartonellaspecies, and the patient has been free from angioedema for 1 year. None of the therapy modalities used to treat the hereditary form or ACE or allergy-induced angioedema affect the detrimental course caused byBartonellaspecies. We therefore suggest that a molecularBartonellatest be included in the analysis of angioedema.
Eating disorders should be considered in the differential diagnosis of patients presenting with acute kidney injury and electrolyte derangement
Authors: Talbot Ben Edward Michael , Lawman Sarah H A
Published: March 2014

We present a case of a 40-year-old woman with a history of ongoing anorexia nervosa and bulimia nervosa who has required multiple admissions to hospital for management of acute kidney injury (AKI) and electrolyte derangement. This case is of interest as recent studies have highlighted the significant prevalence of disordered eating and the major public health implications this may have. We discuss the unusual finding of hypercalcaemia in this case and address the investigation and management of AKI and electrolyte disturbance in a patient with anorexia and bulimia.
The return of a disappearing entity: Dressler's syndrome after transvenous pacemaker implantation
Authors: Tralhão António , Cavaco Diogo , Trabulo Marisa , Ferreira António M
Published: March 2014

A 76-year-old woman with idiopathic dilated cardiomyopathy and left bundle branch block was admitted for biventricular pacemaker implantation. The procedure was complicated by perforation of a coronary sinus tributary vein and ensuing pericardial effusion without tamponade. Three months later, she presented with fever, pleuritic chest pain and functional class worsening. Pericardial and pleural effusions were noted. Sterile blood and pleural fluid cultures and failure to respond to antibiotic therapy led to the hypothesis of a Dressler-like syndrome. The patient improved clinically with a short course of steroid therapy and was discharged on colchicine. A chest X-ray performed after 2 months showed a complete remission of pleural effusion.
Quadrigeminal cistern lipoma mimicking intracranial air
Authors: Mashiko Ryota , Shibata Yasushi
Published: March 2014

Intracranial lipoma concomitant with traumatic pneumocephalus is very rare and, to the best of our knowledge, there has been no report describing this condition. It may be difficult to distinguish lipoma from intracranial air only with CT, but it is necessary to avoid overtreatment. We report a case of quadrigeminal cistern lipoma mimicking intracranial air in a patient with traumatic pneumocephalus.
Is interpregnancy interval associated with cardiovascular risk factors in later life? A cohort study
Authors: Knipe Duleeka W , Fraser Abigail , Lawlor Debbie A , Howe Laura D
Published: March 2014

Objectives

Pregnancy represents a metabolic challenge to women; in a normal pregnancy, transient metabolic changes occur that support the needs of the growing fetus. It is possible that repeating this challenge within a relatively short amount of time may result in lasting damage to the woman's cardiovascular health. Conversely, it is also possible that a long interpregnancy interval (IPI) may reflect subfertility, which has been found to be associated with cardiovascular disease (CVD). We examine the associations of short and long IPI with measures of cardiovascular health.

Design

Prospective cohort.

Setting

Mothers of the Avon Longitudinal Study of Parents and Children (ALSPAC).

Participants

Women with two live births in order to control for confounding by parity.

Outcome measures

Arterial distensibility, common carotid intima, adiposity, blood pressure, lipids, glucose, insulin, proinsulin, triglycerides, C reactive protein.

Results

25% (n=3451) of ALSPAC mothers had provided sufficient data to determine full reproductive history—of these, 1477 had two live births, with 54% mothers having non-missing data on all variables required for our analyses. A total of 1268 mothers with IPI (interbirth interval minus 9 months’ gestation) had CVD risk factors measured/imputed at mean age 48 years. After adjusting for confounding, we found no association of either short (≤15 months) or long (>27 months) IPI and increased levels of cardiovascular risk factors. There was some suggestion that women with long and short IPIs had a more favourable lipid profile compared with women whose IPI was 16–27 months; however, the differences were small in magnitude and imprecisely estimated.

Conclusions

This study does not support the hypothesis that either long or short IPI is a risk factor for later cardiovascular health.
Integrated disease prevention campaigns: assessing country opportunity for implementation via an index approach
Authors: Jiwani Aliya , Matheson Alastair , Kahn James G , Raut Abhishek , Verguet Stéphane , Marseille Elliot , Walson Judd
Published: March 2014

Objectives

To help stakeholders identify and prioritise countries with the best opportunities for implementation of an integrated prevention campaign (IPC) focused on diarrhoea, malaria and HIV prevention.

Design

Cross-sectional analysis of country-specific epidemiological data using an index tool developed for this purpose.

Setting

We calculated the total disability-adjusted life years (DALYs) attributed to diarrhoea, malaria and HIV for 214 World Bank economies. Criteria for inclusion were: low-income and middle-income countries, and total annual DALY burden in the top tertile (≥87 000 DALYs). 70 countries met inclusion criteria and were included in our opportunity analysis.

Outcome measures

We synthesised data on 10 indicators related to the potential reduction in burden and new coverage achievable by an IPC. We scored and ranked countries based on three summary opportunity metrics: DALYs per capita across the diseases, a composite score of tertile rankings of burden for each disease, and a score combining burden and intervention opportunity.

Results

We estimated the total annual global burden attributable to diarrhoea, malaria and HIV at 135 million DALYs. All of the countries with the highest opportunity for implementation of a diarrhoea, malaria and HIV IPC are in sub-Saharan Africa, regardless of opportunity metric used. Although the overall rank order changes, 16 countries rank among the top 23 highest opportunity countries for all three metrics.

Conclusions

Stakeholders can use this objective metric-based approach to prioritise countries for IPC scale-up. Priority countries are largely robust to the opportunity metric chosen.
Stenting of symptomatic intracranial stenosis using balloon mounted coronary stents: a single center experience
Authors: Durst Christopher R , Geraghty Scott R , Southerland Andrew M , Starke Robert M , Rembold Karen , Malik Shaneela , Wintermark Max , Liu Kenneth C , Crowley R Webster , Gaughen John , Jensen Mary E , Evans Avery J
Published: March 2014

Objective

Intracranial atherosclerotic disease is the cause of up to 10% of ischemic strokes and transient ischemic attacks. Intracranial stenting with off-label balloon mounted coronary stents (BMCS) may be a viable alternative for patients with symptomatic intracranial stenosis who fail best medical therapy.

Design

Between December 2005 and June 2012, 42 symptomatic intracranial stenoses were treated with a BMCS after failing medical management. Procedural records, clinical outcomes, and imaging follow-up were reviewed. Outcome measurements included technical success rate, morbidity and mortality, long term stent patency, and clinical outcomes, as measured by the modified Rankin Scale.

Results

The technical success rate was 98% (41 of 42 lesions). Morbidity within the first 30 days was 7.1% (three of 42 lesions). Overall morbidity, including both periprocedural and long term evaluation, was 9.5% (four of 42 lesions). There were no deaths. Follow-up imaging was available for 30 stents (71%) with an average follow-up time of 35.1 months. Restenosis (>50%) and retreatment were observed in 20% and 10% of cases, respectively. Clinical evaluation by a neurologist ≥30 days postprocedure was available in 40 of 42 cases (95%) with an average of 32.1 months. At presentation, 55% of patients had a modified Rankin Scale (mRS) score of ≤2. At follow-up, 74% of patients were found to have an mRS score of ≤2.

Conclusions

This study suggests that BMCS may benefit patients with symptomatic intracranial stenosis who experience stroke or transient ischemic attack in spite of best medical therapy.