bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative Proteomics Identifies Host Factors Modulated during Acute Hepatitis E Virus Infection in the Swine Model
Authors: Rogée Sophie , Le Gall Morgane , Chafey Philippe , Bouquet Jérôme , Cordonnier Nathalie , Frederici Christian , Pavio Nicole
Published: October 2014

Hepatitis E virus (HEV) causes acute enterically transmitted hepatitis. In industrialized
c
ountries, it is a zoonotic disease, with swine being the major reservoir of human HEV contamination. The occurrence and severity of the disease are variable, with clinical symptoms ranging from asymptomatic to self-limiting acute hepatitis, chronic infection, or fulminant hepatitis. In the absence of a robust cell culture system or small-animal models, the HEV life cycle and pathological process remain unclear. To characterize HEV pathogenesis and virulence mechanisms, a quantitative proteomic analysis was carried out to identify cellular factors and pathways modulated during acute infection of swine. Three groups of pigs were inoculated with three different strains of swine HEV to evaluate the possible role of viral determinants in pathogenesis. Liver samples were analyzed by a differential proteomic approach, two-dimensional difference in gel electrophoresis, and 61 modulated proteins were identified by mass spectroscopy. The results obtained show that the three HEV strains replicate similarly in swine and that they modulate several cellular pathways, suggesting that HEV impairs several cellular processes, which can account for the various types of disease expression. Several proteins, such as heterogeneous nuclear ribonucleoprotein K, apolipoprotein E, and prohibitin, known to be involved in other viral life cycles, were upregulated in HEV-infected livers. Some differences were observed between the three strains, suggesting that HEV's genetic variability may induce variations in pathogenesis. This comparative analysis of the liver proteome modulated during infection with three different strains of HEV genotype 3 provides an important basis for further investigations on the factors involved in HEV replication and the mechanism of HEV pathogenesis.

IMPORTANCE
Hepatitis E virus (HEV) is responsible for acute hepatitis, with clinical symptoms ranging from asymptomatic to self-limiting acute hepatitis, chronic infection, or fulminant hepatitis. In industrialized countries, HEV is considered an emerging zoonotic disease, with swine being the principal reservoir for human contamination. The viral and cellular factors involved in the replication and/or pathogenesis of HEV are still not fully known. Here we report that several cellular pathways involved in cholesterol and lipid metabolism or cell survival were modulated during HEV infection in the swine model. Moreover, we observed a difference between the different swine strains, suggesting that HEV's genetic variability could play a role in pathogenesis. We also identified some proteins known to be involved in other viral cycles. Our study provides insight into the mechanisms modulated during HEV infection and constitutes a useful reference for future work on HEV pathogenesis and virulence.
Rhabdovirus-Based Vaccine Platforms against Henipaviruses
Authors: Kurup Drishya , Wirblich Christoph , Feldmann Heinz , Marzi Andrea , Schnell Matthias J.
Published: October 2014

The emerging zoonotic pathogens Hendra virus (HeV) and Nipah virus (NiV) are in the genus
Henipavirus
in the family
Paramyxoviridae
. HeV and NiV infections can be highly fatal to humans and livestock. The goal of this study was to develop candidate vaccines against henipaviruses utilizing two well-established rhabdoviral vaccine vector platforms, recombinant rabies virus (RABV) and recombinant vesicular stomatitis virus (VSV), expressing either the codon-optimized or the wild-type (wt) HeV glycoprotein (G) gene. The RABV vector expressing the codon-optimized HeV G showed a 2- to 3-fold increase in incorporation compared to the RABV vector expressing wt HeV G. There was no significant difference in HeV G incorporation in the VSV vectors expressing either wt or codon-optimized HeV G. Mice inoculated intranasally with any of these live recombinant viruses showed no signs of disease, including weight loss, indicating that HeV G expression and incorporation did not increase the neurotropism of the vaccine vectors. To test the immunogenicity of the vaccine candidates, we immunized mice intramuscularly with either one dose of the live vaccines or 3 doses of 10 μg chemically inactivated viral particles. Increased codon-optimized HeV G incorporation into RABV virions resulted in higher antibody titers against HeV G compared to inactivated RABV virions expressing wt HeV G. The live VSV vectors induced more HeV G-specific antibodies as well as higher levels of HeV neutralizing antibodies than the RABV vectors. In the case of killed particles, HeV neutralizing serum titers were very similar between the two platforms. These results indicated that killed RABV with codon-optimized HeV G should be the vector of choice as a dual vaccine in areas where rabies is endemic.

IMPORTANCE
Scientists have been tracking two new viruses carried by the Pteropid fruit bats: Hendra virus (HeV) and Nipah virus (NiV). Both viruses can be fatal to humans and also pose a serious risk to domestic animals. A recent escalation in the frequency of outbreaks has increased the need for a vaccine that prevents HeV and NiV infections. In this study, we performed an extensive comparison of live and killed particles of two recombinant rhabdoviral vectors, rabies virus and vesicular stomatitis virus (VSV), expressing wild-type or codon-optimized HeV glycoprotein, with the goal of developing a candidate vaccine against HeV. Based on our data from the presented mouse immunogenicity studies, we conclude that a killed RABV vaccine would be highly effective against HeV infections and would make an excellent vaccine candidate in areas where both RABV and henipaviruses pose a threat to human health.
Merkel Cell Polyomavirus Small T Antigen Mediates Microtubule Destabilization To Promote Cell Motility and Migration
Authors: Knight Laura M. , Stakaityte Gabriele , Wood Jennifer, J. , Abdul-Sada Hussein , Griffiths David A. , Howell Gareth J. , Wheat Rachel , Blair G. Eric , Steven Neil M. , Macdonald Andrew , Blackbourn David J. , Whitehouse Adrian
Published: October 2014

Merkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) causes the majority of MCC cases due to the expression of the MCPyV small and large tumor antigens (ST and LT, respectively). Although a number of molecular mechanisms have been attributed to MCPyV tumor antigen-mediated cellular transformation or replication, to date, no studies have investigated any potential link between MCPyV T antigen expression and the highly metastatic nature of MCC. Here we use a quantitative proteomic approach to show that MCPyV ST promotes differential expression of cellular proteins implicated in microtubule-associated cytoskeletal organization and dynamics. Intriguingly, we demonstrate that MCPyV ST expression promotes microtubule destabilization, leading to a motile and migratory phenotype. We further highlight the essential role of the microtubule-associated protein stathmin in MCPyV ST-mediated microtubule destabilization and cell motility and implicate the cellular phosphatase catalytic subunit protein phosphatase 4C (PP4C) in the regulation of this process. These findings suggest a possible molecular mechanism for the highly metastatic phenotype associated with MCC.

IMPORTANCE
Merkel cell polyomavirus (MCPyV) causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer with a high metastatic potential. However, the molecular mechanisms leading to virally induced cancer development have yet to be fully elucidated. In particular, no studies have investigated any potential link between the virus and the highly metastatic nature of MCC. We demonstrate that the MCPyV small tumor antigen (ST) promotes the destabilization of the host cell microtubule network, which leads to a more motile and migratory cell phenotype. We further show that MCPyV ST induces this process by regulating the phosphorylation status of the cellular microtubule-associated protein stathmin by its known association with the cellular phosphatase catalytic subunit PP4C. These findings highlight stathmin as a possible biomarker of MCC and as a target for novel antitumoral therapies.
Topical Herpes Simplex Virus 2 (HSV-2) Vaccination with Human Papillomavirus Vectors Expressing gB/gD Ectodomains Induces Genital-Tissue-Resident Memory CD8+T Cells and Reduces Genital Disease and Viral Shedding after HSV-2 Challenge
Authors: Çuburu Nicolas , Wang Kening , Goodman Kyle N. , Pang Yuk Ying , Thompson Cynthia D. , Lowy Douglas R. , Cohen Jeffrey I. , Schiller John T.
Published: October 2014

No herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8+T cells that were able to secrete gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8+T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection.

IMPORTANCEGenital herpes is a highly prevalent chronic disease caused by HSV infection. To date, there is no licensed vaccine against HSV infection. This study describes intravaginal vaccination with a nonreplicating HPV-based vector expressing HSV glycoprotein antigens. The data presented in this study underscore the potential of HPV-based vectors as a platform for the induction of genital-tissue-resident memory T cell responses and the control of local manifestations of primary HSV infection.
Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7
Authors: Schultz Kimberly L. W. , Vernon Patty S. , Griffin Diane E.
Published: October 2014

Susceptibility to alphavirus infection is age dependent, and host maturation is associated with decreased virus replication and less severe encephalitis. To identify factors associated with maturation-dependent restriction of virus replication, we studied AP-7 rat olfactory bulb neuronal cells, which can differentiatein vitro. Differentiation was associated with a 150- to 1,000-fold decrease in replication of the alphaviruses Sindbis virus and Venezuelan equine encephalitis virus, as well as La Crosse bunyavirus. Differentiation delayed synthesis of SINV RNA and protein but did not alter the susceptibility of neurons to infection or virion maturation. Additionally, differentiation slowed virus-induced translation arrest and death of infected cells. Differentiation of uninfected AP-7 neurons was associated with changes in expression of antiviral genes. Expression of key transcription factors was increased, including interferon regulatory factor 3 and 7 (IRF-3 and IRF-7) and STAT-1, suggesting that neuronal maturation may enhance the capacity for antiviral signaling upon infection. IRF-7 produced by undifferentiated AP-7 neurons was exclusively the short dominant negative γ-isoform, while that produced by differentiated neurons was the full-length α-isoform. A similar switch in IRF-7 isoforms also occurred in the brains of maturing C57BL/6J mice. Silencing of IRF expression did not improve virus multiplication in differentiated neurons. Therefore, neuronal differentiation is associated with upregulation of transcription factors that activate antiviral signaling, but this alone does not account for maturation-dependent restriction of virus replication.

IMPORTANCEViral encephalomyelitis is an important cause of age-dependent morbidity and mortality. Because mature neurons are not readily regenerated, recovery from encephalitis suggests that mature neurons utilize unique antiviral mechanisms to block infection and/or clear virus. To identify maturational changes in neurons that may improve outcome, we compared immature and mature cultured neurons for susceptibility to three encephalitic arboviruses and found that replication of Old World and New World alphaviruses and a bunyavirus was reduced in mature compared to immature neurons. Neuronal maturation was associated with increased baseline expression of interferon regulatory factor 3 and 7 mRNAs and production of distinct isoforms of interferon regulatory factor 7 protein. Overall, our studies identified maturational changes in neurons that likely contribute to assembly of immunoregulatory factors prior to infection, a more rapid antiviral response, increased resistance to virus infection, and improved survival.
Profiling and Characterization of Influenza Virus N1 Strains Potentially Resistant to Multiple Neuraminidase Inhibitors
Authors: Baek Yun Hee , Song Min-Suk , Lee Eun-Young , Kim Young-il , Kim Eun-Ha , Park Su-Jin , Park Kuk Jin , Kwon Hyeok-il , Pascua Philippe Noriel Q. , Lim Gyo-Jin , Kim Semi , Yoon Sun-Woo , Kim Myung Hee , Webby Richard J. , Choi Young-Ki
Published: October 2014

Neuraminidase inhibitors (NAIs) have been widely used to control influenza virus infection, but their increased use could promote the global emergence of resistant variants. Although various mutations associated with NAI resistance have been identified, the amino acid substitutions that confer multidrug resistance with undiminished viral fitness remain poorly understood. We therefore screened a known mutation(s) that could confer multidrug resistance to the currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA-encoding genes (catalytic residues R152K and R292K, framework residues E119A/D/G, D198N, H274Y, and N294S) in the backbones of the 2009 pandemic H1N1 (pH1N1) and highly pathogenic avian influenza (HPAI) H5N1 viruses. Of the 14 single and double mutant viruses recovered in the backbone of pH1N1, four variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition by all of the NAIs and two variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibility
in vitro
and
in vivo
. Of the nine recombinant H5N1 viruses, four variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition by all of the NAIs, though their overall viral fitness was impaired
in vitro
and/or
in vivo
. Thus, single mutations or certain combination of the established mutations could confer potential multidrug resistance on pH1N1 or HPAI H5N1 viruses. Our findings emphasize the urgency of developing alternative drugs against influenza virus infection.

IMPORTANCE
There has been a widespread emergence of influenza virus strains with reduced susceptibility to neuraminidase inhibitors (NAIs). We screened multidrug-resistant viruses by studying the viral fitness of neuraminidase mutants
in vitro
and
in vivo
. We found that recombinant E119D and E119A/D/G/-H274Y mutant viruses demonstrated reduced inhibition by all of the NAIs tested in both the backbone of the 2009 H1N1 pandemic (pH1N1) and highly pathogenic avian influenza H5N1 viruses. Furthermore, E119D and E119D-H274Y mutants in the pH1N1 background maintained overall fitness properties
in vitro
and
in vivo
. Our study highlights the importance of vigilance and continued surveillance of potential NAI multidrug-resistant influenza virus variants, as well as the development of alternative therapeutics.
Phosphorylation of Herpes Simplex Virus 1 dUTPase Regulates Viral Virulence and Genome Integrity by Compensating for Low Cellular dUTPase Activity in the Central Nervous System
Authors: Kato Akihisa , Arii Jun , Koyanagi Yoshio , Kawaguchi Yasushi
Published: October 2014

A mutation in herpes simplex virus 1 dUTPase (vdUTPase), which precluded its phosphorylation at Ser-187, decreased viral neurovirulence and increased mutation frequency in progeny virus genomes in the brains of mice where endogenous cellular dUTPase activity was relatively low, and overexpression of cellular dUTPase restored viral neurovirulence and mutation frequency altered by the mutation. Thus, phosphorylation of vdUTPase appeared to regulate viral virulence and genome integrity by compensating for low cellular dUTPase activity
in vivo
.

IMPORTANCE
Many DNA viruses encode a homolog of host cell dUTPases, which are known to function in accurate replication of cellular DNA genomes. The viral dUTPase activity has long been assumed to play a role in viral replication by preventing mutations in progeny virus genomes if cellular dUTPase activity was not sufficient. Here, we showed that a mutation in herpes simplex virus 1 dUTPase, which precluded its phosphorylation at Ser-187 and reduced its activity, decreased viral neurovirulence and increased mutation frequency in progeny virus genomes in the brains of mice where endogenous cellular dUTPase activity was relatively low. In contrast, overexpression of cellular dUTPase restored viral neurovirulence and mutation frequency altered by the mutation in the brains of mice. This is the first report, to our knowledge, directly showing that viral dUTPase activity regulates viral genome integrity and pathogenicity by compensating for insufficient cellular dUTPase activity
in vivo
.
GHSC70 Is Involved in the Cellular Entry of Nervous Necrosis Virus
Authors: Chang Jui-Shin , Chi Shau-Chi
Published: October 2014

Nervous necrosis virus (NNV) is a devastating pathogen of cultured marine fish and has affected more than 40 fish species. NNV belongs to the betanodaviruses of
Nodaviridae
and is a nonenveloped icosahedral particle with 2 single-stranded positive-sense RNAs. To date, knowledge regarding NNV entry into the host cell remains limited, and no NNV-specific receptor protein has been published. Using grouper fin cell line GF-1 and purified NNV capsid protein in a virus overlay protein binding assay (VOPBA), grouper heat shock cognate protein 70 (GHSC70) and grouper voltage-dependent anion selective channel protein 2 (GVDAC2) were investigated as NNV receptor protein candidates. We cloned and sequenced the genes for GHSC70 and GVDAC2 and expressed them in
Escherichia coli
for antiserum preparation. Knockdown of the expression of GHSC70 and GVDAC2 genes with specific short interfering RNAs (siRNAs) significantly downregulated viral RNA expression in NNV-infected GF-1 cells. By performing an immunoprecipitation assay, we confirmed that GHSC70 interacted with NNV capsid protein, while VDAC2 did not. Immunofluorescence staining and flow cytometry analysis revealed the presence of the GHSC70 protein on the cell surface. After a blocking assay, we detected the NNV RNA2 levels after 1 h of adsorption to GF-1 cells; the level was significantly lower in the cells pretreated with the GHSC70 antiserum than in nontreated cells. Therefore, we suggest that GHSC70 participates in the NNV entry of GF-1 cells, likely functioning as an NNV receptor or coreceptor protein.

IMPORTANCE
Fish nodavirus has caused mass mortality of more than 40 fish species worldwide and resulted in huge economic losses in the past 20 years. Among the four genotypes of fish nodaviruses, the red-spotted grouper nervous necrosis virus (RGNNV) genotype exhibits the widest host range. In our previous study, we developed monoclonal antibodies with high neutralizing efficiency against grouper NNV in GF-1 cells, indicating that NNV-specific receptor(s) may exist on the GF-1 cell membrane. However, no NNV receptor protein has been published. In this study, we found GHSC70 to be an NNV receptor (or coreceptor) candidate through VOBPA and provided several lines of evidence demonstrating that GHSC70 protein has a role in the NNV entry step of GF-1 cells. To the best of our knowledge, this is the first report identifying grouper HSC70 and its role in NNV entry into GF-1 cells.
Nucleocapsid Protein from Fig Mosaic Virus Forms Cytoplasmic Agglomerates That Are Hauled by Endoplasmic Reticulum Streaming
Authors: Ishikawa Kazuya , Miura Chihiro , Maejima Kensaku , Komatsu Ken , Hashimoto Masayoshi , Tomomitsu Tatsuya , Fukuoka Misato , Yusa Akira , Yamaji Yasuyuki , Namba Shigetou
Published: October 2014

Although many studies have demonstrated intracellular movement of viral proteins or viral replication complexes, little is known about the mechanisms of their motility. In this study, we analyzed the localization and motility of the nucleocapsid protein (NP) of
Fig mosaic virus
(FMV), a negative-strand RNA virus belonging to the recently established genus
Emaravirus
. Electron microscopy of FMV-infected cells using immunogold labeling showed that NPs formed cytoplasmic agglomerates that were predominantly enveloped by the endoplasmic reticulum (ER) membrane, while nonenveloped NP agglomerates also localized along the ER. Likewise, transiently expressed NPs formed agglomerates, designated NP bodies (NBs), in close proximity to the ER, as was the case in FMV-infected cells. Subcellular fractionation and electron microscopic analyses of NP-expressing cells revealed that NBs localized in the cytoplasm. Furthermore, we found that NBs moved rapidly with the streaming of the ER in an actomyosin-dependent manner. Brefeldin A treatment at a high concentration to disturb the ER network configuration induced aberrant accumulation of NBs in the perinuclear region, indicating that the ER network configuration is related to NB localization. Dominant negative inhibition of the class XI myosins, XI-1, XI-2, and XI-K, affected both ER streaming and NB movement in a similar pattern. Taken together, these results showed that NBs localize in the cytoplasm but in close proximity to the ER membrane to form enveloped particles and that this causes passive movements of cytoplasmic NBs by ER streaming.

IMPORTANCE
Intracellular trafficking is a primary and essential step for the cell-to-cell movement of viruses. To date, many studies have demonstrated the rapid intracellular movement of viral factors but have failed to provide evidence for the mechanism or biological significance of this motility. Here, we observed that agglomerates of nucleocapsid protein (NP) moved rapidly throughout the cell, and we performed live imaging and ultrastructural analysis to identify the mechanism of motility. We provide evidence that cytoplasmic protein agglomerates were passively dragged by actomyosin-mediated streaming of the endoplasmic reticulum (ER) in plant cells. In virus-infected cells, NP agglomerates were surrounded by the ER membranes, indicating that NP agglomerates form the basis of enveloped virus particles in close proximity to the ER. Our work provides a sophisticated model of macromolecular trafficking in plant cells and improves our understanding of the formation of enveloped particles of negative-strand RNA viruses.
Fatigue and breathlessness in pregnancy: a rare and sinister cause
Authors: Quigley James , Keating Aine , Byrd Louise
Published: October 2014

We describe a rare but sinister presentation of fatigue and dyspnoea in a 39-year-old woman at 16 weeks gestation. Blood tests and bone marrow aspirate confirmed the diagnosis of multiple myeloma. The patient was managed expectantly during pregnancy with plasma exchange and blood transfusion. The pregnancy continued without event; labour was induced at 35 weeks gestation and a healthy female infant weighing 3100 g was delivered vaginally following a 2 h, 5 min labour. The patient subsequently underwent six cycles of cyclophosphamide, thalidomide and dexamethasone (CTD) chemotherapy followed by an autologous stem cell transplant (SCT) and reduced intensity conditioning matched unrelated donor (RIC MUD) transplant.
Sialidosis type I: ophthalmological findings
Authors: Sobral Isa , Cachulo Maria da Luz , Figueira João , Silva Rufino
Published: October 2014

Sialidosis is a lysosomal storage disease caused by deficit of neuraminidase. It is an autosomal recessive disease, heterogeneous in its onset, presentation and prognosis. We report a case of a male patient with molecular and enzymatic confirmation of the diagnosis. Symptoms began at age 26 with reduced visual acuity, bilateral cherry-red spots and later myoclonus. A brother, now deceased, had the same confirmed disease. We describe the symptoms and clinical findings of the patient, as well review the current knowledge on the topic. With this report, we highlight the importance of a clinical history integrating all the patient’s symptoms in order to achieve the diagnosis. In the presence of a cherry-red spot, a comprehensive study is mandatory. Despite being a rare disease, sialidosis carries a significant burden for its patients and its diagnosis should always be considered in the appropriate setting.
Subjective discomfort in children receiving 3 T MRI and experienced adults’ perspective on children’s tolerability of 7 T: a cross-sectional questionnaire survey
Authors: Chou I-Jun , Tench Christopher R , Gowland Penny , Jaspan Tim , Dineen Rob A , Evangelou Nikos , Abdel-Fahim Rasha , Whitehouse William P , Constantinescu Cris S
Published: October 2014

Objectives

To explore the possible discomfort perceived by children participating in 7 T MRI research, and the age range in which children are most likely to tolerate it well.

Design

A cross-sectional survey using age-appropriate questionnaires containing six measures of subjective discomfort (general discomfort, dizziness, noisiness, claustrophobia and feeling of cold or warm).

Setting

For children, 3 T clinical scanner in a tertiary referral teaching hospital; for adults, 3 and 7 T scanner in a university research building.

Participants

Non-sedated children and young people under 18 years of age who underwent 3 T clinical MRI for brain or musculoskeletal scans and adult volunteers attending 7 T with or without 3 T for brain scans.

Results

83% (89/107) of involved individuals returned questionnaires. The most common discomfort among 31 children receiving 3 T MRI was noisiness (39%), followed by cold (19%), general discomfort (16%), dizziness (13%) and claustrophobia (10%). The noise was reported more frequently in children younger than 12 years than those older (p=0.021). The most common discomfort for 58 adults receiving 7 T MRI was noisiness (43%). In adults, there was a higher frequency of general discomfort during 7 than 3 T scans (p=0.031). More than 85% of adult respondents thought children aged 12–17 years would tolerate 7 T scans well, but only 35% and 15% thought children aged 10–11 and 8–9 years, respectively, would.

Conclusions

Noisiness was the most common discomfort across all ages in 3 and 7 T scanners. Although general discomfort was more common during 7 than 3 T scans in adults, most adults thought children aged 12 years or more would tolerate 7 T MRI well. Cautious enrolment of children in 7 T MRI study is warranted, but until there is more evidence of how well those aged 12 years or more tolerate 7 T MRI, we would caution against enrolling younger children.
Pittsburgh Response to Endovascular therapy (PRE) score: optimizing patient selection for endovascular therapy for large vessel occlusion strokes
Authors: Rangaraju Srikant , Aghaebrahim Amin , Streib Christopher , Sun Chung-Huan , Ribo Marc , Muchada Marion , Nogueira Raul , Frankel Michael , Gupta Rishi , Jadhav Ashutosh , Jovin Tudor G
Published: October 2014

Background

Endovascular therapy seems to benefit a subset of patients with large vessel occlusion strokes. We aimed to develop a clinically useful tool to identify patients who are likely to benefit from endovascular therapy.

Methods

In a derivation cohort of consecutively treated patients with anterior circulation large vessel occlusion (Grady Memorial Hospital, N=247), independent predictors (p<0.1) of good outcome (90-day modified Rankin scale score (mRS) 0–2) were determined using logistic regression to derive the Pittsburgh Response to Endovascular therapy (PRE) score as a predictor of good outcome. The PRE score was validated in two institutional cohorts (University of Pittsburgh Medical Center (UPMC): N=393; Unitat d’Ictus Vall d’Hebron: N=204) and its discriminative power for good outcome was compared with other validated tools. Benefit of successful recanalization was assessed in PRE score groups.

Results

Independent predictors of good outcome in the derivation cohort (age, baseline National Institute of Health Stroke Scale (NIHSS) score and Alberta Stroke Program Early CT Score (ASPECTS)) were used in the model: PRE score=age (years)+2×NIHSS−10×ASPECTS. PRE score was highly predictive of good outcome in the derivation cohort (area under the curve (AUC)=0.79) and validation cohorts (UPMC: AUC=0.79; UIVH: AUC=0.72) with comparable rates of good outcome in all PRE risk quartiles. PRE was superior to Totaled Health Risks In Vascular Events (THRIVE) (p=0.03) and Stroke Prognostication using Age and NIHSS (SPAN) (p=0.007), with a trend towards superiority to Houston Intra-Arterial Therapy 2 (HIAT2) (p=0.06) and iSCORE (p=0.051) in predicting good outcomes. Better outcomes were associated with successful recanalization in patients with PRE scores −24 to +49 but not in patients with PRE scores <−24 or ≥50.

Conclusions

The PRE score is a validated tool that predicts outcomes and may facilitate patient selection for endovascular therapy in anterior circulation large vessel occlusions.
Outcome of iridociliary epithelial tumour biopsies in dogs: a retrospective study
Authors: Beckwith‐Cohen Billie , Bentley Ellison , Dubielzig Richard R.
Published: October 2014

To evaluate the outcome of eyes with a confirmed iridociliary epithelial tumour (ICET) following biopsy. Forty‐two specimens were selected from the Comparative Ocular Pathology Laboratory of Wisconsin database, including 11 globes enucleated following ICET biopsy and 31 iridociliary biopsies with a confirmed ICET. Histopathology was performed for all specimens. When identified, the corneal surgical wound was examined in enucleated globes. Tumour type and margins were determined for biopsy specimens and follow‐up was obtained when possible. Biopsies were performed for diagnosis, debulking or excision. 30/31 biopsies had dirty margins, and iridociliary adenomas were indistinguishable from adenocarcinomas by biopsy. Upon biopsy submission 5/23 biopsies were reported as incisional and 18/23 as excisional. Follow‐up information was obtained for 14/18 of those reported as excisional. 8/14 had documented recurrence within 5.0±5.6 months and 6/14 had no recurrence at 21.5±13.6 months postoperatively. Three enucleated globes were diagnosed with iridociliary adenocarcinomas and eight with iridociliary adenomas. The corneal surgical wound was sampled in 8/11 globes. There was a synechia to the surgical wound in 3/8 globes, and in 3/8 globes there were neoplastic cells within or adjacent to the surgical wound. The postoperative success of ICET excision is highly variable; complete excision is rarely achieved and recurrence is common. Biopsy effects on ocular tissues may result in synechia and other surgical complications. ICET can be diagnosed by biopsy, but adenomas are indistinguishable from adenocarcinomas.
Daily chocolate milk consumption does not enhance the effect of resistance training in young and old men: a randomized controlled trial
Authors: Mitchell Cameron J. , Oikawa Sara Y. , Ogborn Dan I. , Nates Nicholas J. , MacNeil Lauren G. , Tarnopolsky Mark , Phillips Stuart M.
Published: October 2014

Older and younger men completed 12 weeks of resistance training and ingested either 500 mL of chocolate milk or placebo daily. Training increased strength in both age groups (p < 0.05), with no supplementation effect. Type I muscle fibre area increased with training (p = 0.008) with no effect of age or supplementation. Type II fibre area increased (p = 0.014) in young men only with no supplementation effect. Chocolate milk did not enhance skeletal muscle hypertrophy following training.
Comparing the relationship between seed germination and temperature forStipaspecies on the Tibetan Plateau
Authors: Yang Shihai , Li Xiong , Yang Yunqiang , Yin Xin , Yang Yongping
Published: October 2014

Alpine steppe grasslands dominated by Stipa species (Poaceae) on the Tibetan Plateau are important model ecosystems. Here, we present data on seed germination of three typical Stipa species (Stipa purpurea Griseb., Stipa glareosa P.A.Smirn., and Stipa capillacea Keng) from the northern core region of the Tibetan Plateau. We carried out laboratory investigations of germination behavior under both constant and alternating temperatures. Germination varied significantly with temperature. Under constant temperature, we found that temperature and species, but not their interaction, had significant effects on seed germination. Under alternating temperatures, species had a significant effect on seed germination, whereas the effects of alternating temperature and the interaction between species and alternating temperature were not significant. In addition, light and the interaction of light and species had no significant effect on seed germination; however, species had a significant effect, implying that Stipa species on the Tibetan Plateau are not inhibited by light. Base temperatures of S. glareosa, S. purpurea, and S. capillacea were 1.0 °C, 0.1 °C, and –1.4 °C, respectively, with corresponding thermal times at suboptimal temperatures of 233 °C-day, 154 °C-day, and 263.2 °C-day. Our results suggest that Stipa seed germination characteristics are adaptions to a harsh environment and are species-specific.
Histologic growth dynamic study of Edmontosaurus regalis (Dinosauria: Hadrosauridae) from a bonebed assemblage of the Upper Cretaceous Horseshoe Canyon Formation, Edmonton, Alberta, Canada
Authors: Vanderven Evan , Burns Michael E. , Currie Philip J.
Published: October 2014

The Danek Bonebed (Edmonton, Alberta, Canada) is a monodominant Edmontosaurus regalis assemblage of the upper Campanian (Upper Cretaceous) Horseshoe Canyon Formation. Bone histology of humeri and femora are used in this paper to test hypotheses about the growth dynamics and palaeobiology of Edmontosaurus. The high number of elements collected from the Danek Bonebed allow for an expansion of the multi-element histological record for hadrosaurs. Results indicate that Edmontosaurus had a growth trajectory similar to other large-bodied dinosaurs and reached the onset of somatic maturity at about 10–15 years of age; however, even the largest elements to preserve lines of arrested growth do not have external fundamental systems. This timing of the onset of somatic maturity agrees with the estimated body size of Edmontosaurus relative to other dinosaurs for which life-history data are available. Vascularity patterns support the hypothesis that edmontosaurs preserved at the Danek Bonebed were not subject to the same extreme seasonal environmental shifts as congenerics preserved at higher latitudes, further supporting overwintering behaviour in the latter.
Annealing temperature dependence of local atomic and electronic structure of polycrystalline La0.5Sr0.5MnO3
Authors: Zhang Hong-Guang , Li Yong-Tao , Xie Liang , Dong Xue-Guang , Li Qi
Published: October 2014

The local atomic and electronic structure of La 0.5 Sr 0.5 MnO 3 was investigated at different annealing temperatures (TA) by X-ray absorption spectroscopy (XAS) and photoemission spectroscopy (XPS). The extended X-ray absorption fine structure indicates that the MnO 6 octahedral distortion is reduced by increasing TA. The chemical shift for the sample with TA = 1350° C measured by XPS of Mn 2p core level demonstrates the increasing of Mn 3+ ions content. From the deconvolution of valence band photoemission spectra, the number of eg electron is also proved to increase with increasing TA. It is also demonstrated that there is a strongest hybridization between O 2p and surrounding atomic orbital states in sample with TA = 1350° C , which is consistent with valence band photoemission.
Architecture and Network-on-Chip Implementation of a New Hierarchical Interconnection Network
Authors: Rahman M. M. Hafizur , Mohd Nor Rizal , Bin Tengku Sembok Tengku Mohd , Akhand M. A. H.
Published: October 2014

A Midimew-connected Mesh Network (MMN) is a minimal distance mesh with wrap-around links network of multiple basic modules (BMs), in which the BMs are 2D-mesh networks that are hierarchically interconnected for higher-level networks. In this paper, we present the architecture of the MMN, addressing of node, routing of message, and evaluate the static network performance of MMN, TESH, mesh and torus networks. In addition, we propose the network-on-chip (NoC) implementation of MMN. With innovative combination of diagonal and hierarchical structure, the MMN possesses several attractive features, including constant degree, small diameter, low cost, small average distance, moderate bisection width and high fault tolerant performance than that of other conventional and hierarchical interconnection networks. The simple architecture of MMN is also highly suitable for NoC implementation. To implement all the links of level-3 MMN, only four layers are needed which is feasible with current and future VLSI technologies.
FINITE ELEMENT MODELING OF THE HUMAN COCHLEA USING FLUID–STRUCTURE INTERACTION METHOD
Authors: XU LIFU , HUANG XINSHENG , TA NA , RAO ZHUSHI , TIAN JIABIN
Published: October 2014

In this paper, a 3D finite element (FE) model of human cochlea is developed. This passive model includes the structure of oval window, round window, basilar membrane (BM) and cochlear duct which is filled with fluid. Orthotropic material property of the BM is varying along its length. The fluid–structure interaction (FSI) method is used to compute the responses in the cochlea. In particular, the viscous fluid element is adopted for the first time in the cochlear FE model, so that the effects of shear viscosity in the fluid are considered. Results on the cochlear impedance, BM response and intracochlear pressure are obtained. The intracochlear pressure includes the scala vestibule and scala tympani pressure are extracted and used to calculate the transfer functions from equivalent ear canal pressures to scala pressures. The reasonable agreements between the model results and the experimental data in the literature prove the validity of the cochlear model for simulating sound transmission in the cochlea. Moreover, this model predicted the transfer function from equivalent ear canal pressures to scala pressures which is the input to the cochlear partition.
Exosomes Biogenesis and Potentials in Disease Diagnosis and Drug Delivery
Authors: Gu Haitao , Overstreet Anne-Marie C. , Yang Yongguang
Published: October 2014

Exosomes were discovered more than 30 years ago. Only recently has their importance been recognized for intercellular communication. Exosomes, with their size ranging from 30 nm to 100 nm, are lipid bilayer nanoparticles and secreted by many different types of cells with versatile functions. Exosomes contain macromolecules and exist in various body fluids, including blood, urine, milk and ascites fluid. Due to their specific property, exosomes are very promising in the fields of disease diagnosis and therapy. Nanotechnology is a great tool that will be helpful in basic research and the application of exosomes. Here, we briefly review the function and potential use of exosomes in nanomedicine.
Interaction between Na-K-ATPase and Bcl-2 proteins BclXL and Bak
Authors: Lauf Peter K. , Alqahtani Tariq , Flues Karin , Meller Jaroslaw , Adragna Norma C.
Published: October 2014

In silico analysis predicts interaction between Na-K-ATPase (NKA) and Bcl-2 protein canonical BH3- and BH1-like motifs, consistent with NKA inhibition by the benzo-phenanthridine alkaloid chelerythrine, a BH3 mimetic, in fetal human lens epithelial cells (FHLCs) (Lauf PK, Heiny J, Meller J, Lepera MA, Koikov L, Alter GM, Brown TL, Adragna NC. Cell Physiol Biochem 31: 257–276, 2013). This report establishes proof of concept: coimmunoprecipitation and immunocolocalization showed unequivocal and direct physical interaction between NKA and Bcl-2 proteins. Specifically, NKA antibodies (ABs) coimmunoprecipitated BclXL (B-cell lymphoma extra large) and BAK (Bcl-2 antagonist killer) proteins in FHLCs and A549 lung cancer cells. In contrast, both anti-Bcl-2 ABs failed to pull down NKA. Notably, the molecular mass of BAK1 proteins pulled down by NKA and BclXL ABs appeared to be some 4-kDa larger than found in input monomers. In silico analysis predicts these higher molecular mass BAK1 proteins as alternative splicing variants, encoding 42 amino acid (aa) larger proteins than the known 211-aa long canonical BAK1 protein. These BAK1 variants may constitute a pool separate from that forming mitochondrial pores by specifically interacting with NKA and BclXL proteins. We propose a NKA-Bcl-2 protein ternary complex supporting our hypothesis for a special sensor role of NKA in Bcl-2 protein control of cell survival and apoptosis.
Fructose- and glucose-conditioned preferences in FVB mice: strain differences in post-oral sugar appetition
Authors: Sclafani Anthony , Zukerman Steven , Ackroff Karen
Published: October 2014

Recent studies indicate that, unlike glucose, fructose has little or no post-oral preference conditioning actions in C57BL/6J (B6) mice. The present study determined whether this is also the case for FVB mice, which overconsume fructose relative to B6 mice. In experiment 1, FVB mice strongly preferred a noncaloric 0.1% sucralose + 0.1% saccharin (S+S) solution to 8% fructose in a 2-day choice test but switched their preference to fructose after separate experience with the two sweeteners. Other FVB mice displayed a stronger preference for 8% glucose over S+S. In a second experiment, ad libitum-fed FVB mice trained 24 h/day acquired a significant preference for a flavor (CS+) paired with intragastric (IG) self-infusions of 16% fructose over a different flavor (CS−) paired with IG water infusions. IG fructose infusions also conditioned flavor preferences in food-restricted FVB mice trained 1 h/day. IG infusions of 16% glucose conditioned stronger preferences in FVB mice trained 24- or 1 h/day. Thus, fructose has post-oral flavor conditioning effects in FVB mice, but these effects are less pronounced than those produced by glucose. Further studies of the differential post-oral conditioning effects of fructose and glucose in B6 and FVB mice should enhance our understanding of the physiological processes involved in sugar reward.
Filtering Based Recursive Least Squares Algorithm for Multi‐Input Multioutput Hammerstein Models
Authors: Wang Ziyun , Wang Yan , Ji Zhicheng
Published: October 2014

This paper considers the parameter estimation problem for Hammerstein multi‐input multioutput finite impulse response (FIR‐MA) systems. Filtered by the noise transfer function, the FIR‐MA model is transformed into a controlled autoregressive model. The key‐term variable separation principle is used to derive a data filtering based recursive least squares algorithm. The numerical examples confirm that the proposed algorithm can estimate parameters more accurately and has a higher computational efficiency compared with the recursive least squares algorithm.
Fano Resonance of the Symmetry‐Reduced Metal Bar Grating Structure
Authors: Xie Suxia , Li Zhijian , Zhou Renlong , Zhan Jie , Liu Qiong , Wu Lingxi , Zhou Bingju
Published: October 2014

We demonstrate that Fano resonance and even multipole Fano resonance can be obtained in a symmetry‐reduced structure composed of gold bars with different bar sizes or bar shapes on a layer of dielectric. There is a transparency window opened within the frequency region of the absorptive dipole resonance by metallic bars, as long as the narrow grating waveguide mode induced by reducing symmetry is coincided in spectrum with the dipole resonance such that a destructive interference happens between these two resonant modes. Line shape of the transmission spectra of the nanostructure can be modulated effectively by changing the size or shape of the series of metal bars. The results found can be useful in the design of novel optical device.
Association of ATM Gene Polymorphism with PTC Metastasis in Female Patients
Authors: Gu Yulu , Liu Xiaoli , Yu Yaqin , Shi Jieping , Ai Lizhe , Sun Hui , Kanu Joseph Sam , Wang Chong , Liu Yawen
Published: October 2014

Ataxia telangiectasia mutated (ATM) gene is critical in the process of recognizing and repairing DNA lesions and is related to invasion and metastasis of malignancy. The incidence rate of papillary thyroid cancer (PTC) has increased for several decades and is higher in females than males. In this study, we want to investigate whether ATM polymorphisms are associated with gender-specific metastasis of PTC. 358 PTC patients in Northern China, including 109 males and 249 females, were included in our study. Four ATM single nucleotide polymorphisms (SNPs) were genotyped using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). Association between genotypes and the gender-specific risk of metastasis was assessed by odds ratios (OR) and 95% confidence intervals (CI) under the unconditional logistic regression analysis. Significant associations were observed between rs189037 and metastasis of PTC in females under different models of inheritance (codominant model:OR=0.15, 95% CI 0.04–0.56,P=0.01for GA versus GG andOR=0.08, 95% CI 0.01–0.74,P=0.03for AA versus GG, resp.; dominant model:OR=0.49, 95% CI 0.25–0.98,P=0.04; overdominant model:OR=0.47, 95% CI 0.25–0.89,P=0.02). However, no association remained significant after Bonferroni correction. Our findings suggest a possible association between ATM rs189037 polymorphisms and metastasis in female PTCs.
Radiograms Obtained during Anterior Cervical Decompression and Fusion Can Mislead Surgeons into Performing Surgery at the Wrong Level
Authors: Mannoji Chikato , Koda Masao , Furuya Takeo , Okamoto Yuzuru , Kon Tamiyo , Takahashi Kazuhisa , Yamazaki Masashi , Murakami Masazumi
Published: October 2014

A 68-year-old woman who suffered from C5 nerve palsy because of a C4-5 disc herniation was referred to our hospital. We conducted anterior cervical decompression and fusion (ACDF) at the C4-5 level. An intraoperative radiogram obtained after exposure of the vertebrae showed that the level at which we were going to perform surgery was exactly at the C4-5 level. After bone grafting and temporary plating, another radiogram was obtained to verify the correct placement of the plate and screws, and it appeared to show that the plate bridged the C5 and C6 vertebrae at the incorrect level. The surgeon was astonished and was about to begin decompression of the upper level. However, carefully double-checking the level with a C-arm image intensifier before additional decompression verified that the surgery was conducted correctly at C4-5. Cautiously double-checking the level of surgery with a C-arm image intensifier is recommended when intraoperative radiograms suggest surgery at the wrong level.