bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene expression profiling of porcine skeletal muscle in the early recovery phase following acute physical activity
Authors: Jensen Jeanette H. , Conley Lene N. , Hedegaard Jakob , Nielsen Mathilde , Young Jette F. , Oksbjerg Niels , Hornshøj Henrik , Bendixen Christian , Thomsen Bo
Published: February 2012

Acute physical activity elicits changes in gene expression in skeletal muscles to promote metabolic changes and to repair exercise‐induced muscle injuries. In the present time‐course study, pigs were submitted to an acute bout of treadmill running until near exhaustion to determine the impact of unaccustomed exercise on global transcriptional profiles in porcine skeletal muscles. Using a combined microarray and candidate gene approach, we identified a suite of genes that are differentially expressed in muscles during postexercise recovery. Several members of the heat shock protein family and proteins associated with proteolytic events, such as the muscle‐specific E3 ubiquitin ligase atrogin‐1, were significantly upregulated, suggesting that protein breakdown, prevention of protein aggregation and stabilization of unfolded proteins are important processes for restoration of cellular homeostasis. We also detected an upregulation of genes that are associated with muscle cell proliferation and differentiation, including MUSTN1, ASB5 and CSRP3, possibly reflecting activation, differentiation and fusion of satellite cells to facilitate repair of muscle damage. In addition, exercise increased expression of the orphan nuclear hormone receptor NR4A3, which regulates metabolic functions associated with lipid, carbohydrate and energy homeostasis. Finally, we observed an unanticipated induction of the long non‐coding RNA transcript NEAT1, which has been implicated in RNA processing and nuclear retention of adenosine‐to‐inosine edited mRNAs in the ribonucleoprotein bodies called paraspeckles. These findings expand the complexity of pathways affected by acute contractile activity of skeletal muscle, contributing to a better understanding of the molecular processes that occur in muscle tissue in the recovery phase.
Experimental Investigation of the Thermal Performance of a Manifold Hierarchical Microchannel Cold Plate
Authors: Dede Ercan M.
Published: February 2012

This article is focused on experimental investigation of the single-phase thermal-fluid performance of a manifold microchannel cold plate with integral hierarchical branching channels. The use of a multiphysics topology optimization technique for the development of the studied microchannel structure is briefly reviewed. An experimental test setup is then described followed by measured temperature and pressure results. Specifically, unit thermal resistance and pressure drop values for the hierarchical microchannel jet impingement cold plate are compared with corresponding results for the jet impingement of a flat plate. These experiments confirm that the hierarchical microchannel system provides increased heat transfer with a negligible change in pressure drop when compared with the standard flat plate system.
Three Dimensional and Nondestructive Evaluation of Thermal Fatigue Crack Propagation Process in Complex-Shaped Solder Joints by Synchrotron Radiation X-Ray Micro-Tomography
Authors: Tsuritani Hiroyuki , Sayama Toshihiko , Okamoto Yoshiyuki , Takayanagi Takeshi , Uesugi Kentaro , Mori Takao
Published: February 2012

The reliability or lifetime of micro-joints on printed circuit boards (PCBs) is significantly affected by fatigue processes, including fatigue crack initiation and propagation to failure. Accordingly, the industries producing electronic devices and components strongly desire a new nondestructive inspection technology, which detects micro-cracks appearing as thermal fatigue fractures in the joints. In this investigation, we applied a synchrotron radiation X-ray micro-tomography system called the SP-μCT to three-dimensionally and nondestructively evaluate the fatigue crack propagation process in complex-shaped solder joints. The observed specimens have a typical joint structure in which chip type resistors 1.0 mm in length and 0.5 mm in width are mounted on an FR-4 substrate by joining with Sn-3.0Ag-0.5Cu solder. A thermal cycle test was carried out, and specimens were collected at fixed cycle numbers. The same solder joints were observed successively using the SP-μCT at beamline BL20XU at SPring-8, the largest synchrotron radiation facility in Japan. An X-ray energy of 29.0 keV was selected to obtain computed tomography (CT) images with high contrast among some components, and a refraction-contrast imaging technique was also applied to the visualization of fatigue cracks in the solder joints. The following results were obtained. At the early stage in the fatigue process of normal joints, the main fatigue cracks were clearly observed to initiate from the region around the solder joint tip and the vicinity of the chip corner. Additionally, many micro-cracks roughly 5 to 10 μm in length also formed in the thin solder layer between the chip and substrate. The important observed fact is that these micro-cracks deform, grow, and connect to each other due to the thermal cyclic loading, prior to main crack propagation. On the other hand, in case of solder joints which included relatively larger initial voids, the voids deformed, and the fatigue cracks initiated and propagated from the surface of the voids. Furthermore, by employing the three-dimensional crack images, the crack dimensions were quantified straightforwardly by measuring the surface area of the fatigue crack, and the fatigue crack propagation process was also accurately evaluated via the average crack propagation rate. Consequently, the obtained CT images clearly illustrate the process of crack propagation due to the thermal cyclic loading of a solder joint. In contrast, such information has not been obtained in any form by industrially employed X-ray CT systems or finite element analyses.
Reliability Evaluation of Fatigue Life for Solder Joints in Chip Components Considering Dispersion of the Shape and the Properties
Authors: Nishimura Yuji , Yu Qiang
Published: February 2012

Recently, the downsizing of car components becomes a big trend for the development of car electronics, and it is becoming very difficult to achieve the reliability results target without managing controlling the dispersion of the fatigue lives. The authors proposed an isothermal fatigue test method using small size solder joints to get the fatigue properties. The Manson-Coffin’s law given by this method could improve the correspondence between the simulation results and experimental results. Based upon the Manson-Coffin’s law and Miner’s law, the authors proposed a fatigue crack propagation simulation approach. Furthermore, in order to consider the heterogeneity of PCB due to the distribution of fiber network, the authors made heterogeneous model considering the distribution of the fiber. And the authors evaluated the fatigue life of solder joints in chip components with considering dispersion of the material properties by using the heterogeneous model.
Simulation of Thermal Positioning in Micro- and Nano-Scale Bridge Structures
Authors: Maghsoudi Elham , Martin Michael James
Published: February 2012

Heat transfer in a thermally-positioned doubly-clamped bridge, at the micro- and nano-scale, is simulated to investigate the effect of convective cooling on the mechanical response of the system. The mechanical response of the system is defined as the displacement at the center of the bridge. The heat conduction equation is solved numerically using a finite difference method to obtain the temperature distribution in the bridge. Then, thermal stress due to the temperature difference with respect to the wall temperature is calculated. The thermo-structural equation is solved numerically to get the displacement along the beam. Two systems are compared: one doubly clamped beam with a length of 100 microns, a width of 10 microns, and a thickness of 3 microns, and a second beam with a length of 10 microns, a width of 1 micron, and a thickness of 300 nanometers, in air at a pressure from 0.01 Pa to 2 MPa. Conduction within the beam as well as convection between the beam and the gas are considered. A constant heat load with respect to the time is applied to the top of the beam varying from 10 to 600 μW/μm2. The simulations use both free molecular and continuum models to define the convective coefficient, h. The simulations are performed for three different materials: silicon, silicon carbide, and diamond. The numerical results show that the displacement and the response of thermally-positioned nano-scale devices are strongly influenced by ambient cooling. The displacement depends on the material properties, the geometry of the beam, and the Biot number. In the free molecular model, the displacement varies significantly with the pressure at high Biot numbers, while it does not depend on cooling gas pressure in the continuum case. The significant variation of displacement starts at Biot number of 0.1 which occurs at gas pressure of 27 KPa in nano-scale. As the Biot number increases, the dimensionless displacement, δ* = δk/q″αl2 decreases. The displacement of the system increases significantly as the bridge length increases, while these variations are negligible when the bridge width and thickness change. Thermal noise analysis shows silicon carbide has the most physically meaningful displacements in comparison with silicon and cvd diamond.
Characterization of a Server Thermal Mass Using Experimental Measurements
Authors: Ibrahim Mahmoud , Afram Furat , Sammakia Bahgat , Ghose Kanad , Murray Bruce , Iyengar Madhusudan , Schmidt Roger
Published: February 2012

The inevitable increase in the heat dissipation of data center facilities is requiring more efficient approaches in the operation of a data center. Dynamic cooling has been proposed as the approach for enhancing the energy efficiency. Dynamic cooling involves close monitoring of the data center environment with time, using sensors, and taking real time decisions on allocating the cooling resources based on the location of hotspots and concentration of workloads. In order to address this approach, knowing the time it takes for a facility to reach steady state after any variation is crucial for ensuring safe operation of the electronic equipment at all times, and it is a function of thermal mass. The thermal mass of an object is the amount of mass capable of withholding heat, and the time it takes to dissipate that heat into the environment is a function of the material properties. In this study, we use a typical 2U server and explain a procedure in obtaining its thermal mass. The server is operated at different controlled power levels while measurements of fans speed, component temperatures, and inlet and outlet temperatures are taken with time. For the first set of experiments, the server is kept inside a chamber and for the second set it is kept in open space. Ultimately the experimental measurements obtained will be used to obtain a compact model to approximate thermal mass of different servers.
Contribution of Heat Pipe to the Energy Conservation of Data Center and Cloud Computers
Authors: Mochizuki Masataka , Nguyen Thang , Mashiko Koichi , Saito Yuji , Wu Xiao Ping , Nguyen Tien , Wuttijumnong Vijit , Singh Randeep
Published: February 2012

With the current increase of the electrical power consumption of the data center imposed a great concern in the world about sustainable energy and global warming and it is therefore required innovative ideas to conserve the energy consumption. Authors propose the use of heat pipe which is a best known passive heat transfer device that is well suitable apply for energy saving system in the current data center cooling system. In this paper, a design and economics of the novel type of thermal control system for data center cooling using heat pipe based cold energy storage system has been proposed and discussed. The cold water storage system is explained and sized for data center with heat output capacity of 8,800 kW. Basically, the cold energy storage will help to downsize the chiller and decrease its runtime that will save electricity related cost and decrease green house gases emissions resulting from the electricity generation. The proposed cold energy storage system can be retrofit or connected in the existing data center facilities without major design changes. Water based cold energy storage system provides more compact size with short term storage (hours to days) and is potential for both small to large size data center with yearly average temperature below the cold storage water temperature (∼ 25 °C). The cold water storage system is sized on the basis of metrological conditions in North America, USA. As an outcome of the thermal and cost analysis, an optimum size of cold energy storage system should be designed to handle 60% of the yearly data center load. The proposed system can be easily integrated into the existing conventional systems without any significant infrastructure changes. Preliminary results obtained from the experimental system design to test the ice formation potential of the heat pipe based cold energy storage system has been shown good result and validated the proposed concept.
Interface Toughness Evaluation With Specimens Fabricated by Focused Ion Beam for Micro Scale Devices and Packages
Authors: Shishido Nobuyuki , Matsumoto Satoru , Chen Chuantong , Sato Hisashi , Omiya Masaki , Kamiya Shoji , Nishida Masahiro , Nokuo Takeshi , Nagasawa Tadahiro , Suzuki Takashi , Nakamura Tomoji
Published: February 2012

Capability of detecting local interface strength variation with 10 ! m scale resolution was investigated in reference to the interface between vapor-deposited gold (Au) and SiO2 with a practically homogeneous strength. Uncertainties in the evaluation procedure were thoroughly examined, which was to be excluded from the apparent scatter of evaluation results. The intrinsic scatter of strength in a damascene Cu/SiN cap interface was successfully specified to be at least 2.45 J/m2.
Estimation of Power Integrity Impact to Low Power Processor Performance Through Pre-Silicon Simulation and Post-Silicon Measurements
Authors: Pan Christopher , Shayan Amirali , Popovich Mikhail , Bowles Kevin
Published: February 2012

The impact of power integrity on processor performance is critical in nano-scale era. We proposed the enhanced pre-silicon simulation to accurately capture the power delivery quality. The post silicon performance measurements correlates well with pre-silicon analysis and demonstrate that power integrity could impact performance up to 15% in low and high frequencies.
Cyanophora paradoxa
Genome Elucidates Origin of Photosynthesis in Algae and Plants
Authors: Price Dana C. , Chan Cheong Xin , Yoon Hwan Su , Yang Eun Chan , Qiu Huan , Weber Andreas P. M. , Schwacke Rainer , Gross Jeferson , Blouin Nicolas A. , Lane Chris , Reyes-Prieto Adrián , Durnford Dion G. , Neilson Jonathan A. D. , Lang B. Franz , Burger Gertraud , Steiner Jürgen M. , Löffelhardt Wolfgang , Meuser Jonathan E. , Posewitz Matthew C. , Ball Steven , Arias Maria Cecilia , Henrissat Bernard , Coutinho Pedro M. , Rensing Stefan A. , Symeonidi Aikaterini , Doddapaneni Harshavardhan , Green Beverley R. , Rajah Veeran D. , Boore Jeffrey , Bhattacharya Debashish
Published: February 2012

Plastid Origins

The glaucophytes, represented by the alga
Cyanophora paradoxa
, are the putative sister group of red and green algae and plants, which together comprise the founding group of photosynthetic eukaryotes, the Plantae. In their analysis of the genome of
C. paradoxa
,

Price
et al.

(p.
843
; see the Perspective by

Spiegel

) demonstrate a unique origin for the plastid in the ancestor of this supergroup, which retains much of the ancestral diversity in genes involved in carbohydrate metabolism and fermentation, as well as in the gene content of the mitochondrial genome. Moreover, about 3.3% of nuclear genes in
C. paradoxa
seem to carry a signal of cyanobacterial ancestry, and key genes involved in starch biosynthesis are derived from energy parasites such as Chlamydiae. Rapid radiation, reticulate evolution via horizontal gene transfer, high rates of gene divergence, loss, and replacement, may have diffused the evolutionary signals within this supergroup, which perhaps explains previous difficulties in resolving its evolutionary history.
A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads
Authors: Douglas Shawn M. , Bachelet Ido , Church George M.
Published: February 2012

Nanorobots Deliver

DNA aptamers are short strands that have high binding affinity for a target protein that can be used as triggers for releasing cargo from delivery vehicles.

Douglas
et al.

(p.
831
) used this strategy to design DNA origami “nanorobots”—complex shaped structures created by manipulating a long DNA strand through binding with shorter “staple” strands—that could deliver payloads such as gold nanoparticles or fluorescently labeled antibody fragments. These nanorobots were designed to open in response to specific cell-surface proteins, releasing molecules that triggered cell signaling.
Plate Motions and Stresses from Global Dynamic Models
Authors: Ghosh Attreyee , Holt William E.
Published: February 2012

Driving Forces

The physical properties that control the motions of Earth's tectonic plates are difficult to predict accurately on a global scale. Large-scale geodynamic models are continually becoming more powerful, but controversies remain regarding plate-driving forces.
Ghosh and Holt
(p.
838
) present a global geodynamic model that achieves a high level of accuracy in fitting surface plate motions, plate boundary deformation, and intraplate stress fields. The model identifies regions where mantle drag drives plate motion and regions where the drag resists plate motion. Based on the relative magnitude of mantle drag forces and lithospheric buoyancies contributing to the stress field, the model also quantifies absolute viscosity—a parameter that has been notoriously difficult to predict for Earth's interior.
A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes
Authors: MacArthur Daniel G. , Balasubramanian Suganthi , Frankish Adam , Huang Ni , Morris James , Walter Klaudia , Jostins Luke , Habegger Lukas , Pickrell Joseph K. , Montgomery Stephen B. , Albers Cornelis A. , Zhang Zhengdong D. , Conrad Donald F. , Lunter Gerton , Zheng Hancheng , Ayub Qasim , DePristo Mark A. , Banks Eric , Hu Min , Handsaker Robert E. , Rosenfeld Jeffrey A. , Fromer Menachem , Jin Mike , Mu Xinmeng Jasmine , Khurana Ekta , Ye Kai , Kay Mike , Saunders Gary Ian , Suner Marie-Marthe , Hunt Toby , Barnes If H. A. , Amid Clara , Carvalho-Silva Denise R. , Bignell Alexandra H. , Snow Catherine , Yngvadottir Bryndis , Bumpstead Suzannah , Cooper David N. , Xue Yali , Romero Irene Gallego ,   1000 Genomes Project Consortium, Wang Jun , Li Yingrui , Gibbs Richard A. , McCarroll Steven A. , Dermitzakis Emmanouil T. , Pritchard Jonathan K. , Barrett Jeffrey C. , Harrow Jennifer , Hurles Matthew E. , Gerstein Mark B. , Tyler-Smith Chris
Published: February 2012

Defective Gene Detective

Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets of genome and exome sequencing, have often turned out to be sequencing errors rather than true genetic variants. In order to identify the true scope of loss-of-function genes within the human genome,

MacArthur
et al.

(p.
823
; see the Perspective by

Quintana-Murci

) extensively validated the genomes from the 1000 Genomes Project, as well as an additional European individual, and found that the average person has about 100 true loss-of-function alleles of which approximately 20 have two copies within an individual. Because many known disease-causing genes were identified in “normal” individuals, the process of clinical sequencing needs to reassess how to identify likely causative alleles.
Science and Diplomacy
Authors: Colglazier E. William
Published: February 2012

The world has much to gain from developing more knowledge- and innovation-based societies and from spreading scientific values, including meritocracy and transparency, that support democracy. This fundamental assumption underlies a renewed interest in science diplomacy, along with the widespread recognition that science and technology (S&T) are strategic assets for U.S. diplomacy. My recent appointment as S&T Adviser to Secretary of State Hillary Clinton has increased my appreciation of the great potential of America's S&T capabilities for enhancing our foreign policy. S&T are strategic assets for U.S. diplomacy because all countries, regardless of their politics, culture, and worldview, respect our S&T capabilities and want to engage with U.S. scientists and engineers. This is true even of countries with which governmental relations are strained. S&T are critical to fostering innovation and economic prosperity in a highly competitive and interconnected world, and are essential for solving national and global problems.
Detection of Taenia solium Taeniasis Coproantigen Is an Early Indicator of Treatment Failure for Taeniasis
Authors: Bustos Javier A. , Rodriguez Silvia , Jimenez Juan A. , Moyano Luz M. , Castillo Yesenia , Ayvar Viterbo , Allan James C. , Craig Philip S. , Gonzalez Armando E. , Gilman Robert H. , Tsang Victor C. W. , Garcia Hector H.
Published: February 2012

Taenia soliumcauses taeniasis and cysticercosis, a zoonotic complex associated with a significant burden of epilepsy in most countries. Reliable diagnosis and efficacious treatment of taeniasis are needed for disease control. Currently, cure can be confirmed only after a period of at least 1 month, by negative stool microscopy. This study assessed the performance of detection by a coproantigen enzyme-linked immunosorbent assay (CoAg-ELISA) for the early evaluation of the efficacy of antiparasitic treatment of humanT. soliumtaeniasis. We followed 69 tapeworm carriers who received niclosamide as standard treatment. Stool samples were collected on days 1, 3, 7, 15, 30, and 90 after treatment and were processed by microscopy and CoAg-ELISA. The efficacy of niclosamide was 77.9% (53/68). Thirteen patients received a second course of treatment and completed the follow-up. CoAg-ELISA was therefore evaluated for a total of 81 cases (68 treatments, 13 retreatments). In successful treatments (n= 64), the proportion of patients who became negative by CoAg-ELISA was 62.5% after 3 days, 89.1% after 7 days, 96.9% after 15 days, and 100% after 30 days. In treatment failures (n= 17), the CoAg-ELISA result was positive for 70.6% of patients after 3 days, 94.1% after 7 days, and 100% after 15 and 30 days. Only 2 of 17 samples in cases of treatment failure became positive by microscopy by day 30. The presence of one scolex, but not multiple scolices, in posttreatment stools was strongly associated with cure (odds ratio [OR], 52.5;P< 0.001). CoAg-ELISA is useful for the assessment of treatment failure in taeniasis. Early assessment at day 15 would detect treatment failure before patients become infective.
Ganciclovir-Resistant Cytomegalovirus (CMV) Retinitis in a Patient with Wild-Type CMV in Her Plasma
Authors: Moss Hart B. , Chavala Sai , Say Emil , Miller Melissa B.
Published: February 2012

A patient with systemic cytomegalovirus (CMV), including chorioretinitis, received localized and systemic ganciclovir, systemic cidofovir analog, and localized foscarnet. Mutations conferring ganciclovir and cidofovir resistance were detected in CMV from the aqueous fluid but not in CMV from plasma. Quantifying CMV from aqueous fluid was valuable for monitoring the clinical response and predicting resistance.
Colonization with Vancomycin-Intermediate Staphylococcus aureus Strains Containing the
vanA
Resistance Gene in a Tertiary-Care Center in North India
Authors: Banerjee Tuhina , Anupurba Shampa
Published: February 2012

A nasal carriage survey for methicillin-resistant
Staphylococcus aureus
(MRSA) in an intensive care unit detected four strains of MRSA with reduced susceptibility to vancomycin. The
vanA
gene was found in two of these vancomycin-intermediate
Staphylococcus aureus
(VISA) strains. The absence of selective vancomycin pressure might have resulted in reduced expression of the resistant gene.
Human Papillomavirus Load Measured by Linear Array Correlates with Quantitative PCR in Cervical Cytology Specimens
Authors: Wentzensen Nicolas , Gravitt Patti E. , Long Rodney , Schiffman Mark , Dunn S. Terence , Carreon J. Daniel , Allen Richard A. , Gunja Munira , Zuna Rosemary E. , Sherman Mark E. , Gold Michael A. , Walker Joan L. , Wang Sophia S.
Published: February 2012

Carcinogenic human papillomavirus (HPV) infections are necessary causes of most anogenital cancers. Viral load has been proposed as a marker for progression to cancer precursors but has been confirmed only for HPV16. Challenges in studying viral load are related to the lack of validated assays for a large number of genotypes. We compared viral load measured by Linear Array (LA) HPV genotyping with the gold standard, quantitative PCR (Q-PCR). LA genotyping and Q-PCR were performed in 143 cytology specimens from women referred to colposcopy. LA signal strength was measured by densitometry. Correlation coefficients and receiver operating characteristic (ROC) analyses were used to evaluate analytical and clinical performance. We observed a moderate to strong correlation between the two quantitative viral load measurements, ranging from an
R
value of 0.61 for HPV31 to an
R
value of 0.86 for HPV52. We also observed agreement between visual LA signal strength evaluation and Q-PCR. Both quantifications agreed on the disease stages with highest viral load, which varied by type (cervical intraepithelial neoplasia grade 2 [CIN2] for HPV52, CIN3 for HPV16 and HPV33, and cancer for HPV18 and HPV31). The area under the curve (AUC) for HPV16 Q-PCR at the CIN3 cutoff was 0.72 (
P
= 0.004), and the AUC for HPV18 LA at the CIN2 cutoff was 0.78 (
P
= 0.04). Quantification of LA signals correlates with the current gold standard for viral load, Q-PCR. Analyses of viral load need to address multiple infections and type attribution to evaluate whether viral load has clinical value beyond the established HPV16 finding. Our findings support conducting comprehensive studies of viral load and cervical cancer precursors using quantitative LA genotyping data.
Brain Abscess Caused by Enterococcus faecalis following a Dental Procedure in a Patient with Hereditary Hemorrhagic Telangiectasia
Authors: Mylona Eleni , Vadala Chariklia , Papastamopoulos Vasilios , Skoutelis Athanasios
Published: February 2012

Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations (AVMs). Brain abscess is a complication of HHT with AVMs. Literature provides evidence that
Enterococcus faecalis
can cause endodontic infections. We present the case of an HHT patient who developed brain abscess due to
E. faecalis
after a dental procedure.
Invasive Serogroup B Neisseria meningitidis in Québec, Canada, 2003 to 2010: Persistence of the ST-269 Clone Since It First Emerged in 2003
Authors: Zhou Jianwei , Lefebvre Brigitte , Deng Saul , Gilca Rodica , Deceuninck Genevieve , Law Dennis K. S. , De Wals Philippe , Tsang Raymond S. W.
Published: February 2012

In the era after the introduction of the meningococcal serogroup C conjugate vaccine, from 1 January 2003 to 31 December 2010, serogroup B meningococci were the major cause of invasive meningococcal disease in the province of Québec, Canada, being responsible for 72% of all meningococcal disease cases. Of the 334 invasive serogroup B
Neisseria meningitidis
strains analyzed, 53.9% belonged to the ST-269 clonal complex (CC). Since it first emerged in 2003, the percentage of invasive serogroup B isolates that belonged to the ST-269 CC had increased from 35% in 2003 to 76% in 2010. Among the 180 meningococci in the ST-269 CC, 91.7% belonged to a single ST (ST-269). The most common PorA genotypes identified in the ST-269 CC were (i) VR1 19-1, VR2 15-11, VR3 36 (84%) and (ii) VR1 18-7, VR2 9, VR3 35-1 (9%). Cases of invasive disease due to the ST-269 CC were commonly found in those aged 11 to 19 years (30.5%) and 20 to 40 years (25.5%). Meningococci of the ST-269 CC were uncommon in other Canadian provinces. In contrast to the ST-269 CC, invasive serogroup B meningococci that belonged to the ST-41/44 CC were much more diverse genetically. However, one ST (ST-571), which is uncommon in the United States, accounted for 35% of all cases due to this CC. The current finding suggests that the ST-269 clone may indeed represent an emerging hypervirulent clone of meningococci.
Effect of γ34.5 Deletions on Oncolytic Herpes Simplex Virus Activity in Brain Tumors
Authors: Kanai Ryuichi , Zaupa Cecile , Sgubin Donatella , Antoszczyk Slawomir J. , Martuza Robert L. , Wakimoto Hiroaki , Rabkin Samuel D.
Published: February 2012

The ICP34.5 protein of herpes simplex virus (HSV) is involved in many aspects of viral pathogenesis; promoting neurovirulence, inhibiting interferon-induced shutoff of protein synthesis, interacting with PCNA and TBK1, inhibiting dendritic cell (DC) maturation, and binding to Beclin 1 to interfere with autophagy. Because of its key role in neuropathogenicity, the γ34.5 gene is deleted in all oncolytic HSVs (oHSVs) currently in clinical trial for treating malignant gliomas. Unfortunately, deletion of γ34.5 attenuates virus replication in cancer cells, especially human glioblastoma stem cells (GSCs). To develop new oHSVs for use in the brain and that replicate in GSCs, we explored the effect of deleting the γ34.5 Beclin 1 binding domain (BBD). To ensure cancer selectivity and safety, we inactivated the ICP6 gene (UL39, large subunit of ribonucleotide reductase), constructing ICP6 mutants with different γ34.5 genotypes: Δ68HR-6, intact γ34.5; Δ68H-6, γ34.5 BBD deleted; and 1716-6, γ34.5 deleted. Multimutated Δ68H-6 exhibited minimal neuropathogenicity in HSV-1-susceptible mice, as opposed to Δ68H and Δ68HR-6. It replicated well in human glioma cell lines and GSCs, effectively killing cells
in vitro
and prolonging survival of mice bearing orthotopic brain tumors. In contrast, 1716 and 1716-6 barely replicated in GSCs. Infection of glioma cells with Δ68H-6 and 1716-6 induced autophagy and increased phosphorylation of eIF2α, while inhibition of autophagy, by Beclin 1 short hairpin RNA (shRNA) knockdown or pharmacological inhibition, had no effect on virus replication or phosphorylated eIF2α (p-eIF2α) levels. Thus, Δ68H-6 represents a new oHSV vector that is safe and effective against a variety of brain tumor models.
Herpes B Virus Utilizes Human Nectin-1 but Not HVEM or PILRα for Cell-Cell Fusion and Virus Entry
Authors: Fan Qing , Amen Melanie , Harden Mallory , Severini Alberto , Griffiths Anthony , Longnecker Richard
Published: February 2012

To investigate the requirements of herpesvirus entry and fusion, the four homologous glycoproteins necessary for herpes simplex virus (HSV) fusion were cloned from herpes B virus (BV) (or macacine herpesvirus 1, previously known as cercopithecine herpesvirus 1) and cercopithecine herpesvirus 2 (CeHV-2), both related simian simplexviruses belonging to the alphaherpesvirus subfamily. Western blots and cell-based enzyme-linked immunosorbent assay (ELISA) showed that glycoproteins gB, gD, and gH/gL were expressed in whole-cell lysates and on the cell surface. Cell-cell fusion assays indicated that nectin-1, an HSV-1 gD receptor, mediated fusion of cells expressing glycoproteins from both BV and CeHV-2. However, herpesvirus entry mediator (HVEM), another HSV-1 gD receptor, did not facilitate BV- and CeHV-2-induced cell-cell fusion. Paired immunoglobulin-like type 2 receptor alpha (PILRα), an HSV-1 gB fusion receptor, did not mediate fusion of cells expressing glycoproteins from either simian virus. Productive infection with BV was possible only with nectin-1-expressing cells, indicating that nectin-1 mediated entry while HVEM and PILRα did not function as entry receptors. These results indicate that these alphaherpesviruses have differing preferences for entry receptors. The usage of the HSV-1 gD receptor nectin-1 may explain interspecies transfer of the viruses, and altered receptor usage may result in altered virulence, tropism, or pathogenesis in the new host. A heterotypic cell fusion assay resulting in productive fusion may provide insight into interactions that occur to trigger fusion. These findings may be of therapeutic significance for control of deadly BV infections.
Opposing Effects of Bacitracin on Human Papillomavirus Type 16 Infection: Enhancement of Binding and Entry and Inhibition of Endosomal Penetration
Authors: Campos Samuel K. , Chapman Janice A. , Deymier Martin J. , Bronnimann Matthew P. , Ozbun Michelle A.
Published: February 2012

Cell invasion by human papillomavirus type 16 (HPV16) is a complex process relying on multiple host cell factors. Here we describe an investigation into the role of cellular protein disulfide isomerases (PDIs) by studying the effects of the commonly used PDI inhibitor bacitracin on HPV16 infection. Bacitracin caused an unusual time-dependent opposing effect on viral infection. Enhanced cellular binding and entry were observed at early times of infection, while inhibition was observed at later times postentry. Bacitracin was rapidly taken up by host cells and colocalized with HPV16 at late times of infection. Bacitracin had no deleterious effect on HPV16 entry, capsid disassembly, exposure of L1/L2 epitopes, or lysosomal trafficking but caused a stark inhibition of L2/viral DNA (vDNA) endosomal penetration and accumulation at nuclear PML bodies. γ-Secretase has recently been implicated in the endosomal penetration of L2/vDNA, but bacitracin had no effect on γ-secretase activity, indicating that blockage of this step occurs through a γ-secretase-independent mechanism. Transient treatment with the reductant β-mercaptoethanol (β-ME) was able to partially rescue the virus from bacitracin, suggesting the involvement of a cellular reductase activity in HPV16 infection. Small interfering RNA (siRNA) knockdown of cellular PDI and the related PDI family members ERp57 and ERp72 reveals a potential role for PDI and ERp72 in HPV infection.
Spike Protein VP8* of Human Rotavirus Recognizes Histo-Blood Group Antigens in a Type-Specific Manner
Authors: Huang Pengwei , Xia Ming , Tan Ming , Zhong Weiming , Wei Chao , Wang Leyi , Morrow Ardythe , Jiang Xi
Published: February 2012

Rotaviruses (RVs), an important cause of severe diarrhea in children, have been found to recognize sialic acid as receptors for host cell attachment. While a few animal RVs (of P[1], P[2], P[3], and P[7]) are sialidase sensitive, human RVs and the majority of animal RVs are sialidase insensitive. In this study, we demonstrated that the surface spike protein VP8* of the major P genotypes of human RVs interacts with the secretor histo-blood group antigens (HBGAs). Strains of the P[4] and P[8] genotypes shared reactivity with the common antigens of Lewis b (Le
b
) and H type 1, while strains of the P[6] genotype bound the H type 1 antigen only. The bindings between recombinant VP8* and human saliva, milk, or synthetic HBGA oligosaccharides were demonstrated, which was confirmed by blockade of the bindings by monoclonal antibodies (MAbs) specific to Le
b
and/or H type 1. In addition, specific binding activities were observed when triple-layered particles of a P[8] (Wa) RV were tested. Our results suggest that the spike protein VP8* of RVs is involved in the recognition of human HBGAs that may function as ligands or receptors for RV attachment to host cells.
C7L Family of Poxvirus Host Range Genes Inhibits Antiviral Activities Induced by Type I Interferons and Interferon Regulatory Factor 1
Authors: Meng Xiangzhi , Schoggins John , Rose Lloyd , Cao Jingxin , Ploss Alexander , Rice Charles M. , Xiang Yan
Published: February 2012

Vaccinia virus (VACV) K1L and C7L function equivalently in many mammalian cells to support VACV replication and antagonize antiviral activities induced by type I interferons (IFNs). While K1L is limited to orthopoxviruses, genes that are homologous to C7L are found in diverse mammalian poxviruses. In this study, we showed that the C7L homologues from sheeppox virus and swinepox virus could rescue the replication defect of a VACV mutant deleted of both K1L and C7L (vK1L
−
C7L
−
). Interestingly, the sheeppox virus C7L homologue could rescue the replication of vK1L
−
C7L
−
in human HeLa cells but not in murine 3T3 and LA-4 cells, in contrast to all other C7L homologues. Replacing amino acids 134 and 135 of the sheeppox virus C7L homologue, however, made it functional in the two murine cell lines, suggesting that these two residues are critical for antagonizing a putative host restriction factor which has some subtle sequence variation in human and murine cells. Furthermore, the C7L family of host range genes from diverse mammalian poxviruses were all capable of antagonizing type I IFN-induced antiviral activities against VACV. Screening of a library of more than 350 IFN-stimulated genes (ISGs) identified interferon-regulated factor 1 (IRF1) as an inhibitor of vK1L
−
C7L
−
but not wild-type VACV. Expression of either K1L or C7L, however, rendered vK1L
−
C7L
−
resistant to IRF1-induced antiviral activities. Altogether, our data show that K1L and C7L antagonize IRF1-induced antiviral activities and that the host modulation function of C7L is evolutionally conserved in all poxviruses that can readily replicate in tissue-cultured mammalian cells.
Genetic Evidence of a Long-Range RNA-RNA Interaction between the Genomic 5′ Untranslated Region and the Nonstructural Protein 1 Coding Region in Murine and Bovine Coronaviruses
Authors: Guan Bo-Jhih , Su Yu-Pin , Wu Hung-Yi , Brian David A.
Published: February 2012

Higher-order RNA structures in the 5′ untranslated regions (UTRs) of the mouse hepatitis coronavirus (MHV) and bovine coronavirus (BCoV), separate species in the betacoronavirus genus, appear to be largely conserved despite an ∼36% nucleotide sequence divergence. In a previous study, each of three 5′-end-proximal
cis
-acting stem-loop domains in the BCoV genome, I/II, III, and IV, yielded near-wild-type (wt) MHV phenotypes when used by reverse genetics to replace its counterpart in the MHV genome. Replacement with the BCoV 32-nucleotide (nt) inter-stem-loop fourth domain between stem-loops III and IV, however, required blind cell passaging for virus recovery. Here, we describe suppressor mutations within the transplanted BCoV 32-nt domain that along with appearance of potential base pairings identify an RNA-RNA interaction between this domain and a 32-nt region ∼200 nt downstream within the nonstructural protein 1 (Nsp1)-coding region. Mfold and phylogenetic covariation patterns among similarly grouped betacoronaviruses support this interaction, as does cotransplantation of the BCoV 5′ UTR and its downstream base-pairing domain. Interestingly, cotransplantation of the BCoV 5′ UTR and BCoV Nsp1 coding region directly yielded an MHV wt-like phenotype, which demonstrates a cognate interaction between these two BCoV regions, which in the MHV genome act in a fully interspecies-compliant manner. Surprisingly, the 30-nt inter-stem-loop domain in the MHV genome can be deleted and viral progeny, although debilitated, are still produced. These results together identify a previously undescribed long-range RNA-RNA interaction between the 5′ UTR and Nsp1 coding region in MHV-like and BCoV-like betacoronaviruses that is
cis
acting for viral fitness but is not absolutely required for viral replication in cell culture.
The Human Cytomegalovirus-Specific
UL1
Gene Encodes a Late-Phase Glycoprotein Incorporated in the Virion Envelope
Authors: Shikhagaie Medya , Mercé-Maldonado Eva , Isern Elena , Muntasell Aura , Albà M. Mar , López-Botet Miguel , Hengel Hartmut , Angulo Ana
Published: February 2012

We have investigated the previously uncharacterized human cytomegalovirus (HCMV)
UL1
open reading frame (ORF), a member of the rapidly evolving HCMV RL11 family.
UL1
is HCMV specific; the absence of
UL1
in chimpanzee cytomegalovirus (CCMV) and sequence analysis studies suggest that
UL1
may have originated by the duplication of an ancestor gene from the
RL11-TRL
cluster (
TRL11
,
TRL12
, and
TRL13
). Sequence similarity searches against human immunoglobulin (Ig)-containing proteins revealed that HCMV pUL1 shows significant similarity to the cellular carcinoembryonic antigen-related (CEA) protein family N-terminal Ig domain, which is responsible for CEA ligand recognition. Northern blot analysis revealed that
UL1
is transcribed during the late phase of the viral replication cycle in both fibroblast-adapted and endotheliotropic strains of HCMV. We characterized the protein encoded by hemagglutinin (HA)-tagged UL1 in the AD169-derived HB5 background. UL1 is expressed as a 224-amino-acid type I transmembrane glycoprotein which becomes detectable at 48 h postinfection. In infected human fibroblasts, pUL1 colocalized at the cytoplasmic site of virion assembly and secondary envelopment together with TGN-46, a marker for the
trans
-Golgi network, and viral structural proteins, including the envelope glycoprotein gB and the tegument phosphoprotein pp28. Furthermore, analyses of highly purified AD169 UL1-HA epitope-tagged virions revealed that pUL1 is a novel constituent of the HCMV envelope. Importantly, the deletion of
UL1
in HCMV TB40/E resulted in reduced growth in a cell type-specific manner, suggesting that pUL1 may be implicated in regulating HCMV cell tropism.
An Alternative Kaposi's Sarcoma-Associated Herpesvirus Replication Program Triggered by Host Cell Apoptosis
Authors: Prasad Alka , Lu Michael , Lukac David M. , Zeichner Steven L.
Published: February 2012

Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to several neoplastic diseases: Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV replicates actively, via a controlled gene expression program, but can also remain latent. It had been thought that the transition from latent to lytic replication was controlled exclusively by the replication and transcription activator protein RTA (open reading frame 50 [ORF50] gene product). A dominant-negative (DN) ORF50 mutant, ORF50ΔSTAD, blocks gene expression and replication. We produced a PEL cell line derivative containing both latent KSHV genomes and an inducible ORF50ΔSTAD. We unexpectedly found that induction of apoptosis triggered high-level viral replication, even when DN ORF50ΔSTAD was present, suggesting that apoptosis triggers KSHV replication through a distinct RTA-independent pathway. We verified that apoptosis triggers KSHV replication independent of RTA using ORF50 small interfering RNA (siRNA) and also showed that caspase activity is required to trigger KSHV replication. We showed that when apoptosis triggers KSHV replication, the kinetics of late gene expression is accelerated by 12 to 24 h and that virus produced following apoptosis has reduced infectivity. KSHV therefore appears to replicate via two distinct pathways, a conventional pathway requiring RTA, with slower replication kinetics, producing virus with higher infectivity, and an alternative apoptosis-triggered pathway that does not require RTA, has faster replication kinetics, and produces virus with lower infectivity. The existence of a distinct apoptosis-triggered, accelerated replication pathway may have evolutionary advantages for the virus and clinical significance for the treatment of KSHV-associated neoplasms. It also provides further evidence that KSHV can sense and react to its environment.
Posttranslational Modification of Vesicular Stomatitis Virus Glycoprotein, but Not JNK Inhibition, Is the Antiviral Mechanism of SP600125
Authors: Marozin Sabrina , Altomonte Jennifer , Apfel Sibylle , Dinh Phat X. , De Toni Enrico N. , Rizzani Antonia , Nüssler Andreas , Kato Nobuyuki , Schmid Roland M. , Pattnaik Asit K. , Ebert Oliver
Published: February 2012

Vesicular stomatitis virus (VSV), a negative-sense single-stranded-RNA rhabdovirus, is an extremely promising oncolytic agent for cancer treatment. Since oncolytic virotherapy is moving closer to clinical application, potentially synergistic combinations of oncolytic viruses and molecularly targeted antitumor agents are becoming a meaningful strategy for cancer treatment. Mitogen-activated protein kinase (MAPK) inhibitors have been shown to impair liver cell proliferation and tumor development, suggesting their potential use as therapeutic agents for hepatocellular carcinoma (HCC). In this work, we show that the impairment of MAPKin vitrodid not interfere with the oncolytic properties of VSV in HCC cell lines. Moreover, the administration of MAPK inhibitors did not restore the responsiveness of HCC cells to alpha/beta interferon (IFN-α/β). In contrast to previous reports, we show that JNK inhibition by the inhibitor SP600125 is not responsible for VSV attenuation in HCC cells and that this compound acts by causing a posttranslational modification of the viral glycoprotein.
Kinase Control Prevents HIV-1 Reactivation in Spite of High Levels of Induced NF-κB Activity
Authors: Wolschendorf Frank , Bosque Alberto , Shishido Takao , Duverger Alexandra , Jones Jennifer , Planelles Vicente , Kutsch Olaf
Published: February 2012

Despite its clinical importance, the molecular biology of HIV-1 latency control is at best partially understood, and the literature remains conflicting. The most recent description that latent HIV-1 is integrated into actively expressed host genes has further confounded the situation. This lack of molecular understanding complicates our efforts to identify therapeutic compounds or strategies that could reactivate latent HIV-1 infection in patients, a prerequisite for the eradication of HIV-1 infection. Currently, many therapeutic development efforts operate under the assumption that a restrictive histone code could govern latent infection and that either dissipation of the histone-based restrictions or NF-κB activation could be sufficient to trigger HIV-1 reactivation. We here present data that suggest an additional, higher level of molecular control. During a high-content drug screening effort, we identified AS601245 as a potent inhibitor of HIV-1 reactivation in latently infected primary T cells and T cell lines. In either system, AS601245 inhibited HIV-1 reactivation despite high levels of induced NF-κB activation. This finding suggests the presence of a gatekeeper kinase activity that controls latent HIV-1 infection even in the presence of high levels of NF-κB activity. Potential therapeutic stimuli that do not target this gatekeeper kinase will likely fail to trigger efficient system-wide HIV-1 reactivation.