bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human SCARB2-Dependent Infection by Coxsackievirus A7, A14, and A16 and Enterovirus 71
Authors: Yamayoshi Seiya , Iizuka Setsuko , Yamashita Teruo , Minagawa Hiroko , Mizuta Katsumi , Okamoto Michiko , Nishimura Hidekazu , Sanjoh Kanako , Katsushima Noriko , Itagaki Tsutomu , Nagai Yukio , Fujii Ken , Koike Satoshi 
Published: March 2012

ABSTRACTHuman enterovirus species A (HEV-A) consists of at least 16 members of different serotypes that are known to be the causative agents of hand, foot, and mouth disease (HFMD), herpangina, and other diseases, such as respiratory disease and polio-like flaccid paralysis. Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative agents of HFMD. CVA5, CVA6, CVA10, and CVA12 mainly cause herpangina or are occasionally involved with sporadic cases of HFMD. We have previously shown that human scavenger receptor class B, member 2 (SCARB2) is a cellular receptor for EV71 and CVA16. Using a large number of clinical isolates of HEV-A, we explored whether all clinical isolates of EV71 and other serotypes of HEV-A infected cells via SCARB2. We tested this possibility by infecting L-SCARB2 cells, which are L929 cells expressing human SCARB2, by infecting human RD cells that had been treated with small interfering RNAs for SCARB2 and by directly binding the viruses to a soluble SCARB2 protein. We showed that all 162 clinical isolates of EV71 propagated in L-SCARB2 cells, suggesting that SCARB2 is the critical receptor common to all EV71 strains. In addition, CVA7, CVA14, and CVA16, which are most closely related to each other, also utilized SCARB2 for infection. EV71, CVA14, and CVA16 are highly associated with HFMD, and EV71 and CVA7 are occasionally associated with neurological diseases, suggesting that SCARB2 plays important roles in the development of these diseases. In contrast, another group of viruses, such as CVA2, CVA3, CVA4, CVA5, CVA6, CVA8, CVA10, and CVA12, which are relatively distant from the EV71 group, is associated mainly with herpangina. None of these clinical isolates infected via the SCARB2-dependent pathway. HEV-A viruses can be divided into at least two groups depending on the use of SCARB2, and the receptor usage plays an important role in developing the specific diseases for each group.
Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Interacts with Multifunctional Angiogenin To Utilize Its Antiapoptotic Functions
Authors: Paudel Nitika , Sadagopan Sathish , Chakraborty Sayan , Sarek Grzegorz , Ojala Päivi M. , Chandran Bala 
Published: March 2012

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with the angioproliferative Kaposi's sarcoma (KS). KSHV infection and the expression of latency-associated nuclear antigen (LANA-1) upregulates the angiogenic multifunctional 123-amino-acid, 14-kDa protein angiogenin (ANG), which is detected in KS lesions and in KSHV-associated primary effusion lymphoma (PEL) cells. ANG knockdown or the inhibition of ANG's nuclear translocation resulted in decreased LANA-1 gene expression and reduced KSHV-infected endothelial and PEL cell survival (Sadagopan et al., J. Virol.
83:
3342–3364, 2009). Further studies here demonstrate that LANA-1 and ANG colocalize and coimmunoprecipitate in
de novo
infected endothelial cells and in latently infected PEL (BCBL-1 and BC-3) cells. LANA-1 and ANG interaction occurred in the absence of the KSHV genome and other viral proteins. In gel filtration chromatography analyses of BC-3 cell lysates, ANG coeluted with LANA-1, p53, and Mdm2 in high-molecular-weight fractions, and LANA-1, p53, and Mdm2 also coimmunoprecipitated with ANG. LANA-1, ANG, and p53 colocalized in KSHV-infected cells, and colocalization between ANG and p53 was also observed in LANA-1-negative cells. The deletion constructs of ANG suggested that the C-terminal region of amino acids 104 to 123 is involved in LANA-1 and p53 interactions. Silencing ANG or inhibiting its nuclear translocation resulted in decreased nuclear LANA-1 and ANG levels, decreased interactions between ANG-LANA-1, ANG-p53, and LANA-1-p53, the induction of p53, p21, and Bax proteins, the increased cytoplasmic localization of p53, the downregulation of Bcl-2, the increased cleavage of caspase-3, and the apoptosis of cells. No such effects were observed in KSHV-negative BJAB cells. The phosphorylation of p53 at serine 15, which is essential for p53 stabilization and for p53's apoptotic and cell cycle regulation functions, was increased in BCBL-1 cells transduced with short hairpin RNA targeting ANG. Together, these studies suggest that the antiapoptosis observed in KSHV-infected cells and the suppression of p53 functions are mediated in part by ANG, and KSHV has probably evolved to utilize angiogenin's multiple functions for the maintenance of its latency and cell survival. Thus, targeting ANG to induce the apoptosis of cells latently infected with KSHV is an attractive therapeutic strategy against KSHV infection and associated malignancies.
Effects of Manipulating Apoptosis on Sindbis Virus Infection of Aedes aegypti Mosquitoes
Authors: Wang Hua , Gort Taryn , Boyle Daniel L. , Clem Rollie J. 
Published: March 2012

ABSTRACT

Improved control of vector-borne diseases requires an understanding of the molecular factors that determine vector competence. Apoptosis has been shown to play a role in defense against viruses in insects and mammals. Although some observations suggest a correlation between apoptosis and resistance to arboviruses in mosquitoes, there is no direct evidence tying apoptosis to arbovirus vector competence. To determine whether apoptosis can influence arbovirus replication in mosquitoes, we manipulated apoptosis in
Aedes aegypti
mosquitoes by silencing the expression of genes that either positively or negatively regulate apoptosis. Silencing of the
A. aegypti
anti-apoptotic gene
iap1
(
Aeiap1
) caused apoptosis in midgut epithelium, alterations in midgut morphology, and 60 to 70% mosquito mortality. Mortality induced by
Aeiap1
silencing was rescued by cosilencing the initiator caspase gene
Aedronc
, indicating that the mortality was due to apoptosis. When mosquitoes which had been injected with
Aeiap1
double-stranded RNA (dsRNA) were orally infected with Sindbis virus (SINV), increased midgut infection and virus dissemination to other organs were observed. This increase in virus infection may have been due to the effects of widespread apoptosis on infection barriers or innate immunity. In contrast, silencing the expression of
Aedronc
, which would be expected to inhibit apoptosis, reduced SINV midgut infection and virus dissemination. Thus, our data suggest that some level of caspase activity and/or apoptosis may be necessary for efficient virus replication and dissemination in mosquitoes. This is the first study to directly test the roles of apoptosis and caspases in determining mosquito vector competence for arboviruses.
RNA Interference-Mediated Targeting of Human Cytomegalovirus Immediate-Early or Early Gene Products Inhibits Viral Replication with Differential Effects on Cellular Functions
Authors: E Xiaofei , Stadler Bradford M. , Debatis Michelle , Wang Shixia , Lu Shan , Kowalik Timothy F. 
Published: March 2012

ABSTRACT

Viral drug toxicity, resistance, and an increasing immunosuppressed population warrant continued research into new avenues for limiting diseases associated with human cytomegalovirus (HCMV). In this study, a small interfering RNA (siRNA), siX3, was designed to target coding sequences within shared exon 3 of
UL123
and
UL122
transcripts encoding IE1 and IE2 immediate-early proteins of HCMV. Pretreatment of cells with siX3 reduced the levels of viral protein expression, DNA replication, and progeny virus production compared to control siRNA. Two siRNAs against
UL54
and overlapping transcripts (
UL55-57
) were compared to siX3 in HCMV infection and were also found to be effective at inhibiting HCMV replication. Further investigation into the effects of the siRNAs on viral replication showed that pretreatment with each of the siRNAs resulted in an inhibition in the formation of mature replication compartments. The ability of these siRNAs to prevent or reduce certain cytopathic effects associated with HCMV infection was also examined. Infected cells pretreated with siX3, but not siUL54, retained promyelocytic leukemia (PML) protein in cellular PML bodies, an essential component of this host intrinsic antiviral defense. DNA damage response proteins, which are localized in nuclear viral replication compartments, were reduced in the siX3- and siUL54-treated cells. siX3, but not siUL54, prevented DNA damage response signaling early after infection. Therapeutic efficacy was demonstrated by treating cells with siRNAs after HCMV replication had commenced. Together, these findings suggest that siRNAs targeting exon 3 of the major
IE
genes or the
UL54-57
transcripts be further studied for their potential development into anti-HCMV therapeutics.
Visualizing Coronavirus RNA Synthesis in Time by Using Click Chemistry
Authors: Hagemeijer Marne C. , Vonk Annelotte M. , Monastyrska Iryna , Rottier Peter J. M. , de Haan Cornelis A. M. 
Published: March 2012

ABSTRACT
Coronaviruses induce in infected cells the formation of replicative structures, consisting of double-membrane vesicles (DMVs) and convoluted membranes, where viral RNA synthesis supposedly takes place and to which the nonstructural proteins (nsp's) localize. Double-stranded RNA (dsRNA), the presumed intermediate in RNA synthesis, is localized to the DMV interior. However, as pores connecting the DMV interior with the cytoplasm have not been detected, it is unclear whether RNA synthesis occurs at these same sites. Here, we studied coronavirus RNA synthesis by feeding cells with a uridine analogue, after which nascent RNAs were detected using click chemistry. Early in infection, nascent viral RNA and nsp's colocalized with or occurred adjacent to dsRNA foci. Late in infection, the correlation between dsRNA dots, then found dispersed throughout the cytoplasm, and nsp's and nascent RNAs was less obvious. However, foci of nascent RNAs were always found to colocalize with the nsp12-encoded RNA-dependent RNA polymerase. These results demonstrate the feasibility of detecting viral RNA synthesis by using click chemistry and indicate that dsRNA dots do not necessarily correspond with sites of active viral RNA synthesis. Rather, late in infection many DMVs may harbor dsRNA molecules that are no longer functioning as intermediates in RNA synthesis.
Suppression of Injuries Caused by a Lytic RNA Virus (Mengovirus) and Their Uncoupling from Viral Reproduction by Mutual Cell/Virus Disarmament
Authors: Mikitas Olga V. , Ivin Yuri Y. , Golyshev Sergey A. , Povarova Natalia V. , Galkina Svetlana I. , Pletjushkina Olga Y. , Nadezhdina Elena S. , Gmyl Anatoly P. , Agol Vadim I. 
Published: March 2012

ABSTRACTViruses often elicit cell injury (cytopathic effect [CPE]), a major cause of viral diseases. CPE is usually considered to be a prerequisite for and/or consequence of efficient viral growth. Recently, we proposed that viral CPE may largely be due to host defensive and viral antidefensive activities. This study aimed to check the validity of this proposal by using as a model HeLa cells infected with mengovirus (MV). As we showed previously, infection of these cells with wild-type MV resulted in necrosis, whereas a mutant with incapacitated antidefensive (“security”) viral leader (L) protein induced apoptosis. Here, we showed that several major morphological and biochemical signs of CPE (e.g., alterations in cellular and nuclear shape, plasma membrane, cytoskeleton, chromatin, and metabolic activity) in cells infected with L−mutants in the presence of an apoptosis inhibitor were strongly suppressed or delayed for long after completion of viral reproduction. These facts demonstrate that the efficient reproduction of a lytic virus may not directly require development of at least some pathological alterations normally accompanying infection. They also imply that L protein is involved in the control of many apparently unrelated functions. The results also suggest that the virus-activated program with competing necrotic and apoptotic branches is host encoded, with the choice between apoptosis and necrosis depending on a variety of intrinsic and extrinsic conditions. Implementation of this defensive suicidal program could be uncoupled from the viral reproduction. The possibility of such uncoupling has significant implications for the pathogenesis and treatment of viral diseases.
Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells
Authors: Qi Nan , Zhang Lei , Qiu Yang , Wang Zhaowei , Si Jie , Liu Yongxiang , Xiang Xue , Xie Jiazheng , Qin Cheng-Feng , Zhou Xi , Hu Yuanyang 
Published: March 2012

ABSTRACT

RNA interference (RNAi) is a eukaryotic gene-silencing mechanism that functions in antiviral immunity in diverse organisms. To combat RNAi-mediated immunity, viruses encode viral suppressors of RNA silencing (VSRs) that target RNA and protein components in the RNAi machinery. Although the endonuclease Dicer plays key roles in RNAi immunity, little is known about how VSRs target Dicer. Here, we show that the B2 protein from Wuhan nodavirus (WhNV), the counterpart of Flock House virus (FHV), suppresses
Drosophila melanogaster
RNAi by directly interacting with Dicer-2 (Dcr-2) and sequestering double-stranded RNA (dsRNA) and small interfering RNA (siRNA). Further investigations reveal that WhNV B2 binds to the RNase III and Piwi-Argonaut-Zwille (PAZ) domains of Dcr-2 via its C-terminal region, thereby blocking the activities of Dcr-2 in processing dsRNA and incorporating siRNA into the RNA-induced silencing complex (RISC). Moreover, we uncover an interrelationship among diverse activities of WhNV B2, showing that RNA binding enhances the B2–Dcr-2 interaction by promoting B2 homodimerization. Taken together, our findings establish a model of suppression of
Drosophila
RNAi by WhNV B2 targeting both Dcr-2 and RNA and provide evidence that an interrelationship exists among diverse activities of VSRs to antagonize RNAi.
Sickle cell trait associated with a RR of death of 37 times in national collegiate athletic association football athletes: a database with 2 million athlete-years as the denominator
Authors: Harmon Kimberly G , Drezner Jonathan A , Klossner David , Asif Irfan M 
Published: March 2012

BackgroundThis study examines sickle cell trait (SCT) as a cause of sudden death in National Collegiate Athletic Association (NCAA) athletes and explores the cost-effectiveness of different screening models.MethodsThe authors reviewed the cause of all cases of sudden death in NCAA student-athletes from January 2004 through December 2008. The authors also explored the cost-effectiveness of screening for this condition in selected populations assuming that identifying athletes with SCT would prevent death.ResultsThere were 273 deaths and a total of 1 969 663 athlete-participant-years. Five (2%) deaths were associated with SCT. In football athletes, there were 72 (26%) deaths. Of these, 52 (72%) were due to trauma unrelated to sports activity and 20 (28%) were due to medical causes; nine deaths were cardiac (45%), five were associated with SCT (25%). Thirteen of the 20 deaths due to medical causes occurred during exertion; cardiac (6, 46%) SCT associated (5, 39%), and heat stroke unrelated to SCT (2, 15%). All deaths associated with SCT occurred in black Division I football athletes. The risk of exertional death in Division I football players with SCT was 1:827 which was 37 times higher than in athletes without SCT. The cost per case identified varied widely depending on the population screened and the price of the screening test.ConclusionsExertional death in athletes with SCT occurs at a higher rate than previously appreciated. More research is needed to (1) understand the pathophysiology of death in SCT-positive athletes and (2) determine whether screening high-risk populations reduces mortality.
Serial multiple biomarkers in the assessment of suspected acute coronary syndrome: multiple infarct markers in chest pain (MIMIC) study
Authors: Macdonald Stephen PJ , Nagree Yusuf , Fatovich Daniel M , Phillips Michael , Brown Simon GA 
Published: March 2012

ObjectiveTo evaluate the accuracy of a 2-h serial multiple biomarker (SMB) protocol for exclusion of myocardial infarction (MI) in the Emergency Department.MethodsA prospective, multicentre, observational study enrolled patients undergoing evaluation for possible MI. Blood samples at presentation and 2 h later were analysed for myoglobin, creatinine kinase-MB, troponin-I and B-natriuretic peptide. Thrombolysis in Myocardial Infarction (TIMI) score and National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand (NHF/CSANZ) guideline for acute coronary syndrome were used to determine clinical risk. Primary outcome was MI diagnosed at index presentation. Secondary outcome was composite of all-cause mortality, MI and previously unplanned coronary revascularisation within 30 days.Results1758 patients were recruited. 168 (11%) of 1501 with data sufficient for analysis had MI, and 223 (14%) of 1620 had a secondary outcome. SMB sensitivity and specificity were 0.90 (95% CI 0.84 to 0.94) and 0.41 (95% CI 0.39 to 0.44) for MI. For 30-day outcome, SMB sensitivity and specificity were 0.84 (95% CI 0.78 to 0.88) and 0.41 (95% CI 0.39 to 0.44), compared with standard 8–12 h troponin sensitivity and specificity of 0.79 (95% CI 0.73 to 0.84) and 0.96 (95% CI 0.95 to 0.97). Combined with risk scores, SMB had sensitivity and specificity for MI of 0.99 (0.96 to 1.00) and 0.11 (95% CI 0.09 to 0.12) for TIMI score 0, compared with 0.98 (95% CI 0.94 to 0.99) and 0.31 (95% CI 0.29 to 0.34) for NHF/CSANZ low/intermediate risk groups.ConclusionsSMB alone is not sufficiently sensitive to exclude MI. Combined with risk scoring, SMB appears to identify patients at lower risk. This requires prospective validation.
Dithiolethiones Inhibit NF-κB Activity via Covalent Modification in Human Estrogen Receptor–Negative Breast Cancer
Authors: Switzer Christopher H. , Cheng Robert Y.-S. , Ridnour Lisa A. , Murray Margaret C. , Tazzari Valerio , Sparatore Anna , Del Soldato Piero , Hines Harry B. , Glynn Sharon A. , Ambs Stefan , Wink David A. 
Published: March 2012

Abstract
The NF-κB transcription factor family influences breast cancer outcomes by regulating genes involved in tumor progression, angiogenesis, and metastasis. Dithiolethiones, a class of naturally occurring compounds with cancer chemoprevention effects that have become clinically available, have been found to inhibit NF-κB activity. However, the mechanism of this inhibition has not been identified, and the influence of dithiolethines on NF-κB pathway in breast cancer cells has not been examined. Here, we investigated the chemical and biochemical effects of dithiolethione on NF-κB and downstream effector molecules in estrogen receptor–negative breast cancer cells and murine tumor xenografts. The dithiolethiones ACS-1 and ACS-2 inhibited NF-κB transcriptional activity. Interestingly, this inhibition was not due to H2S release or protein phosphatase 2A activation, which are key properties of dithiolethiones, but occurred via a covalent reaction with the NF-κB p50 and p65 subunits to inhibit DNA binding. Dithiolethione-mediated inhibition of NF-κB–regulated genes resulted in the inhibition of interleukin (IL)-6, IL-8, urokinase-type plasminogen activator, and VEGF production. ACS-1 also inhibited matrix metalloproteinase-9 activity, cellular migration, and invasion, and ACS-2 reduced tumor burden and resulted in increased tumor host interactions. Together, our findings suggest that dithiolethiones show potential clinical use for estrogen negative breast cancer as a chemotherapeutic or adjuvant therapy. Cancer Res; 72(9); 2394–404. ©2012 AACR.
Reduced coagulation at high altitude identified by thromboelastography
Authors: Martin Daniel , Pate Jim , Vercueil Andre , Doyle Patrick , Mythen Michael , Grocott Mike ,   for the Caudwell Xtreme Everest Research Group
Published: March 2012

SummaryThe impact of hypoxaemia on blood coagulation remains unclear despite use of a variety of measures to address the issue. We report the first use of thromboelastography (TEG) at high altitude to describe the dynamics of clot formation in whole blood samples. Seventeen healthy volunteers ascended to 5,300 m following an identical ascent profile; TEG measurements at 4,250 m and 5,300 m were compared with those from sea level. Peripheral oxygen saturation (SpO2) and haematocrit were also measured. Ascent resulted in a decline in SpO2 from 97.8 (± 1.2) % at sea level to 86.9 (± 3.3) % at 4,250 m and 79.5 (± 5.8) % at 5,300 m (p<0.001); haematocrit rose from 43.7 (± 2.8) % at sea level, to 46.7 (± 3.9) % and 52.6 (± 3.2) % at 4,250 m and 5,300 m, respectively (p<0.01). TEG reaction (R)-time and kinetic (K)-time were both increased at 5,300 m compared to sea level, 8.95 (± 1.37) minutes (min) to 11.69 (± 2.91) min (p=0.016) and 2.40 (± 0.66) min to 4.99 (± 1.67) min (p<0.001), respectively. Additionally the alpha (α)- angle was decreased from 57.7 (± 8.2) to 51.6 (± 6.4) (p<0.001). There was no change in maximum amplitude (MA) on ascent to altitude. These changes are consistent with an overall pattern of slowed coagulation at high altitude.
Stroke in Children With Posterior Fossa Brain Malformations, Hemangiomas, Arterial Anomalies, Coarctation of the Aorta and Cardiac Defects, and Eye Abnormalities (PHACE) Syndrome
Authors: Siegel Dawn H. , Tefft Kimberly A. , Kelly Teresa , Johnson Craig , Metry Denise , Burrows Patricia , Pope Elena , Cordisco Maria , Holland Kristen E. , Maheshwari Mohit , Keith Phillip , Garzon Maria , Hess Christopher , Frieden Ilona J. , Fullerton Heather J. , Drolet Beth A. 
Published: March 2012

Background and Purpose—
PHACE is an acronym for posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Several case reports of arterial ischemic stroke (AIS) in individuals with PHACE have been published, but risk factors for AIS in PHACE have not been clearly defined. The objective of this article is to review all cases of stroke in PHACE in children and describe clinical characteristics that may be associated with an increased risk of AIS.

Methods—
A literature and registry search was conducted to identify patients with PHACE who had experienced AIS. Data were analyzed to determine age of onset, presenting signs and symptoms, and clinical features among this cohort compared with PHACE without AIS.

Results—
Twenty-two individuals with PHACE and AIS were identified. Imaging of the arteries of the head and neck was reported in 20 of 22. Narrowing or nonvisualization of at least 1 great cerebral vessel was present in 19 of 20 and of those, 15 had ≥2 vessels involved. Aortic arch anomalies were reported in 13 of 22 individuals.

Conclusions—
Aplasia, hypoplasia, or occlusion of a major cerebral artery appears to be a significant risk factor for AIS in children with PHACE, especially when >1 vessel is involved or if there is coarctation of the aorta.