bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synonymous Deoptimization of Foot-and-Mouth Disease Virus Causes Attenuation
In Vivo
while Inducing a Strong Neutralizing Antibody Response
Authors: Diaz-San Segundo Fayna , Medina Gisselle N. , Ramirez-Medina Elizabeth , Velazquez-Salinas Lauro , Koster Marla , Grubman Marvin J. , de los Santos Teresa 
Published: November 2015

ABSTRACT
Codon bias deoptimization has been previously used to successfully attenuate human pathogens, including poliovirus, respiratory syncytial virus, and influenza virus. We have applied a similar technology to deoptimize the capsid-coding region (P1) of foot-and-mouth disease virus (FMDV). Despite the introduction of 489 nucleotide changes (19%), synonymous deoptimization of the P1 region rendered a viable FMDV progeny. The resulting strain was stable and reached cell culture titers similar to those obtained for wild-type (WT) virus, but at reduced specific infectivity. Studies in mice showed that 100% of animals inoculated with the FMDV A12 P1 deoptimized mutant (A12-P1 deopt) survived, even when the animals were infected at doses 100 times higher than the dose required to cause death by WT virus. All mice inoculated with the A12-P1 deopt mutant developed a strong antibody response and were protected against subsequent lethal challenge with WT virus at 21 days postinoculation. Remarkably, the vaccine safety margin was at least 1,000-fold higher for A12-P1 deopt than for WT virus. Similar patterns of attenuation were observed in swine, in which animals inoculated with A12-P1 deopt virus did not develop clinical disease until doses reached 1,000 to 10,000 times the dose required to cause severe disease in 2 days with WT A12. Consistently, high levels of antibody titers were induced, even at the lowest dose tested. These results highlight the potential use of synonymous codon pair deoptimization as a strategy to safely attenuate FMDV and further develop live attenuated vaccine candidates to control such a feared livestock disease.

IMPORTANCE
Foot-and-mouth disease (FMD) is one of the most feared viral diseases that can affect livestock. Although this disease appeared to be contained in developed nations by the end of the last century, recent outbreaks in Europe, Japan, Taiwan, South Korea, etc., have demonstrated that infection can spread rapidly, causing devastating economic and social consequences. The Global Foot-and-Mouth Disease Research Alliance (GFRA), an international organization launched in 2003, has set as part of their five main goals the development of next-generation control measures and strategies, including improved vaccines and biotherapeutics. Our work demonstrates that newly developed codon pair bias deoptimization technologies can be applied to FMD virus to obtain attenuated strains with potential for further development as novel live attenuated vaccine candidates that may rapidly control disease without reverting to virulence.
Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel
cis
-Acting Regulatory Sequence
Authors: Cavallari Ilaria , Rende Francesca , Bona Marion K. , Sztuba-Solinska Joanna , Silic-Benussi Micol , Tognon Martina , LeGrice Stuart F. J. , Franchini Genoveffa , D'Agostino Donna M. , Ciminale Vincenzo 
Published: November 2015

ABSTRACT

Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex–wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the
p21rex
mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the
p30tof
,
p13
, and
p12/8
mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system.

IMPORTANCE
HTLV-1 is a complex retrovirus that causes two distinct pathologies termed adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-1-associated myelopathy in about 5% of infected individuals. Expression of the virus depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of virus expression. The findings reported in this study revealed a novel
cis
-acting regulatory element and indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. Our results add a layer of complexity to the mechanisms controlling the expression of alternatively spliced HTLV-1 mRNAs and suggest a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system.
RNA Replication and Membrane Modification Require the Same Functions of Alphavirus Nonstructural Proteins
Authors: Kallio Katri , Hellström Kirsi , Jokitalo Eija , Ahola Tero 
Published: November 2015

ABSTRACT

The alphaviruses induce membrane invaginations known as spherules as their RNA replication sites. Here, we show that inactivation of any function (polymerase, helicase, protease, or membrane association) essential for RNA synthesis also prevents the generation of spherule structures in a Semliki Forest virus
trans
-replication system. Mutants capable of negative-strand synthesis, including those defective in RNA capping, gave rise to spherules. Recruitment of RNA to membranes in the absence of spherule formation was not detected.
Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice
Authors: Xie Guorui , Luo Huanle , Pang Lan , Peng Bi-hung , Winkelmann Evandro , McGruder Brenna , Hesse Joseph , Whiteman Melissa , Campbell Gerald , Milligan Gregg N. , Cong Yingzi , Barrett Alan D. , Wang Tian 
Published: November 2015

ABSTRACT
The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), a mosquito-borne flavivirus, has induced severe neurological symptoms, mostly in the elderly population. No vaccines are available for human use. Recent work showed that an attenuated WNV, a nonstructural (NS) 4B-P38G mutant, induced no lethality but strong immune responses in young (6- to 10-week-old) mice. While studying protective efficacy, we found unexpectedly that old (21- to 22-month) mice were susceptible to WNV NS4B-P38G mutant infection but were protected from subsequent lethal wild-type WNV challenge. Compared to responses in young mice, the NS4B-P38G mutant triggered higher inflammatory cytokine and interleukin-10 (IL-10) production, a delayed γδ T cell expansion, and lower antibody and WNV-specific T cell responses in old mice. Toll-like receptor 7 (TLR7) is expressed on multiple types of cells. Impaired TLR7 signaling in old mice led to dendritic cell (DC) antigen-presenting function compromise and a reduced γδ T cell and regulatory T cell (Treg) expansion during NS4B-P38G mutant infection. R848, a TLR7 agonist, decreased host vulnerability in NS4B-P38G-infected old mice by enhancing γδ T cell and Treg expansion and the antigen-presenting capacity of DCs, thereby promoting T cell responses. In summary, our results suggest that dysregulation of TLR7 partially contributes to impaired innate and adaptive T cell responses and an enhanced vulnerability in old mice during WNV NS4B-P38G mutant infection. R848 increases the safety and efficacy during immunization of old mice with the WNV NS4B-P38G mutant.

IMPORTANCE
The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), an emerging mosquito-borne flavivirus, has induced severe neurological symptoms more frequently in the elderly population. No vaccines are available for human use. Here, we used an aged mouse model to investigate the protective efficacy of an attenuated WNV, the nonstructural 4B-P38G mutant, which was previously shown to induce no lethality but strong immune responses in young adult mice. Studies that contribute to a mechanistic understanding of immune defects in the elderly will allow the development of strategies to improve responses to infectious diseases and to increase vaccine efficacy and safety in aging individuals.
Generation of an Avian-Mammalian Rotavirus Reassortant by Using a Helper Virus-Dependent Reverse Genetics System
Authors: Johne Reimar , Reetz Jochen , Kaufer Benedikt B. , Trojnar Eva 
Published: November 2015

ABSTRACT
The genetic diversity of rotavirus A (RVA) strains is facilitated in part by genetic reassortment. Although this process of genome segment exchange has been reported frequently among mammalian RVAs, it remained unknown if mammalian RVAs also could package genome segments from avian RVA strains. We generated a simian RVA strain SA11 reassortant containing the VP4 gene of chicken RVA strain 02V0002G3. To achieve this, we transfected BSR5/T7 cells with a T7 polymerase-driven VP4-encoding plasmid, infected the cells with a temperature-sensitive SA11 VP4 mutant, and selected the recombinant virus by increasing the temperature. The reassortant virus could be stably passaged and exhibited cytopathic effects in MA-104 cells, but it replicated less efficiently than both parental viruses. Our results show that avian and mammalian rotaviruses can exchange genome segments, resulting in replication-competent reassortants with new genomic and antigenic features.

IMPORTANCE
This study shows that rotaviruses of mammals can package genome segments from rotaviruses of birds. The genetic diversity of rotaviruses could be broadened by this process, which might be important for their antigenic variability. The reverse genetics system applied in the study could be useful for targeted generation and subsequent characterization of distinct rotavirus reassortant strains.
Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a
Authors: Grauwet K. , Vitale M. , De Pelsmaeker S. , Jacob T. , Laval K. , Moretta L. , Parodi M. , Parolini S. , Cantoni C. , Favoreel H. W. 
Published: November 2015

ABSTRACTSeveral reports have indicated that natural killer (NK) cells are of particular importance in the innate response against herpesvirus infections. As a consequence, herpesviruses have developed diverse mechanisms for evading NK cells, although few such mechanisms have been identified for the largest herpesvirus subfamily, the alphaherpesviruses. The antiviral activity of NK cells is regulated by a complex array of interactions between activating/inhibitory receptors on the NK cell surface and the corresponding ligands on the surfaces of virus-infected cells. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) displays previously uncharacterized immune evasion properties: it triggers the binding of the inhibitory NK cell receptor CD300a to the surface of the infected cell, thereby providing increased CD300a-mediated protection of infected cells against NK cell-mediated lysis. US3-mediated CD300a binding was found to depend on aminophospholipid ligands of CD300a and on group I p21-activated kinases. These data identify a novel alphaherpesvirus strategy for evading NK cells and demonstrate, for the first time, a role for CD300a in regulating NK cell activity upon contact with virus-infected target cells.IMPORTANCEHerpesviruses have developed fascinating mechanisms to evade elimination by key elements of the host immune system, contributing to their ability to cause lifelong infections with recurrent reactivation events. Natural killer (NK) cells are central in the innate antiviral response. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus displays a previously uncharacterized capacity for evasion of NK cells. Expression of US3 protects infected cells from NK cell-mediated lysis via increased binding of the inhibitory NK cell receptor CD300a. We show that this US3-mediated increase in CD300a binding depends on aminophospholipids and on cellular p21-activated kinases (PAKs). The identification of this novel NK cell evasion strategy may contribute to the design of improved herpesvirus vaccines and may also have significance for other PAK- and CD300a-modulating viruses and cancer cells.
Effectiveness and safety of 1 vs 4 h blood pressure profile with clinical and laboratory assessment for the exclusion of gestational hypertension and pre-eclampsia: a retrospective study in a university affiliated maternity hospital
Authors: McCarthy Elizabeth Anne , Carins Thomas A , Hannigan Yolanda , Bardien Nadia , Shub Alexis , Walker Susan P 
Published: November 2015

ObjectiveWe asked whether 60 compared with 240 min observation is sufficiently informative and safe for pregnancy day assessment (PDAC) of suspected pre-eclampsia (PE).DesignA retrospective study of 209 pregnant women (475 PDAC assessments, 6 months) with routinely collected blood pressure (BP), symptom and laboratory information. We proposed a 60 min screening algorithm comprising: absence of symptoms, normal laboratory parameters and ≤1high-BP reading (systolic blood pressure, SBP 140 mm Hg or higher or diastolic blood pressure, DBP 90 mm Hg or higher). We also evaluated two less inclusive screening algorithms. We determined short-term outcomes (within 4 h): severe hypertension, proteinuric hypertension and pregnancy-induced hypertension, as well as long-term outcome: PE-related diagnoses up to the early puerperium. We assessed performance of alternate screening algorithms performance using 2×2 tables.Results1 in 3 women met all screen negative criteria at 1 h. Their risk of hypertension requiring treatment in the next 3 h was 1.8% and of failing to diagnose proteinuric hypertensive PE at 4 h was 5.1%. If BP triggers were 5 mm Hg lower, 1 in 6 women would be screen-negative of whom 1.1% subsequently develops treatment-requiring hypertension and 4.5% demonstrate short-term proteinuric hypertension. We present sensitivity, specificity, negative and positive likelihood ratios for alternate screening algorithms.ConclusionsWe endorse further research into the safest screening test where women are considered for discharge after 60 min. Safety, patient and staff satisfaction should be assessed prospectively. Any screening test should be used in conjunction with good clinical care to minimise maternal and perinatal hazards of PE.
Acupuncture for postoperative pain following total knee arthroplasty: a systematic review protocol
Authors: Jung Jae-Young , Cho Jae-Heung , Chung Seok-hee 
Published: November 2015

IntroductionTotal knee arthroplasty (TKA) is a common surgical method in orthopaedics; however, pain management after TKA remains a significant challenge. This review provides a comprehensive evaluation of the effects of acupuncture for postoperative pain after TKA.Methods and analysisThe following 10 databases will be searched until August 2015: MEDLINE, EMBASE, CENTRAL, AMED, CINAHL, three Chinese databases (the China National Knowledge Infrastructure Database, the Chongqing VIP Chinese Science and Technology Periodical Database, and Wanfang Database) and five Korean databases (the Korean Medical Database, the Korean Studies Information Service System, the National Discovery for Science Leaders, the Database Periodical Information Academic, and the Oriental Medicine Advanced Searching Integrated System). All eligible randomised controlled trials related to the use of acupuncture for postoperative pain after TKA will be included. Assessment of risk of bias will be performed with the Cochrane risk-of-bias method. Mean differences or standardised mean differences will be calculated with 95% CIs for continuous data; the risk ratio will be used with 95% CIs for dichotomous data.DisseminationThis systematic review will be presented in a peer-reviewed journal. The result of this review will also be disseminated at a relevant conference presentation.Trial registration numberPROSPERO 2015: CRD42015020924.
Discontinuation rates of biologics in patients with rheumatoid arthritis: are TNF inhibitors different from non-TNF inhibitors?
Authors: Ramiro Sofia , Landewé Robert , van der Heijde Désirée , Harrison David , Collier David , Michaud Kaleb 
Published: November 2015

ObjectiveTo compare discontinuation rates of first and second biologics in rheumatoid arthritis (RA) by tumour-necrosis factor inhibitor (TNFi) status and identify predictors and reasons for discontinuation.MethodsFrom 1998 to 2011, self-reported medication use for RA was assessed every 6 months via questionnaire in a longitudinal study in the USA. Time-on-drug analyses were conducted for individual biologics and groups, and annual rates reported. Time to discontinuation of TNFi and non-TNFi was compared, unadjusted and adjusted using propensity score analyses. Baseline and time-varying predictors of biologic discontinuation were derived through Cox regression.ResultsOf 2281 patients initiating their first biologic, 1100 (48%) discontinued and of 1097 initiating a second biologic, 537 (49%) discontinued. The annual discontinuation rate was 17% (median 4 years) for first biologic and 20% (median 3.3 years) for second biologic. TNFi had lower discontinuation rates than non-TNFi after propensity score adjustment: HR for first biologic 0.49 (0.34 to 0.71) and 0.68 (0.51 to 0.90) for second biologic. The annual discontinuation rate was significantly lower in patients starting their first biologic before January 2005 vs after (16 vs 25%, p=0.005). Predictors of discontinuation for the first biologic included smoking, higher comorbidity index, worse overall health and not using concomitant methotrexate.ConclusionsIn this large cohort, patients with RA tended to remain on their first and second biologics for relatively long periods suggesting the drugs’ effectiveness. Discontinuation rates were lower in patients using TNFi, and all rates increased after January 2005 when the number of biologics available increased.
Nicotine and Toxicant Exposure among U.S. Smokeless Tobacco Users: Results from 1999 to 2012 National Health and Nutrition Examination Survey Data
Authors: Rostron Brian L. , Chang Cindy M. , van Bemmel Dana M. , Xia Yang , Blount Benjamin C. 
Published: November 2015

Abstract
Background: It has been suggested that smokeless tobacco users have high nicotine and toxicant exposure, but studies with nationally representative data have been limited.
Methods: We analyzed biomarkers of tobacco exposure for 23,684 adult participants from the National Health and Nutrition Examination Survey from 1999 to 2012. The biomarkers analyzed were serum cotinine, urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), blood lead, blood cadmium, blood mercury, urinary arsenic, and urinary N-acetyl-S-(2-cyanoethyl)-L-cysteine. We calculated geometric mean concentrations for each biomarker by tobacco use category and geometric mean ratios adjusting for demographic factors.
Results: Exclusive smokeless tobacco users had higher geometric mean concentrations of serum cotinine [178.9 ng/mL, 95% confidence interval (CI), 145.5–220.0] and NNAL (583.0 pg/mg creatinine, 95% CI, 445.2–763.5) than exclusive cigarette smokers (130.6 ng/mL, 95% CI, 122.3–139.6 and 217.6 pg/mg creatinine, 95% CI, 193.0–245.2, respectively). Smokeless tobacco users also had higher concentrations of blood lead compared with nontobacco users (adjusted geometric mean ratio = 1.30, 95% CI, 1.21–1.38). Based on limited sample sizes, NNAL concentrations for smokeless tobacco users appear to have declined from 2007 to 2008 (geometric mean = 1013.7 pg/mg creatinine, 95% CI, 738.9–1390.8) to 2011 to 2012 (geometric mean = 325.7 pg/mg creatinine, 95% CI, 159.6–664.9).
Conclusions: Exclusive smokeless tobacco users have higher observed levels of exposure to nicotine and carcinogenic tobacco-specific nitrosamines, as measured by cotinine and NNAL biomarker concentrations, than exclusive cigarette smokers. These patterns in NNAL levels for smokeless tobacco users may be changing over time.
Impact: High exposure to harmful constituents among smokeless tobacco users is a continuing health issue. Cancer Epidemiol Biomarkers Prev; 24(12); 1829–37. ©2015 AACR.
Are Doses and Schedules of Small-Molecule Targeted Anticancer Drugs Recommended by Phase I Studies Realistic?
Authors: Roda Desamparados , Jimenez Begoña , Banerji Udai 
Published: November 2015

Abstract
Tolerability of molecularly targeted agents (MTA) used in cancer therapeutics is determined in phase I trials. We reviewed the reported incidence of toxicity in phase III trials at doses and schedules recommended by phase I trials to evaluate whether these recommendations are realistic when drugs are used in larger populations of patients. We systematically reviewed a safety profile of small molecule (SM-MTA) and mAb MTA (MA-MTA) approved by the FDA in the last 12 years. There was a significantly increased percentage of grade 3 or 4 adverse events reported with SM-MTA compared with MA-MTA [40% vs. 27%; RR 1.5; 95% confidence interval (CI), 1.10–2.25, P = 0.038] in phase III studies. Importantly, a substantial proportion of patients (45%) treated with SM-MTA required dose modifications due to drug-related toxicity in phase III trials. However, this toxicity was associated to a definitive study drug discontinuation in only 9%. Overall, 25% of SM-MTA declared recommended phase II doses below MTD based on pharmacokinetic–pharmacodynamic data and these trials were associated with a significantly reduced number of dose modifications in registration trials (32% vs. 50%; RR 0.64; 95% CI, 0.43–0.88, P = 0.01). Tolerability is going to come into further focus due to the need for combinations of SM-MTA and other anticancer agents. There was a higher incidence of grade 3–4 toxicity in phase III trials in combinations versus single-agent SM-MTAs (64% vs. 37%; RR 1.73; 95% CI, 1.3–2.3, P = 0.001). These results indicate that phase I studies underestimate toxicity while recommending doses of SM-MTA. Clin Cancer Res; 22(9); 2127–32. ©2015 AACR.
A checklist of birds of Kerala, India
Authors: J Praveen 
Published: November 2015

<p>A checklist of birds of Kerala State is presented in this paper. Accepted English names, scientific binomen, prevalent vernacular names in Malayalam, IUCN conservation status, endemism, Wildlife (Protection) Act schedules, and the appendices in the CITES, pertaining to the birds of Kerala are also given. The State of Kerala has 500 species of birds, 17 of which are endemic to Western Ghats, and 24 species fall under the various threatened categories of IUCN.</p><div> </div>