bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthesis and Antiviral Activities of Methylenecyclopropane Analogs with 6-Alkoxy and 6-Alkylthio Substitutions That Exhibit Broad-Spectrum Antiviral Activity against Human Herpesviruses
Authors: Prichard Mark N. , Williams John D. , Komazin-Meredith Gloria , Khan Atiyya R. , Price Nathan B. , Jefferson Geraldine M. , Harden Emma A. , Hartline Caroll B. , Peet Norton P. , Bowlin Terry L. 
Published: May 2013

ABSTRACT

Methylenecyclopropane nucleosides have been reported to be active against many of the human herpesviruses. The most active compound of this class is cyclopropavir (CPV), which exhibits good antiviral activity against human cytomegalovirus (HCMV), Epstein-Barr virus, both variants of human herpesvirus 6, and human herpesvirus 8. CPV has two hydroxymethyl groups on the methylenecyclopropane ring, but analogs with a single hydroxymethyl group, such as the prototypical (
S
)-synguanol, are also active and exhibit a broader spectrum of antiviral activity that also includes hepatitis B virus and human immunodeficiency virus. Here, a large set of monohydroxymethyl compounds with ether and thioether substituents at the 6 position of the purine was synthesized and evaluated for antiviral activity against a range of human herpesviruses. Some of these analogs had a broader spectrum of antiviral activity than CPV, in that they also inhibited the replication of herpes simplex viruses 1 and 2 and varicella-zoster virus. Interestingly, the antiviral activity of these compounds appeared to be dependent on the activity of the HCMV UL97 kinase but was relatively unaffected by the absence of thymidine kinase activity in HSV. These data taken together indicate that the mechanism of action of these analogs is distinct from that of CPV. They also suggest that they might be useful as broad-spectrum antiherpesvirus agents and may be effective in the treatment of resistant virus infections.
Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics
Authors: Kamal Mohamed A. , Van Wart Scott A. , Rayner Craig R. , Subramoney Vishak , Reynolds Daniel K. , Bulik Catharine C. , Smith Patrick F. , Bhavnani Sujata M. , Ambrose Paul G. , Forrest Alan 
Published: May 2013

ABSTRACTOseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individualpost hocpredictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2= 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.
Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies
Authors: Rayner C. R. , Bulik C. C. , Kamal M. A. , Reynolds D. K. , Toovey S. , Hammel J. P. , Smith P. F. , Bhavnani S. M. , Van Wart S. A. , Ambrose P. G. , Forrest A. 
Published: May 2013

ABSTRACTGiven the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC50] = 0.18 nM) or B/Yamagata (IC50= 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC0–24), minimum concentration of OC in plasma (Cmin), and maximum concentration of OC in plasma (Cmax). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC0–24evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC0–24threshold (∼14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.
Interaction of Mycobacterium leprae with Human Airway Epithelial Cells: Adherence, Entry, Survival, and Identification of Potential Adhesins by Surface Proteome Analysis
Authors: Silva Carlos A. M. , Danelishvili Lia , McNamara Michael , Berredo-Pinho Márcia , Bildfell Robert , Biet Franck , Rodrigues Luciana S. , Oliveira Albanita V. , Bermudez Luiz E. , Pessolani Maria C. V. 
Published: May 2013

ABSTRACT

This study examined the
in vitro
interaction between
Mycobacterium leprae
, the causative agent of leprosy, and human alveolar and nasal epithelial cells, demonstrating that
M. leprae
can enter both cell types and that both are capable of sustaining bacterial survival. Moreover, delivery of
M. leprae
to the nasal septum of mice resulted in macrophage and epithelial cell infection in the lung tissue, sustaining the idea that the airways constitute an important
M. leprae
entry route into the human body. Since critical aspects in understanding the mechanisms of infection are the identification and characterization of the adhesins involved in pathogen-host cell interaction, the nude mouse-derived
M. leprae
cell surface-exposed proteome was studied to uncover potentially relevant adhesin candidates. A total of 279 cell surface-exposed proteins were identified based on selective biotinylation, streptavidin-affinity purification, and shotgun mass spectrometry; 11 of those proteins have been previously described as potential adhesins.
In vitro
assays with the recombinant forms of the histone-like protein (Hlp) and the heparin-binding hemagglutinin (HBHA), considered to be major mycobacterial adhesins, confirmed their capacity to promote bacterial attachment to epithelial cells. Taking our data together, they suggest that the airway epithelium may act as a reservoir and/or portal of entry for
M. leprae
in humans. Moreover, our report sheds light on the potentially critical adhesins involved in
M. leprae
-epithelial cell interaction that may be useful in designing more effective tools for leprosy control.
Protective Role of Murine β-Defensins 3 and 4 and Cathelin-Related Antimicrobial Peptide in Fusarium solani Keratitis
Authors: Kolar Satya Sree N. , Baidouri Hasna , Hanlon Samuel , McDermott Alison M. 
Published: May 2013

ABSTRACTAntimicrobial peptides (AMPs), such as β-defensins and cathelicidins, are essential components of innate and adaptive immunity owing to their extensive multifunctional activities. However, their role in fungal infectionin vivoremains elusive. In this study, we investigated the protective effect of murine β-defensin 3 (mBD3), mBD4, and the cathelicidin cathelin-related antimicrobial peptide (CRAMP) in a murine model ofFusarium solanikeratitis. C57BL/6 mice showed significant corneal disease 1 and 3 days after infection, which was accompanied by enhanced expression of β-defensins and CRAMP. Disease severity was significantly improved 7 days after infection, at which time AMP expression was returning to baseline. Mice deficient in mBD3 (genetic knockout), mBD4 (short interfering RNA knockdown), or CRAMP (genetic knockout) exhibited enhanced disease severity and progression, increased neutrophil recruitment, and delayed pathogen elimination compared to controls. Taken together, these data suggest a vital role for AMPs in defense againstF. solanikeratitis, a potentially blinding corneal disease.
Suppression of Ser/Thr Phosphatase 4 (PP4C/PPP4C) Mimics a Novel Post-Mitotic Action of Fostriecin, Producing Mitotic Slippage Followed by Tetraploid Cell Death
Authors: Theobald Benjamin , Bonness Kathy , Musiyenko Alla , Andrews Joel F. , Urban Gudrun , Huang Xizhong , Dean Nicholas M. , Honkanen Richard E. 
Published: May 2013

Abstract
Fostriecin is a natural product purified from Sterptomyces extracts with antitumor activity sufficient to warrant human clinical trials. Unfortunately, difficulties associated with supply and stable drug formulation stalled further development. At a molecular level, fostriecin is known to act as a catalytic inhibitor of four PPP-family phosphatases, and reports describing the design of molecules in this class suggest derivatives targeting enzymes within the fostriecin-sensitive subfamily can be successful. However, it is not clear if the tumor-selective cytotoxicity of fostriecin results from the inhibition of a specific phosphatase, multiple phosphatases, or a limited subset of fostriecin sensitive phosphatases. How the inhibition of sensitive phosphatases contributes to tumor-selective cytotoxicity is also not clear. Here, high-content time-lapse imaging of live cells revealed novel insight into the cellular actions of fostriecin, showing that fostriecin-induced apoptosis is not simply induced following a sustained mitotic arrest. Rather, apoptosis occurred in an apparent second interphase produced when tetraploid cells undergo mitotic slippage. Comparison of the actions of fostriecin and antisense-oligonucleotides specifically targeting human fostriecin-sensitive phosphatases revealed that the suppression PP4C alone is sufficient to mimic many actions of fostriecin. Importantly, targeted suppression of PP4C induced apoptosis, with death occurring in tetraploid cells following mitotic slippage. This effect was not observed following the suppression of PP1C, PP2AC, or PP5C. These data clarify PP4C as a fostriecin-sensitive phosphatase and demonstrate that the suppression of PP4C triggers mitotic slippage/apoptosis.
Implications: Future development of fostriecin class inhibitors should consider PP4C as a potentially important target. Mol Cancer Res; 11(8); 845–55. ©2013 AACR.
Directional Wind–Wave Coupling in Fully Coupled Atmosphere–Wave–Ocean Models: Results from CBLAST-Hurricane
Authors: Chen Shuyi S. , Zhao Wei , Donelan Mark A. , Tolman Hendrik L. 
Published: May 2013

Abstract
The extreme high winds, intense rainfall, large ocean waves, and copious sea spray in hurricanes push the surface-exchange parameters for temperature, water vapor, and momentum into untested regimes. The Coupled Boundary Layer Air–Sea Transfer (CBLAST)-Hurricane program is aimed at developing improved coupling parameterizations (using the observations collected during the CBLAST-Hurricane field program) for the next-generation hurricane research prediction models. Hurricane-induced surface waves that determine the surface stress are highly asymmetric, which can affect storm structure and intensity significantly. Much of the stress is supported by waves in the wavelength range of 0.1–10 m, which is the unresolved “spectral tail” in present wave models. A directional wind–wave coupling method is developed to include effects of directionality of the wind and waves in hurricanes. The surface stress vector is calculated using the two-dimensional wave spectra from a wave model with an added short-wave spectral tail. The wind and waves are coupled in a vector form rather than through the traditional roughness scalar. This new wind–wave coupling parameterization has been implemented in a fully coupled atmosphere–wave–ocean model with 1.67-km grid resolution in the atmospheric model, which can resolve finescale features in the extreme high-wind region of the hurricane eyewall. It has been tested in a number of storms including Hurricane Frances (2004), which is one of the best-observed storms during the CBLAST-Hurricane 2004 field program. This paper describes the new wind–wave coupling parameterization and examines the characteristics of the coupled model simulations of Hurricane Frances (2004). Observations of surface waves and winds are used to evaluate the coupled model results.
CYP19A1 gene polymorphisms and risk of lung cancer
Authors: Zhang Jie , Yin Yue , Niu Xiao-Min , Liu Yun , Garfield David , Chen Su-Feng , Wang Rui , Wang Lei , Chen Hai-Quan 
Published: May 2013

Objectives To investigate the association between polymorphisms of aromatase (encoded by the CYP19A1 gene and a key enzyme in biosynthesis of oestradiol) and the risk of lung cancer, and whether there were differences stratified by sex and smoking history. Methods This case–control study included consecutive, nonselected and pathologically-confirmed lung cancer patients and healthy people. Participants were classed as nonsmokers or smokers by questionnaire. Peripheral blood samples from all participants were genotyped for three single-nucleotide polymorphism (SNPs; rs727479, rs730154 and rs10046); allelic frequencies were compared across genotype and clinical records. Results A total of 529 patients with lung cancer and 567 age- and sex-matched controls were included. After adjustment for age, sex and smoking history, rs727479 was significantly associated with the incidence of lung cancer (for alleles AC vs AA). There was also a significant difference between patients and controls in haplotype CCA, while haplotype ACA was only significantly associated with nonsmokers and female nonsmokers. Conclusions Polymorphisms of CYP19A1 may be related to the increased risk of lung cancer; in particular, haplotype ACA may contribute to lung-cancer progression in nonsmokers. Further validation with larger populations is required.
Randomized controlled trial of zoledronic acid for treatment of osteoporosis in women
Authors: Bai Hua , Jing Danqing , Guo Aitao , Yin Shinan 
Published: May 2013

Objective To assess the effect of zoledronic acid (ZOL) on bone mineral density (BMD) and fracture risk at the L1–L4 vertebrae, femoral neck, hip and trochanter in Chinese women with osteoporosis. Methods A randomized controlled trial was conducted in female patients with osteoporosis, randomized to receive one 5-mg ZOL intravenous infusion per year or placebo equivalent. Facture risk and BMD were measured over a 2-year follow-up period. Results A statistically significant reduction in the risk of fracture was observed at the trochanter in the ZOL group ( n = 242) compared with the placebo group ( n = 241); (odds ratio 0.54 [95% confidence interval 0.29, 0.98]): BMD was 0.24, 0.28, 0.31 and 0.22 greater at the L1–L4 vertebrae, total hip, femoral neck and trochanter, respectively, in the ZOL group. The incidence of adverse events was comparable between treatment groups. Conclusions This study indicated that ZOL could increase BMD and reduce fracture risk in women with osteoporosis over a 2-year follow-up period, and was not associated with any serious drug-related adverse effects.
Association between cytotoxic T-lymphocyte associated protein 4 gene +49 A/G polymorphism and chronic infection with hepatitis B virus: A meta-analysis
Authors: Xu Hangdi , Zhao Mingfei , He Jiliang , Chen Zhi 
Published: May 2013

Objective This meta-analysis determined the relationship between polymorphisms of the cytotoxic T-lymphocyte-associated protein 4 ( CTLA4) gene and hepatitis B virus (HBV) clearance in chronic hepatitis B. Methods Published studies reporting associations between CTLA4 gene +49A/G polymorphisms and chronic HBV infection were reviewed. Odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the risk of persistent HBV according to genotype. Results Six studies, involving 1076 chronic HBV patients and 1294 controls, were included. The risk of persistent HBV in patients with a +49 GG/AG genotype decreased significantly compared with the AA genotype (OR 0.65; 95% CI 0.52, 0.82). The variant G allele was negatively associated with chronic HBV infection versus the A allele (OR 0.77; 95% CI 0.68, 0.88). When stratifying by type of study control, a significantly decreased risk was associated with CTLA4+49 variant genotypes (AG and GG) in both spontaneous recovery control group and healthy control group. Conclusions Findings of this meta-analysis suggest that A at position +49 of the CTLA4 gene may significantly increase the risk of persistent HBV infection, whereas G at position +49 may positively influence virus clearance.
Aliskiren improves vascular smooth muscle function in the skin microcirculation of type 2 diabetic patients with normal renal function
Authors: Dushay Jody R , Tecilazich Francesco , Kafanas Antonios , Magargee Mary L , Auster Michael E , Gnardellis Charalambos , Dinh Thanh , Veves Aristidis 
Published: May 2013

Objective: The objective of this paper is to study the effect of aliskiren on metabolic parameters and micro- and macrovascular reactivity in individuals diagnosed with or at high risk for developing type 2 diabetes mellitus (T2DM). Research design and methods: We studied 47 T2DM and 41 at-risk individuals in a randomized, double-blinded, placebo-controlled trial. All subjects were treated with 150 mg aliskiren or placebo daily for 12 weeks. Twenty-six (55%) of T2DM and four (8%) at-risk subjects were also treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers. Results: Aliskiren treatment was associated with improvement in systolic and diastolic blood pressure and endothelium-independent vasodilation at the skin microcirculation in those with T2DM but not in those at risk. There were no incidences of hypotension and no significant changes in serum potassium or creatinine levels with aliskiren treatment in either study group. Conclusions: Aliskiren improves blood pressure and vascular smooth muscle function in the skin microcirculation of T2DM patients.
Action research and public relations: Dialogue, peer learning, and the issue of alcohol
Authors: Pieczka Magda , Wood Emma 
Published: May 2013

This article presents an action research project that transformed dialogic techniques used in, policy making and community development into an innovative approach to education about alcohol. The project was developed by a group of teenage volunteers, the AlcoLOLs, and two public relations researchers, tested in a local school, presented at the Scottish Parliament to policy stakeholders concerned with alcohol, and subsequently extended to a number of schools across the city of Edinburgh (Scotland). The article contributes to public relations research by offering a detailed analytical account of dialogue as a method of inquiry and a mechanism for change. The article also introduces the concept of extended epistemology as a fresh perspective on the phenomenon of relationship and relationship management. Finally, the article argues that action research has the transformative potential for the development of academic knowledge in the field and as an approach to education and training of practitioners.
Subcellular mislocalization of the transcription factor NF-E2 in erythroid cells discriminates prefibrotic primary myelofibrosis from essential thrombocythemia
Authors: Aumann Konrad , Frey Anna-Verena , May Annette M. , Hauschke Dieter , Kreutz Clemens , Marx Jan P. , Timmer Jens , Werner Martin , Pahl Heike L. 
Published: May 2013

Key Points
The transcription factor NF-E2 is mislocalized in patients with primary myelofibrosis. Immunohistochemical staining for NF-E2 distinguishes essential thrombocythemia from primary myelofibrosis.
Comparative transcriptome analysis and marker development of two closely related Primrose species (Primula poissonii and Primula wilsonii)
Authors: Zhang Lu , Yan Hai-Fei , Wu Wei , Yu Hui , Ge Xue-Jun 
Published: May 2013

Abstract

Background

Primula species are important early spring garden plants with a centre of diversity and speciation in the East Himalaya-Hengduan Mountains in Western China. Studies on population genetics, speciation and phylogeny of Primula have been impeded by a lack of genomic resources. In the present study, we sequenced the transcriptomes of two closely related primrose species, Primula poissonii and Primula wilsonii, using short reads on the Illumina Genome Analyzer platform.

Results
We obtained 55,284 and 55,011 contigs with N50 values of 938 and 1,085 for P. poissonii and P. wilsonii, respectively, and 6,654 pairs of putative orthologs were identified between the two species. Estimations of non-synonymous/synonymous substitution rate ratios for these orthologs indicated that 877 of the pairs may be under positive selection (Ka/Ks > 0.5), and functional enrichment analysis revealed that significant proportions of the orthologs were in the categories DNA repair, stress resistance, which may provide some hints as to how the two closely related Primula species adapted differentially to extreme environments, such as habitats characterized by aridity, high altitude and high levels of ionizing radiation. It was possible for the first time to estimate the divergence time between the radiated species pair, P. poissonii and P. wilsonii; this was found to be approximately 0.90 ± 0.57 Mya, which falls between the Donau and Gunz glaciation in the Middle Pleistocene. Primers based on 54 pairs of orthologous SSR-containing sequences between the two Primula species were designed and verified. About half of these pairs successfully amplified for both species. Of the 959 single copy nuclear genes shared by four model plants (known as APVO genes), 111 single copy nuclear genes were verified as being present in both Primula species and exon-anchored and intron-spanned primers were designed for use.

Conclusion
We characterized the transcriptomes for the two Primula species, and produced an unprecedented amount of genomic resources for these important garden plants. Evolutionary analysis of these two Primula species not only revealed a more precise divergence time, but also provided some novel insights into how differential adaptations occurred in extreme habitats. Furthermore, we developed two sets of genetic markers, single copy nuclear genes and nuclear microsatellites (EST-SSR). Both these sets of markers will facilitate studies on the genetic improvement, population genetics and phylogenetics of this rapidly adapting taxon.