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71.
Joanne Van Der Velden Grace Sum Donna Barker Emmanuel Koumoundouros Garry Barcham Heike Wulff Neil Castle Peter Bradding Kenneth Snibson 《PloS one》2013,8(6)
Background
The Ca2+-activated K+ channel KCa3.1 is expressed in several structural and inflammatory airway cell types and is proposed to play an important role in the pathophysiology of asthma. The aim of the current study was to determine whether inhibition of KCa3.1 modifies experimental asthma in sheep.Methodology and Principal Findings
Atopic sheep were administered either 30 mg/kg Senicapoc (ICA-17073), a selective inhibitor of the KCa3.1-channel, or vehicle alone (0.5% methylcellulose) twice daily (orally). Both groups received fortnightly aerosol challenges with house dust mite allergen for fourteen weeks. A separate sheep group received no allergen challenges or drug treatment. In the vehicle-control group, twelve weeks of allergen challenges resulted in a 60±19% increase in resting airway resistance, and this was completely attenuated by treatment with Senicapoc (0.25±12%; n = 10, P = 0.0147). The vehicle-control group had a peak-early phase increase in lung resistance of 82±21%, and this was reduced by 58% with Senicapoc treatment (24±14%; n = 10, P = 0.0288). Senicapoc-treated sheep also demonstrated reduced airway hyperresponsiveness, requiring a significantly higher dose of carbachol to increase resistance by 100% compared to allergen-challenged vehicle-control sheep (20±5 vs. 52±18 breath-units of carbachol; n = 10, P = 0.0340). Senicapoc also significantly reduced eosinophil numbers in bronchoalveolar lavage taken 48 hours post-allergen challenge, and reduced vascular remodelling.Conclusions
These findings suggest that KCa3.1-activity contributes to allergen-induced airway responses, inflammation and vascular remodelling in a sheep model of asthma, and that inhibition of KCa3.1 may be an effective strategy for blocking allergen-induced airway inflammation and hyperresponsiveness in humans. 相似文献72.
Estienne C. Swart John R. Bracht Vincent Magrini Patrick Minx Xiao Chen Yi Zhou Jaspreet S. Khurana Aaron D. Goldman Mariusz Nowacki Klaas Schotanus Seolkyoung Jung Robert S. Fulton Amy Ly Sean McGrath Kevin Haub Jessica L. Wiggins Donna Storton John C. Matese Lance Parsons Wei-Jen Chang Michael S. Bowen Nicholas A. Stover Thomas A. Jones Sean R. Eddy Glenn A. Herrick Thomas G. Doak Richard K. Wilson Elaine R. Mardis Laura F. Landweber 《PLoS biology》2013,11(1)
The macronuclear genome of the ciliate Oxytricha trifallax displays an extreme and unique eukaryotic genome architecture with extensive genomic variation. During sexual genome development, the expressed, somatic macronuclear genome is whittled down to the genic portion of a small fraction (∼5%) of its precursor “silent” germline micronuclear genome by a process of “unscrambling” and fragmentation. The tiny macronuclear “nanochromosomes” typically encode single, protein-coding genes (a small portion, 10%, encode 2–8 genes), have minimal noncoding regions, and are differentially amplified to an average of ∼2,000 copies. We report the high-quality genome assembly of ∼16,000 complete nanochromosomes (∼50 Mb haploid genome size) that vary from 469 bp to 66 kb long (mean ∼3.2 kb) and encode ∼18,500 genes. Alternative DNA fragmentation processes ∼10% of the nanochromosomes into multiple isoforms that usually encode complete genes. Nucleotide diversity in the macronucleus is very high (SNP heterozygosity is ∼4.0%), suggesting that Oxytricha trifallax may have one of the largest known effective population sizes of eukaryotes. Comparison to other ciliates with nonscrambled genomes and long macronuclear chromosomes (on the order of 100 kb) suggests several candidate proteins that could be involved in genome rearrangement, including domesticated MULE and IS1595-like DDE transposases. The assembly of the highly fragmented Oxytricha macronuclear genome is the first completed genome with such an unusual architecture. This genome sequence provides tantalizing glimpses into novel molecular biology and evolution. For example, Oxytricha maintains tens of millions of telomeres per cell and has also evolved an intriguing expansion of telomere end-binding proteins. In conjunction with the micronuclear genome in progress, the O. trifallax macronuclear genome will provide an invaluable resource for investigating programmed genome rearrangements, complementing studies of rearrangements arising during evolution and disease. 相似文献
73.
74.
Mohlopheni J. Marakalala Simon Vautier Joanna Potrykus Louise A. Walker Kelly M. Shepardson Alex Hopke Hector M. Mora-Montes Ann Kerrigan Mihai G. Netea Graeme I. Murray Donna M. MacCallum Robert Wheeler Carol A. Munro Neil A. R. Gow Robert A. Cramer Alistair J. P. Brown Gordon D. Brown 《PLoS pathogens》2013,9(4)
75.
Nikisha Carty Kevin R. Nash Milene Brownlow Dana Cruite Donna Wilcock Maj-Linda B. Selenica Daniel C. Lee Marcia N. Gordon Dave Morgan 《PloS one》2013,8(3)
The accumulation of β-amyloid peptides in the brain has been recognized as an essential factor in Alzheimer’s disease pathology. Several proteases, including Neprilysin (NEP), endothelin converting enzyme (ECE), and insulin degrading enzyme (IDE), have been shown to cleave β-amyloid peptides (Aβ). We have previously reported reductions in amyloid in APP+PS1 mice with increased expression of ECE. In this study we compared the vector-induced increased expression of NEP and IDE. We used recombinant adeno-associated viral vectors expressing either native forms of NEP (NEP-n) or IDE (IDE-n), or engineered secreted forms of NEP (NEP-s) or IDE (IDE-s). In a six-week study, immunohistochemistry staining for total Aβ was significantly decreased in animals receiving the NEP-n and NEP-s but not for IDE-n or IDE-s in either the hippocampus or cortex. Congo red staining followed a similar trend revealing significant decreases in the hippocampus and the cortex for NEP-n and NEP-s treatment groups. Our results indicate that while rAAV-IDE does not have the same therapeutic potential as rAAV-NEP, rAAV-NEP-s and NEP-n are effective at reducing amyloid loads, and both of these vectors continue to have significant effects nine months post-injection. As such, they may be considered reasonable candidates for gene therapy trials in AD. 相似文献
76.
Masayasu Naito Ursula Hainz Ute E. Burkhardt Buyin Fu Deborah Ahove Kristen E. Stevenson Mohini Rajasagi Baogong Zhu Anselmo Alonso Elizabeth Witten Ken-ichi Matsuoka Donna Neuberg Jonathan S. Duke-Cohan Catherine J. Wu Gordon J. Freeman 《Cancer immunology, immunotherapy : CII》2013,62(2):347-357
CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen-specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker. 相似文献
77.
Elaine T. Lim Soumya Raychaudhuri Stephan J. Sanders Christine Stevens Aniko Sabo Daniel G. MacArthur Benjamin M. Neale Andrew Kirby Douglas M. Ruderfer Menachem Fromer Monkol Lek Li Liu Jason Flannick Stephan Ripke Uma Nagaswamy Donna Muzny Jeffrey G. Reid Alicia Hawes Mark J. Daly 《Neuron》2013,77(2):235-242
78.
Donna S. Francy Erin A. Stelzer Joseph W. Duris Amie M. G. Brady John H. Harrison Heather E. Johnson Michael W. Ware 《Applied and environmental microbiology》2013,79(5):1676-1688
Predictive models, based on environmental and water quality variables, have been used to improve the timeliness and accuracy of recreational water quality assessments, but their effectiveness has not been studied in inland waters. Sampling at eight inland recreational lakes in Ohio was done in order to investigate using predictive models for Escherichia coli and to understand the links between E. coli concentrations, predictive variables, and pathogens. Based upon results from 21 beach sites, models were developed for 13 sites, and the most predictive variables were rainfall, wind direction and speed, turbidity, and water temperature. Models were not developed at sites where the E. coli standard was seldom exceeded. Models were validated at nine sites during an independent year. At three sites, the model resulted in increased correct responses, sensitivities, and specificities compared to use of the previous day''s E. coli concentration (the current method). Drought conditions during the validation year precluded being able to adequately assess model performance at most of the other sites. Cryptosporidium, adenovirus, eaeA (E. coli), ipaH (Shigella), and spvC (Salmonella) were found in at least 20% of samples collected for pathogens at five sites. The presence or absence of the three bacterial genes was related to some of the model variables but was not consistently related to E. coli concentrations. Predictive models were not effective at all inland lake sites; however, their use at two lakes with high swimmer densities will provide better estimates of public health risk than current methods and will be a valuable resource for beach managers and the public. 相似文献
79.
In 2008, one of the worst public health crises occurred in the state of Nevada,
where authorities discovered up to 63,000 patients were potentially exposed to
hepatitis C infection, largely due to substandard infection control and other
negligent practices at two endoscopy clinics in Las Vegas. In the subsequent
grand jury proceedings that followed, it was discovered that several clinic
employees not only participated in these egregious practices, but doctors,
nurses, and other health care professionals witnessed yet failed to report these
incidents, largely due to fears of whistleblower retaliation. In response, the
Nevada state legislature attempted to strengthen whistleblower protection laws,
but it remains unclear if such laws actually protect employees who attempt to
report patient safety concerns. As the push for quality patient outcomes becomes
more prominent with health care reform, whistleblower concerns must be
effectively addressed to ensure that health care professionals can report
patient safety concerns without fear of retaliation. 相似文献
80.
Giovanni Widmer Julia Dilo James K. Tumwine Saul Tzipori Donna E. Akiyoshi 《Applied and environmental microbiology》2013,79(17):5357-5362
Enterocytozoon bieneusi (phylum Microsporidia) is a human pathogen with a broad host range. Following the sequencing of 3.8 Mb of the estimated 6-Mb E. bieneusi genome, simple sequence repeats (micro- and minisatellites) were identified. Sequencing of four such repeats from various human and animal E. bieneusi isolates identified extensive sequence polymorphism and enabled the development of a multilocus genotyping method to study the epidemiology of this pathogen. We genotyped E. bieneusi DNA extracted from 197 fecal samples originating from children with diarrhea who were residing in Kampala, Uganda. Three newly identified microsatellite markers and the internal transcribed spacer were PCR amplified, and multiple cloned amplicons for each marker were sequenced from each individual. Most microsatellite sequences were unique to the Ugandan population. Significantly, polymorphism not only was present among isolates but was also found within isolates. This observation suggests that infections with heterogeneous E. bieneusi populations are common in this region. However, the data do not exclude that some of the polymorphism originates from divergent paralogs within the genome. The frequent occurrence of multiple sequences within an isolate precluded the identification of multilocus genotypes. This observation raises the possibility that in a region in which the prevalence of E. bieneusi is high, sequencing of uncloned PCR products may not be adequate for multilocus genotyping. 相似文献