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Search Results: 1 - 10 of 263241 matches for " Michael R Knowles "
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'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations
Peadar G Noone, Michael R Knowles
Respiratory Research , 2001, DOI: 10.1186/rr82
Abstract: Cystic fibrosis (CF) is a recessive genetic disease that is caused by mutations on both CFTR alleles, resulting in abnormal sweat electrolytes, sino-pulmonary disease, male infertility, and pancreatic exocrine insufficiency in 95% of patients [1,2]. In its classic form, the disease is easily diagnosed early in life, through a combination of clinical evaluation and laboratory testing (including sweat testing, and CFTR mutation analysis) [3]. Depending on the ethnic background of the populations tested, common genetic mutations are identified in the majority of cases of CF. In the USA, two-thirds of patients carry at least one copy of the ΔF508 mutation, with approximately 50% of CF patients being homozygous for this mutation [4].A wide spectrum of molecular abnormalities may occur in the CFTR gene, and uncommon mutations that result in partial (residual) CFTR function may be associated with nonclassic presentations of disease. Overall, 7% of CF patients are not diagnosed until age 10 years, with a proportion not diagnosed until after age 15 years; some of these patients present a considerable challenge in establishing a diagnosis of CF. Moreover, the phenotype in these patients may vary widely [5,6]. The focus of the present review is on nonclassic phenotypes associated with mutations in the CFTR gene, which may manifest as male infertility (congenital bilateral absence of the vas deferens [CBAVD]), mild pulmonary disease and idiopathic chronic pancreatitis (ICP). These phenotypes are included within the definition of 'atypical CF'.CFTR is a transmembrane spanning protein with multiple activities that are related to normal epithelial cell function [2]. Mutations in CFTR result in abnormalities in epithelial ion and water transport, which are associated with derangements in airway mucociliary clearance and other cellular functions related to normal cell biology [7]. Depending on the molecular abnormality, the defect in CFTR may be the equivalent of that associated wit
Conservation in the face of diversity: multistrain analysis of an intracellular bacterium
Michael J Dark, David R Herndon, Lowell S Kappmeyer, Mikel P Gonzales, Elizabeth Nordeen, Guy H Palmer, Donald P Knowles, Kelly A Brayton
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-16
Abstract: These comparisons revealed that A. marginale has a closed-core genome with few highly plastic regions, which include the msp2 and msp3 genes, as well as the aaap locus. Comparison of the Florida and St. Maries genome sequences found that SNPs comprise 0.8% of the longer Florida genome, with 33.5% of the total SNPs between all five strains present in at least two strains and 3.0% of SNPs present in all strains except Florida. Comparison of genomes from three strains of Mycobacterium tuberculosis, Bacillus anthracis, and Nessieria meningiditis, as well as four Chlamydophila pneumoniae strains found that 98.8%–100% of SNPs are unique to each strain, suggesting A. marginale, with 76.0%, has an intermediate level of strain-specific SNPs. Comparison of genomes from other organisms revealed variation in diversity that did not segregate with the environmental niche the bacterium occupies, ranging from 0.00% to 8.00% of the larger pairwise-compared genome.Analysis of multiple A. marginale strains suggests intracellular bacteria have more variable SNP retention rates than previously reported, and may have closed-core genomes in response to the host organism environment and/or reductive evolution.While the recent boom in genome sequencing projects has provided a wealth of information about bacterial metabolism and evolution, we know little about interstrain variation. A firm understanding of the rates and sites of variation is useful in determining genotypic differences associated with phenotypic traits and in formulating control strategies for a number of pathogens. Further, knowledge about the pan-genome of organisms will aid in determining the core genomic requirements, as well as shed more light on events that occur in the various environmental niches bacteria occupy.Most studies of bacterial diversity to date have either utilized specific genomic loci [1,2] or have examined metagenomics of specific environmental niches [3,4]. While these types of studies help elucidate th
Lack of correlation between pulmonary disease and cystic fibrosis transmembrane conductance regulator dysfunction in cystic fibrosis: a case report
Hara Levy, Carolynn L Cannon, Daniel Asher, Christopher García, Robert H Cleveland, Gerald B Pier, Michael R Knowles, Andrew A Colin
Journal of Medical Case Reports , 2010, DOI: 10.1186/1752-1947-4-117
Abstract: We describe a pair of African-American brothers, aged 21 and 27, with cystic fibrosis. They were homozygous for a rare frameshift mutation in the cystic fibrosis transmembrane conductance regulator 3791delC, which would be expected to cause significant morbidity. Although 80% of cystic fibrosis patients are colonized with Pseudomonas aeruginosa by eight years of age, the older brother had no serum opsonic antibody titer to P. aeruginosa by age 13 and therefore would have failed to mount an effective antibody response to the alginate (mucoid polysaccharide) capsule of P. aeruginosa. He was not colonized with P. aeruginosa until 24 years of age. Similarly, the younger brother was not colonized with P. aeruginosa until age 20 and had no significant lung disease.Despite a prevailing idea in cystic fibrosis research that the amount of functional cystic fibrosis transmembrane conductance regulator predicts clinical status, our results indicated that respiratory disease severity in cystic fibrosis exhibits phenotypic heterogeneity. If this heterogeneity is, in part, genetic, it is most likely derived from genes outside the cystic fibrosis transmembrane conductance regulator locus.Mutations in both alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in the disease cystic fibrosis (CF), which manifests classically as chronic sinopulmonary disease, pancreatic insufficiency, elevated sodium chloride loss in sweat, infertility among men is due to agenesis of the vas deferens and other symptoms like liver disease. Except for patients with significant liver disease, the primary disease morbidity is linked to the chronic pulmonary infections and consequent decline in lung function. CFTR mutations are classified as severe (class I-III mutations) or mild (class IV-V mutations) based on their effect on protein synthesis and function, implying that the less CFTR that is made or is functional, the more severe the clinical course of a patient with cysti
Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis
Mary J. Emond?,Tin Louie?,Julia Emerson?,Jessica X. Chong?,Rasika A. Mathias?,Michael R. Knowles,Mark J. Rieder?,Holly K. Tabor?,Debbie A. Nickerson?,Kathleen C. Barnes
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005273
Abstract: Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were explored.
Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis
Lindsay B. Henderson,Vishal K. Doshi,Scott M. Blackman,Kathleen M. Naughton,Rhonda G. Pace,Jackob Moskovitz,Michael R. Knowles,Peter R. Durie,Mitchell L. Drumm,Garry R. Cutting
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002580
Abstract: Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5′ to and within the MSRA gene were associated with MI (P = 1.99×10?5 to 1.08×10?6; Bonferroni P = 0.057 to 3.1×10?3). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53–0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2×10?4). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr?/? and Cftr?/?Msra?/? mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.
Implementing International Refugee Law in the People’s Republic of China  [PDF]
Abdul Knowles
Beijing Law Review (BLR) , 2018, DOI: 10.4236/blr.2018.91005
Abstract: China’s implementation of international refugee law and its asylum policies have long been of interest to numerous state and international non-state actors, especially regarding specific migrant groups in China. Despite China’s high regards for international refugee law and a firm belief in the importance of international protection of refugees and asylum-seekers, international observers often argue that China is not meeting its legal obligations under international refugee law. The finding of this research is, despite China’s past implementation of favorable asylum policies, and improvements in its application of international refugee law, including the beginning stages of drafting a national refugee law; there remains a gap between China’s implementation of international refugee law and international norms. Thus, reforms are needed in China’s asylum practices so that it is consistent with international practices. One key factor for this gap is, China’s current legal framework and policies do not offer a long-term and durable solution for some refugees and asylum-seekers. Additionally, its asylum framework does not provide all conditions expected of a State that is a party to the “Refugee Convention”. Furthermore, China’s asylum policies differ among “persons in need of protection” regarding treatment and reception policy. The next crucial step for China in implementing international refugee law should be completing the drafting and adoption of national refugee law that is in line with the “1951 Refugee Convention” and “1967 Protocol”.
Projected Evolution of California's San Francisco Bay-Delta-River System in a Century of Climate Change
James E. Cloern, Noah Knowles, Larry R. Brown, Daniel Cayan, Michael D. Dettinger, Tara L. Morgan, David H. Schoellhamer, Mark T. Stacey, Mick van der Wegen, R. Wayne Wagner, Alan D. Jassby
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024465
Abstract: Background Accumulating evidence shows that the planet is warming as a response to human emissions of greenhouse gases. Strategies of adaptation to climate change will require quantitative projections of how altered regional patterns of temperature, precipitation and sea level could cascade to provoke local impacts such as modified water supplies, increasing risks of coastal flooding, and growing challenges to sustainability of native species. Methodology/Principal Findings We linked a series of models to investigate responses of California's San Francisco Estuary-Watershed (SFEW) system to two contrasting scenarios of climate change. Model outputs for scenarios of fast and moderate warming are presented as 2010–2099 projections of nine indicators of changing climate, hydrology and habitat quality. Trends of these indicators measure rates of: increasing air and water temperatures, salinity and sea level; decreasing precipitation, runoff, snowmelt contribution to runoff, and suspended sediment concentrations; and increasing frequency of extreme environmental conditions such as water temperatures and sea level beyond the ranges of historical observations. Conclusions/Significance Most of these environmental indicators change substantially over the 21st century, and many would present challenges to natural and managed systems. Adaptations to these changes will require flexible planning to cope with growing risks to humans and the challenges of meeting demands for fresh water and sustaining native biota. Programs of ecosystem rehabilitation and biodiversity conservation in coastal landscapes will be most likely to meet their objectives if they are designed from considerations that include: (1) an integrated perspective that river-estuary systems are influenced by effects of climate change operating on both watersheds and oceans; (2) varying sensitivity among environmental indicators to the uncertainty of future climates; (3) inevitability of biological community changes as responses to cumulative effects of climate change and other drivers of habitat transformations; and (4) anticipation and adaptation to the growing probability of ecosystem regime shifts.
Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC
XueLiang Guo, Rhonda G. Pace, Jaclyn R. Stonebraker, Clayton W. Commander, Anthony T. Dang, Mitchell L. Drumm, Ann Harris, Fei Zou, Dallas M. Swallow, Fred A. Wright, Wanda K. O'Neal, Michael R. Knowles
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025452
Abstract: Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2×10?4 after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.
Mutational and Topological Analysis of the Escherichia coli BamA Protein
Douglas F. Browning, Sophie A. Matthews, Amanda E. Rossiter, Yanina R. Sevastsyanovich, Mark Jeeves, Jessica L. Mason, Timothy J. Wells, Catherine A. Wardius, Timothy J. Knowles, Adam F. Cunningham, Vassiliy N. Bavro, Michael Overduin, Ian R. Henderson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084512
Abstract: The multi-protein β-barrel assembly machine (BAM) of Escherichia coli is responsible for the folding and insertion of β-barrel containing integral outer membrane proteins (OMPs) into the bacterial outer membrane. An essential component of this complex is the BamA protein, which binds unfolded β-barrel precursors via the five polypeptide transport-associated (POTRA) domains in its N-terminus. The C-terminus of BamA contains a β-barrel domain, which tethers BamA to the outer membrane and is also thought to be involved in OMP insertion. Here we mutagenize BamA using linker scanning mutagenesis and demonstrate that all five POTRA domains are essential for BamA protein function in our experimental system. Furthermore, we generate a homology based model of the BamA β-barrel and test our model using insertion mutagenesis, deletion analysis and immunofluorescence to identify β-strands, periplasmic turns and extracellular loops. We show that the surface-exposed loops of the BamA β-barrel are essential.
Histo-Blood Group Gene Polymorphisms as Potential Genetic Modifiers of Infection and Cystic Fibrosis Lung Disease Severity
Jennifer L. Taylor-Cousar, Maimoona A. Zariwala, Lauranell H. Burch, Rhonda G. Pace, Mitchell L. Drumm, Hollin Calloway, Haiying Fan, Brent W. Weston, Fred A. Wright, Michael R. Knowles, for the Gene Modifier Study Group
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004270
Abstract: Background The pulmonary phenotype in cystic fibrosis (CF) is variable; thus, environmental and genetic factors likely contribute to clinical heterogeneity. We hypothesized that genetically determined ABO histo-blood group antigen (ABH) differences in glycosylation may lead to differences in microbial binding by airway mucus, and thus predispose to early lung infection and more severe lung disease in a subset of patients with CF. Methods and Principal Findings Clinical information and DNA was collected on >800 patients with the ΔF508/ΔF508 genotype. Patients in the most severe and mildest quartiles for lung phenotype were enrolled. Blood samples underwent lymphocyte transformation and DNA extraction using standard methods. PCR and sequencing were performed using standard techniques to identify the 9 SNPs required to determine ABO blood type, and to identify the four SNPs that account for 90–95% of Lewis status in Caucasians. Allele identification of the one nonsynonymous SNP in FUT2 that accounts for >95% of the incidence of nonsecretor phenotype in Caucasians was completed using an ABI Taqman assay. The overall prevalence of ABO types, and of FUT2 (secretor) and FUT 3 (Lewis) alleles was consistent with that found in the Caucasian population. There was no difference in distribution of ABH type in the severe versus mild patients, or the age of onset of Pseudomonas aeruginosa infection in the severe or mild groups. Multivariate analyses of other clinical phenotypes, including gender, asthma, and meconium ileus demonstrated no differences between groups based on ABH type. Conclusions and Significance Polymorphisms in the genes encoding ABO blood type, secretor or Lewis genotypes were not shown to associate with severity of CF lung disease, or age of onset of P. aeruginosa infection, nor was there any association with other clinical phenotypes in a group of 808 patients homozygous for the ΔF508 mutation.
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