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  • 1
    Language: English
    In: Journal of Bacteriology, 2012, Vol. 194(8), p.1927
    Description: We previously demonstrated that one or more products of the genes in the pil and com gene clusters of the opportunistic human respiratory pathogen nontypeable Haemophilus influenzae (NTHI) are required for type IV pilus (Tfp) biogenesis and function. Here, we have now demonstrated that the pilABCD and comABCDEF gene clusters are operons and that the product of each gene is essential for normal pilus function. Mutants with nonpolar deletions in each of the 10 pil and com genes had an adherence defect when primary human airway cells were used as the target. These mutants were also diminished in their ability to form a biofilm in vitro and, additionally, were deficient in natural transformation. Collectively, our data demonstrate that the product of each gene within these operons is required for the normal biogenesis and/or function of NTHI Tfp. Based on the similarity of PilA to other type IV pilins, we further predicted that the product of the pilA gene would be the major pilin subunit. Toward that end, we also demonstrated by immunogold labeling and mass spectrometry that PilA is indeed the majority type IV pilin protein expressed by NTHI. These new observations set the stage for experiments designed to dissect the function of each of the proteins encoded by genes within the pil and com gene clusters. The ability to characterize individual proteins with vital roles in NTHI colonization or pathogenesis has the potential to reduce the burden of NTHI-induced diseases through development of a Tfp-derived vaccine or a pilus-directed therapeutic. ; p. 1927-1933.
    Keywords: Vaccines ; Haemophilus Influenzae ; Biogenesis ; Pathogenesis ; Humans ; Pathogens ; Multigene Family ; Mutants ; Fimbriae ; Biofilm ; Mass Spectrometry ; Operon ; Bacteriology ; Proteins;
    ISSN: 1098-5530
    ISSN: 10985530
    ISSN: 00219193
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  • 2
    Language: English
    In: Journal of Bacteriology, April, 2012, Vol.194(7-8), p.1927(7)
    Description: We previously demonstrated that one or more products of the genes in the pil and com gene clusters of the opportunistic human respiratory pathogen nontypeable Haemophilus influenzae (NTHI) are required for type IV pilus (Tfp) biogenesis and function. Here, we have now demonstrated that the pilABCD and comABCDEF gene clusters are operons and that the product of each gene is essential for normal pilus function. Mutants with nonpolar deletions in each of the 10 pil and com genes had an adherence defect when primary human airway cells were used as the target. These mutants were also diminished in their ability to form a biofilm in vitro and, additionally, were deficient in natural transformation. Collectively, our data demonstrate that the product of each gene within these operons is required for the normal biogenesis and/or function of NTHI Tfp. Based on the similarity of PilA to other type IV pilins, we further predicted that the product of the pilA gene would be the major pilin subunit. Toward that end, we also demonstrated by immunogold labeling and mass spectrometry that PilA is indeed the majority type IV pilin protein expressed by NTHI. These new observations set the stage for experiments designed to dissect the function of each of the proteins encoded by genes within the pil and com gene clusters. The ability to characterize individual proteins with vital roles in NTHI colonization or pathogenesis has the potential to reduce the burden of NTHI-induced diseases through development of a Tfp-derived vaccine or a pilus-directed therapeutic.
    Keywords: Bacterial Genetics -- Research ; Gene Expression -- Research ; Haemophilus Influenzae -- Genetic Aspects ; Operons -- Research
    ISSN: 0021-9193
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(3), p.e59388
    Description: Type VI secretion systems (T6SS) are a class of macromolecular secretion machines that are utilized by a number of bacteria for inter-bacterial competition or to elicit responses in eukaryotic cells. Acinetobacter baumannii is an opportunistic...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(12)
    Description: The correct versions of Figures 1-3 can be viewed here: thumbnail Download: * PPT PowerPoint slide * PNG larger image * TIFF original image thumbnail Download: * PPT PowerPoint slide * PNG larger image * TIFF original image and thumbnail Download: * PPT PowerPoint slide * PNG larger image * TIFF original...
    Keywords: Sciences (General)
    ISSN: PLoS ONE
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Training and Education in Professional Psychology, 2011, Vol.5(2), pp.97-101
    Description: Inconsistent training requirements across predoctoral internships have problematic implications for psychologists seeking licensure and for the profession as a whole. This investigation is an 11-year follow-up to a previous study ( Bartle & Rodolfa, 1999 ) that explored the variation in hours accrued across predoctoral internship programs. The current study examined the total number of supervised training hours provided by internships and the methods utilized by training directors to calculate these hours. The total number of supervised hours reported by training directors ranged from 1,840 to 2,080, with 58.2% calculating hours by approximation, rounding off, or estimation. As training directors reported more total hours, they were increasingly likely to include holiday, vacation, and sick leave. Recommendations for state licensing boards and internship training programs are provided, including a national licensure requirement of 1,800 hours accrued during internship.
    Keywords: Internship Hours ; Training Directors ; Licensure
    ISSN: 1931-3918
    E-ISSN: 1931-3926
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  • 6
    In: Acta Crystallographica Section F, 01 March 2012, Vol.68(3), pp.284-287
    Description: The type IV pili of nontypeable (NTHi) are involved in twitching motility, adherence, competence and biofilm formation. They are potential virulence factors for this important human pathogen and are thus considered to be vaccine targets. To characterize these pili, an attempt to solve the atomic structure of the major pilin subunit PilA was initiated. A 1.73 Å resolution X‐ray diffraction data set was collected from native N‐terminally truncated PilA (ΔN‐PilA). Data processing indicated a hexagonal crystal system, which was determined to belong to space group 6 or 6 based on the systematic absences and near‐perfect twinning of the crystal. The unit‐cell parameters were = = 68.08, = 197.03 Å with four molecules in the asymmetric unit, giving a solvent content of 50%. Attempts to solve the ΔN‐PilA structure by molecular replacement with existing type IV pilin and type II secretion pseudopilin structures are in progress.
    Keywords: Nontypeable Haemophilus Influenzae ; Type Iv Pili ; Otitis Media
    ISSN: 1744-3091
    E-ISSN: 1744-3091
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  • 7
    Language: English
    In: mBio, 06 August 2013, Vol.4(4)
    Description: Acinetobacter baumannii is a Gram-negative, opportunistic pathogen. Recently, multiple A. baumannii genomes have been sequenced; these data have led to the identification of many genes predicted to encode proteins required for the biogenesis of type IV pili (TFP). However, there is no experimental evidence demonstrating that A. baumannii strains actually produce functional TFP. Here, we demonstrated that A. baumannii strain M2 is naturally transformable and capable of twitching motility, two classical TFP-associated phenotypes. Strains were constructed with mutations in pilA, pilD, and pilT, genes whose products have been well characterized in other systems. These mutants were no longer naturally transformable and did not exhibit twitching motility. These TFP-associated phenotypes were restored when these mutations were complemented. More PilA was detected on the surface of the pilT mutant than the parental strain, and TFP were visualized on the pilT mutant by transmission electron microscopy. Thus, A. baumannii produces functional TFP and utilizes TFP for both natural transformation and twitching motility. Several investigators have hypothesized that TFP might be responsible, in part, for the flagellum-independent surface-associated motility exhibited by many A. baumannii clinical isolates. We demonstrated that surface-associated motility was not dependent on the products of the pilA, pilD, and pilT genes and, by correlation, TFP. The identification of functional TFP in A. baumannii lays the foundation for future work determining the role of TFP in models of virulence that partially recapitulate human disease. Several investigators have documented the presence of genes predicted to encode proteins required for the biogenesis of TFP in many A. baumannii genomes. Furthermore, some have speculated that TFP may play a role in the unique surface-associated motility phenotype exhibited by many A. baumannii clinical isolates, yet there has been no experimental evidence to prove this. Unfortunately, progress in understanding the biology and virulence of A. baumannii has been slowed by the difficulty of constructing and complementing mutations in this species. Strain M2, a recently characterized clinical isolate, is amenable to genetic manipulation. We have established a reproducible system for the generation of marked and/or unmarked mutations using a modified recombineering strategy as well as a genetic complementation system utilizing a modified mini-Tn7 element in strain M2. Using this strategy, we demonstrated that strain M2 produces TFP and that TFP are not required for surface-associated motility exhibited by strain M2.
    Keywords: Locomotion ; Transformation, Bacterial ; Acinetobacter Baumannii -- Physiology ; Fimbriae, Bacterial -- Metabolism
    E-ISSN: 2150-7511
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  • 8
    In: Molecular Microbiology, June 2015, Vol.96(5), pp.1023-1041
    Description: Multiple species within the genus are nosocomial opportunistic pathogens of increasing relevance worldwide. Among the virulence factors utilized by these bacteria are the type pili and a protein ‐glycosylation system. Glycosylation is mediated by ‐oligosaccharyltransferases (ases), enzymes that transfer the glycan from a lipid carrier to target proteins. ‐oligosaccharyltransferases are difficult to identify due to similarities with the ligases that catalyze the last step in lipopolysaccharide synthesis. A bioinformatics analysis revealed the presence of two genes encoding putative ‐ases or WaaL ligases in most of the strains within the genus . Employing  2 and  1 as model systems, we show that these genes encode two ‐ases, one devoted uniquely to type pilin, and the other one responsible for glycosylation of multiple proteins. With the exception of 1, the pilin‐specific ases in resemble the Tase from . In 1 instead, the two ases are closely related to , the general ase first discovered in . However, one of them is exclusively dedicated to the glycosylation of the pilin‐like protein . Our data reveal an intricate and remarkable evolutionary pathway for bacterial ases and provide novel tools for glycoengineering. Protein glycosylation consist of the addition of sugars to proteins, and it is catalyzed by an oligosaccharyltransferase (Otase). Here we show that members of the genus Acinetobacter, which includes several opportunistic pathogens, carry two Otases. In these bacteria, one OTase is exclusively dedicated to the glycosylation of proteins than constitute the pili, whereas the other glycosylates multiple proteins. Our data uncovers a fascinating evolutionary pathway for bacterial ‐OTases and provides novel tools for glycoengineering.
    Keywords: Ligases – Analysis ; Virulence (Microbiology) – Analysis;
    ISSN: 0950-382X
    E-ISSN: 1365-2958
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  • 9
    Language: English
    In: Journal of Medicinal Chemistry, 01/08/2015, Vol.58(1), pp.433-442
    Description: The cyclin groove is an important recognition site for substrates of the cell cycle cyclin dependent kinases and provides an opportunity for highly selective inhibition of kinase activity through a non-ATP competitive mechanism. The key peptide residues of the cyclin binding motif have been studied in order to precisely define the structure–activity relationship for CDK kinase inhibition. Through this information, new insights into the interactions of peptide CDK inhibitors with key subsites of the cyclin binding groove provide for the replacement of binding determinants with more druglike functionality through REPLACE, a strategy for the iterative conversion of peptidic blockers of protein–protein interactions into pharmaceutically relevant compounds. As a result, REPLACE is further exemplified in combining optimized peptidic sequences with effective N-terminal capping groups to generate more stable compounds possessing antitumor activity consistent with on-target inhibition of cell cycle CDKs. The compounds described here represent prototypes for a next generation of kinase therapeutics with high efficacy and kinome selectivity, thus avoiding problems observed with first generation CDK inhibitors.
    Keywords: Pharmacy, Therapeutics, & Pharmacology ; Chemistry;
    ISSN: 0022-2623
    E-ISSN: 1520-4804
    Source: American Chemical Society (via CrossRef)
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  • 10
    Language: English
    In: Osteopathic Family Physician, 2011, Vol.3(4), pp.141-148
    Description: Chronic pain is an important cause of morbidity among adults worldwide. Its management presents a greater challenge in the unique demographic of Appalachia. “Physician reluctance to prescribe opioids” has been identified as a major barrier to effective management of chronic pain nationally. The aim of this study was to determine whether prescribers in Appalachian Ohio encountered similar barriers as prescribers elsewhere. A 29-item questionnaire was distributed to all 1719 physicians practicing in 29 counties in Ohio designated as “Appalachia.” The questionnaire evaluated demographics, assessed aspects of pain management, and asked participants to rank a list of 11 perceived barriers to effective chronic pain management. The overall survey return rate was 25.9%. The average respondent was male, 51 years old, with 20 years of experience practicing medicine, spending 86% of the working week with patients. Most participants (72.5%) reported being involved with chronic pain management “several times each week” or more. Of the potential barriers, those identified as important were (1) patient reluctance to make lifestyle or behavioral changes, (2) inadequate access to pain specialists, (3) inadequate access to health care because of financial burden, (4) lack of an objective measurement of pain, and (5) physician reluctance to prescribe opioids. Prescribers in Appalachian Ohio identified issues of patient behaviors and health care accessibility as important barriers, in addition to top barriers previously described in the literature. Further research must be done to determine whether these results are unique to Appalachian populations.
    Keywords: Appalachia ; Barriers ; Chronic Pain ; Pain Management ; Questionnaire ; Medicine
    ISSN: 1877-573X
    E-ISSN: 1877-5748
    Source: ScienceDirect Journals (Elsevier)
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