bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human α-Defensins Inhibit Hemolysis Mediated by Cholesterol-Dependent Cytolysins
Authors: Lehrer Robert I. , Jung Grace , Ruchala Piotr , Wang Wei , Micewicz Ewa D. , Waring Alan J. , Gillespie Eugene J. , Bradley Kenneth A. , Ratner Adam J. , Rest Richard F. , Lu Wuyuan 
Published: July 2009

ABSTRACTMany pathogenic gram-positive bacteria release exotoxins that belong to the family of cholesterol-dependent cytolysins. Here, we report that human α-defensins HNP-1 to HNP-3 acted in a concentration-dependent manner to protect human red blood cells from the lytic effects of three of these exotoxins: anthrolysin O (ALO), listeriolysin O, and pneumolysin. HD-5 was very effective against listeriolysin O but less effective against the other toxins. Human α-defensins HNP-4 and HD-6 and human β-defensin-1, -2, and -3 lacked protective ability. HNP-1 required intact disulfide bonds to prevent toxin-mediated hemolysis. A fully linearized analog, in which all six cysteines were replaced by aminobutyric acid (Abu) residues, showed greatly reduced binding and protection. A partially unfolded HNP-1 analog, in which only cysteines 9 and 29 were replaced by Abu residues, showed intact ALO binding but was 10-fold less potent in preventing hemolysis. Surface plasmon resonance assays revealed that HNP-1 to HNP-3 bound all three toxins at multiple sites and also that solution-phase HNP molecules could bind immobilized HNP molecules. Defensin concentrations that inhibited hemolysis by ALO and listeriolysin did not prevent these toxins from binding either to red blood cells or to cholesterol. Others have shown that HNP-1 to HNP-3 inhibit lethal toxin ofBacillus anthracis, toxin B ofClostridium difficile, diphtheria toxin, and exotoxin A ofPseudomonas aeruginosa; however, this is the first time these defensins have been shown to inhibit pore-forming toxins. An “ABCDE mechanism” that can account for the ability of HNP-1 to HNP-3 to inhibit so many different exotoxins is proposed.
Complement C3 Plays an Essential Role in the Control of Opportunistic Fungal Infections
Authors: Tsoni S. Vicky , Kerrigan Ann M. , Marakalala Mohlopheni J. , Srinivasan Naren , Duffield Maureen , Taylor Philip R. , Botto Marina , Steele Chad , Brown Gordon D. 
Published: July 2009

ABSTRACT

The innate recognition of fungal pathogens is a crucial first step in the induction of protective antifungal immunity. Complement is thought to be one key component in this process, facilitating fungal recognition and inducing early inflammation. However, the roles of the individual complement components have not been examined extensively. Here we have used mice lacking C3 to examine its role in immunity to opportunistic fungal pathogens and show that this complement component is essential for resistance to infections with
Candida albicans
and
Candida glabrata
. We demonstrate that the absence of C3 impairs fungal clearance but does not affect inflammatory responses. We also show that the presence of C3 contributes to mortality in mice challenged with very high doses of
Saccharomyces cerevisiae
, although these effects were found to be mouse strain dependent.
Gr1+Cells Control Growth of YopM-NegativeYersinia pestisduring Systemic Plague
Authors: Ye Zhan , Kerschen Edward J. , Cohen Donald A. , Kaplan Alan M. , van Rooijen Nico , Straley Susan C. 
Published: July 2009

ABSTRACTYopM, a protein toxin ofYersinia pestis, is necessary for virulence in a mouse model of systemic plague. We previously reported YopM-dependent natural killer (NK) cell depletion from blood and spleen samples of infected mice. However, in this study we found that infection withY.pestisKIM5 (YopM+) caused depletion of NK cells in the spleen, but not in the liver, and antibody-mediated ablation of NK cells had no effect on bacterial growth. There was no YopM-associated effect on the percentage of dendritic cells (DCs) or polymorphonuclear leukocytes (PMNs) in the early stage of infection; however, there was a YopM-associated effect on PMN integrity and on the influx of monocytes into the spleen. Ablation of Gr1+cells caused loss of the growth defect of YopM−Y.pestisin both the liver and spleen. In contrast, ablation of macrophages/DCs inhibited growth of both parent and mutant bacteria, accompanied by significantly fewer lesion sites in the liver. These results point toward PMNs and inflammatory monocytes as major cell types that control growth of YopM−Y.pestis. Infection with fully virulentY.pestisCO92 and a YopM−derivative by intradermal and intranasal routes showed that the absence of YopM significantly increased the 50% lethal dose only in the intradermal model, suggesting a role for YopM in bubonic plague, in which acute inflammation occurs soon after infection.
Adhesion of
Candida albicans
to Endothelial Cells under Physiological Conditions of Flow
Authors: Grubb Sarah E. W. , Murdoch Craig , Sudbery Peter E. , Saville Stephen P. , Lopez-Ribot Jose L. , Thornhill Martin H. 
Published: July 2009

ABSTRACT

Candida albicans
is a commensal organism that under certain circumstances can become pathogenic. During systemic infection
C. albicans
is disseminated via the circulation to distant organs, where it causes multiple organ failure. Despite the severity of systemic
C. albicans
infection, little is known about the mechanisms involved in the adhesion of this organism to the endothelium lining blood vessels. Previous studies have used static assays to examine adhesion. However, these do not realistically model blood vessels, where circulating
C. albicans
cells must adhere to the endothelium under conditions of flow and shear stress. Furthermore, there is conflicting evidence concerning the role played by yeast, pseudohyphal, and hyphal forms of
C. albicans
in adhesion to endothelium. To test the hypothesis that there may be differences in the abilities of these three morphogenic forms of
C. albicans
to adhere to endothelium under conditions of flow, we developed an in vitro flow adhesion assay. We found that all three forms of
C. albicans
rapidly bound to confluent endothelial cells under conditions of flow. Maximum adhesion was found at low shear stress levels similar to that found in postcapillary venules. Moreover, yeast forms bound in significantly greater numbers than did pseudohyphal and hyphal forms, respectively, contrasting with previous findings from static assays. These findings are consistent with recent in vivo data suggesting that yeast forms may be capable of adhering to the endothelium and migrating into the tissues before undergoing morphogenic change to cause tissue damage.
The CheZ Binding Interface of CheA
S
Is Located in α-Helix E
Authors: O'Connor Christopher , Matsumura Philip , Campos Andres 
Published: July 2009

ABSTRACT

Specific CheA-short (CheA
S
) residues, L123 and L126, were identified as critical for CheZ binding. In the CheA
S
′P1-CheZ nuclear magnetic resonance structure, these residues form an interaction surface on α-helix E in the ′P1 domain. Both L123 and L126 are buried in CheA-long (CheA
L
), providing an explanation for why CheA
L
fails to bind CheZ.
Selection, Recombination, and Virulence Gene Diversity among Group B Streptococcal Genotypes
Authors: Springman A. Cody , Lacher David W. , Wu Guangxi , Milton Nicole , Whittam Thomas S. , Davies H. Dele , Manning Shannon D. 
Published: July 2009

ABSTRACTTransmission of group BStreptococcus(GBS) from mothers to neonates during childbirth is a leading cause of neonatal sepsis and meningitis. Although subtyping tools have identified specific GBS phylogenetic lineages that are important in neonatal disease, little is known about the genetic diversity of these lineages or the roles that recombination and selection play in the generation of emergent genotypes. Here, we examined genetic variation, selection, and recombination in seven multilocus sequence typing (MLST) loci from 94 invasive, colonizing, and bovine strains representing 38 GBS sequence types and performed DNA sequencing and PCR-based restriction fragment length polymorphism analysis of several putative virulence genes to identify gene content differences between genotypes. Despite the low level of diversity in the MLST loci, a neighbor net analysis revealed a variable range of genetic exchange among the seven clonal complexes (CCs) identified, suggesting that recombination is partly responsible for the diversity observed between genotypes. Recombination is also important for several virulence genes, as some gene alleles had evidence for lateral gene exchange across divergent genotypes. The CC-17 lineage, which is associated with neonatal disease, is relatively homogeneous and therefore appears to have diverged independently with an exclusive set of virulence characteristics. These data suggest that different GBS genetic backgrounds have distinct virulence gene profiles that may be important for disease pathogenesis. Such profiles could be used as markers for the rapid detection of strains with an increased propensity to cause neonatal disease and may be considered useful vaccine targets.
The Germination-Specific Lytic Enzymes SleB, CwlJ1, and CwlJ2 Each Contribute to
Bacillus anthracis
Spore Germination and Virulence
Authors: Giebel Jonathan D. , Carr Katherine A. , Anderson Erica C. , Hanna Philip C. 
Published: July 2009

ABSTRACT

The bacterial spore cortex is critical for spore stability and dormancy and must be hydrolyzed by germination-specific lytic enzymes (GSLEs), which allows complete germination and vegetative cell outgrowth. We created in-frame deletions of three genes that encode GSLEs that have been shown to be active in
Bacillus anthracis
germination:
sleB
,
cwlJ1
, and
cwlJ2
. Phenotypic analysis of individual null mutations showed that the removal of any one of these genes was not sufficient to disrupt spore germination in nutrient-rich media. This finding indicates that these genes have partially redundant functions. Double and triple deletions of these genes resulted in more significant defects. Although a small subset of Δ
sleB
Δ
cwlJ1
spores germinate with wild-type kinetics, for the overall population there is a 3-order-of-magnitude decrease in the colony-forming efficiency compared with wild-type spores. Δ
sleB
Δ
cwlJ1
Δ
cwlJ2
spores are unable to complete germination in nutrient-rich conditions in vitro. Both Δ
sleB
Δ
cwlJ1
and Δ
sleB
Δ
cwlJ1
Δ
cwlJ2
spores are significantly attenuated, but are not completely devoid of virulence, in a mouse model of inhalation anthrax. Although unable to germinate in standard nutrient-rich media, spores lacking SleB, CwlJ1, and CwlJ2 are able to germinate in whole blood and serum in vitro, which may explain the persistent low levels of virulence observed in mouse infections. This work contributes to our understanding of GSLE activation and function during germination. This information may result in identification of useful therapeutic targets for the disease anthrax, as well as provide insights into ways to induce the breakdown of the protective cortex layer, facilitating easier decontamination of resistant spores.
Smoking uptake and prevalence in Ghana
Authors: Owusu-Dabo E , Lewis S , McNeill A , Gilmore A , Britton J 
Published: July 2009

Background:Developing countries are at high risk of epidemic increases in tobacco smoking, but the extent of this problem is not clearly defined because few collect detailed smoking data. We have surveyed tobacco smoking in the Ashanti region of Ghana, a rapidly developing African country with a long-established tobacco industry.Methods:We took a random sample of 30 regional census enumeration areas, each comprising about 100 households, and a systematic sample of 20 households from each. These were visited, a complete listing of residents obtained and questionnaire interviews on current and past smoking, age at smoking uptake, sources of cigarettes and other variables carried out in all consenting residents aged 14 or over.Results:Of 7096 eligible individuals resident in the sampled households, 6258 (88%; median age 31 (range 14–105) years; 64% female) participated. The prevalence of self-reported current smoking (weighted for gender differences in response) was 3.8% (males 8.9%, females 0.3%) and of ever smoking 9.7% (males 22.0%, females 1.2%). Smoking was more common in older people, those of Traditionalist belief, those of low educational level, the unemployed and the less affluent. Smokers were more likely to drink alcohol and to have friends who smoke. About 10% of cigarettes were smuggled brands. About a third of smokers were highly or very highly dependent.Conclusions:Despite rapid economic growth and a sustained tobacco industry presence, smoking prevalence in Ghana is low, particularly among younger people. This suggests that progression of an epidemic increase in smoking has to date been avoided.
Dietary Chemopreventive Phytochemicals: Too Little or Too Much?
Authors: Moiseeva Elena P. , Manson Margaret M. 
Published: July 2009

AbstractThere is a large body of evidence that the consumption of fruit and vegetables can decrease the risk of cancer. However, the link between diet and health is extremely complex. Some dietary phytochemicals seem to offer protection in an exposure-related manner and many molecular targets and signaling pathways affected by phytochemicals have been discovered. Although in vitro studies have contributed significantly to our understanding, quite a number use concentrations orders of magnitude greater than those achievable in humans or toxic to normal tissues (exemplified by toxic concentrations of indole-3-carbinol, epigallocatechin-3-gallate, curcumin, and genistein for breast cells). Such studies may produce results that are physiologically irrelevant, thus hindering predictions of efficacy. Here, we argue for careful consideration to be given to the in vitro experimental conditions under which dietary phytochemicals are investigated. Design features, such as the use of appropriate nontoxic concentrations, extended treatment times, three-dimensional cultures, primary tumor cultures, and comparison of susceptibility of various cancer subtypes, should improve our understanding of their molecular targets. This in turn would facilitate predictions as to their potential usefulness in the clinic.
Topical Treatment with Black Raspberry Extract Reduces Cutaneous UVB-Induced Carcinogenesis and Inflammation
Authors: Duncan F J. , Martin Jason R. , Wulff Brian C. , Stoner Gary D. , Tober Kathleen L. , Oberyszyn Tatiana M. , Kusewitt Donna F. , Van Buskirk Anne M. 
Published: July 2009

Abstract
Light in the UVB spectrum (280-320 nm) induces a number of changes in the epidermis and dermis of mice and humans, resulting in a robust inflammatory response. A standardized black raspberry extract (BRE) has been effective in reducing signaling pathways commonly initiated by inflammatory stimuli. In this study, we determined whether this extract could reduce cutaneous UVB-induced inflammation and carcinogenesis. In our carcinogenesis model, female SKH-1 hairless mice were exposed to one minimal erythemal dose of UVB thrice weekly on nonconsecutive days for 25 weeks. Immediately after each exposure, the mice were treated topically with either BRE dissolved in vehicle or with vehicle only. Beginning on week 19, mice treated with BRE had a significant reduction in tumor number and in average tumor size. This reduction correlated with a significant reduction in tumor-infiltrating CD3+foxp3+ regulatory T-cells. In the acute model, mice were exposed to a single minimal erythemal dose of UVB and treated topically with BRE or with vehicle. At 48 hours post-UVB exposure, topical BRE treatment significantly reduced edema, p53 protein levels, oxidative DNA damage, and neutrophil activation. The ability of topical BRE to reduce acute UVB-induced inflammation and to decrease tumor development in a long-term model provides compelling evidence to explore the clinical efficacy of BRE in the prevention of human skin cancers.
Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention
Authors: Thomasset Sarah , Berry David P. , Cai Hong , West Kevin , Marczylo Tim H. , Marsden Debbie , Brown Karen , Dennison Ashley , Garcea Giuseppe , Miller Andrew , Hemingway David , Steward William P. , Gescher Andreas J. 
Published: July 2009

AbstractNaturally occurring anthocyanins possess colorectal cancer chemopreventive properties in rodent models. We investigated whether mirtocyan, an anthocyanin-rich standardized bilberry extract, causes pharmacodynamic changes consistent with chemopreventive efficacy and generates measurable levels of anthocyanins in blood, urine, and target tissue. Twenty-five colorectal cancer patients scheduled to undergo resection of primary tumor or liver metastases received mirtocyan 1.4, 2.8, or 5.6 grams (containing 0.5-2.0 grams anthocyanins) daily for 7 days before surgery. Bilberry anthocyanins were analyzed by high performance liquid chromatography (HPLC) with visible or mass spectrometric detection. Proliferation was determined by immunohistochemistry of Ki-67 in colorectal tumor. Concentrations of insulin-like growth factor (IGF)-I were measured in plasma. Mirtocyan anthocyanins and methyl and glucuronide metabolites were identified in plasma, colorectal tissue, and urine, but not in liver. Anthocyanin concentrations in plasma and urine were roughly dose-dependent, reaching ∼179 ng/gram in tumor tissue at the highest dose. In tumor tissue from all patients on mirtocyan, proliferation was decreased by 7% compared with preintervention values. The low dose caused a small but nonsignificant reduction in circulating IGF-I concentrations. In conclusion, repeated administration of bilberry anthocyanins exerts pharmacodynamic effects and generates concentrations of anthocyanins in humans resembling those seen in ApcMin mice, a model of FAP adenomas sensitive to the chemopreventive properties of anthocyanins. Studies of doses containing &lt;0.5 gram bilberry anthocyanins are necessary to adjudge whether they may be appropriate for development as colorectal cancer chemopreventive agents.
Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Authors: Wu Xifeng , Spitz Margaret R. , Lee J. Jack , Lippman Scott M. , Ye Yuanqing , Yang Hushan , Khuri Fadlo R. , Kim Edward , Gu Jian , Lotan Reuben , Hong Waun K. 
Published: July 2009

Abstract
This study was aimed to identify novel susceptibility variants for second primary tumor (SPT) or recurrence in curatively treated early-stage head and neck squamous cell carcinoma (HNSCC) patients.
We constructed a custom chip containing a comprehensive panel of 9,645 chromosomal and mitochondrial single nucleotide polymorphisms (SNP) representing 998 cancer-related genes selected by a systematic prioritization schema. Using this chip, we genotyped 150 early-stage HNSCC patients with and 300 matched patients without SPT/recurrence from a prospectively conducted randomized trial and assessed the association of these SNPs with risk of SPT/recurrence.
Individually, six chromosomal SNPs and seven mitochondrial SNPs were significantly associated with risk of SPT/recurrence after adjustment for multiple comparisons. A strong gene-dosage effect was observed when these SNPs were combined, as evidenced by a progressively increasing SPT/recurrence risk as the number of unfavorable genotypes increased (P for trend &lt; 1.00 × 10−20). Several polygenic analyses suggest an important role of interconnected functional network and gene-gene interaction in modulating SPT/recurrence. Furthermore, incorporation of these genetic markers into a multivariate model improved significantly the discriminatory ability over the models containing only clinical and epidemiologic variables.
This is the first large-scale systematic evaluation of germ-line genetic variants for their roles in HNSCC SPT/recurrence. The study identified several promising susceptibility loci and showed the cumulative effect of multiple risk loci in HNSCC SPT/recurrence. Furthermore, this study underscores the importance of incorporating germ-line genetic variation data with clinical and risk factor data in constructing prediction models for clinical outcomes.
Chemoprevention of Lung Squamous Cell Carcinoma in Mice by a Mixture of Chinese Herbs
Authors: Wang Yian , Zhang Zhongqiu , Garbow Joel R. , Rowland Doug J. , Lubet Ronald A. , Sit Daniel , Law Francis , You Ming 
Published: July 2009

Abstract
Antitumor B (ATB) is a Chinese herbal mixture of six plants. Previous studies have shown significant chemopreventive efficacy of ATB against human esophageal and lung cancers. We have recently developed a new mouse model for lung squamous cell carcinomas (SCC). In this study, lung SCC mouse model was characterized using small-animal imaging techniques (magnetic resonance imaging and computed tomography). ATB decreased lung SCC significantly (3.1-fold; P &lt; 0.05) and increased lung hyperplastic lesions by 2.4-fold (P &lt; 0.05). This observation suggests that ATB can block hyperplasia from progression to SCC. ATB tissue distribution was determined using matrine as a marker chemical. We found that ATB is rapidly absorbed and then distributes to various tissues including the lung. These results indicate that ATB is a potent chemopreventive agent against the development of mouse lung SCCs.
Evidence for Early Morphological Decomposition in Visual Word Recognition
Authors: Solomyak Olla , Marantz Alec 
Published: July 2009

Abstract
We employ a single-trial correlational MEG analysis technique to investigate early processing in the visual recognition of morphologically complex words. Three classes of affixed words were presented in a lexical decision task: free stems (e.g., taxable), bound roots (e.g., tolerable), and unique root words (e.g., vulnerable, the root of which does not appear elsewhere). Analysis was focused on brain responses within 100–200 msec poststimulus onset in the previously identified letter string and visual word-form areas. MEG data were analyzed using cortically constrained minimum-norm estimation. Correlations were computed between activity at functionally defined ROIs and continuous measures of the words' morphological properties. ROIs were identified across subjects on a reference brain and then morphed back onto each individual subject's brain (n = 9). We find evidence of decomposition for both free stems and bound roots at the M170 stage in processing. The M170 response is shown to be sensitive to morphological properties such as affix frequency and the conditional probability of encountering each word given its stem. These morphological properties are contrasted with orthographic form features (letter string frequency, transition probability from one string to the next), which exert effects on earlier stages in processing (∼130 msec). We find that effects of decomposition at the M170 can, in fact, be attributed to morphological properties of complex words, rather than to purely orthographic and form-related properties. Our data support a model of word recognition in which decomposition is attempted, and possibly utilized, for complex words containing bound roots as well as free word-stems.