bluuebunny/crossref_metadata_2025 huggingface dataset:
The Scotopic Sensitivity Tester‐1 and the detection of early age‐related macular degeneration1
Authors: Jackson Gregory R. , Felix Tiffany , Owsley Cynthia
Published: June 2006

Purpose:  Previous research shows that dark adaptation is a marker of early age‐related macular degeneration (ARMD), even when visual acuity remains good. This study evaluates whether a commercially available, off‐the‐shelf device for measuring dark adaptation, the Scotopic Sensitivity Tester‐1 (SST‐1), which uses a full‐field stimulus, detects early ARMD as defined by fundus appearance. Fundus appearance is the gold standard method for defining the presence of ARMD.

Methods:  Dark adaptation was measured using the SST‐1 in 12 young adults (mean age 23 years), 17 old adults with normal retinal health (mean age 69) and 19 old adults with early ARMD (mean age 74). Normal retinal health and presence of early ARMD were defined by masked grading of dilated fundus photographs using the Wisconsin Age‐Related Maculopathy Grading System.

Results:  Older adults in normal retinal health exhibited slower dark adaptation as compared with young adults. No difference in the rate of dark adaptation was found between early ARMD patients and older adults in normal retinal health.

Conclusions:  Although the SST‐1 differentiated between young and older adults, it failed to detect dark adaptation abnormalities in early ARMD when referenced against older adults in normal retinal health. This may be attributable to the full‐field stimulation used by the SST‐1, which may be better suited for characterizing retinal degenerations affecting large retinal areas than for focal macular diseases like ARMD.
Shape, size, spatial distribution and composition of garnet crystals in highly deformed gneiss of the Otter Lake area, Québec, and a model for garnet crystallization
Authors: KRETZ R.
Published: June 2006

Garnet–biotite–(sillimanite) gneiss (∼700 °C, 7 kbar) of the Otter Lake area in the Western Grenville Province (Canadian Shield) occurs as granitic gneiss (group 4) that forms a large part of the Otter Complex, and as widely distributed, more heterogenous metasedimentary gneiss (group 2). In one sample of group 4 gneiss (Qtz25Pl34Kfs28Bt10Grt2.5Sil1) the true diameter (determined by serial grinding) of subhedral garnet crystals ranges from 0.2 to 3.0 mm, with a mode at 1.0 mm. Nearest‐neighbour measurements in this sample, and in surfaces of nine additional samples (all <5% garnet) confirm that garnet crystals are distributed mainly at random; slight clustering was detected in two samples. In one sample of group 4 gneiss, microprobe analyses on sections through crystal centres (obtained by serial slicing), reveal that small crystals and margins to large crystals contain more Fe and Mn and less Mg than the broad central regions of large crystals. Based on these and previous results, together with theoretical considerations, a crystallization model is proposed, in which, (i) garnet was produced by the continuous reaction, Ms + Bt + Qtz → Grt + Kfs + H2O, (ii) nucleation occurred by the random selection of randomly distributed Ms–Bt–Qtz triple junctions, (iii) the rate of linear growth remained constant, and (iv) as temperature increased, the rate of nucleation first increased slowly, then remained nearly constant, and finally declined. Within‐population compositional homogenization was followed, on cooling, by local Fe–Mg–Mn exchange with biotite.
Flood Risk Acceptability and Economic Value of Evacuation
Authors: Zhai Guofang , Ikeda Saburo
Published: June 2006

The economic value of evacuation and its relationship with flood risk acceptability in Japan were studied by applying the contingent valuation method (CVM). Flood risk acceptability here refers to the extent to which people accept the occurrence of floods, in terms of scale and frequency. The economic value of evacuation refers to people's willingness to pay (WTP) for avoiding evacuation inconvenience because of its inconvenience and the potential for certain losses as a result of evacuation. Our main finding was that over half of the people (56%) who actually evacuated in a real flood situation reported inconvenience. The greatest inconveniences were the shortages of information and food. Evacuation inconvenience can be regarded as an important factor causing the low rate of evacuation in Japan. The WTP for avoiding current inconvenience was approximately half of the estimated economic value of evacuation, implying that the current budget for evacuation is too small and should be increased to improve the conditions of evacuation sites. The economic value of evacuation can be taken into consideration in the risk assessment process in order to evaluate the efficiency of risk reduction measures. Flood risk acceptability and home ownership are two major statistically significantly determinants of the WTP. Considering that those who accept flood risk have a lower WTP for flood risk control (ex ante measures) than those who reject it, it is reasonable to think that there may be a tradeoff between the public WTPs for ex ante or ex post measures.
The Role of the Affect and Availability Heuristics in Risk Communication
Authors: Keller Carmen , Siegrist Michael , Gutscher Heinz
Published: June 2006

Results of past research suggest that affect plays an important role in risk perception. Because affect may also increase the availability of risks, affect and availability are closely related concepts. Three studies tested the hypothesis that evoking negative affect (fear), either through past experience or through experimental manipulation, results in greater perceived risk. The present research focused on perception of flooding risk. Study 1 and Study 2 showed that participants who received risk information concerning a longer time period (e.g., 30 years) perceived more danger compared with participants who received risk information for one year. Study 2 showed that the interpretation of risk information was influenced by participants' own experiences with flooding. In Study 3, affect was experimentally manipulated. After looking at photographs depicting houses in a flooded region, participants perceived greater risk compared with participants in a control group. Taken together, the results of these three studies suggest that affect is important for successful risk communication. Results of the present research are in line with the affect heuristic proposed by Slovic and colleagues.
Enabling a Powerful Marine and Offshore Decision‐Support Solution Through Bayesian Network Technique
Authors: Eleye‐Datubo A. G. , Wall A. , Saajedi A. , Wang J.
Published: June 2006

A powerful practical solution is by far the most desired output when making decisions under the realm of uncertainty on any safety‐critical marine or offshore units and their systems. With data and information typically being obtained incrementally, adopting Bayesian network (BN) is shown to realistically deal with the random uncertainties while at the same time making risk assessments easier to build and to check. A well‐matched methodology is proposed to formalize the reasoning in which the focal mechanism of inference processing relies on the sound Bayes's rule/theorem that permits the logic. Expanding one or more influencing nodal parameters with decision and utility node(s) also yields an influence diagram (ID). BN and ID feasibility is shown in a marine evacuation scenario and that of authorized vessels to floating, production, storage, and offloading collision, developed via a commercial computer tool. Sensitivity analysis and validation of the produced results are also presented.
Terrorist Population Dynamics Model
Authors: Kaminskiy Mark P. , Ayyub Bilal M.
Published: June 2006

A system that includes a number of terrorist cells is considered. The cells can consist of one or more terrorists. The current number of terrorist cells is further denoted by N(t), where t is a current time counted from any appropriate origin. The objective is to find the evolution of the system in terms of N(t) and some interpretable parameters, such as the initial number of the terrorist cells N0=N(0), the cell disabling rate constant λ (or the cell half‐life t1/2), and the rate of formation of new cells P. The cost‐effectiveness analysis, performed in the framework of the model, reveals that the effectiveness of disabling a terrorist cell is getting worse after 2–3 half‐lives of a cell, which shows that if the anti‐terrorist actions have not reached their goal during that time, the respective policy should be considered for revision, using the risk assessment consideration. Another important issue raised concerns balancing the efforts related to counterterrorism actions inside the system and the efforts protecting its borders. The respective data analysis is suggested and illustrated using simulated data.
The Precautionary Principle Is Incoherent
Authors: Peterson Martin
Published: June 2006

This article argues that no version of the precautionary principle can be reasonably applied to decisions that may lead to fatal outcomes. In support of this strong claim, a number of desiderata are proposed, which reasonable rules for rational decision making ought to satisfy. Thereafter, two impossibility theorems are proved, showing that no version of the precautionary principle can satisfy the proposed desiderata. These theorems are directly applicable to recent discussions of the precautionary principle in medicine, biotechnology, environmental management, and related fields. The impossibility theorems do not imply, however, that the precautionary principle is of no relevance at all in policy discussions. Even if it is not a reasonable rule for rational decision making, it is possible to interpret the precautionary principle in other ways, e.g., as an argumentative tool or as an epistemic principle favoring a reversed burden of proof.
Transparency, Political Polarization, and Political Budget Cycles in OECD Countries
Authors: Alt James E. , Lassen David Dreyer
Published: June 2006

We investigate the effects of fiscal transparency and political polarization on the prevalence of electoral cycles in fiscal balance. While some recent political economy literature on electoral cycles identifies such cycles mainly in weak and recent democracies, in contrast we show, conditioning on a new index of institutional fiscal transparency, that electoral cycles in fiscal balance are a feature of many advanced industrialized economies. Using a sample of 19 OECD countries in the 1990s, we identify a persistent pattern of electoral cycles in low(er) transparency countries, while no such cycles can be observed in high(er) transparency countries. Furthermore, we find, in accordance with recent theory, that electoral cycles are larger in politically more polarized countries.
Democratic Transitions
Authors: Epstein David L. , Bates Robert , Goldstone Jack , Kristensen Ida , O'Halloran Sharyn
Published: June 2006

Przeworski et al. (2000)challenge the key hypothesis in modernization theory: political regimes do not transition to democracy as per capita incomes rise, they argue. Rather, democratic transitions occur randomly, but once there, countries with higher levels of GDP per capita remain democratic. We retest the modernization hypothesis using new data, new techniques, and a three‐way rather than dichotomous classification of regimes. Contrary toPrzeworski et al. (2000)we find that the modernization hypothesis stands up well. We also find that partial democracies emerge as among the most important and least understood regime types.
Still Supermadres? Gender and the Policy Priorities of Latin American Legislators
Authors: Schwindt‐Bayer Leslie A.
Published: June 2006

This article examines the effect of gender on legislators' attitudes and bill initiation behavior in three Latin American countries—Argentina, Colombia, and Costa Rica. I argue that sex role changes in Latin America over the past 35 years have led to changes in how female legislators perceive their political roles, and consequently, changes in their attitudes and behavior. Specifically, female legislators will place higher priority than male legislators on women's issues and children/family concerns, but their attitudes in other areas, such as education, health, the economy, agriculture, and employment, will be similar. However, I expect that gender dynamics in the legislative arena lead to marginalization of women such that gender differences will emerge for bill initiation behavior where they did not appear for attitudes. I test this using a survey of legislators' issue preferences and archival data on the bills that legislators sponsor and find statistical support for the hypotheses.
Dialogue in American Political Campaigns? An Examination of Issue Convergence in Candidate Television Advertising
Authors: Kaplan Noah , Park David K. , Ridout Travis N.
Published: June 2006

The theory of issue ownership holds that competing candidates should avoid discussing many of the same issues during a campaign. In contrast, theories of democracy suggest that competitive elections are the mechanism by which the public can hold politicians accountable. To determine the extent to which each theory depicts current campaigns, we develop a new measure of “issue convergence” and test whether or not issue convergence increases as the competitiveness of the race increases. Using new data based upon television advertising aired in U.S. Senate campaigns from 1998 through 2002, we find that issue engagement or dialogue occurs more frequently than indicated by previous research. We also find that issue engagement increases with the competitiveness of the race but that issue engagement decreases as the gap in financial resources between candidates increases.
Political Appointments, Civil Service Systems, and Bureaucratic Competence: Organizational Balancing and Executive Branch Revenue Forecasts in the American States
Authors: Krause George A. , Lewis David E. , Douglas James W.
Published: June 2006

Scholarship on executive politics provides conflicting views about whether staffing administrative agencies through politicized or (politically) autonomous means is the best method for maximizing bureaucratic competence. We offer a theoretical account which maintains that obtaining a proper balance between both types of personnel systems across the supervisory and subordinate levels of an organization will best foster bureaucratic competence. We evaluate our organizational balancing thesis using data on executive branch general revenue fund forecasts in the American states from 1987 to 2002. States with a combination of politically appointed agency executives and merit‐selected subordinates generally provide more accurate revenue forecasts than states that possess uniformly politicized personnel selection systems. Conversely, states with a combination of department head–appointed executives and subordinates chosen from an at‐will system (i.e., nonmerit) produce more accurate forecasts than states with uniformly autonomous personnel selection systems. Our statistical findings underscore the positive consequences associated with balancing politicized and autonomous means of selecting personnel within hierarchies of political organizations.
Is Spending More Potent For or Against a Proposition? Evidence from Ballot Measures
Authors: Stratmann Thomas
Published: June 2006

The recent academic literature suggests that pressure from special interest groups has little or no influence on whether initiatives and referendums are passed or defeated. Further, there is a consensus that, to the degree that groups' campaigning is important for explaining outcomes, groups opposing the initiative and favoring the status quo have an advantage over groups that support change. These studies have not considered that interest groups campaign strategically and therefore that campaigning is endogenous in ballot measure elections. This study examines the effect of campaigning on ballot proposition elections and develops a research design that accounts for strategic and endogenous campaign advertising. The research design uses a two‐way fixed‐effects model to estimate the effect of interest group pressure on ballot measure outcomes. The data are based on television advertising for or against California ballot measures from 2000 to 2004. The results show that supporting and opposing interest groups' campaigning has a quantitatively important and statistically significant influence on ballot measure outcomes. The campaigning of supporting interest groups is at least as productive as that of opposing interest groups.
The Consequences of Collective Action: An Incomplete‐Contracts Approach
Authors: Gehlbach Scott
Published: June 2006

Public policy may be determined as much by what cannot be agreed to by politicians and organized interests as by what can. Focusing on the inability of organized groups to credibly promise that their members will fully report revenues to tax authorities, I develop an incomplete‐contracts lobbying model that shows that the provision of collective goods may be influenced by the anticipated tax compliance of economic sectors as well as by the organization of interests. Data from a survey of firms in Eastern Europe and the former Soviet Union are broadly supportive of the theory: the ability of firms to hide revenues from tax authorities rivals conventional collective‐action variables in explaining variation in collective‐goods provision, but only in that part of the postcommunist world where differences in revenue hiding across sectors are especially large.
Juries, Judges, and Punitive Damages: Empirical Analyses Using the Civil Justice Survey of State Courts 1992, 1996, and 2001 Data
Authors: Eisenberg Theodore , Hannaford‐Agor Paula L. , Heise Michael , LaFountain Neil , Munsterman G. Thomas , Ostrom Brian , Wells Martin T.
Published: June 2006

We analyze thousands of trials from a substantial fraction of the nation's most populous counties. Evidence across 10 years and three major data sets suggests that: (1) juries and judges award punitive damages in approximately the same ratio to compensatory damages, (2) the level of punitive damages awards has not increased, and (3) juries' and judges' tendencies to award punitive damages differ in bodily injury and no‐bodily‐injury cases. Jury trials are associated with a greater rate of punitive damages awards in financial injury cases. Judge trials are associated with a greater rate of punitive damages awards in bodily injury cases.
The Use of Foreign Decisions by Federal Courts: An Empirical Analysis
Authors: Zaring David
Published: June 2006

This article adds an empirical perspective to the debate over the use of foreign authority by federal courts. It surveys 60 years of federal court practice in citing opinions from foreign high courts using a citation count analysis. The data reveal that federal courts rarely cite to foreign decisions, they do so no more now than they did in the past, and on those few occasions where they do cite to foreign decisions, it's usually not to help them interpret domestic law. Instead, the citation of foreign decisions is best understood as a relatively rare phenomenon of judicial dialogue in cases where international issues are squarely presented by the facts. The article examines those few cases where federal courts have cited foreign decisions in some detail, and briefly considers some implications of the limited use of foreign decisions by federal courts.
A Note on the Censoring Problem in Empirical Case‐Outcome Studies
Authors: Finkelstein Michael O. , Levin Bruce , McKeague Ian W. , Tsai Wei‐Yann
Published: June 2006

In outcome studies of cases filed within a study window, the sample may be skewed if many cases are still pending when the window closes and not included in the study. We refer to cases that are completed within the window as “observed” and those still pending as “censored.” We propose two methods for reducing possible bias: a “self‐consistent” estimator that imputes values to the censored cases and an “inverse probability weighting” estimator that assigns weights to the observed cases. In the body of the article we describe these methods for the nonmathematical reader and in the Appendix give a more mathematical treatment. We then apply the self‐consistent estimator first to simulated data and then to the landmark study of reversals in death penalty cases by Professor James S. Liebman and his colleagues. In these examples the two methods are equivalent. Liebman et al. simply excluded censored cases and reported a reversal rate of 68%. Application of our methods to the Liebman data reduces the reversal rate to 62.2% (95% c.i. 60.1%, 64.4%). In general, our method largely removes the bias that affects sample estimates when censored cases are just ignored.
Statistics and Risk in the Nuclear Industry
Authors: Wilson Granville Tunnicliffe
Published: June 2006

Nuclear power, after a decade of being ignored, is again becoming an option—perhaps the preferred option—for future power generation in Britain. Can it be done safely? As importantly, can existing plant be decommissioned safely? Granville Tunnicliffe Wilson has worked on a series of statistical projects with the nuclear industry, stretching over a period of 30 years. He looks at the part statistics has played in past safety assurance and the questions that are now being asked about its role. He also reveals past cases where operators failed to follow valid statistical indicators of plant failure.
Smoke Gets in Your Eyes—Well, Only Until Mid-2007
Authors: Hackshaw Allan
Published: June 2006

After three decades of research, recommendations from professional organisations, campaigns and controversies, the UK parliament has finally voted for a complete ban on smoking in enclosed public places. It is expected to come into force around mid-2007. Is it justified? Allan Hackshaw of Cancer Research UK looks at a long statistical battle.
Monitoring and Evaluation in Malawi
Authors: Barahono Carlos , Wilson Ian
Published: June 2006

When Ian Wilson and Carlos Barahona of the Statistical Services Centre at the University of Reading were asked to review an evaluation of the effectiveness of an aid package in Malawi, they expected a simple enough task. But few things in the developing world are simple. Where aid for the poorest is concerned, is evidence collected and analysed with enough rigour to enable well-informed decisions to be made?
15 Minutes of Statistical Fame
Authors: Lawrance Tony
Published: June 2006

Tony Lawrance surveyed his email one morning to find an urgent request from the West Mercia Police Authority to give a statistical opinion on a government report recommending the merger of the current 43 police forces into as few as 12. The Authority asked for an independent objective assessment, “even if we don't like the answer.” Persuaded by this freedom, he submitted his report within the 2-day deadline and returned, as he thought, to the day job. Well, not quite—a media storm followed.
Line Plots
Authors: Reese R. Allan
Published: June 2006

You can see line plots or line graphs in any quality newspaper most days, presenting business data. Even the downmarket papers use them occasionally to illustrate trends. They are so common that we might assume that they are well understood. Most spreadsheets and statistical packages can produce them with ease. But all is not as it seems. R. Allan Reese explains the pitfalls.
Reduced Radiative Conductivity of Low-Spin (Mg,Fe)O in the Lower Mantle
Authors: Goncharov Alexander F. , Struzhkin Viktor V. , Jacobsen Steven D.
Published: June 2006

Optical absorption spectra have been measured at pressures up to 80 gigapascals (GPa) for the lower-mantle oxide magnesiowüstite (Mg,Fe)O. Upon reaching the high-spin to low-spin transition of Fe
2+
at about 60 GPa, we observed enhanced absorption in the mid- and near-infrared spectral range, whereas absorption in the visible-ultraviolet was reduced. The observed changes in absorption are in contrast to prediction and are attributed to
d-d
orbital charge transfer in the Fe
2+
ion. The results indicate that low-spin (Mg,Fe)O will exhibit lower radiative thermal conductivity than high-spin (Mg,Fe)O, which needs to be considered in future geodynamic models of convection and plume stabilization in the lower mantle.
Cancer BiomarkersAn Invitation to the Table
Authors: Dalton William S. , Friend Stephen H.
Published: June 2006

The allure of the emerging genomic technologies in cancer is their ability to generate new biomarkers that predict how individual cancer patients will respond to various treatments. However, productive implementation of cancer biomarkers into patient care will require fundamental changes in how we consider approvals for cancer indications and how we track patient responses. Here we briefly describe ongoing efforts to identify and to validate cancer biomarkers, discuss the technological hurdles that lie ahead, and then focus on the more pressing political and cultural issues that, if left unheeded, could derail many of the anticipated benefits of biomarker research.
Antiangiogenic Therapy: A Universal Chemosensitization Strategy for Cancer?
Authors: Kerbel Robert S.
Published: June 2006

For more than 50 years, a major goal of research in cancer therapeutics has been to develop universally effective agents that render cancer cells more sensitive to cytotoxic chemotherapy without substantially increasing toxicity to normal cells. The results of recent clinical trials indicate that certain antiangiogenic drugs may produce this long-sought effect. Here, I describe three distinct mechanisms that may help to explain the chemosensitizing activity of these drugs: normalizing tumor vasculature, preventing rapid tumor cell repopulation, and augmenting the antivascular effects of chemotherapy. I then discuss how these potential mechanisms might be exploited to maximize therapeutic efficacy.
Imaging Bond Formation Between a Gold Atom and Pentacene on an Insulating Surface
Authors: Repp Jascha , Meyer Gerhard , Paavilainen Sami , Olsson Fredrik E. , Persson Mats
Published: June 2006

A covalent bond between an individual pentacene molecule and a gold atom was formed by means of single-molecule chemistry inside a scanning tunneling microscope junction. The bond formation is reversible, and different structural isomers can be produced. The single-molecule synthesis was done on ultrathin insulating films that electronically isolated the reactants and products from their environment. Direct imaging of the orbital hybridization upon bond formation provides insight into the energetic shifts and occupation of the molecular resonances.
Pituitary Adenoma Predisposition Caused by Germline Mutations in the
AIP
Gene
Authors: Vierimaa Outi , Georgitsi Marianthi , Lehtonen Rainer , Vahteristo Pia , Kokko Antti , Raitila Anniina , Tuppurainen Karoliina , Ebeling Tapani M. L. , Salmela Pasi I. , Paschke Ralf , Gündogdu Sadi , De Menis Ernesto , Mäkinen Markus J. , Launonen Virpi , Karhu Auli , Aaltonen Lauri A.
Published: June 2006

Pituitary adenomas are common in the general population, and understanding their molecular basis is of great interest. Combining chip-based technologies with genealogy data, we identified germline mutations in the
aryl hydrocarbon receptor interacting protein
(
AIP
) gene in individuals with pituitary adenoma predisposition (PAP). AIP acts in cytoplasmic retention of the latent form of the aryl hydrocarbon receptor and also has other functions. In a population-based series from Northern Finland, two
AIP
mutations account for 16% of all patients diagnosed with pituitary adenomas secreting growth hormone and for 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients do not display a strong family history of pituitary adenoma; thus,
AIP
is an example of a low-penetrance tumor susceptibility gene.
Search for Life's Beginnings
Authors: Fry Iris
Published: June 2006

Genesis
. The Scientific Quest for Life's Origin.
By Robert M. Hazen
. Joseph Henry Press, Washington, DC, 2005. 359 pp. $27.95, C$37.95. ISBN 0-309-09432-1.

The author provides nonspecialists a comprehensive and balanced survey of research on the origins of life.
Strong Top-Down Control in Southern California Kelp Forest Ecosystems
Authors: Halpern Benjamin S. , Cottenie Karl , Broitman Bernardo R.
Published: June 2006

Global-scale changes in anthropogenic nutrient input into marine ecosystems via terrestrial runoff, coupled with widespread predator removal via fishing, have created greater urgency for understanding the relative role of top-down versus bottom-up control of food web dynamics. Yet recent large-scale studies of community regulation in marine ecosystems have shown dramatically different results that leave this issue largely unresolved. We combined a multiyear, large-scale data set of species abundances for 46 species in kelp forests from the California Channel Islands with satellite-derived primary production and found that top-down control explains 7- to 10-fold more of the variance in abundance of bottom and mid-trophic levels than does bottom-up control. This top-down control was propagated via a variety of species-level direct and indirect responses to predator abundance. Management of top-down influences such as fishing may be more important in coastal marine ecosystems, particularly in kelp forest systems, than is commonly thought.
Relapsing Fever SpirochetesBorrelia recurrentisandB. duttoniiAcquire Complement Regulators C4b-Binding Protein and Factor H
Authors: Meri T. , Cutler S. J. , Blom A. M. , Meri S. , Jokiranta T. S.
Published: June 2006

Relapsing fever is a rapidly progressive and severe septic disease caused by certainBorreliaspirochetes. The disease is divided into two forms, i.e., epidemic relapsing fever, caused byBorrelia recurrentisand transmitted by lice, and the endemic form, caused by severalBorreliaspecies, such asB. duttonii, and transmitted by soft-bodied ticks. The spirochetes enter the bloodstream by the vector bite and live persistently in plasma even after the development of specific antibodies. This leads to fever relapses and high mortality and clearly indicates that theBorreliaorganisms utilize effective immune evasion strategies. In this study, we show that the epidemic relapsing fever pathogenB. recurrentisand an endemic relapsing fever pathogen,B. duttonii, are serum resistant, i.e., resistant to complement in vitro. They acquire the host alternative complement pathway regulator factor H on their surfaces in a similar way to that of the less serum-resistant Lyme disease pathogen,B. burgdorferisensu stricto. More importantly, the relapsing fever spirochetes specifically bind host C4b-binding protein, a major regulator of the antibody-mediated classical complement pathway. Both complement regulators retained their functional activities when bound to the surfaces of the spirochetes. In conclusion, this is the first report of complement evasion byBorrelia recurrentisandB. duttoniiand the first report showing capture of C4b-binding protein by spirochetes.
CPS1
, a Homolog of the
Streptococcus pneumoniae
Type 3 Polysaccharide Synthase Gene, Is Important for the Pathobiology of
Cryptococcus neoformans
Authors: Chang Y. C. , Jong A. , Huang S. , Zerfas P. , Kwon-Chung K. J.
Published: June 2006

The polysaccharide capsule is known to be the major factor required for the virulence of
Cryptococcus neoformans
. We have cloned and characterized a gene, designated
CPS1
, that encodes a protein containing a glycosyltransferase moiety and shares similarity with the type 3 polysaccharide synthase encoded by the
cap3B
gene of
Streptococcus pneumoniae
. Cps1p also shares similarity with hyaluronan synthase of higher eukaryotes. Deletion of the
CPS1
gene from a serotype D strain of
C. neoformans
resulted in a slight reduction of the capsule size as observed by using an India ink preparation. The growth at 37°C was impaired, and the ability to associate with human brain endothelial cells in vitro was also significantly reduced by the deletion of
CPS1
. Using site-specific mutagenesis, we showed that the conserved glycosyltransferase domains are critical for the ability of the strain to grow at elevated temperatures. A hyaluronan enzyme-linked immunosorbent assay method demonstrated that
CPS1
is important for the synthesis of hyaluronan or its related polysaccharides in
C. neoformans
. Comparisons between the wild-type and the
cps1Δ
strains, using three different transmission electron microscopic methods, indicated that the
CPS1
gene product is involved in the composition or maintenance of an electron-dense layer between the outer cell wall and the capsule. These and the virulence studies in a mouse model suggested that the
CPS1
gene is important in the pathobiology of
C. neoformans
.
Role of Calcineurin in Stress Resistance, Morphogenesis, and Virulence of a
Candida albicans
Wild-Type Strain
Authors: Bader Teresa , Schröppel Klaus , Bentink Stefan , Agabian Nina , Köhler Gerwald , Morschhäuser Joachim
Published: June 2006

By generating a calcineurin mutant of the
Candida albicans
wild-type strain SC5314 with the help of a new recyclable dominant selection marker, we confirmed that calcineurin mediates tolerance to a variety of stress conditions but is not required for the ability of
C. albicans
to switch to filamentous growth in response to hypha-inducing environmental signals. While calcineurin was essential for virulence of
C. albicans
in a mouse model of disseminated candidiasis, deletion of
CMP1
did not significantly affect virulence during vaginal or pulmonary infection, demonstrating that the requirement for calcineurin for a successful infection depends on the host niche.
Characterization of a Novel Porin Involved in Systemic
Yersinia enterocolitica
Infection
Authors: Mildiner-Earley Shirly , Miller Virginia L.
Published: June 2006

Yersinia enterocolitica
is an enteric pathogen capable of causing systemic disease in a murine model. We have identified a novel protein,
s
ystemic
f
actor
p
rotein A (SfpA), conserved in other pathogenic bacteria that is involved in systemic disease. Analysis of bacterial colonization revealed that a Δ
sfpA
strain is defective in mesenteric lymph node colonization. Bioinformatics and functional studies suggest that SfpA is a porin.
Alcohol Dehydrogenase Restricts the Ability of the Pathogen
Candida albicans
To Form a Biofilm on Catheter Surfaces through an Ethanol-Based Mechanism
Authors: Mukherjee Pranab K. , Mohamed Sotohy , Chandra Jyotsna , Kuhn Duncan , Liu Shuqing , Antar Omar S. , Munyon Ryan , Mitchell Aaron P. , Andes David , Chance Mark R. , Rouabhia Mahmoud , Ghannoum Mahmoud A.
Published: June 2006

Candida
biofilms formed on indwelling medical devices are increasingly associated with severe infections. In this study, we used proteomics and Western and Northern blotting analyses to demonstrate that alcohol dehydrogenase (ADH) is downregulated in
Candida
biofilms. Disruption of
ADH1
significantly (
P
= 0.0046) enhanced the ability of
Candida albicans
to form biofilm. Confocal scanning laser microscopy showed that the
adh1
mutant formed thicker biofilm than the parent strain (210 μm and 140 μm, respectively). These observations were extended to an engineered human oral mucosa and an in vivo rat model of catheter-associated biofilm. Inhibition of
Candida
ADH enzyme using disulfiram and 4-methylpyrazole resulted in thicker biofilm (
P
< 0.05). Moreover, biofilms formed by the
adh1
mutant strain produced significantly smaller amounts of ethanol, but larger amounts of acetaldehyde, than biofilms formed by the parent and revertant strains (
P
< 0.0001), demonstrating that the effect of Adh1p on biofilm formation is mediated by its enzymatic activity. Furthermore, we found that 10% ethanol significantly inhibited biofilm formation in vitro, with complete inhibition of biofilm formation at ethanol concentrations of ≥20%. Similarly, using a clinically relevant rabbit model of catheter-associated biofilm, we found that ethanol treatment inhibited biofilm formation by
C. albicans
in vivo (
P
< 0.05) but not by
Staphylococcus
spp. (
P
> 0.05), indicating that ethanol specifically inhibits
Candida
biofilm formation. Taken together, our studies revealed that Adh1p contributes to the ability of
C. albicans
to form biofilms in vitro and in vivo and that the protein restricts biofilm formation through an ethanol-dependent mechanism. These results are clinically relevant and may suggest novel antibiofilm treatment strategies.
Intrastrain Heterogeneity of the
mgpB
Gene in
Mycoplasma genitalium
Is Extensive In Vitro and In Vivo and Suggests that Variation Is Generated via Recombination with Repetitive Chromosomal Sequences
Authors: Iverson-Cabral Stefanie L. , Astete Sabina G. , Cohen Craig R. , Rocha Eduardo P. C. , Totten Patricia A.
Published: June 2006

Mycoplasma genitalium
is associated with reproductive tract disease in women and may persist in the lower genital tract for months, potentially increasing the risk of upper tract infection and transmission to uninfected partners. Despite its exceptionally small genome (580 kb), approximately 4% is composed of repeated elements known as MgPar sequences (MgPa repeats) based on their homology to the
mgpB
gene that encodes the immunodominant MgPa adhesin protein. The presence of these MgPar sequences, as well as
mgpB
variability between
M. genitalium
strains, suggests that
mgpB
and MgPar sequences recombine to produce variant MgPa proteins. To examine the extent and generation of diversity within single strains of the organism, we examined
mgpB
variation within
M. genitalium
strain G-37 and observed sequence heterogeneity that could be explained by recombination between the
mgpB
expression site and putative donor MgPar sequences. Similarly, we analyzed
mgpB
sequences from cervical specimens from a persistently infected woman (21 months) and identified 17 different
mgpB
variants within a single infecting
M. genitalium
strain, confirming that
mgpB
heterogeneity occurs over the course of a natural infection. These observations support the hypothesis that recombination occurs between the
mgpB
gene and MgPar sequences and that the resulting antigenically distinct MgPa variants may contribute to immune evasion and persistence of infection.
Identification, Recombinant Expression, Immunolocalization in Macrophages, and T-Cell Responsiveness of the Major Extracellular Proteins of
Francisella tularensis
Authors: Lee Bai-Yu , Horwitz Marcus A. , Clemens Daniel L.
Published: June 2006

A safer and more effective vaccine than the previously developed live attenuated vaccine is needed for combating
Francisella tularensis
, a highly infectious bacterial pathogen. To search for potential candidates for inclusion in a new vaccine, we characterized the proteins present in the culture filtrates of a virulent recent clinical isolate and the attenuated live vaccine strain of
F. tularensis
using a proteomic approach. We identified a total of 12 proteins; among these, catalase-peroxidase was much more abundant in the culture filtrate of the virulent clinical isolate, whereas bacterioferritin was more abundant in the culture filtrate of the live vaccine strain. Streptolysin O treatment of infected human macrophages indicated that catalase-peroxidase and the heat shock protein GroEL are released intracellularly by actively growing
F. tularensis
. Mice immunized with
F. tularensis
developed significant cell-mediated immune responses to catalase-peroxidase, the heat shock protein GroEL, and bacterioferritin as measured by splenic lymphocyte proliferation and gamma interferon production. Finally, we expressed the major culture filtrate proteins that are promising vaccine candidates in
Escherichia coli
at high levels in soluble form to facilitate study of their immunobiology and potential role in vaccines.
Expression of Putative Virulence Factors of
Escherichia coli
O157:H7 Differs in Bovine and Human Infections
Authors: Rashid Rebecca A. , Tabata Tami A. , Oatley Melissa J. , Besser Thomas E. , Tarr Phillip I. , Moseley Steve L.
Published: June 2006

Escherichia coli
O157:H7 is a commensal organism in cattle, but it is a pathogen in humans. This differential expression of virulence suggests that specific virulence factors are regulated differently in human and bovine hosts. To test this hypothesis, relative real-time reverse transcription-PCR was used to relate the expression of several putative virulence genes (
eae
,
espA
,
stx
2
,
rfbE
,
ehxA
, and
iha
) to that of the “housekeeping” gene
gnd
during natural human and experimental bovine infection with
E. coli
O157:H7. We examined these genes in fecal samples from eight humans and four calves.
iha
and
espA
were significantly more expressed in bovine infections.
rfbE
and
ehxA
appeared to be more highly expressed in human infections, though these differences did not achieve statistical significance. Our results support the hypothesis that some virulence-associated genes of O157:H7 are differentially expressed in a host-specific manner.
Blastocystis rattiInduces Contact-Independent Apoptosis, F-Actin Rearrangement, and Barrier Function Disruption in IEC-6 Cells
Authors: Puthia Manoj K. , Sio Selena W. S. , Lu Jia , Tan Kevin S. W.
Published: June 2006

Blastocystisis an enteric protozoan purportedly associated with numerous clinical cases of diarrhea, flatulence, vomiting, and other gastrointestinal symptoms. Despite new knowledge ofBlastocystiscell biology, genetic diversity, and epidemiology, its pathogenic potential remains controversial. Numerous clinical and epidemiological studies either implicate or exonerate the parasite as a cause of intestinal disease. Therefore, the aim of this study was to investigate the pathogenic potential ofBlastocystisby studying the interactions ofBlastocystis rattiWR1, an isolate of zoonotic potential, with a nontransformed rat intestinal epithelial cell line, IEC-6. Here, we report thatB. rattiWR1 induces apoptosis in IEC-6 cells in a contact-independent manner. Furthermore, we found thatB. rattiWR1 rearranges F-actin distribution, decreases transepithelial resistance, and increases epithelial permeability in IEC-6 cell monolayers. In addition, we found that the effects ofB. rattion transepithelial electrical resistance and epithelial permeability were significantly abrogated by treatment with metronidazole, an antiprotozoal drug. Our results suggest for the first time thatBlastocystis-induced apoptosis in host cells and altered epithelial barrier function might play an important role in the pathogenesis ofBlastocystisinfections and that metronidazole has therapeutic potential in alleviating symptoms associated withBlastocystis.
cDNA Microarray Analysis of Host-Pathogen Interactions in a Porcine In Vitro Model forToxoplasma gondiiInfection
Authors: Okomo-Adhiambo Margaret , Beattie Craig , Rink Anette
Published: June 2006

Toxoplasma gondiiinduces the expression of proinflammatory cytokines, reorganizes organelles, scavenges nutrients, and inhibits apoptosis in infected host cells. We used a cDNA microarray of 420 annotated porcine expressed sequence tags to analyze the molecular basis of these changes at eight time points over a 72-hour period in porcine kidney epithelial (PK13) cells infected withT. gondii. A total of 401 genes with Cy3 and Cy5 spot intensities of ≥500 were selected for analysis, of which 263 (65.6%) were induced ≥2-fold (expression ratio, ≥2.0;P≤ 0.05 [ttest]) over at least one time point and 48 (12%) were significantly down-regulated. At least 12 functional categories of genes were modulated (up- or down-regulated) byT. gondii. The majority of induced genes were clustered as transcription, signal transduction, host immune response, nutrient metabolism, and apoptosis related. The expression of selected genes altered byT. gondiiwas validated by quantitative real-time reverse transcription-PCR. These results suggest that significant changes in gene expression occur in response toT. gondiiinfection in PK13 cells, facilitating further analysis of host-pathogen interactions in toxoplasmosis in a secondary host.
Molecular and Functional Characterization of a ToxR-Regulated Lipoprotein from a Clinical Isolate ofAeromonas hydrophila
Authors: Pillai Lakshmi , Sha Jian , Erova Tatiana E. , Fadl Amin A. , Khajanchi Bijay K. , Chopra Ashok K.
Published: June 2006

Human diseases caused by species ofAeromonashave been classified into two major groups: septicemia and gastroenteritis. In this study, we reported the molecular and functional characterization of a new virulence factor, ToxR-regulated lipoprotein, or TagA, from a diarrheal isolate, SSU, ofAeromonas hydrophila. ThetagAgene ofA. hydrophilaexhibited 60% identity with that of a recently identifiedstcEgene fromEscherichia coliO157:H7, which encoded a protein (StcE) that provided serum resistance to the bacterium and prevented erythrocyte lysis by controlling classical pathway of complement activation by cleaving the complement C1-esterase inhibitor (C1-INH). We purifiedA. hydrophilaTagA as a histidine-tagged fusion protein (rTagA) fromE. coliDE3 strain using a T7 promoter-based pET30 expression vector and nickel affinity column chromatography. rTagA cleaved C1-INH in a time-dependent manner. ThetagAisogenic mutant ofA. hydrophila, unlike its corresponding wild-type (WT) or the complemented strain, was unable to cleave C1-INH, which is required to potentiate the C1-INH-mediated lysis of host and bacterial cells. We indeed demonstrated colocalization of C1-INH and TagA on the bacterial surface by confocal fluorescence microscopy, which ultimately resulted in increased serum resistance of the WT bacterium. Likewise, we delineated the role of TagA in contributing to the enhanced ability of C1-INH to inhibit the classical complement-mediated lysis of erythrocytes. Importantly, we provided evidence that thetagAmutant was significantly less virulent in a mouse model of infection (60%) than the WT bacterium at two 50% lethal doses, which resulted in 100% mortality within 48 h. Taken together, our data provided new information on the role of TagA as a virulence factor in bacterial pathogenesis. This is the first report of TagA characterization from any species ofAeromonas.
α-2,3-Sialyltransferase EnhancesNeisseria gonorrhoeaeSurvival during Experimental Murine Genital Tract Infection
Authors: Wu Hong , Jerse Ann E.
Published: June 2006

The addition of host-derived sialic acid toNeisseria gonorrhoeaelipooligosaccharide is hypothesized to be an important mechanism by which gonococci evade host innate defenses. This hypothesis is based primarily on in vitro assays of complement-mediated and phagocytic killing. Here we report that a nonpolar α-2,3-sialyltransferase (lst) mutant ofN. gonorrhoeaewas significantly attenuated in its capacity to colonize the lower genital tract of 17-β estradiol-treated female BALB/c mice during competitive infection with the wild-type strain. Genetic complementation of thelstmutation restored recovery of the mutant to wild-type levels. Studies with B10.D2-HCoH2dH2-T18c/OSN (C5-deficient) mice showed that attenuation of thelstmutant was not due to increased sensitivity to complement-mediated bacteriolysis, a result that is consistent with recently reported host restrictions in the complement cascade. However, Lst-deficient gonococci were killed more rapidly than sialylated wild-type gonococci following intraperitoneal injection into normal mice, which is consistent with sialylation conferring protection against killing by polymorphonuclear leukocytes (PMNs). As reported for human PMNs, sialylated gonococci were more resistant to killing by murine PMNs, and sialylation led to reduced association with and induction of a weaker respiratory burst in PMNs from estradiol-treated mice. In summary, these studies suggest sialylation confers a survival advantage toN. gonorrhoeaein mice by increasing resistance to PMN killing. This report is the first direct demonstration that α-2,3-sialyltransferase contributes toN. gonorrhoeaepathogenesis in an in vivo model. This study also validates the use of experimental murine infection to study certain aspects of gonococcal pathogenesis.