bluuebunny/crossref_metadata_2025 huggingface dataset:
Exhaled breath temperature in elite swimmers: The effects of a training session in adolescents with or without asthma
Authors: Couto Mariana , Santos Paulo , Silva Diana , Delgado Luís , Moreira André
Published: June 2015

Background

Cooling of the airways and inflammation have been pointed as possible mechanisms for exercise‐induced asthma (EIA). We aimed to investigate the effect of training and asthma on exhaled breath temperature (EBT) of elite swimmers.

Methods

Elite swimmers annually screened (skin prick tests, spirometry before and after salbutamol inhalation, induced sputum cell counts, and methacholine bronchial challenge) at our department (n = 27) were invited to this prospective study. Swimmers who agreed to participate in the present study (n = 22, 10 with asthma) had axillary temperature and EBT measured (X‐halo®) before and after a swimming training session (aerobic/non‐aerobic). Linear regression models were used to assess the effect of asthma and other possible explanatory variables (demographics, PD20, baseline EBT, training intensity, axillary temperature, and the number of hours trained in that week) on EBT change.

Results

EBT significantly increased after training independently of lung function, airway responsiveness, and inflammation in all swimmers (mean ± SD: 0.32 ± 0.57; p = 0.016). No differences were observed between asthmatic swimmers and others. A significant correlation was observed between baseline and post‐exercise EBTs (r = 0.827, p < 0.001). Asthma was not a predictor of ΔEBT after adjusting for confounders; baseline EBT was the variable most strongly associated with ΔEBT, explaining by itself alone 46% of the outcome (r2 = 0.464).

Conclusion

Although these are preliminary data, a relationship between airway's inflammation and respiratory heat loss during exercise could not be confirmed, suggesting that the increase in exhaled breath temperature is a physiologic rather than a pathological response to exercise.
From Confrontation to Congruence: The Potential Role of Payments in Lieu of Taxes in the Economic Development Conversation
Authors: Mayhew Fred , Waymire Tammy R.
Published: June 2015

This study uses survey and interview methodologies to gain an understanding of the scope of payments in lieu of taxes (PILOTs) in Illinois municipalities. While the number of PILOTs in this setting is consistent with previous studies, less revenue is generated. We find that while PILOTs can generate revenue, greater potential lies in their ability to broaden the economic development discussion, expanding stakeholder involvement and increasing the potential for collaboration. Drawing upon a proposed economic development model, we present recommendations to encourage participation in economic development efforts by nonprofit organizations, which may otherwise have inherent incentives to resist PILOTs.
The Effects of Recessions on Contracting Moderated by Institutional Arrangements of Government: Evidence From California Cities, 1993–2009
Authors: Kim Cheongsin
Published: June 2015

This study aims to uncover the different effects of economic recessions on city contracting, which vary with institutional characteristics. Drawing on the literatures of public finance and management, it is hypothesized that recessions have a positive relationship with contracting and this relationship will be stronger in governments with the council–manager form or the charter status than in those with the mayor–council form or the general‐law status, respectively. The hypotheses are tested on all available California cities over 17 years, from 1993 to 2009. Interestingly, the results indicate that recessions actually decrease contracting in governments with both the mayor–council form and the general‐law status, but the extent of the decrease is moderated if they adopt either the council–manager form or the charter status. For cities with these two institutional characteristics, finally, it turns out that recessions increase contracting. These uneven effects of recessions imply that governments experience environmental shock very differently one from another because they differ in institutional characteristics.
Budgeting for Fiscal Uncertainty and Bias: A Federal Process Proposal
Authors: Bhatti Imtiaz , Phaup Marvin
Published: June 2015

Balanced budget constraints have forced sub‐national governments to anticipate and mitigate the adverse effects of fiscal shocks on budget balance, services, and tax rates. By contrast, the federal government responds to negative budget surprises with increased borrowing. That response is consistent with short‐term economic stabilization, national security, and assisting those suffering loss. Nonetheless, an automatic default‐to‐debt response requires a routine means of restoring debt to planned levels. Otherwise, increases in public debt imply unplanned increases in future tax rates, reduced fiscal flexibility, lower income, and allocative inefficiency. We propose a procedural offset to debt drift from shocks and planning bias.
Progesterone 5β‐reductase genes of theBrassicaceae family as function‐associated molecular markers
Authors: Munkert J. , Costa C. , Budeanu O. , Petersen J. , Bertolucci S. , Fischer G. , Müller‐Uri F. , Kreis W.
Published: June 2015

This study aimed to define progesterone 5β‐reductases (P5βR,EC1.3.99.6, enone 1,4‐reductases) as function‐associated molecular markers at the plant family level. ThereforecDNAs were isolated from 25 Brassicaceae species, including two species,Erysimum crepidifoliumandDraba aizoides, known to produce cardiac glycosides. The sequences were used in a molecular phylogeny study. The cladogram created is congruent to the existing molecular analyses. Recombinant His‐tagged forms of theP5βRcDNAs fromAethionema grandiflorum, Draba aizoides, Nasturtium officinale, Raphanus sativusandSisymbrium officinalewere expressed inE. coli. Enone 1,4‐reductase activity was demonstratedin vitrousing progesterone and 2‐cyclohexen‐1‐one as substrates. Evidence is provided that functional P5βRs are ubiquitous in the Brassicaceae. The recombinant P5βR enzymes showed different substrate preferences towards progesterone and 2‐cyclohexen‐1‐one. Sequence comparison of the catalytic pocket of the P5βR enzymes and homology modelling usingDigitalis lanataP5βR (PDB ID: 2V6G) as template highlighted the importance of the hydrophobicity of the binding pocket for substrate discrimination. It is concluded thatP5βRgenes or P5βR proteins can be used as valuable function‐associated molecular markers to infer taxonomic relationship and evolutionary diversification from a metabolic/catalytic perspective.
Is There Such a Thing as Relative Analyticity?
Authors: Büttner Kai Michael
Published: June 2015

Fine bases his influential conception of essence on a particular account of definitions. And he complements it with a specific account of analyticity. I will argue that Fine's conception of relative analyticity confuses the idea of a sentence's being true in virtue of a term's definition with the idea of a sentence's being true in virtue of a term's meaning. His idea that correct definitions specify essential properties of meanings is mistaken. The correctness of definitions can only be assessed by reference to the actual usage of the terms involved. The resulting conception of definitions leads to a deflationary interpretation of claims about essences.
Validation of a questionnaire for asthma case identification in pre‐schools in Latin America
Authors: Busi Luciano E. , Sly Peter D. , Llancaman Lidia
Published: June 2015

Background and objective

We recently developed and validated a screening questionnaire for determining which school‐aged children may need further investigation to diagnose and manage asthma. In the present study we sought to extend this to pre‐school aged children.

Methods

Questions from the school‐aged questionnaire and literature on pre‐school asthma were used to inform a focus group of parents with pre‐school‐aged children with asthma to develop a screening questionnaire. Parents of children attending 6 randomly selected kindergartens in Trelew, Argentina (n = 639) were invited to respond to the questionnaire. A reliability test–retest was undertaken in 187 randomly selected parents who completed the same questionnaire twice within 2–5 weeks. Clinical assessment included a standardized history and physical examination, spirometry before and after a β‐agonist inhaler, and chest X‐ray. Asthma was diagnosed by the pulmonologist.

Results

Completed surveys were returned for 620 children, 607 of whom underwent clinical evaluation. The mean age was 4.21 years (range of 3.01–5.50) and included 82.5% white and 49.4% male children. Asthma was diagnosed in 103 (17.0%) children); 72 (69.9%) of these children did not have a previous diagnosis of asthma. The specificity, sensitivity, positive predictive value and negative predictive value of the questionnaire were 93.2%, 86.1%, 57.8% and 98.4%, respectively.

Conclusions

We have demonstrated the utility of a screening questionnaire for identifying pre‐school‐aged children who may benefit from further assessment for asthma.
Painlevé III Asymptotics of Hankel Determinants for a Perturbed Jacobi Weight
Authors: Zeng Zhao‐Yun , Xu Shuai‐Xia , Zhao Yu‐Qiu
Published: June 2015

We study the Hankel determinants associated with the weight

urn:x-wiley:00222526:media:sapm12090:sapm12090-math-0001where , , , is analytic in a domain containing [ − 1, 1] and for . In this paper, based on the Deift–Zhou nonlinear steepest descent analysis, we study the double scaling limit of the Hankel determinants as and . We obtain the asymptotic approximations of the Hankel determinants, evaluated in terms of the Jimbo–Miwa–Okamoto σ‐function for the Painlevé III equation. The asymptotics of the leading coefficients and the recurrence coefficients for the perturbed Jacobi polynomials are also obtained.
Targets for Ibrutinib Beyond B Cell Malignancies
Authors: Berglöf A. , Hamasy A. , Meinke S. , Palma M. , Krstic A. , Månsson R. , Kimby E. , Österborg A. , Smith C. I. E.
Published: June 2015

Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.
Nucleated erythrocytes in blood smears of dogs undergoing chemotherapy
Authors: Moretti P. , Giordano A. , Stefanello D. , Ferrari R. , Castellano S. , Paltrinieri S.
Published: June 2015

The frequency of normoblastemia in dogs receiving chemotherapy is unknown. To provide this information, we calculated the percentage and number of nucleated erythrocytes (nRBCs) in blood of dogs treated for lymphoma (n = 284), mast cell tumour (n = 40) or carcinoma (n = 46). Relative normoblastemia (>1 or >5%) and absolute normoblastemia (>0.1 or >0.4 × 103 µL−1) were found after administration of vincristine (49.3, 20.5, 42.5, 19.2%, respectively), carboplatin (37.0, 2.2, 34.8, 13.0%), cyclophosphamide (30.8, 7.7, 23.1, 7.7%), doxorubicin (25.0, 8.3, 21.7, 6.7%), vinblastine and prednisone (25.0; 5.0; 22.5; 7.5%). Absolute normoblastemia was very severe (>1.0 × 103 nRBC µL−1) after administration of vincristine (9.6%), doxorubicin (3.3%), vinblastine and prednisone (2.5%). Absolute normoblastemia negatively correlated with RBC counts (P < 0.001) and positively (P < 0.001) with reticulocyte and WBC counts, but correlation coefficients were low (−0.19, 0.37, 0.15). Vincristine, doxorubicin or vinblastine and prednisone may induce severe normoblastemia. This may increase WBC counts and mask neutropenia associated with chemotherapy.
A Reflection on the Implementation of Second National Fadama Development Project in Kaduna and Katsina States of Nigeria
Authors: Anyebe Adam Adem , Mudi Ibrahim Kurfi
Published: June 2015

This study attempts to reflect on the implementation of the Second National Fadama Project in Kaduna and Katsina states of Nigeria with a view to assessing whether the project implementation has been effective in reducing poverty among the participating communities. It was therefore, hypothesized that there is no significant relationship between the Community-Driven Development Strategy and effective implementation of Fadama II project in the area of access to rural financial services and poverty reduction in the host communities. The primary data were obtained through the use of questionnaire and personal interview while secondary data were sourced from books, journals, unpublished materials and internet. The study showed that there is a significant relationship between Community-Driven Development and effective implementation of the project in the host communities. The research recommended that to enhance the success of future projects, the government should not interfere with the activities of such projects, especially in the selection of members of such associations and government should provide loan facilities to the beneficiaries in order to boost their assets acquisition capacity.
Acute flavanol consumption improves the cerebral vasodilatory capacity in college‐aged African Americans
Authors: Hurr Chansol , Harrison Michelle L. , Brothers R. Matthew
Published: June 2015

New Findings

What is the central question of this study?

The purpose was to determine whether acute flavanol consumption improves cerebral vasodilatory capacity during rebreathing‐induced hypercapnia in African Americans.

What is the main finding and its importance?

The reduced cerebral vasodilatory response to hypercapnia in young healthy African Americans was improved acutely following consumption of a flavanol‐rich beverage. This may have important clinical implications regarding racial differences in cerebrovascular disease risk and possible interventional approaches to offset this risk.

African Americans (AAs) have increased risk for cardiovascular and cerebrovascular disease. African Americans have attenuated cerebral vasodilator capacity during hypercapnia relative to Caucasian Americans (CAs). This study tested the hypothesis, using a placebo‐controlled crossover design, that acute flavanol consumption improves the range of change in cerebral vascular conductance [CVCI, (a)] and the maximal CVCI (y0) achieved during rebreathing‐induced increases in end‐tidal carbon dioxide tension. Fourteen college‐aged AAs and 14 CAs participated. Both a and y0 were lower in AAs prior to flavanols (for a, AAs, 46 ± 16 versus CAs, 74 ± 18% CVCI, P < 0.001; and for y0, AAs, 151 ± 18 versus CAs, 176 ± 20% CVCI, P = 0.002); however, these variables were increased after flavanols such that there were no differences between groups (for a, AAs, 64 ± 19 versus CAs, 72 ± 22% CVCI, P = 0.35; and for y0, AAs, 166 ± 22 versus CAs, 176 ± 22% CVCI, P = 0.26). Both a and y0 were also lower in AAs prior to placebo (for a, AAs, 52 ± 19 versus CAs, 76 ± 15% CVCI, P = 0.002; and for y0, AAs, 156 ± 20 versus CAs, 177 ± 21% CVCI, P = 0.015), and these differences remained following placebo (for a, AAs, 52 ± 17 versus CAs, 80 ± 20% CVCI, P < 0.001; and for y0, AAs, 152 ± 18 versus CAs, 181 ± 25% CVCI, P = 0.003). These data suggest that acute flavanol consumption improves cerebral vasodilatory capacity during hypercapnia in AAs.
Nanoparticle Dispersions on Ternary Nitrate Salts for Heat Transfer Fluid Applications in Solar Thermal Power
Authors: Devaradjane Ramaprasath , Shin Donghyun
Published: June 2015

In this study, we report enhancement in heat capacity of SiO2 nanoparticle dispersions in a molten ternary nitrate salt (NaNO3, KNO3, and Ca(NO3)2) to obtain an effective heat transfer fluid (HTF)/thermal energy storage (TES) for concentrated solar power (CSP) application. The enhanced heat capacity of the molten salt mixture is expected to greatly increase thermal storage density of HTF/TES, and thus the cost of electricity produced by CSP plant can be significantly reduced. A custom two-step method was used to synthesize SiO2 nanoparticle/ternary salt mixture. The nanoparticle concentration of the mixture was fixed at 1% by weight for comparison with the previous studies. A modulated differential scanning calorimeter (MDSC) was employed to measure heat capacity of the mixture, and it was found to be enhanced by ∼19% compared to the pure ternary salt.
Prediction of Vapor Film Thickness Below a Leidenfrost Drop
Authors: Dasgupta Arnab , Chandraker D. K. , Nayak A. K. , Vijayan P. K.
Published: June 2015

In this work, the vapor film thickness below a stagnant Leidenfrost drop at saturation temperature is predicted by performing a balance of the dominant forces acting on the drop. Inclusion of a new momentum force term is proposed. Two assumptions are considered for the radial velocity of vapor at drop–vapor interface. One of them is zero radial velocity at interface and the other is zero shear at interface. The actual scenario is expected to lie between these extremes. This is also supported by the comparison against experimental data on vapor film thickness. The effect of convection in the vapor layer is also modeled and it is shown that the use of ad hoc heat transfer coefficients in the vapor layer to explain difference between experiments and prediction is incorrect. Finally, it is highlighted that accurate prediction of the vapor layer characteristics also requires proper quantification of the shape of the drop–vapor interface.
Boiling of R134a in a Plate-Fin Heat Exchanger Having Offset Fins
Authors: Ranganayakulu Chennu , Kabelac Stephan
Published: June 2015

This paper presents experimental results on boiling heat transfer of R134a in a compact plate fin heat exchanger. The exchanger is made of aluminum and has high density offset fins (30 fins/in.). Such heat exchangers are widely used in air separation industry and aerospace applications because of their high compactness and low weight. The test heat exchanger is attached to a vapor cycle refrigeration basic module to study the effects of boiling phenomena and its influence on performance as there is limited information available for this type of fins. This in turn allows for discussion on boiling mechanism of R134a inside the fins using the water circuit on the other side of the test heat exchanger. The water side single phase heat transfer coefficient (Colburn j factor) is calculated using the cfd tool fluent and validated with available open literature. The results are presented for heat fluxes up to 5500 W/m2 and mass fluxes up to 20 kg/(m2s) with water side flow rate varying from 0.033 to 0.17 kg/s for water temperatures of 10, 15, 20, 25, and 30 °C.
Comparing the Well-Being of Para and Olympic Sport Athletes: A Systematic Review
Authors: Macdougall Hannah , O’Halloran Paul , Shields Nora , Sherry Emma
Published: June 2015

This systematic review included 12 studies that compared the well-being of Para and Olympic sport athletes. Meta-analyses revealed that Para athletes, compared with Olympic sport athletes, had lower levels of self-acceptance, indicated by athletic identity, d = -0.47, 95% confidence interval (CI) [-0.77, -0.16], and body-image perceptions, d = -0.33, 95% CI [-0.59, -0.07], and differed from Olympic sport athletes in terms of their motivation, indicated by a greater mastery-oriented climate, d = 0.74, 95% CI [0.46, 1.03]. Given an inability to pool the remaining data for meta-analysis, individual standardized mean differences were calculated for other dimensions of psychological and subjective well-being. The results have implications for professionals and coaches aiming to facilitate the well-being needs of athletes under their care. Future research would benefit from incorporating established models of well-being based on theoretical rationale combined with rigorous study designs.
The Applied Behavior Analysis Research Paradigm and Single-Subject Designs in Adapted Physical Activity Research
Authors: Haegele Justin A. , Hodge Samuel Russell
Published: June 2015

There are basic philosophical and paradigmatic assumptions that guide scholarly research endeavors, including the methods used and the types of questions asked. Through this article, kinesiology faculty and students with interests in adapted physical activity are encouraged to understand the basic assumptions of applied behavior analysis (ABA) methodology for conducting, analyzing, and presenting research of high quality in this paradigm. The purposes of this viewpoint paper are to present information fundamental to understanding the assumptions undergirding research methodology in ABA, describe key aspects of single-subject research designs, and discuss common research designs and data-analysis strategies used in single-subject studies.
Psychological Preparation for Paralympic Athletes: A Preliminary Study
Authors: Blumenstein Boris , Orbach Iris
Published: June 2015

Since the first Paralympics in 1960 there has been an increase in social and scientific interest in Paralympic athletes’ personality, their preparation, and their sport results. During the last 20 yr, researchers and practitioners have been focused on psychological-skills programs for athletes with disabilities. The purpose of this article was to describe a psychological-preparation program for Israeli Paralympic athletes. Two subprograms, the learning-modification-application approach and the Simulation Training Exercise Program, were adapted to athletes’ disability and sport demands. Two case studies, from table tennis and sailing (Sonar 3-person keelboat), are described to demonstrate how systematic sport psychology preparation can be effectively integrated into the training process of Paralympic athletes. Some recommendations for Paralympic athletes are presented.
An enhanced view of gene control
Authors: Pennisi Elizabeth
Published: June 2015

Chromosomal loops and domains help enhancers turn on genes.
Breaking the light barrier
Authors: Service Robert F.
Published: June 2015

Trick for pushing more bits through optical fibers could ease looming “capacity crunch.”
Tapping a nuclear test ban treasure-trove
Authors: Clery Daniel
Published: June 2015

Treaty chief offers academics surveillance data.
Comment on “Global diversity and geography of soil fungi”
Authors: Schadt Christopher W. , Rosling Anna
Published: June 2015

Tedersoo
et al
. (Research Article, 28 November 2014, p. 1078) present a compelling study regarding patterns of biodiversity of fungi, carried out at a scale unprecedented to date for fungal biogeographical studies. The study demonstrates strong global biogeographic patterns in richness and community composition of soil fungi. What concerns us with the study is what we do not see. Unfortunately, this study underestimates the fungal diversity of one key group of soil fungi due to reliance on a single primer with known flaws.
Direct observation of an abrupt insulator-to-metal transition in dense liquid deuterium
Authors: Knudson M. D. , Desjarlais M. P. , Becker A. , Lemke R. W. , Cochrane K. R. , Savage M. E. , Bliss D. E. , Mattsson T. R. , Redmer R.
Published: June 2015

Driving liquid deuterium into metal

Quick and powerful compression can force materials to change their properties dramatically. Knudson
et al.
compressed liquid deuterium to extreme temperatures and pressures using high-energy magnetic pulses at the Sandia Z-machine (see the Perspective by Ackland). Deuterium began to reflect like a mirror during compression, as the electrical conductivity sharply increased. The observed conditions for metallization of deuterium and hydrogen help us to build theoretical models for the universe's most abundant element. This a our understanding of the internal layering of gas giant planets such as Jupiter and Saturn.

Science
, this issue p.
1455
; see also p.
1429
A parvalbumin-positive excitatory visual pathway to trigger fear responses in mice
Authors: Shang Congping , Liu Zhihui , Chen Zijun , Shi Yingchao , Wang Qian , Liu Su , Li Dapeng , Cao Peng
Published: June 2015

Looming in on the threat-response circuit

What are the neural elements that transmit threat-relevant inputs in the brain? Shang
et al.
systematically identified the key neuronal subtypes in the mouse superior colliculus underlying active avoidance and defensive-like behaviors. They found a pathway that responded to looming objects, linking input from the retina to the fear center in the brain.

Science
, this issue p.
1472
Quantum spin Hall effect of light
Authors: Bliokh Konstantin Y. , Smirnova Daria , Nori Franco
Published: June 2015

A quantum twist on classical optics

Interpreting recent experimental results of light interactions with matter shows that the classical Maxwell theory of light has intrinsic quantum spin Hall effect properties even in free space. Complex effects in condensed-matter systems can often find analogs in cleaner optical systems. Bliokh
et al.
argue that the optical systems exhibiting such complex phenomena should also be simpler (see the Perspective by Stone). Their theoretical study shows that free-space light has a nonzero topological spin Chern number and thus should have counterpropagating surface modes. Such modes are actually well known and can be described as evanescent modes of Maxwell equations.

Science
, this issue p.
1448
; see also p.
1432
A Cas9–guide RNA complex preorganized for target DNA recognition
Authors: Jiang Fuguo , Zhou Kaihong , Ma Linlin , Gressel Saskia , Doudna Jennifer A.
Published: June 2015

An RNA seed poised to meet its target

The CRISPR-Cas system in prokaryotes precisely identifies infecting parasitic DNAs and viruses and destroys them. The CRISPR-Cas system has been adapted for facile genome editing, heralding a new age in molecular biology. Jiang
et al.
show that the Cas9 nuclease adopts a distinct confirmation when it binds to the targeting guide RNA. The guide RNA then assumes a preordered shape. This RNA “seed region” is thus poised to initiate recognition of the DNA target sequence.

Science
, this issue p.
1477
Promoting an open research culture
Authors: Nosek B. A. , Alter G. , Banks G. C. , Borsboom D. , Bowman S. D. , Breckler S. J. , Buck S. , Chambers C. D. , Chin G. , Christensen G. , Contestabile M. , Dafoe A. , Eich E. , Freese J. , Glennerster R. , Goroff D. , Green D. P. , Hesse B. , Humphreys M. , Ishiyama J. , Karlan D. , Kraut A. , Lupia A. , Mabry P. , Madon T. , Malhotra N. , Mayo-Wilson E. , McNutt M. , Miguel E. , Paluck E. Levy , Simonsohn U. , Soderberg C. , Spellman B. A. , Turitto J. , VandenBos G. , Vazire S. , Wagenmakers E. J. , Wilson R. , Yarkoni T.
Published: June 2015

Author guidelines for journals could help to promote transparency, openness, and reproducibility
Best practices for digital teaching
Teaching Online A Guide to Theory, Research, and Practice
Claire Howell Major
Johns Hopkins University Press, 2015. 330 pp.
Authors: Dolan Erin
Published: June 2015

A handbook for the 21st-century educator
Self-correction in science at work
Authors: Alberts Bruce , Cicerone Ralph J. , Fienberg Stephen E. , Kamb Alexander , McNutt Marcia , Nerem Robert M. , Schekman Randy , Shiffrin Richard , Stodden Victoria , Suresh Subra , Zuber Maria T. , Pope Barbara Kline , Jamieson Kathleen Hall
Published: June 2015

Improve incentives to support research integrity
Mother's littlest helpers
Authors: Hinde Katie , Lewis Zachery T.
Published: June 2015

Breastmilk nourishes the microbes colonizing the neonatal intestinal tract
IP-10 Is a Sensitive Biomarker of Antigen Recognition in Whole-Blood Stimulation Assays Used for the Diagnosis of Mycobacterium bovis Infection in African Buffaloes (Syncerus caffer)
Authors: Goosen Wynand J. , Cooper David , Miller Michele A. , van Helden Paul D. , Parsons Sven D. C.
Published: June 2015

African buffaloes (
Syncerus caffer
) are maintenance hosts of
Mycobacterium bovis
, the causative agent of bovine tuberculosis. They act as reservoirs of this infection for a wide range of wildlife and domestic species, and the detection of infected animals is important to control the geographic spread and transmission of the disease. Interferon gamma (IFN-γ) release assays (IGRAs) utilizing pathogen-derived peptide antigens are highly specific tests of
M. bovis
infection; however, the diagnostic sensitivities of these assays are suboptimal. We evaluated the diagnostic utility of measuring antigen-dependent interferon gamma-induced protein 10 (IP-10) release as an alternative to measuring IFN-γ levels.
M. bovis
-exposed buffaloes were tested using the Bovigam PC-EC and Bovigam PC-HP assays and a modified QuantiFERON TB-Gold (mQFT) assay. IP-10 was measured in the harvested plasma and was produced in significantly greater abundance in response to
M. bovis
antigens in Bovigam-positive than in Bovigam-negative animals. For each assay, using the Bovigam results as a reference, receiver operating characteristic curve analysis was done to determine diagnostically relevant cutoff values for IP-10. Thereafter, mQFT test results derived from measurement of IP-10 and IFN-γ were compared and a larger number of Bovigam-positive animals were detected using IP-10 as a diagnostic marker. Moreover, using IP-10, agreement between the mQFT assay and the Bovigam assays was increased, while the excellent agreement between the Bovigam assays was retained. We conclude that IP-10 is a sensitive marker of antigen recognition and that measurement of this cytokine in antigen-stimulated whole blood might increase the sensitivity of conventional IGRAs in African buffaloes.
Genomic Epidemiology of Clostridium botulinum Isolates from Temporally Related Cases of Infant Botulism in New South Wales, Australia
Authors: McCallum Nadine , Gray Timothy J. , Wang Qinning , Ng Jimmy , Hicks Leanne , Nguyen Trang , Yuen Marion , Hill-Cawthorne Grant A. , Sintchenko Vitali
Published: June 2015

Infant botulism is a potentially life-threatening paralytic disease that can be associated with prolonged morbidity if not rapidly diagnosed and treated. Four infants were diagnosed and treated for infant botulism in NSW, Australia, between May 2011 and August 2013. Despite the temporal relationship between the cases, there was no close geographical clustering or other epidemiological links.
Clostridium botulinum
isolates, three of which produced botulism neurotoxin serotype A (BoNT/A) and one BoNT serotype B (BoNT/B), were characterized using whole-genome sequencing (WGS).
In silico
multilocus sequence typing (MLST) found that two of the BoNT/A-producing isolates shared an identical novel sequence type, ST84. The other two isolates were single-locus variants of this sequence type (ST85 and ST86). All BoNT/A-producing isolates contained the same chromosomally integrated BoNT/A2 neurotoxin gene cluster. The BoNT/B-producing isolate carried a single plasmid-borne
bont
/B gene cluster, encoding BoNT subtype B6. Single nucleotide polymorphism (SNP)-based typing results corresponded well with MLST; however, the extra resolution provided by the whole-genome SNP comparisons showed that the isolates differed from each other by >3,500 SNPs. WGS analyses indicated that the four infant botulism cases were caused by genomically distinct strains of
C. botulinum
that were unlikely to have originated from a common environmental source. The isolates did, however, cluster together, compared with international isolates, suggesting that
C. botulinum
from environmental reservoirs throughout NSW have descended from a common ancestor. Analyses showed that the high resolution of WGS provided important phylogenetic information that would not be captured by standard seven-loci MLST.
First Human Case of Fungal Keratitis Caused by a Putatively Novel Species of Lophotrichus
Authors: Eghrari Allen O. , Gibas Connie , Watkins Tonya , Vahedi Sina , Lee Rick , Houle Elizabeth , Suarez Maria Jose , Eberhart Charles , Sutton Deanna A. , Wiederhold Nathan P. , Sikder Shameema , Zhang Sean X.
Published: June 2015

We report an aggressive fungal keratitis caused by a putatively novel species of
Lophotrichus
in a patient with traumatic injury to the cornea from a dog paw. The organism was isolated from the patient's necrotic cornea, which perforated despite coverage with hourly fortified broad-spectrum topical antibiotic therapy. This report represents the first case of human infection caused by this species.
Comparison of Established Diagnostic Methodologies and a Novel Bacterial
smpB
Real-Time PCR Assay for Specific Detection of Haemophilus influenzae Isolates Associated with Respiratory Tract Infections
Authors: Reddington Kate , Schwenk Stefan , Tuite Nina , Platt Gareth , Davar Danesh , Coughlan Helena , Personne Yoann , Gant Vanya , Enne Virve I. , Zumla Alimuddin , Barry Thomas
Published: June 2015

Haemophilus influenzae
is a significant causative agent of respiratory tract infections (RTI) worldwide. The development of a rapid
H. influenzae
diagnostic assay that would allow for the implementation of infection control measures and also improve antimicrobial stewardship for patients is required. A number of nucleic acid diagnostics approaches that detect
H. influenzae
in RTIs have been described in the literature; however, there are reported specificity and sensitivity limitations for these assays. In this study, a novel real-time PCR diagnostic assay targeting the
smpB
gene was designed to detect all serogroups of
H. influenzae
. The assay was validated using a panel of well-characterized
Haemophilus
spp. Subsequently, 44
Haemophilus
clinical isolates were collected, and 36 isolates were identified as
H. influenzae
using a gold standard methodology that combined the results of matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and a
fucK
diagnostic assay. Using the novel
smpB
diagnostic assay, 100% concordance was observed with the gold standard, demonstrating a sensitivity of 100% (95% confidence interval [CI], 90.26% to 100.00%) and a specificity of 100% (95% CI, 63.06% to 100.00%) when used on clinical isolates. To demonstrate the clinical utility of the diagnostic assay presented, a panel of lower RTI samples (
n
= 98) were blindly tested with the gold standard and
smpB
diagnostic assays. The results generated were concordant for 94/98 samples tested, demonstrating a sensitivity of 90.91% (95% CI, 78.33% to 97.47%) and a specificity of 100% (95% CI, 93.40% to 100.00%) for the novel
smpB
assay when used directly on respiratory specimens.
Vertebral Osteomyelitis Caused by Helicobacter cinaedi
Authors: Yoshizaki Aisa , Takegawa Hiroshi , Doi Asako , Mizuno Yasushi , Nishioka Hiroaki
Published: June 2015

Helicobacter cinaedi
causes bacteremia, cellulitis, and gastroenteritis. We report the first case of vertebral osteomyelitis caused by
H. cinaedi
in an elderly man with low back pain and fever. The pathogen was detected in blood and lumbar disc, and the infection was successfully treated with oral doxycycline for 11 weeks.
Prospective Two-Center Comparison of Three Chromogenic Agars for Methicillin-Resistant Staphylococcus aureus Screening in Hospitalized Patients
Authors: Dodémont Magali , Verhulst Carlo , Nonhoff Claire , Nagant Carole , Denis Olivier , Kluytmans Jan
Published: June 2015

Three chromogenic media, chromID MRSA SMART (SMART), chromID MRSA first generation (chromID), and
Brilliance
MRSA (OX2), were evaluated for methicillin-resistant
Staphylococcus aureus
(MRSA) screening using 1,220 samples. The sensitivity at 24 h was significantly better with the SMART agar (66.4%) than that with chromID agar (50.5%). Enrichment and incubation until 48 h are still needed for an optimal yield.
HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry
Authors: Zhou Jing , Price Amanda J. , Halambage Upul D. , James Leo C. , Aiken Christopher
Published: June 2015

During HIV-1 infection of cells, the viral capsid plays critical roles in reverse transcription and nuclear entry of the virus. The capsid-targeting small molecule PF74 inhibits HIV-1 at early stages of infection. HIV-1 resistance to PF74 is complex, requiring multiple amino acid substitutions in the viral CA protein. Here we report the identification and analysis of a novel PF74-resistant mutant encoding amino acid changes in both domains of CA, three of which are near the pocket where PF74 binds. Interestingly, the mutant virus retained partial PF74 binding, and its replication was stimulated by the compound. The mutant capsid structure was not significantly perturbed by binding of PF74; rather, the mutations inhibited capsid interactions with CPSF6 and Nup153 and altered HIV-1 dependence on these host factors and on TNPO3. Moreover, the replication of the mutant virus was markedly impaired in activated primary CD4
+
T cells and macrophages. Our results suggest that HIV-1 escapes a capsid-targeting small molecule inhibitor by altering the virus's dependence on host factors normally required for entry into the nucleus. They further imply that clinical resistance to inhibitors targeting the PF74 binding pocket is likely to be strongly limited by functional constraints on HIV-1 evolution.

IMPORTANCE
The HIV-1 capsid plays critical roles in early steps of infection and is an attractive target for therapy. Here we show that selection for resistance to a capsid-targeting small molecule inhibitor can result in viral dependence on the compound. The mutant virus was debilitated in primary T cells and macrophages—cellular targets of infection
in vivo
. The mutations also altered the virus's dependence on cellular factors that are normally required for HIV-1 entry into the nucleus. This work provides new information regarding mechanisms of HIV-1 resistance that should be useful in efforts to develop clinically useful drugs targeting the HIV-1 capsid.
Tetherin Sensitivity of Influenza A Viruses Is Strain Specific: Role of Hemagglutinin and Neuraminidase
Authors: Gnirß Kerstin , Zmora Pawel , Blazejewska Paulina , Winkler Michael , Lins Anika , Nehlmeier Inga , Gärtner Sabine , Moldenhauer Anna-Sophie , Hofmann-Winkler Heike , Wolff Thorsten , Schindler Michael , Pöhlmann Stefan
Published: June 2015

The expression of the antiviral host cell factor tetherin is induced by interferon and can inhibit the release of enveloped viruses from infected cells. The Vpu protein of HIV-1 antagonizes the antiviral activity of tetherin, and tetherin antagonists with Vpu-like activity have been identified in other viruses. In contrast, it is incompletely understood whether tetherin inhibits influenza A virus (FLUAV) release and whether FLUAV encodes tetherin antagonists. Here, we show that release of several laboratory-adapted FLUAV strains and a seasonal FLUAV strain is inhibited by tetherin, while pandemic FLUAV A/Hamburg/4/2009 is resistant. Studies with a virus-like particle system and analysis of reassortant viruses provided evidence that the viral hemagglutinin (HA) is an important determinant of tetherin antagonism but requires the presence of its cognate neuraminidase (NA) to inhibit tetherin. Finally, tetherin antagonism by FLUAV was dependent on the virion context, since retrovirus release from tetherin-positive cells was not rescued, and correlated with an HA- and NA-dependent reduction in tetherin expression. In sum, our study identifies HA and NA proteins of certain pandemic FLUAV as tetherin antagonists, which has important implications for understanding FLUAV pathogenesis.

IMPORTANCE
Influenza A virus (FLUAV) infection is responsible for substantial global morbidity and mortality, and understanding how the virus evades the immune defenses of the host may uncover novel targets for antiviral intervention. Tetherin is an antiviral effector molecule of the innate immune system which can contribute to control of viral invasion. However, it has been unclear whether FLUAV is inhibited by tetherin and whether these viruses encode tetherin-antagonizing proteins. Our observation that several pandemic FLUAV strains can counteract tetherin via their HA and NA proteins identifies these proteins as novel tetherin antagonists and indicates that HA/NA-dependent inactivation of innate defenses may contribute to the efficient spread of pandemic FLUAV.
Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry
Authors: Mainou Bernardo A. , Ashbrook Alison W. , Smith Everett Clinton , Dorset Daniel C. , Denison Mark R. , Dermody Terence S.
Published: June 2015

Mammalian orthoreoviruses (reoviruses) are nonenveloped double-stranded RNA viruses that infect most mammalian species, including humans. Reovirus binds to cell surface glycans, junctional adhesion molecule A (JAM-A), and the Nogo-1 receptor (depending on the cell type) and enters cells by receptor-mediated endocytosis. Within the endocytic compartment, reovirus undergoes stepwise disassembly, which is followed by release of the transcriptionally active viral core into the cytoplasm. In a small-molecule screen to identify host mediators of reovirus infection, we found that treatment of cells with 5-nonyloxytryptamine (5-NT), a prototype serotonin receptor agonist, diminished reovirus cytotoxicity. 5-NT also blocked reovirus infection. In contrast, treatment of cells with methiothepin mesylate, a serotonin antagonist, enhanced infection by reovirus. 5-NT did not alter cell surface expression of JAM-A or attachment of reovirus to cells. However, 5-NT altered the distribution of early endosomes with a concomitant impairment of reovirus transit to late endosomes and a delay in reovirus disassembly. Consistent with an inhibition of viral disassembly, 5-NT treatment did not alter infection by
in vitro
-generated infectious subvirion particles, which bind to JAM-A but bypass a requirement for proteolytic uncoating in endosomes to infect cells. We also found that treatment of cells with 5-NT decreased the infectivity of alphavirus chikungunya virus and coronavirus mouse hepatitis virus. These data suggest that serotonin receptor signaling influences cellular activities that regulate entry of diverse virus families and provides a new, potentially broad-spectrum target for antiviral drug development.

IMPORTANCE
Identification of well-characterized small molecules that modulate viral infection can accelerate development of antiviral therapeutics while also providing new tools to increase our understanding of the cellular processes that underlie virus-mediated cell injury. We conducted a small-molecule screen to identify compounds capable of inhibiting cytotoxicity caused by reovirus, a prototype double-stranded RNA virus. We found that 5-nonyloxytryptamine (5-NT) impairs reovirus infection by altering viral transport during cell entry. Remarkably, 5-NT also inhibits infection by an alphavirus and a coronavirus. The antiviral properties of 5-NT suggest that serotonin receptor signaling is an important regulator of infection by diverse virus families and illuminate a potential new drug target.
Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens
Authors: Fonville Judith M.
Published: June 2015

Adaptation is a common theme in both pathogen emergence, for example, in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen's fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediate mutations on pathogen adaptation is smaller than their name might suggest: when two mutations are required and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutants that is 20-fold lower than that in the situation where the fitness of all mutants is neutral. The negative effects of deleterious intermediates are typically substantially smaller and outweighed by the fitness advantages of the adapted mutant. Moreover, requiring a specific mutation order has a substantially smaller effect on pathogen adaptation than the effect of all intermediates being deleterious. These results can be rationalized when the number of routes of mutation available to the pathogen is calculated, providing a simple approach to estimate the effect of deleterious mutations. The calculations discussed here are applicable when the effect of deleterious mutations on the within-host adaptation of pathogens is assessed, for example, in the context of zoonotic emergence, antigenic escape, and drug resistance.

IMPORTANCE
Adaptation is critical for pathogens after zoonotic transmission into a new host species or to achieve antigenic immune escape and drug resistance. Using a deterministic approach, the effects of deleterious intermediate mutations on pathogen adaptation were calculated while avoiding commonly made simplifications that do not apply to large pathogen populations replicating with high mutation rates. Perhaps unexpectedly, pathogen adaptation does not halt when the intermediate mutations are fully deleterious. The negative effects of deleterious mutations are substantially outweighed by the fitness gains of adaptation. To gain an understanding of the effect of deleterious mutations on pathogen adaptation, a simple approach that counts the number of routes available to the pathogen with and without deleterious intermediate mutations is introduced. This methodology enables a straightforward calculation of the proportion of the pathogen population that will cross a fitness valley or traverse a fitness ridge, without reverting to more complicated mathematical models.