bluuebunny/crossref_metadata_2025 huggingface dataset:
Optogenetic probing of mitochondrial damage responses
Authors: Yang Wei Yuan
Published: June 2015

It is now possible to functionally impair mitochondria through light illumination with high specificity. These optogenetic tools permit precise control on the timing, location, and extent of mitochondrial damage within a cell population with subcellular resolution, allowing quantitative probing of the various types of mitochondrial damage responses within cells. This approach can generally be extended toward the probing of other organelle damage responses.
Domestic Violence and Football in Glasgow: Are Reference Points Relevant?
Authors: Dickson Alex , Jennings Colin , Koop Gary
Published: June 2015

A growing body of evidence suggests that people exhibit loss aversion – the displeasure from suffering a loss is larger than the pleasure enjoyed from an equivalent‐sized gain – and that expectations are important in determining what is perceived as a loss. Recent research suggests that disappointing results in sporting fixtures relative to prematch expectations play an important role in triggering domestic violence (Card and Dahl, 2011), consistent with the idea of loss aversion around expectations‐based reference points. This paper seeks to investigate whether such behaviour is exhibited by football fans in Glasgow by looking at the relationship between match outcomes relative to expectations and levels of domestic violence using a data set that contains every domestic violence incident in Glasgow over a period of more than eight years. Whilst we find that when the ‘Old‐Firm’ Glasgow rivals Celtic and Rangers play there are large increases in domestic violence (regardless of the outcome of the match), in other matches disappointing results relative to expectations are not linked to increased domestic violence, except when those matches occur at the very end of the season where the title is still being contended.
Can electricity consumption be useful in predicting Nigerian economic growth? Evidence from error correction model
Authors: Adedokun Adebayo
Published: June 2015

This paper investigatesGranger causality between electricity consumption andNigerian realGDP, usingVectorErrorCorrection (VEC)GrangerCausality/BlockExogeneityWaldTest. The empirical result supports long run bidirectional relationship, which means that electricity consumption predicts economic growth and vice versa in the country, though causality from electricity consumption to economic growth is stronger. This finding is evidence in support of the country's electricity deregulation and reform programme, which is a core component of various projects towards the realisation ofTransformationAgenda (TA) andVision 20: 2020, in whichNigeria aims to become one of the 20 largest economies by the year 2020.
Is it possible to make a diagnosis of raw, heated, and baked egg allergy in children using cutoffs? A systematic review
Authors: Calvani Mauro , Arasi Stefania , Bianchi Annamaria , Caimmi Davide , Cuomo Barbara , Dondi Arianna , Indirli Giovanni Cosimo , La Grutta Stefania , Panetta Valentina , Verga Maria Carmen
Published: June 2015

The diagnosis of IgE‐mediated egg allergy lies both on a compatible clinical history and on the results of skin prick tests (SPTs) and IgEs levels. Both tests have good sensitivity but low specificity. For this reason, oral food challenge (OFC) is the ultimate gold standard for the diagnosis. The aim of this study was to systematically review the literature in order to identify, analyze, and synthesize the predictive value of SPT and specific IgEs both to egg white and to main egg allergens and to review the cutoffs suggested in the literature. A total of 37 articles were included in this systematic review. Studies were grouped according to the degree of cooking of the egg used for OFC, age, and type of allergen used to perform the allergy workup. In children <2 years, raw egg allergy seems very likely when SPTs with egg white extract are ≥4 mm or specific IgEs are ≥1.7 kUA/l. In children ≥2 years, OFC could be avoided when SPTs with egg white extract are ≥10 mm or prick by prick with egg white is ≥14 mm or specific IgE is ≥7.3 kUA/l. Likewise, heated egg allergy can be diagnosed if SPTs with egg white extract are >5 and >11 mm in children <2 and ≥2 years, respectively. Further and better‐designed studies are needed to determine the remaining diagnostic cutoff of specific IgE and SPT for heated and baked egg allergy.
Sexually transmitted infections in pediatric renal transplant recipients: Time to take notice!
Authors: Ashoor Isa , Aviles Diego , Pasternak Ryan , Vehaskari Vesa M.
Published: June 2015

We sought to assess the prevalence of STIs, contraception use, and unintentional pregnancy in our pediatric renal transplant recipients. We performed a retrospective chart review. Forty‐nine of 65 patients in our program are currently in the high‐risk age window of 13 yr or older (34 men, 15 women; mean age 17 yr old, range 13–23 yr old). There was a disproportionate difference in sexual behavior among the men and women, such that while only 15% of the men reported being sexually active, 53% of the women were sexually active. Among high‐risk age‐group women, 40% were on hormonal contraception. This increased to 75% in sexually active women. There were no cases of unintentional pregnancy. Thirty percent of sexually active recipients had at least one STI. This was higher among sexually active women (37.5%) compared to men (20%). STIs identified included gonococcal and chlamydial urethritis/cervicitis, Trichomonas vaginitis, HSV‐2 genital sores, pelvic inflammatory disease, and HIV. In conclusion, STIs are a realistic public health concern in our pediatric renal transplant recipients. Consensus guidelines on STI screening and reproductive health counseling are needed to address this understudied problem.
Clinical Role of Human Leukocyte Antigen in Health and Disease
Authors: Mosaad Y. M.
Published: June 2015

Most of the genes in the major histocompatibility complex (MHC) region express high polymorphism that is fundamental for their function. The most important function of human leukocyte antigen (HLA) molecule is in the induction, regulation of immune responses and the selection of the T cell repertoire. A clinician's attention is normally drawn to a system only when it malfunctions. The HLA system is no exception in this regard, but in contrast to other systems, it also arouses interest when it functions well – too well, in fact. Population studies carried out over the last several decades have identified a long list of human diseases that are significantly more common among individuals that carry particular HLA alleles including inflammatory, autoimmune and malignant disorders. HLA‐disease association is the name of this phenomenon, and the mechanism underlying is still a subject of hot debate. Social behaviours are affected by HLA genes and preference for HLA disparate mates may provide ‘good genes’ for an individual's offspring. Also, certain HLA genes may be associated with shorter life and others with longer lifespan, but the effects depend both on the genetic background and on the environmental conditions. The following is a general overview of the important functional aspects of HLA in health and diseases.
Systemic Lupus Erythematosus – A Disease with A Dysregulated Type I Interferon System
Authors: Hagberg N. , Rönnblom L.
Published: June 2015

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the loss of tolerance to nuclear antigens, immune complex formation and inflammation in multiple organs. The disease is very heterogeneous, and most clinicians consider SLE as a group of diseases with similar features where the pathogenesis is driven by a combination of genetic and environmental factors. One of the most prominent features, shared by the majority of patients with SLE, is a continuous activation of the type I interferon (IFN) system, which manifests as increased serum levels of IFNα and/or an increased expression of type I IFN‐induced genes, a so‐called type I IFN signature. The mechanisms behind this IFN signature have partly been clarified during recent years, although the exact function of the IFN‐regulated genes in the disease process is unclear. In this review, we will describe the type I IFN system and its regulation and summarize the numerous findings implicating an important ethiopathogenic role of a dysregulated type I IFN system in SLE. Furthermore, strategies to therapeutically target the type I IFN system that are currently evaluated preclinically and in clinical trials will be mentioned.
Nanoscale alterations of corneocytes indicate skin disease
Authors: Franz J. , Beutel M. , Gevers K. , Kramer A. , Thyssen J. P. , Kezic S. , Riethmüller C.
Published: June 2015

Background

The skin barrier protects the organism against exogenous stressors and simultaneously prevents excessive water loss. While the delicate regulation of skin barrier is not completely understood, morphological and histological evaluation remain key features of clinical investigations. Here, we extended the phenotypic perspective down to the nanoscale.

Methods

Corneocyte samples were obtained non‐invasively by a standard tape stripping procedure from 21 indviduals. Scanning electron (SEM) and atomic force microcopy (AFM) were used to record nanoscale topography. Circular nano‐objects were identified and these were quantitated through computer vision.

Results

Typical dimensions of 273 nm height and 305 nm width. We showed that their density does not correlate to age or pigmentation in healthy subjects, but that they were clearly elevated in corneocytes from patients with atopic dermatitis, a common inflammatory skin condition.

Conclusion

The presence of these corneocyte‐nanostructures might be used as a diagnostic parameter for skin disorders ‐ even in cases below a clinical threshold.
The Impact of Exporting and Importing Goods and Services on Productivity in the UK
Authors: Harris Richard , Moffat John
Published: June 2015

This paper investigates the impact of exporting and importing on productivity for UK plants using a combination of regression and propensity score matching. Unlike earlier papers, the data allows us to distinguish the effects of trade in goods and services. In confirmation of the results from other countries, we find that plants that both export and import have higher productivity than plants that only do one of these activities. In manufacturing, this is the case regardless of whether the trade is in goods or services (which suggests that servitisation of manufacturing is beneficial).In services, the results are more mixed and the benefits from involvement in international goods networks that are seen in manufacturing do not occur to the same extent (however, for the wholesale and retail sectors, trade in both goods and services is generally productivity enhancing).
Fire Risk Assessment and Computer Simulation of Fire Scenario in Underground Mines
Authors: Adjiski Vancho , Despodov Zoran , Mirakovski Dejan , Mijalkovski Stojance
Published: June 2015

Unsafe working conditions in underground mines have led to a number of accidents, loss of life, damage to property, interruption of production, etc. Safety is essential in mining industry, which in recent years mainly focuses on injury prevention in the workplace through a variety of procedures and employee training. The primary goal of this paper is to present a methodology with systematic analysis to determine the most risky places for fire occurrence in underground mines and using a computer simulation to determine the movement of smoke and fire gases trough underground mining facilities from which depends the safe evacuation of all employees.
Cloud-Based Global Supply Chain: A Conceptual Model and Multilayer Architecture
Authors: Akbaripour Hossein , Houshmand Mahmoud , Fatahi Valilai Omid
Published: June 2015

The cloud manufacturing (C-Manufacturing) paradigm, as an advanced form of networked manufacturing, has recently been proposed based on a combination of existing manufacturing systems and emerging technologies, such as cloud computing, virtual manufacturing, agile manufacturing, manufacturing grid, Internet-of-things (IOT), and service-oriented technologies. In this study, through investigating the main goals of C-Manufacturing and today's hypercompetitive global marketplace circumstances, a prospective conceptual model called cloud-based global supply chain (CBGSC) has been developed which can overcome or mitigate the issues and risks associated with supply chain processes on a global scale. CBGSC extends the conventional three-tier customer–manufacturer–supplier supply chain model into a new five-tier customer–cloud provider of manufacturing applications (CPMA)–manufacturer–cloud provider of supplying applications (CPSA)–supplier model, in which the CPMA and CPSA tiers act as intermediators in order to enhance the diversity and intensity of the markets and businesses of conventional supply chain parties while securing their own profits. On the other hand, CBGSC enriches the notion of C-Manufacturing by incorporating CPSAs to safeguard smooth and continuous supply of raw materials and goods to manufacturers (physical resource providers), thus prevailing the “share to gain” philosophy within the whole network. Also, aiming to facilitate practicalizing the CBGSC, we have proposed a multilayer architecture for the CBGSC with seven layers of user, interface, application, service, resource virtualization and service encapsulation, perception, and resource, which are blended together via four basic aspects of security, optimality, resilience, and information technology (IT) and information and communications technology (ICT) infrastructure.
The Effect of Fiber Orientation on the Formability and Failure Behavior of a Woven Self-Reinforced Composite
Authors: Zanjani Nima A. , Wang Wentian , Kalyanasundaram Shankar
Published: June 2015

This article investigates the effect of fiber orientation on forming and failure behaviors of a preconsolidated woven self-reinforced polypropylene (SRPP) composite during the stamp-forming process. Specimens with different aspect ratios were employed to study their formability during forming through a hemispherical punch in an open die configuration. The strain evolution in specimens was captured using a real-time strain measurement system (the aramis). A forming limit diagram (FLD), inspired from metal forming, was constructed to investigate the failure onset in the woven composite. The FLD revealed dominant failure mechanisms in [0 deg,90 deg] specimens were yarn splitting and fiber fracture as depicted by optical microscopy. A modified FLD was proposed to investigate failure mechanisms in [45 deg,−45 deg] samples. It was shown that delamination and intralaminar shear are the main causes of failure in this set of specimens. The outcomes of this study suggest that by changing forming parameters, such as fiber orientation, boundary condition, and aspect ratio, the formability of a preconsolidated SRPP can be improved. These results show the possibility of producing cost-effective, flawless, and fully recyclable products from consolidated woven composites. The proposed criterion can accurately predict failure in a woven composite by considering the combined strain interactions. This is reflected in the implementation of induced deformation modes and strain history into the failure criterion, making it a practical measure for rapid manufacturing techniques, such as stamping. The novel path-dependent failure criterion, introduced in this study, attempts to fill the gap for a reliable and accurate failure measure for woven composites.
Subcooled Boiling Heat Transfer for Cooling of Power Electronics in Hybrid Electric Vehicles
Authors: Zhao Weihuan , France David M. , Yu Wenhua , Singh Dileep
Published: June 2015

At present, single-phase liquid, forced convection cooled heat sinks with fins are used to cool power electronics in hybrid electric vehicles (HEVs). Although use of fins in the cooling channels increases heat transfer rates considerably, a second low-temperature radiator and associated pumping system are still required in HEVs. This additional cooling system adds weight and cost while decreasing the efficiency of HEVs. With the objective of eliminating this additional low-temperature radiator and pumping system in HEVs, an alternative cooling technology, subcooled boiling in the cooling channels, was investigated in the present study. Numerical heat transfer simulations were performed using subcooled boiling in the power electronics cooling channels with the coolant supplied from the existing main engine cooling system. Results show that this subcooled boiling system is capable of removing 25% more heat from the power electronics than the conventional forced convection cooling technology, or it can reduce the junction temperature of the power electronics at the current heat removal rate. With the 25% increased heat transfer option, high heat fluxes up to 250 W/cm2 (typical for wideband-gap semiconductor applications) are possible by using the subcooled boiling system.
Development of a Nanoparticle-Embedded Chitosan Sponge for Topical and Local Administration of Chemotherapeutic Agents
Authors: Goldberg Manijeh , Manzi Aaron , Aydin Erkin , Singh Gurtej , Khoshkenar Payam , Birdi Amritpreet , LaPorte Brandon , Krauskopf Alejandro , Powell Geralle , Chen Julie , Langer Robert
Published: June 2015

The following work describes the development of a novel noninvasive transmucosal drug delivery system, the chitosan sponge matrix (CSM). It is composed of cationic chitosan (CS) nanoparticles (NPs) that encapsulate cisplatin (CDDP) embedded within a polymeric mucoadhesive CS matrix. CSM is designed to swell up when exposed to moisture, facilitating release of the NPs via diffusion across the matrix. CSM is intended to be administered topically and locally to mucosal tissues, with its initial indication being oral cancer (OC). Currently, intravenous (IV) administered CDDP is the gold standard chemotherapeutic agent used in the treatment of OC. However, its clinical use has been limited by its renal and hemotoxicity profile. We aim to locally administer CDDP via encapsulation in CS NPs and deliver them directly to the oral cavity with CSM. It is hypothesized that such a delivery device will greatly reduce any systemic toxicity and increase antitumor efficacy. This paper describes the methods for developing CSM and maintaining the integrity of CDDP NPs embedded in the CSM.
Reducing Dynamic Response Variation Using NURBS Finite Element-Based Geometry Perturbation
Authors: Zhou K. , Tang J.
Published: June 2015

The uncertainties in real structures usually lead to variations in their dynamic responses. In order to reduce the likelihood of unexpected failures in structures, it is necessary to reduce the response variations. Among various design manipulations, the modification of surface geometry could be a viable option to achieve performance robustness against uncertainties. However, such design modification is difficult to achieve based on conventional finite element methods, primarily due to the inevitable discrepancy between the conventional finite element mesh and the corresponding surface geometry. This issue may become even more severe in design optimization, as an optimized mesh based on conventional finite element analysis may yield nonsmooth surface geometry. In this research, we adopt the nonuniform rational B-splines (NURBS) finite element method to facilitate the robust design optimization (RDO), where the fundamental advantage is that the NURBS finite element mesh is conformal to the underlying NURBS geometry. Furthermore, this conformal feature ensures that, upon finite element-based optimization, the resulting surface geometry is smooth. Taking advantage of that both the uncertainties and the design modifications are small, we formulate a sensitivity-based algorithm to rapidly evaluate the response variations. Based on the direct relation between the response variations and design parameters, the optimal surface geometry that yields the minimal response variation can be identified. Systematic case analyses are carried out to validate the effectiveness and efficiency of the proposed approach.
Crystal structure development of vanadium oxide thin films deposited by a magnetron sputtering technique
Authors: Asadov Alec , Mukhtar Surayya , Gao Wei
Published: June 2015

Crystal structure of vanadium oxide films with different thickness, deposited on glass and F:SnO2 coated (FTO) substrates, was studied. It was found that all the films annealed at 450 °C developed a metastable β-V2O5 monoclinic crystal structure, represented by crystals of up to 100 nm. At higher temperatures, the original crystals of relatively thick films of 400 nm on the glass substrate first increased in size and improved their crystal structure symmetry from the monoclinic to tetragonal, then gradually intergrew into spectacular superstructures of crystal “leaves” (500 °C) and “needles” (550 °C). Thin films of 130 nm exhibited a similar crystallization processes but at a higher rate. It was found that the FTO substrate supported the slowest crystal growth dynamics with annealing temperature. The original crystals did not grow in size and retained their low β monoclinic symmetry in the whole temperature range up to 550 °C. The superstructure appeared around film imperfections in the form of plate macroscopic crystals with improved tetragonal symmetry, and it covered only one third of the film surface. The metastable β phase growth and its development were discussed and explained in terms of the combined effect of high crystal/substrate surface tension and crystal surface energy.
Internal respiratory surrogate in multislice 4D CT using a combination of Fourier transform and anatomical features
Authors: Hui Cheukkai , Suh Yelin , Robertson Daniel , Pan Tinsu , Das Prajnan , Crane Christopher H. , Beddar Sam
Published: June 2015

Purpose:

The purpose of this study was to develop a novel algorithm to create a robust internal respiratory signal (IRS) for retrospective sorting of four‐dimensional (4D) computed tomography (CT) images.

Methods:

The proposed algorithm combines information from the Fourier transform of the CT images and from internal anatomical features to form the IRS. The algorithm first extracts potential respiratory signals from low‐frequency components in the Fourier space and selected anatomical features in the image space. A clustering algorithm then constructs groups of potential respiratory signals with similar temporal oscillation patterns. The clustered group with the largest number of similar signals is chosen to form the final IRS. To evaluate the performance of the proposed algorithm, the IRS was computed and compared with the external respiratory signal from the real‐time position management (RPM) system on 80 patients.

Results:

In 72 (90%) of the 4D CT data sets tested, the IRS computed by the authors’ proposed algorithm matched with the RPM signal based on their normalized cross correlation. For these data sets with matching respiratory signals, the average difference between the end inspiration times (Δtins) in the IRS and RPM signal was 0.11 s, and only 2.1% of Δtins were more than 0.5 s apart. In the eight (10%) 4D CT data sets in which the IRS and the RPM signal did not match, the average Δtins was 0.73 s in the nonmatching couch positions, and 35.4% of them had a Δtins greater than 0.5 s. At couch positions in which IRS did not match the RPM signal, a correlation‐based metric indicated poorer matching of neighboring couch positions in the RPM‐sorted images. This implied that, when IRS did not match the RPM signal, the images sorted using the IRS showed fewer artifacts than the clinical images sorted using the RPM signal.

Conclusions:

The authors’ proposed algorithm can generate robust IRSs that can be used for retrospective sorting of 4D CT data. The algorithm is completely automatic and requires very little processing time. The algorithm is cost efficient and can be easily adopted for everyday clinical use.
Time and irreversibility in axiomatic thermodynamics
Authors: Marsland Robert , Brown Harvey R. , Valente Giovanni
Published: June 2015

Thermodynamics is the paradigm example in physics of a time-asymmetric theory, but the origin of the asymmetry lies deeper than the second law. A primordial arrow can be defined by the way of the equilibration principle (“minus first law”). By appealing to this arrow, the nature of the well-known ambiguity in Carathéodory's 1909 version of the second law becomes clear. Following Carathéodory's seminal work, formulations of thermodynamics have gained ground that highlight the role of the binary relation of adiabatic accessibility between equilibrium states, the most prominent recent example being the important 1999 axiomatization due to Lieb and Yngvason. This formulation can be shown to contain an ambiguity strictly analogous to that in Carathéodory's treatment.
Special relativity from the dynamical viewpoint
Authors: Nelson William M.
Published: June 2015

Arguments are reviewed and extended in favor of presenting special relativity at least in part from a more mechanistic point of view. A number of generic mechanisms are catalogued and illustrated with the goal of making relativistic effects seem more natural by connecting with more elementary aspects of physics, particularly the physics of waves.
The effect of trapped charge on series capacitors
Authors: James Mark C. , Solheim Jonathan R.
Published: June 2015

If capacitors are initially charged before placing them in series, charge becomes trapped on the electrically isolated internal plates. The effect of this “trapped charge” on the final charge and voltage distributions in series capacitor networks provides instructors with a new class of engaging capacitor problems not currently addressed in introductory physics textbooks. We present formulae for the final charges on two series capacitors connected to a battery in terms of initial charge values. Various special cases are also considered. Results are verified experimentally using dc voltage and RC time constant measurements. Practical considerations for experimental design are discussed.
The Canadian Assessment of Physical Literacy: Development of a Model of Children’s Capacity for a Healthy, Active Lifestyle Through a Delphi Process
Authors: Francis Claire E. , Longmuir Patricia E. , Boyer Charles , Andersen Lars Bo , Barnes Joel D. , Boiarskaia Elena , Cairney John , Faigenbaum Avery D. , Faulkner Guy , Hands Beth P. , Hay John A. , Janssen Ian , Katzmarzyk Peter T. , Kemper Han C. G. , Knudson Duane , Lloyd Meghann , McKenzie Thomas L. , Olds Tim S. , Sacheck Jennifer M. , Shephard Roy J. , Zhu Weimo , Tremblay Mark S.
Published: June 2015

Background:

The Canadian Assessment of Physical Literacy (CAPL) was conceptualized as a tool to monitor children’s physical literacy. The original model (fitness, activity behavior, knowledge, motor skill) required revision and relative weights for calculating/interpreting scores were required.

Methods:

Nineteen childhood physical activity/fitness experts completed a 3-round Delphi process. Round 1 was open-ended questions. Subsequent rounds rated statements using a 5-point Likert scale. Recommendations were sought regarding protocol inclusion, relative importance within composite scores and score interpretation.

Results:

Delphi participant consensus was achieved for 64% (47/73) of statement topics, including a revised conceptual model, specific assessment protocols, the importance of longitudinal tracking, and the relative importance of individual protocols and composite scores. Divergent opinions remained regarding the inclusion of sleep time, assessment/scoring of the obstacle course assessment of motor skill, and the need for an overall physical literacy classification.

Conclusions:

The revised CAPL model (overlapping domains of physical competence, motivation, and knowledge, encompassed by daily behavior) is appropriate for monitoring the physical literacy of children aged 8 to 12 years. Objectively measured domains (daily behavior, physical competence) have higher relative importance. The interpretation of CAPL results should be reevaluated as more data become available.
Biodiversity and distribution of polar freshwater DNA viruses
Authors: Aguirre de Cárcer Daniel , López-Bueno Alberto , Pearce David A. , Alcamí Antonio
Published: June 2015

A metagenomics analysis of Arctic freshwater viral DNA communities uncovers unique genetics and bipolar lineages.
Role of Toll-like receptors in diabetic renal lesions in a miniature pig model
Authors: Feng Yuanyuan , Yang Shulin , Ma Yuxiang , Bai Xue-Yuan , Chen Xiangmei
Published: June 2015

Metabolic inflammation activated by the TLR pathway plays an important role in kidney injuries in a mini-pig model of diabetes.
Oklahoma’s recent earthquakes and saltwater disposal
Authors: Walsh F. Rall , Zoback Mark D.
Published: June 2015

Increasingly frequent earthquakes in Oklahoma are linked to saltwater disposal.
Critical feedback against bone metastasis
Authors: Ferrarelli Leslie K.
Published: June 2015

Loss of a negative feedback regulator enables TGF-β signaling to promote prostate cancer metastasis to the bone.
A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression
Authors: Kamal Mohamed A. , Gieschke Ronald , Lemenuel-Diot Annabelle , Beauchemin Catherine A. A. , Smith Patrick F. , Rayner Craig R.
Published: June 2015

A population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate β, free virus produced at rate
p
and cleared at rate
c
, and infected cells cleared at rate δ, was implemented in NONMEM with an inhibitory Hill function on virus production (
p
), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75-mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (β) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (
c
) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation.
Differences in Antibiotic-Induced Oxidative Stress Responses between Laboratory and Clinical Isolates of Streptococcus pneumoniae
Authors: Dridi Bédis , Lupien Andréanne , Bergeron Michel G. , Leprohon Philippe , Ouellette Marc
Published: June 2015

Oxidants were shown to contribute to the lethality of bactericidal antibiotics in different bacterial species, including the laboratory strain
Streptococcus pneumoniae
R6. Resistance to penicillin among
S. pneumoniae
R6 mutants was further shown to protect against the induction of oxidants upon exposure to unrelated bactericidal compounds. In the work described here, we expanded on these results by studying the accumulation of reactive oxygen species in the context of antibiotic sensitivity and resistance by including
S. pneumoniae
clinical isolates. In
S. pneumoniae
R6, penicillin, ciprofloxacin, and kanamycin but not the bacteriostatic linezolid, erythromycin, or tetracycline induced the accumulation of reactive oxygen species. For the three bactericidal compounds, resistance to a single molecule prevented the accumulation of oxidants upon exposure to unrelated bactericidal antibiotics, and this was accompanied by a reduced lethality. This phenomenon does not involve target site mutations but most likely implicates additional mutations occurring early during the selection of resistance to increase survival while more efficient resistance mechanisms are being selected or acquired. Bactericidal antibiotics also induced oxidants in sensitive
S. pneumoniae
clinical isolates. The importance of oxidants in the lethality of bactericidal antibiotics was less clear than for
S. pneumoniae
R6, however, since ciprofloxacin induced oxidants even in ciprofloxacin-resistant
S. pneumoniae
clinical isolates. Our results provide a clear example of the complex nature of the mode of action of antibiotics. The adaptive approach to oxidative stress of
S. pneumoniae
is peculiar, and a better understanding of the mechanism implicated in response to oxidative injury should also help clarify the role of oxidants induced by antibiotics.
Characterization of IncI1 Sequence Type 71 Epidemic Plasmid Lineage Responsible for the Recent Dissemination of CTX-M-65 Extended-Spectrum β-Lactamase in the Bolivian Chaco Region
Authors: Riccobono Eleonora , Di Pilato Vincenzo , Di Maggio Tiziana , Revollo Carmen , Bartoloni Alessandro , Pallecchi Lucia , Rossolini Gian Maria
Published: June 2015

During the last decade, a significant diffusion of CTX-M-type extended-spectrum β-lactamases (ESBLs) was observed in commensal
Escherichia coli
from healthy children in the Bolivian Chaco region, with initial dissemination of CTX-M-2, which was then replaced by CTX-M-15 and CTX-M-65. In this work, we demonstrate that the widespread dissemination of CTX-M-65 observed in this context was related to the polyclonal spreading of an IncI1 sequence type 71 (ST71) epidemic plasmid lineage. The structure of the epidemic plasmid population was characterized by complete sequencing of four representatives and PCR mapping of the remainder (
n
= 16). Sequence analysis showed identical plasmid backbones (similar to that of the reference IncI1 plasmid, R64) and a multiresistance region (MRR), which underwent local microevolution. The MRR harbored genes responsible for resistance to β-lactams, aminoglycosides, florfenicol, and fosfomycin (with microevolution mainly consisting of deletion events of resistance modules). The
bla
CTX-M-65
module harbored by the IncI1 ST71 epidemic plasmid was apparently derived from IncN-type plasmids, likely via IS
26
-mediated mobilization. The plasmid could be transferred by conjugation to several different enterobacterial species (
Escherichia coli
,
Cronobacter sakazakii
,
Enterobacter cloacae
,
Klebsiella oxytoca
,
Klebsiella pneumoniae
, and
Salmonella enterica
) and was stably maintained without selective pressure in these species, with the exception of
K. oxytoca
and
S. enterica
. Fitness assays performed in
E. coli
recipients demonstrated that the presence of the epidemic plasmid was apparently not associated with a significant biological cost.
Resistance Analysis of Baseline and Treatment-Emergent Variants in Hepatitis C Virus Genotype 1 in the AVIATOR Study with Paritaprevir-Ritonavir, Ombitasvir, and Dasabuvir
Authors: Krishnan Preethi , Tripathi Rakesh , Schnell Gretja , Reisch Thomas , Beyer Jill , Irvin Michelle , Xie Wangang , Larsen Lois , Cohen Daniel , Podsadecki Thomas , Pilot-Matias Tami , Collins Christine
Published: June 2015

AVIATOR, a phase 2 clinical trial, evaluated ritonavir-boosted paritaprevir (a protease inhibitor), ombitasvir (an NS5A inhibitor), and dasabuvir (a nonnucleoside polymerase inhibitor) (the three-drug [3D] regimen) with or without ribavirin (RBV) for 8, 12, or 24 weeks in 406 HCV genotype 1 (GT1)-infected patients. The rate of sustained virologic response 24 weeks after treatment ranged from 88% to 100% across the arms of the 3D regimen with or without RBV; 20 GT1a-infected patients and 1 GT1b-infected patient experienced virologic failure (5.2%). Baseline resistance-conferring variants in NS3 were rare. M28V in GT1a and Y93H in GT1b were the most prevalent preexisting variants in NS5A, and C316N in GT1b and S556G in both GT1a and GT1b were the most prevalent variants in NS5B. Interestingly, all the GT1a sequences encoding M28V in NS5A were from the United States, while GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. Variants preexisting at baseline had no significant impact on treatment outcome. The most prevalent treatment-emergent resistance-associated variants (RAVs) in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The single GT1b-infected patient experiencing virologic failure had no RAVs in any target. A paritaprevir-ritonavir dose of 150/100 mg was more efficacious in suppressing R155K in NS3 than a 100/100-mg dose. In patients who failed after receiving 12 or more weeks of treatment, RAVs were selected in all 3 targets, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. Results from this study guided the selection of the optimal treatment regimen, treatment duration, and paritaprevir dose for further development of the 3D regimen. (This study has been registered at ClinicalTrials.gov under registration number NCT01464827.)
Toxicity and SidJ-Mediated Suppression of Toxicity Require Distinct Regions in the SidE Family of Legionella pneumophila Effectors
Authors: Havey James C. , Roy Craig R.
Published: June 2015

Intracellular bacteria use a variety of strategies to evade degradation and create a replicative niche.
Legionella pneumophila
is an intravacuolar pathogen that establishes a replicative niche through the secretion of more than 300 effector proteins. The function of most effectors remains to be determined. Toxicity in yeast has been used to identify functional domains and elucidate the biochemical function of effectors. A library of
L. pneumophila
effectors was screened using an expression plasmid that produces low levels of each protein. This screen identified the effector SdeA as a protein that confers a strong toxic phenotype that inhibits yeast replication. The toxicity of SdeA was suppressed in cells producing the effector SidJ. The effector SdeA is a member of the SidE family of
L. pneumophila
effector proteins. All SidE orthologs encoded by the Philadelphia isolate of
Legionella pneumophila
were toxic to yeast, and SidJ suppressed the toxicity of each. We identified a conserved central region in the SidE proteins that was sufficient to mediate yeast toxicity. Surprisingly, SidJ did not suppress toxicity when this central region was produced in yeast. We determined that the amino-terminal region of SidE was essential for SidJ-mediated suppression of toxicity. Thus, there is a genetic interaction that links the activity of SidJ and the amino-terminal region of SidE, which is required to modulate the toxic activity displayed by the central region of the SidE protein. This suggests a complex mechanism by which the
L. pneumophila
effector SidJ modulates the function of the SidE proteins after translocation into host cells.
Interactions and Localization of Escherichia coli Error-Prone DNA Polymerase IV after DNA Damage
Authors: Mallik Sarita , Popodi Ellen M. , Hanson Andrew J. , Foster Patricia L.
Published: June 2015

Escherichia coli
's DNA polymerase IV (Pol IV/DinB), a member of the Y family of error-prone polymerases, is induced during the SOS response to DNA damage and is responsible for translesion bypass and adaptive (stress-induced) mutation. In this study, the localization of Pol IV after DNA damage was followed using fluorescent fusions. After exposure of
E. coli
to DNA-damaging agents, fluorescently tagged Pol IV localized to the nucleoid as foci. Stepwise photobleaching indicated ∼60% of the foci consisted of three Pol IV molecules, while ∼40% consisted of six Pol IV molecules. Fluorescently tagged Rep, a replication accessory DNA helicase, was recruited to the Pol IV foci after DNA damage, suggesting that the
in vitro
interaction between Rep and Pol IV reported previously also occurs
in vivo
. Fluorescently tagged RecA also formed foci after DNA damage, and Pol IV localized to them. To investigate if Pol IV localizes to double-strand breaks (DSBs), an I-SceI endonuclease-mediated DSB was introduced close to a fluorescently labeled LacO array on the chromosome. After DSB induction, Pol IV localized to the DSB site in ∼70% of SOS-induced cells. RecA also formed foci at the DSB sites, and Pol IV localized to the RecA foci. These results suggest that Pol IV interacts with RecA
in vivo
and is recruited to sites of DSBs to aid in the restoration of DNA replication.

IMPORTANCE
DNA polymerase IV (Pol IV/DinB) is an error-prone DNA polymerase capable of bypassing DNA lesions and aiding in the restart of stalled replication forks. In this work, we demonstrate
in vivo
localization of fluorescently tagged Pol IV to the nucleoid after DNA damage and to DNA double-strand breaks. We show colocalization of Pol IV with two proteins: Rep DNA helicase, which participates in replication, and RecA, which catalyzes recombinational repair of stalled replication forks. Time course experiments suggest that Pol IV recruits Rep and that RecA recruits Pol IV. These findings provide
in vivo
evidence that Pol IV aids in maintaining genomic stability not only by bypassing DNA lesions but also by participating in the restoration of stalled replication forks.
Cyclic Di-GMP-Regulated Periplasmic Proteolysis of a Pseudomonas aeruginosa Type Vb Secretion System Substrate
Authors: Cooley Richard B. , Smith T. Jarrod , Leung Wilfred , Tierney Valerie , Borlee Bradley R. , O'Toole George A. , Sondermann Holger
Published: June 2015

We previously identified a second-messenger-regulated signaling system in the environmental bacterium
Pseudomonas fluorescens
which controls biofilm formation in response to levels of environmental inorganic phosphate. This system contains the transmembrane cyclic di-GMP (c-di-GMP) receptor LapD and the periplasmic protease LapG. LapD regulates LapG and controls the ability of this protease to process a large cell surface adhesin protein, LapA. While LapDG orthologs can be identified in diverse bacteria, predictions of LapG substrates are sparse. Notably, the opportunistic pathogen
Pseudomonas aeruginosa
harbors LapDG orthologs, but neither the substrate of LapG nor any associated secretion machinery has been identified to date. Here, we identified
P. aeruginosa
CdrA, a protein known to mediate cell-cell aggregation and biofilm maturation, as a substrate of LapG. We also demonstrated LapDG to be a minimal system sufficient to control CdrA localization in response to changes in the intracellular concentration of c-di-GMP. Our work establishes this biofilm signaling node as a regulator of a type Vb secretion system substrate in a clinically important pathogen.

IMPORTANCE
Here, the biological relevance of a conserved yet orphan signaling system in the opportunistic pathogen
Pseudomonas aeruginosa
is revealed. In particular, we identified the adhesin CdrA, the cargo of a two-partner secretion system, as a substrate of a periplasmic protease whose activity is controlled by intracellular c-di-GMP levels and a corresponding transmembrane receptor via an inside-out signaling mechanism. The data indicate a posttranslational control mechanism of CdrA via c-di-GMP, in addition to its established transcriptional regulation via the same second messenger.
Kidney transplantation in an adult patient with VACTERL association
Authors: Cimen Sertac , Nantais Jordan , Guler Sanem , Lawen Joseph
Published: June 2015

The vertebral, anal, cardiac, tracheoesophageal, renal, and limb birth defects (VACTERL) association is a rare, non-random constellation of congenital abnormalities among which urinary tract anomalies can be included. In the presence of these anomalies, patients are suspected to have a higher rate of renal failure than average. We report a case of a 22-year-old woman with VACTERL association and consequent end stage renal failure. A live-related kidney transplant was carried out successfully and the postoperative course was uncomplicated. The patient had immediate graft function. Risk factors that may complicate kidney transplant surgery in this patient population as well as considerations relevant to peritransplant management are discussed.
Diffuse idiopathic skeletal hyperostosis and isotretinoin in cystic acne
Authors: Zhao Sizheng , Goodson Nicola J
Published: June 2015

We present the case of a 35-year-old man with thoracic back pain and stiffness, whose only medical history was cystic acne treated with repeated courses of retinoids. His thoracic spine was severely limited in range of movement and was found, on X-ray, to have unilateral hyperostosis typical of diffuse idiopathic skeletal hyperostosis (DISH)—an often asymptomatic condition rarely found in those under 50. Back stiffness in young patients with prolonged retinoid exposure should be investigated.
Cost-effectiveness of the New Zealand diabetes in pregnancy guideline screening recommendations
Authors: Coop Catherine , Edlin Richard , Brown Julie , Farquhar Cindy
Published: June 2015

Objective

To compare the cost-effectiveness of 2 possible screening strategies for gestational diabetes mellitus (GDM) from the perspective of the New Zealand health system, developed as part of a gestational diabetes guideline.

Design

A decision analytic model was built comparing 2-step screening (glycated haemoglobin (HbA1c) test at first booking and a 2 h 75 g oral glucose tolerance test (OGTT) as a single test at 24–28 weeks) with 3-step screening (HbA1c test at first booking and a 1 h glucose challenge test (GCT) followed by a 2 h 75 g OGTT when indicated from 24–28 weeks) using a 9-month time horizon.

Setting

A hypothetical cohort of 62 000 pregnant women in New Zealand.

Methods

Probabilities, costs and benefits were derived from the literature, and supplementary data was obtained from National Women's Annual Clinical Reports. Main outcome measures, screening and treatment costs (NZ$2013) and effect on health outcomes (incidence of complications).

Results

The total cost for both strategies under baseline assumptions shows that the 2-step screening strategy would cost NZ$1.38 m more than the 3-step screening strategy overall. The additional cost per case detected was NZ$12 460 per case. The model found that the 2-step screening strategy identifies 12 more women with diabetes and 111 more women with GDM when compared against the 3-step screening strategy. We assessed the effect of changing the sensitivity and specificity of the OGTT. The baseline model assumed that the 2 h 75 g OGTT has a sensitivity and specificity of 95%. The 2-step strategy becomes more cost-effective when the diagnostic accuracy measures are improved.

Conclusions

Adopting a 2-step strategy would moderately increase the number of GDM cases detected at the same time as moderately increasing the number of women with false negatives at a significant cost to the health system. Further evidence on the benefits of the 2 different approaches would be welcome.