bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis C virus infection: a risk factor for Parkinson's disease
Authors: Wu W. Y.‐Y. , Kang K.‐H. , Chen S. L.‐S. , Chiu S. Y.‐H. , Yen A. M.‐F. , Fann J. C.‐Y. , Su C.‐W. , Liu H.‐C. , Lee C.‐Z. , Fu W.‐M. , Chen H.‐H. , Liou H.‐H.
Published: January 2015

Recent studies found that hepatitis C virus (HCV) may invade the central nervous system, and both HCV and Parkinson's disease (PD) have in common the overexpression of inflammatory biomarkers. We analysed data from a community‐based integrated screening programme based on a total of 62 276 subjects. We used logistic regression models to investigate association between HCV infection and PD. The neurotoxicity of HCV was evaluated in the midbrain neuron–glia coculture system in rats. The cytokine/chemokine array was performed to measure the differences of amounts of cytokines released from midbrain in the presence and absence of HCV. The crude odds ratios (ORs) for having PD were 0.62 [95% confidence interval (CI), 0.48–0.81] and 1.91 (95% CI, 1.48–2.47) for hepatitis B virus (HBV) and HCV. After controlling for potential confounders, the association between HCV and PD remained statistically significant (adjusted OR = 1.39; 95% CI, 1.07–1.80), but not significantly different between HBV and PD. The HCV induced 60% dopaminergic neuron death in the midbrain neuron–glia coculture system in rats, similar to that of 1‐methyl‐4‐phenylpyridinium (MPP+) but not caused by HBV. This link was further supported by the finding that HCV infection may release the inflammatory cytokines, which may play a role in the pathogenesis of PD. In conclusion, our study demonstrated a significantly positive epidemiological association between HCV infection and PD and corroborated the dopaminergic toxicity of HCV similar to that of MPP+.
Responses of artificially reared cat fleas Ctenocephalides felis felis (Bouché, 1835) to different mammalian bloods
Authors: KERNIF T. , STAFFORD K. , COLES G. C. , BITAM I. , PAPA K. , CHIARONI J. , RAOULT D. , PAROLA P.
Published: January 2015

The cat flea, Ctenocephalides felis felis (Bouche, 1835) (Siphonaptera: Pulicidae), which is found worldwide and which parasitizes many species of wild and domestic animal, is a vector and/or reservoir of bacteria, protozoa and helminths. To aid in the study of the physiology and behaviour of fleas and of their transmission of pathogens, it would be of value to improve the laboratory rearing of pathogen‐free fleas. The conditions under which artificially reared fleas at the University of Bristol (U.K.) and the Rickettsial Diseases Institute (France) are maintained were studied, with different ratios of male to female fleas per chamber (25 : 50, 50 : 100, 100 : 100, 200 : 200). The fleas were fed with bovine, ovine, caprine, porcine or human blood containing the anticoagulants sodium citrate or EDTA. Egg production was highest when fleas were kept in chambers with a ratio of 25 males to 100 females. In addition, the use of EDTA as an anticoagulant rather than sodium citrate resulted in a large increase in the number of eggs produced per female; however, the low percentage of eggs developing through to adult fleas was lower with EDTA. The modifications described in our rearing methods will improve the rearing of cat fleas for research.
The Power to Oblige: Power, Gender, Negotiation Behaviors, and Their Consequences
Authors: Nelson Noa , Bronstein Ilan , Shacham Rotem , Ben‐Ari Rachel
Published: January 2015

This study experimentally examined how power and gender affect negotiation behaviors and how those behaviors affect negotiated outcomes. One hundred and forty‐six dyads, in four combinations of power and gender, negotiated compensation agreements. In line with gender stereotypes, male negotiators were more dominating and females more obliging and somewhat more compromising. However, partially challenging the common association of power and masculinity, high‐power negotiators were less dominating and more collaborating, obliging and avoiding than their low‐power opponents. Generally, feminine and high‐power behaviors induced agreement while masculine and low‐power behaviors enhanced distributive personal gain. The study also assessed patterns of behavioral reciprocity and used sophisticated analytic tools to control for dyadic interdependence. Therefore it helps to elucidate the negotiation process and the role that power and its interplay with gender play in it.
The ubiquity of alpine plant radiations: from the Andes to the Hengduan Mountains
Authors: Hughes Colin E. , Atchison Guy W.
Published: January 2015

Alpine plant radiations are compared across the world's major mountain ranges and shown to be overwhelmingly young and fast, largely confined to the Pliocene and Pleistocene, and some of them apparently in the early explosive phase of radiation. Accelerated diversification triggered by island‐like ecological opportunities following the final phases of mountain uplift, and in many cases enabled by the key adaptation of perennial habit, provides a general model for alpine plant radiations. Accelerated growth form evolution facilitated by perenniality provides compelling evidence of ecological release and suggests striking parallels between island‐like alpine, and especially tropicalpine radiations, and island radiations more generally. These parallels suggest that the world's mountains offer an excellent comparative system for explaining evolutionary radiation.

Contents

Summary
275

I.
Introduction
275

II.
Mountains as islands
277

III.
Lupinus: a model for alpine plant radiation
277

IV.
Perenniality and life‐form disparification
279

V.
A comparative system for understanding evolutionary radiation
279

VI.
Future perspectives
280

Acknowledgements
280

References
280
On the Behaviour of Phillips–Perron Tests in the Presence of Persistent Cycles
Authors: Del Barrio Castro Tomás , Rodrigues Paulo M. M. , Taylor A. M. Robert
Published: January 2015

In this paper, we analyse the impact of persistent cycles on the well‐known semi‐parametric unit root tests of Phillips and Perron (1988, Biometrika, Vol. 75, pp. 335–346). It is shown, both analytically and through Monte Carlo simulations, that the presence of complex (near) unit roots can severely bias the size properties of these tests. Given the popularity of these tests with applied researchers and their routine presence in most econometric software packages, the results presented in this paper suggest that practitioners should treat the outcomes of these tests with some caution when applied to data which display a strong cyclical component.
The influence of trauma and patient characteristics on provider burnout in VA post‐traumatic stress disorder specialty programmes
Authors: Garcia Hector A. , McGeary Cindy A. , Finley Erin P. , McGeary Donald D. , Ketchum Norma S. , Peterson Alan L.
Published: January 2015

Objective

Prolonged exposure (PE) and cognitive processing therapy (CPT) – post‐traumatic stress disorder (PTSD) treatments now available at the Veterans Health Administration (VHA) – expose the provider to graphic traumatic material. Little is known about the impact of traumatic material on VHA providers. The purpose of this study was to examine the relationship between trauma content, patient characteristics, and burnout among VHA PTSD Clinical Team (PCT) providers. It was hypothesized that trauma content and patient characteristics would significantly predict burnout in this population.

Design

This cross‐sectional study consisted of 137 participants. The sample was mostly female (67%), Caucasian (non‐Hispanic; 81%), and married (70%) with a mean age of 44.3 years (SD = 11.3).

Methods

Participants completed an electronic survey that assessed demographics, patient characteristics (i.e., anger, personality disorder, malingering), trauma content characteristics (e.g., killing of women and children) as well as burnout as measured by the Maslach Burnout Inventory‐General Survey (MBI‐GS; Maslach et al., 1996, Burnout inventory manual. Palo Alto: Consulting Psychologist Press).

Results

Over half of the study population reported being bothered by trauma content; however, trauma content did not predict burnout. Treating patients with personality disorders and suspected malingering predicted burnout in PCT providers. High numbers (77%) reported perceiving that emotional exhaustion impacted the quality of care they provided.

Conclusion

These findings suggest an important role of burnout assessment, prevention, and treatment strategies at the VHA.

Practitioner points

This paper addresses the impact of provider burnout on perceived quality of care.

This paper also addresses potential predictors of burnout in PCT settings.

This paper outlines potential remedies to provider burnout in the VHA.
Effectiveness of Saltwater Baths in the Treatment of Epidermolysis Bullosa
Authors: Petersen Brian Woodford , Arbuckle Harvey A. , Berman Stephen
Published: January 2015

Current management of epidermolysis bullosa (EB) focuses on preventing secondary infections—a leading cause of mortality—by regularly cleaning and bandaging blisters and erosions and preventive bandaging of high‐friction areas. Unfortunately the baths and showers used to remove bandages and clean the skin are often painful, causing lack of adherence and subsequent increases in infections, pain, and antimicrobial use. This study evaluates the hypothesis that bathing individuals with EB in saltwater is less painful than in normal bath water. The study also explores whether taking saltwater baths reduces infections as measured through skin pruritus, odor, discharge, and nonbathing pain. Participants recruited from the Children's Hospital Colorado Outpatient EB Clinic completed standardized questionnaires assessing the effects of the clinic's saltwater bathing recommendations; the data were analyzed using frequencies and Fisher tests. After starting saltwater baths, patients reported a significant reduction in pain (91%), pain medication use (66%), skin odor (31%), and skin discharge (44%). No significant differences were found with respect to the type of EB, age, length of time using baths, or amount of salt added. Saltwater baths are a noninvasive, low‐cost, effective treatment that significantly reduces bathing pain, pain medication use, and some signs of skin infection. This treatment can be recommended to patients with all studied EB types without regard to age, the specific amount of salt used, bathing frequency, or pain level. Given the central role bathing and dressing changes play in the management of EB, the use of saltwater baths can lead to significant improvement in quality of life.
Childhood Generalized Pustular Psoriasis: Longtime Remission With Combined Infliximab and Methotrexate Treatment
Authors: Skrabl‐Baumgartner Andrea , Weger Wolfgang , Salmhofer Wolfgang , Jahnel Jörg
Published: January 2015

An 8‐year old boy with generalized pustular psoriasis unresponsive to several topical and systemic treatments responded dramatically with long‐lasting remission to infliximab in combination with methotrexate. Combined therapy might offer a new therapeutic strategy yielding long‐term remission.
Effects of Co‐culture of Cumulus Oocyte Complexes with Denuded Oocytes During In Vitro Maturation on the Developmental Competence of Cloned Bovine Embryos
Authors: Ha A‐N , Fakruzzaman M , Lee K‐L , Bang J‐I , Deb G‐K , Wang Z , Kong I‐K
Published: January 2015

Contents

This study evaluated the effects of co‐culture of immature cumulus oocyte complexes (COCs) with denuded immature oocytes (DO) during in vitro maturation on the developmental competence and quality of cloned bovine embryos. We demonstrated that developmental competence, judged by the blastocyst formation rate, was significantly higher in the co‐cultured somatic cell nuclear transfer (SCNT+DO, 37.1 ± 1.1%) group than that in the non‐co‐cultured somatic cell nuclear transfer (SCNT‐DO, 25.1 ± 0.9%) group and was very similar to that in the control IVF (IVF, 38.8 ± 2.8%) group. Moreover, the total cell number per blastocyst in the SCNT+DO group (101.7 ± 6.2) was higher than that in the SCNT‐DO group (81.7 ± 4.3), while still less than that in the IVF group (133.3 ± 6.0). Furthermore, our data showed that mRNA levels of the methylation‐related genes DNMT1 and DNMT3a in the SCNT+DO group were similar to that in the IVF group, while they were significantly higher in the SCNT‐DO group. Similarly, while the mRNA levels of the deacetylation‐related genes HDAC2 and HDAC3 were significantly higher in the SCNT‐DO group, they were comparable between the IVF and SCNT+DO groups. However, the mRNA levels of HDAC1 and DNMT3B were significantly higher in the SCNT+DO group than in the other groups. In conclusion, the present study demonstrated that co‐culture of COCs with DO improves the in vitro developmental competence and quality of cloned embryos, as evidenced by increased total cell number.
Effect of equipment dead space on multiple breath washout measures
Authors: Benseler Anouk , Stanojevic Sanja , Jensen Renee , Gustafsson Per , Ratjen Felix
Published: January 2015

Background and objective

Multiple breath inert gas washout (MBW) systems are designed to minimize equipment dead space volume (Vd). Animal and infant studies have demonstrated the impact of increased Vd on MBW measurements. In this study, we investigate the effect of Vd of a nitrogen (N2) MBW system on MBW measurements in preschool children.

Methods

N2 MBW measurements were performed in healthy adults under standard conditions; Vd was added to match the relationship between Vd and lung volumes observed in preschool children. Subsequently, subjects were measured on a sulfur hexafluoride (SF6) MBW system under standard conditions and with Vd added to match that of the N2 MBW system. Healthy preschool children and children with cystic fibrosis were tested on both the N2 MBW and SF6 MBW in random order on the same day. A correction equation was derived based on the adult experiments and tested on the preschool data.

Results

Increasing the Vd of the N2 MBW system resulted in a higher lung clearance index (LCI). A strong non‐linear relationship between N2 LCI and the Vd/tidal volume was observed. When the Vd was equivalent between systems, LCI measured by the SF6 MBW system was similar to that measured by the N2 MBW. LCI was higher on the N2 MBW than the SF6 MBW in preschool children. Correcting for the equipment Vd of the N2 MBW resulted in better agreement.

Conclusions

Equipment Vd affects LCI measurements especially in young children where Vd is large relative to lung volumes.
Between Activation and Supporting Women – Alternative Operation of Welfare‐to‐work Programmes
Authors: Herbst Anat , Benjamin Orly
Published: January 2015

With the emergence of activation policies, researchers are intrigued by the extent to which welfare‐to‐work (WTW) programmes reflect the ideological orientation of policymakers, while leaving the ideological orientation of their operators unexamined. This aspect may be of particular importance when women's non‐governmental organizations operate non‐coercive WTW programmes. Directing attention to the contribution of the operator, we ask how women who operate these programmes distinguish between the feminist goal of increasing women's independent access to material resources, and the activation rhetoric of ‘work first’.

Moreover, as not enough is known about how participants benefit from the incongruence between the feminist discourse and the activation one, scholarship contemplating women's resistance to WTW programmes remains focused on specific welfare histories, and this form of feminist work remains neglected.

The importance of the specific operators and the policy implications of the benefits of feminist operation of WTW programmes receive attention in the study reported on herein. We used a non‐coercive activation programme operated by a feminist organization in Israel (among other operators) as an opportunity to deepen our understanding of how programme trainers voice their position between feminism and activation discourse, and how their form of speech enables participants to insist on decent employment as a policy issue. Implications for policy are discussed.
The use of murine‐derived fundic organoids in studies of gastric physiology
Authors: Schumacher Michael A. , Aihara Eitaro , Feng Rui , Engevik Amy , Shroyer Noah F. , Ottemann Karen M. , Worrell Roger T. , Montrose Marshall H. , Shivdasani Ramesh A. , Zavros Yana
Published: January 2015

Key points

An in vitro approach to study gastric development is primary mouse‐derived epithelium cultured as three‐dimensional spheroids known as organoids.

We have devised two unique gastric fundic‐derived organoid cultures: model 1 for the expansion of gastric fundic stem cells, and model 2 for the maintenance of mature cell lineages.

Organoids maintained in co‐culture with immortalized stomach mesenchymal cells express robust numbers of surface pit, mucous neck, chief, endocrine and parietal cells.

Histamine induced a significant decrease in intraluminal pH that was reversed by omeprazole in fundic organoids and indicated functional activity and regulation of parietal cells. Localized photodamage resulted in rapid cell exfoliation coincident with migration of neighbouring cells to the damaged area, sustaining epithelial continuity.

We report the use of these models for studies of epithelial cell biology and cell damage and repair.

Studies of gastric function and disease have been limited by the lack of extended primary cultures of the epithelium. An in vitro approach to study gastric development is primary mouse‐derived antral epithelium cultured as three‐dimensional spheroids known as organoids. There have been no reports on the use of organoids for gastric function. We have devised two unique gastric fundic‐derived organoid cultures: model 1 for the expansion of gastric fundic stem cells, and model 2 for the maintenance of mature cell lineages. Both models were generated from single glands dissociated from whole fundic tissue and grown in basement membrane matrix (Matrigel) and organoid growth medium. Model 1 enriches for a stem cell‐like niche via simple passage of the organoids. Maintained in Matrigel and growth medium, proliferating organoids expressed high levels of stem cell markers CD44 and Lgr5. Model 2 is a system of gastric organoids co‐cultured with immortalized stomach mesenchymal cells (ISMCs). Organoids maintained in co‐culture with ISMCs express robust numbers of surface pit, mucous neck, chief, endocrine and parietal cells. Histamine induced a significant decrease in intraluminal pH that was reversed by omeprazole in fundic organoids and indicated functional activity and regulation of parietal cells. Localized photodamage resulted in rapid cell exfoliation coincident with migration of neighbouring cells to the damaged area, sustaining epithelial continuity. Thus, we report the use of these models for studies of epithelial cell biology and cell damage and repair.
A novel partial volume effects correction technique integrating deconvolution associated with denoising within an iterative PET image reconstruction
Authors: Merlin Thibaut , Visvikis Dimitris , Fernandez Philippe , Lamare Frederic
Published: January 2015

Purpose:

Partial volume effect (PVE) plays an important role in both qualitative and quantitative PET image accuracy, especially for small structures. A previously proposed voxelwise PVE correction method applied on PET reconstructed images involves the use of Lucy–Richardson deconvolution incorporating wavelet‐based denoising to limit the associated propagation of noise. The aim of this study is to incorporate the deconvolution, coupled with the denoising step, directly inside the iterative reconstruction process to further improve PVE correction.

Methods:

The list‐mode ordered subset expectation maximization (OSEM) algorithm has been modified accordingly with the application of the Lucy–Richardson deconvolution algorithm to the current estimation of the image, at each reconstruction iteration. Acquisitions of the NEMA NU2‐2001 IQ phantom were performed on a GE DRX PET/CT system to study the impact of incorporating the deconvolution inside the reconstruction [with and without the point spread function (PSF) model] in comparison to its application postreconstruction and to standard iterative reconstruction incorporating the PSF model. The impact of the denoising step was also evaluated. Images were semiquantitatively assessed by studying the trade‐off between the intensity recovery and the noise level in the background estimated as relative standard deviation. Qualitative assessments of the developed methods were additionally performed on clinical cases.

Results:

Incorporating the deconvolution without denoising within the reconstruction achieved superior intensity recovery in comparison to both standard OSEM reconstruction integrating a PSF model and application of the deconvolution algorithm in a postreconstruction process. The addition of the denoising step permitted to limit the SNR degradation while preserving the intensity recovery.

Conclusions:

This study demonstrates the feasibility of incorporating the Lucy–Richardson deconvolution associated with a wavelet‐based denoising in the reconstruction process to better correct for PVE. Future work includes further evaluations of the proposed method on clinical datasets and the use of improved PSF models.
A low-cost mirror mount control system for optics setups
Authors: Gopalakrishnan Maithreyi , Gühr Markus
Published: January 2015

We describe a flexible, simple to build, low-cost, and computer-controlled optical mirror actuator system, developed for undergraduate research laboratories. Geared motors for hobby robotics are controlled by an Arduino microcontroller in combination with an H bridge to finely position mirror mount actuators. We present a graphical user interface based on the Python script language. The price of the fully controlled actuator system is only a small fraction of the price of a commercial system. It can be quickly implemented due to the use of open-hardware electronics. We discuss the performance of the system and give an outlook for future expansions and use in advanced optical setups.
Experimental method to characterize the retardance function of optical variable retarders
Authors: López-Téllez Juan M. , Bruce Neil C. , Delgado-Aguillón Jesús , Garduño-Mejía Jesús , Avendaño-Alejo Maximino
Published: January 2015

In this work, we present an experimental method to characterize variable optical retarders, which can have linear or non-linear behavior of the retardance variation. A theoretical analysis of such is presented using a combination of Stokes vectors and Mueller matrixes for three different optical retarders. A straightforward method for phase unwrapping, or reconstructing the original phase from the measured retardance, is proposed that yields high-accuracy results. This work can be used in an undergraduate optics lab to help students understand the concepts of retardance and its control and also how variable retardance devices work.
The physical origin of torque and of the rotational second law
Authors: Cross Daniel J.
Published: January 2015

We derive the rotational form of Newton's second law τ=Iα from the translational form F→=ma→ by performing a force analysis of a simple body consisting of two discrete masses. Curiously, a truly rigid body model leads to an incorrect statement of the rotational second law. The failure of this model is traced to its violation of the strong form of Newton's third law. This leads us to consider a slightly modified non-rigid model that respects the third law, produces the correct rotational second law, and makes explicit the importance of the product of the tangential force with the radial distance: the torque.
Magic mass ratios of complete energy-momentum transfer in one-dimensional elastic three-body collisions
Authors: Ee June-Haak , Lee Jungil
Published: January 2015

We consider the one-dimensional scattering of two identical blocks of mass M that exchange energy and momentum via elastic collisions with an intermediary ball of mass m=αM. Initially, one block is incident upon the ball with the other block at rest. For α<1, the three objects will make multiple collisions with one another. In our analysis, we construct a Euclidean vector Vn whose components are proportional to the velocities of the objects. Energy-momentum conservation then requires a covariant recurrence relation for Vn that transforms like a pure rotation in three dimensions. The analytic solutions of the terminal velocities result in a remarkable prediction for values of α, in cases where the initial energy and momentum of the incident block are completely transferred to the scattered block. We call these values for α “magic mass ratios.”
Exogenous and evoked oxytocin restores social behavior in the
Cntnap2
mouse model of autism
Authors: Peñagarikano Olga , Lázaro María T. , Lu Xiao-Hong , Gordon Aaron , Dong Hongmei , Lam Hoa A. , Peles Elior , Maidment Nigel T. , Murphy Niall P. , Yang X. William , Golshani Peyman , Geschwind Daniel H.
Published: January 2015

Mice carrying a genetic mutation that causes autistic symptoms show improved sociability after being treated with oxytocin, a hormone promoting mothering and trust.
Potentiation of Antibacterial Activity of the MB-1 Siderophore-Monobactam Conjugate Using an Efflux Pump Inhibitor
Authors: Tomaras Andrew P. , Crandon Jared L. , McPherson Craig J. , Nicolau David P.
Published: January 2015

Preliminary enthusiasm over the encouraging spectrum and
in vitro
activities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in
in vivo
efficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in
Pseudomonas aeruginosa
and provide evidence that efflux inhibition may circumvent this
in vivo
-relevant resistance liability.
In Vitro
Susceptibility Testing of Eravacycline Is Unaffected by Medium Age and Nonstandard Assay Parameters
Authors: Grossman Trudy H. , Pillar Chris M. , Sahm Daniel F. , Sutcliffe Joyce A.
Published: January 2015

Eravacycline is a fluorocycline antibiotic in phase 3 clinical development for complicated intra-abdominal and urinary tract infections. To support its clinical development, a study was conducted to evaluate the effects of various susceptibility test parameters on the MIC values for aerobic bacteria. The results showed that eravacycline appears to be largely unaffected by medium age, medium additives, and other nonstandard assay conditions.
VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model
Authors: Garvey E. P. , Hoekstra W. J. , Moore W. R. , Schotzinger R. J. , Long L. , Ghannoum M. A.
Published: January 2015

Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent
in vitro
antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential
in vivo
efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizing
Trichophyton mentagrophytes
and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (
P
< 0.001) and improvement in clinical scores (
P
< 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (
P
< 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.
Apparent Role for Borrelia burgdorferi LuxS during Mammalian Infection
Authors: Arnold William K. , Savage Christina R. , Antonicello Alyssa D. , Stevenson Brian
Published: January 2015

The Lyme disease spirochete,
Borrelia burgdorferi
, controls protein expression patterns during its tick-mammal infection cycle. Earlier studies demonstrated that
B. burgdorferi
synthesizes 4,5-dihydroxy-2,3-pentanedione (autoinducer-2 [AI-2]) and responds to AI-2 by measurably changing production of several infection-associated proteins.
luxS
mutants, which are unable to produce AI-2, exhibit altered production of several proteins.
B. burgdorferi
cannot utilize the other product of LuxS, homocysteine, indicating that phenotypes of
luxS
mutants are not due to the absence of that molecule. Although a previous study found that a
luxS
mutant was capable of infecting mice, a critical caveat to those results is that bacterial loads were not quantified. To more precisely determine whether LuxS serves a role in mammalian infection, mice were simultaneously inoculated with congenic wild-type and
luxS
strains, and bacterial numbers were assessed using quantitative PCR. The wild-type bacteria substantially outcompeted the mutants, suggesting that LuxS performs a significant function during mammalian infection. These data also provide further evidence that nonquantitative infection studies do not necessarily provide conclusive results and that regulatory factors may not make all-or-none, black-or-white contributions to infectivity.
Identification of ElpA, a Coxiella burnetii Pathotype-Specific Dot/Icm Type IV Secretion System Substrate
Authors: Graham Joseph G. , Winchell Caylin G. , Sharma Uma M. , Voth Daniel E.
Published: January 2015

Coxiella burnetii
causes human Q fever, a zoonotic disease that presents with acute flu-like symptoms and can result in chronic life-threatening endocarditis. In human alveolar macrophages,
C. burnetii
uses a Dot/Icm type IV secretion system (T4SS) to generate a phagolysosome-like parasitophorous vacuole (PV) in which to replicate. The T4SS translocates effector proteins, or substrates, into the host cytosol, where they mediate critical cellular events, including interaction with autophagosomes, PV formation, and prevention of apoptosis. Over 100
C. burnetii
Dot/Icm substrates have been identified, but the function of most remains undefined. Here, we identified a novel Dot/Icm substrate-encoding open reading frame (CbuD1884) present in all
C. burnetii
isolates except the Nine Mile reference isolate, where the gene is disrupted by a frameshift mutation, resulting in a pseudogene. The CbuD1884 protein contains two transmembrane helices (TMHs) and a coiled-coil domain predicted to mediate protein-protein interactions. The C-terminal region of the protein contains a predicted Dot/Icm translocation signal and was secreted by the T4SS, while the N-terminal portion of the protein was not secreted. When ectopically expressed in eukaryotic cells, the TMH-containing N-terminal region of the CbuD1884 protein trafficked to the endoplasmic reticulum (ER), with the C terminus dispersed nonspecifically in the host cytoplasm. This new Dot/Icm substrate is now termed ElpA (
E
R-
l
ocalizing
p
rotein
A
). Full-length ElpA triggered substantial disruption of ER structure and host cell secretory transport. These results suggest that ElpA is a pathotype-specific T4SS effector that influences ER function during
C. burnetii
infection.
Type IV Pilus Glycosylation Mediates Resistance of Pseudomonas aeruginosa to Opsonic Activities of the Pulmonary Surfactant Protein A
Authors: Tan Rommel M. , Kuang Zhizhou , Hao Yonghua , Lee Francis , Lee Timothy , Lee Ryan J. , Lau Gee W.
Published: January 2015

Pseudomonas aeruginosa
is a major bacterial pathogen commonly associated with chronic lung infections in cystic fibrosis (CF). Previously, we have demonstrated that the type IV pilus (Tfp) of
P. aeruginosa
mediates resistance to antibacterial effects of pulmonary surfactant protein A (SP-A). Interestingly,
P. aeruginosa
strains with group I pilins are
O
-glycosylated through the TfpO glycosyltransferase with a single subunit of O-antigen (O-ag). Importantly, TfpO-mediated
O
-glycosylation is important for virulence in mouse lungs, exemplified by more frequent lung infection in CF with TfpO-expressing
P. aeruginosa
strains. However, the mechanism underlying the importance of Tfp glycosylation in
P. aeruginosa
pathogenesis is not fully understood. Here, we demonstrated one mechanism of increased fitness mediated by
O
-glycosylation of group 1 pilins on Tfp in the
P. aeruginosa
clinical isolate 1244. Using an acute pneumonia model in SP-A
+/+
versus SP-A
−/−
mice, the
O
-glycosylation-deficient Δ
tfpO
mutant was found to be attenuated in lung infection. Both 1244 and Δ
tfpO
strains showed equal levels of susceptibility to SP-A-mediated membrane permeability. In contrast, the Δ
tfpO
mutant was more susceptible to opsonization by SP-A and by other pulmonary and circulating opsonins, SP-D and mannose binding lectin 2, respectively. Importantly, the increased susceptibility to phagocytosis was abrogated in the absence of opsonins. These results indicate that
O
-glycosylation of Tfp with O-ag specifically confers resistance to opsonization during host-mediated phagocytosis.
Interleukin-10 from T Cells, but Not Macrophages and Granulocytes, Is Required for Chronic Disease in Leishmania mexicana Infection
Authors: Buxbaum Laurence U.
Published: January 2015

Chronic cutaneous disease of mice caused by the protozoan parasiteLeishmania mexicanarequires interleukin-10 (IL-10) and FcγRIII (an activating IgG receptor). Macrophages readily secrete IL-10 in response to IgG-coated amastigotes, making macrophages a prime candidate as the critical source of IL-10. However, indirect evidence suggested that macrophage IL-10 is not essential for chronic disease. I now show directly that mice lacking IL-10 from macrophages and granulocytes still have chronic disease, like wild-type C57BL/6 mice. However, T cell-derived IL-10 is required for chronic disease. CD4-cre IL-10flox/floxmice lack IL-10 from T cells (both CD4+and CD8+) and heal theirL. mexicanalesions, with parasite control. I had previously shown that depletion of CD25+T cells had no effect on chronic disease, and thus, T cells other than CD25+regulatory T (Treg) cells should be the important source of IL-10. Given that conventional T cells do not express FcγRs, there is likely to be an indirect pathway by which FcγRIII on some other cell engaged by IgG1-amastigote immune complexes induces IL-10 from T cells. Further work is needed to delineate these pathways.
Role of the Carboxy Terminus of SecA in Iron Acquisition, Protein Translocation, and Virulence of the Bacterial Pathogen Acinetobacter baumannii
Authors: Fiester Steven E. , Nwugo Chika C. , Penwell William F. , Neary John M. , Beckett Amber C. , Arivett Brock A. , Schmidt Robert E. , Geiger Sarah C. , Connerly Pamela L. , Menke Sharon M. , Tomaras Andrew P. , Actis Luis A.
Published: January 2015

Acinetobacter baumannii
is a Gram-negative opportunistic nosocomial pathogen that causes pneumonia and soft tissue and systemic infections. Screening of a transposon insertion library of
A. baumannii
ATCC 19606
T
resulted in the identification of the 2010 derivative, which, although capable of growing well in iron-rich media, failed to prosper under iron chelation. Genetic, molecular, and functional assays showed that 2010's iron utilization-deficient phenotype is due to an insertion within the 3′ end of
secA
, which results in the production of a C-terminally truncated derivative of SecA. SecA plays a critical role in protein translocation through the SecYEG membrane channel. Accordingly, the
secA
mutation resulted in undetectable amounts of the ferric acinetobactin outer membrane receptor protein BauA while not affecting the production of other acinetobactin membrane protein transport components, such as BauB and BauE, or the secretion of acinetobactin by 2010 cells cultured in the presence of subinhibitory concentrations of the synthetic iron chelator 2,2′-dipyridyl. Outer membrane proteins involved in nutrient transport, adherence, and biofilm formation were also reduced in 2010. The SecA truncation also increased production of 30 different proteins, including proteins involved in adaptation/tolerance responses. Although some of these protein changes could negatively affect the pathobiology of the 2010 derivative, its virulence defect is mainly due to its inability to acquire iron via the acinetobactin-mediated system. These results together indicate that although the C terminus of the
A. baumannii
ATCC 19606
T
SecA is not essential for viability, it plays a critical role in the production and translocation of different proteins and virulence.
Cryptococcal Phospholipase B1 Is Required for Intracellular Proliferation and Control of Titan Cell Morphology during Macrophage Infection
Authors: Evans Robert J. , Li Zhongming , Hughes William S. , Djordjevic Julianne T. , Nielsen Kirsten , May Robin C.
Published: January 2015

Cryptococcus neoformans
is an opportunistic fungal pathogen and a leading cause of fungal-infection-related fatalities, especially in immunocompromised hosts. Several virulence factors are known to play a major role in the pathogenesis of cryptococcal infections, including the enzyme phospholipase B1 (Plb1). Compared to other well-studied
Cryptococcus neoformans
virulence factors such as the polysaccharide capsule and melanin production, very little is known about the contribution of Plb1 to cryptococcal virulence. Phospholipase B1 is a phospholipid-modifying enzyme that has been implicated in multiple stages of cryptococcal pathogenesis, including initiation and persistence of pulmonary infection and dissemination to the central nervous system, but the underlying reason for these phenotypes remains unknown. Here we demonstrate that a Δ
plb1
knockout strain of
C. neoformans
has a profound defect in intracellular growth within host macrophages. This defect is due to a combination of a 50% decrease in proliferation and a 2-fold increase in cryptococcal killing within the phagosome. In addition, we show for the first time that the Δ
plb1
strain undergoes a morphological change during
in vitro
and
in vivo
intracellular infection, resulting in a subpopulation of very large titan cells, which may arise as a result of the attenuated mutant's inability to cope within the macrophage.
Structural Insights into the Multispecific Recognition of Dipeptides of Deep-Sea Gram-Negative Bacterium Pseudoalteromonas sp. Strain SM9913
Authors: Li Chun-Yang , Chen Xiu-Lan , Qin Qi-Long , Wang Peng , Zhang Wei-Xin , Xie Bin-Bin , Su Hai-Nan , Zhang Xi-Ying , Zhou Bai-Cheng , Zhang Yu-Zhong
Published: January 2015

Peptide uptake is important for nutrition supply for marine bacteria. It is also an important step in marine nitrogen cycling. However, how marine bacteria absorb peptides is still not fully understood. DppA is the periplasmic dipeptide binding protein of dipeptide permease (Dpp; an important peptide transporter in bacteria) and exclusively controls the substrate specificity of Dpp. Here, the substrate binding specificity of deep-sea
Pseudoalteromonas
sp. strain SM9913 DppA (
Ps
DppA) was analyzed for 25 different dipeptides with various properties by using isothermal titration calorimetry measurements.
Ps
DppA showed binding affinities for 8 dipeptides. To explain the multispecific substrate recognition mechanism of
Ps
DppA, we solved the crystal structures of unliganded
Ps
DppA and of
Ps
DppA in complex with 4 different types of dipeptides (Ala-Phe, Met-Leu, Gly-Glu, and Val-Thr).
Ps
DppA alternates between an “open” and a “closed” form during substrate binding. Structural analyses of the 4
Ps
DppA-substrate complexes combined with mutational assays indicate that
Ps
DppA binds to different substrates through a precise mechanism: dipeptides are bound mainly by the interactions between their backbones and
Ps
DppA, in particular by anchoring their N and C termini through ion-pair interactions; hydrophobic interactions are important in binding hydrophobic dipeptides; and Lys457 is necessary for the binding of dipeptides with a C-terminal glutamic acid or glutamine. Additionally, sequence alignment suggests that the substrate recognition mechanism of
Ps
DppA may be common in Gram-negative bacteria. All together, our results provide structural insights into the multispecific substrate recognition mechanism of marine Gram-negative bacterial DppA, which provides a better understanding of the mechanisms of marine bacterial peptide uptake.

IMPORTANCE
Peptide uptake plays a significant role in nutrition supply for marine bacteria. It is also an important step in marine nitrogen cycling. However, how marine bacteria recognize and absorb peptides is still unclear. This study analyzed the substrate binding specificity of deep-sea
Pseudoalteromonas
sp. strain SM9913 DppA (
Ps
DppA; the dipeptide-binding protein of dipeptide permease) and solved the crystal structures of unliganded
Ps
DppA and
Ps
DppA in complex with 4 different types of dipeptides. The multispecific recognition mechanism of
Ps
DppA for dipeptides is explained based on structural and mutational analyses. We also find that the substrate-binding mechanism of
Ps
DppA may be common in Gram-negative bacteria. This study sheds light on marine Gram-negative bacterial peptide uptake and marine nitrogen cycling.
Osteomyelitis, discitis, epidural and psoas abscess secondary toSalmonella entericain a man with diabetes mellitus and newly diagnosed α-thalassaemia trait
Authors: Farrar Helen , Abbey Aoife , Patel Vinod , Nair Rajiv
Published: January 2015

We report the case of a 65-year-old man with type 2 diabetes mellitus and α-thalassaemia trait. Investigations for relapsing and remitting fever found vertebral osteomyelitis, discitis and epidural and psoas abscess secondary toSalmonella enterica.
Body composition and bone health in long-term survivors of acute lymphoblastic leukaemia in childhood and adolescence: the protocol for a cross-sectional cohort study
Authors: Barr Ronald , Nayiager Trishana , Gordon Christopher , Marriott Christopher , Athale Uma
Published: January 2015

Introduction

Success in the treatment of young people with cancer, as measured conventionally by survival rates, is mitigated by late effects of therapy that impose a burden of morbidity and limit life expectancy. Among these adverse sequelae are altered body composition, especially obesity, and compromised bone health in the form of osteoporosis and increased fragility. These outcomes are potentially reversible and even preventable. This study will examine measures of body composition and bone health in long-term survivors of acute lymphoblastic leukaemia (ALL) in childhood and adolescence. These measures will be complemented by measures of physical activity and health-related quality of life (HRQL).

Methods and analysis

Survivors of ALL who are at least 10 years from diagnosis, following treatment on uniform protocols, will undergo measurements of body mass index; triceps skin fold thickness and mid-upper arm circumference; fat mass, lean body mass, skeletal muscle mass and bone mineral density by dual energy X-ray absorptiometry; trabecular and cortical bone indices and muscle density by peripheral quantitative CT; physical activity by the Habitual Activity Estimation Scale; and HRQL by Health Utilities Index instruments. Descriptive measures will be used for continuous variables and number (percent) for categorical variables. Associations between variables will be assessed using Fisher's exact t test and the χ2test; correlations will be tested by the Pearson correlation coefficient.

Ethics and dissemination

The study is approved by the institutional research ethics board and is supported by a competitive funding award. Dissemination of the results will occur by presentations to scientific meetings and publications in peer-reviewed journals, and by posting summaries of the results on websites accessed by adolescent and young adult survivors of cancer.
Comparing risk behaviours of human papillomavirus-vaccinated and non-vaccinated women
Authors: Sadler Laura , Roberts Stephen A , Hampal Gail , McManus Dona , Mandal Debashis , Brabin Loretta
Published: January 2015

Background

Since September 2008, a national vaccine programme in the UK has offered routine human papillomavirus (HPV) vaccination to young women aged 12–13 years. A catch-up programme also offered HPV vaccination to women born after 1 September 1990.

Aim

To compare indicators of risk and preventive behaviours among young women attending genitourinary medicine (GUM) clinics who had, and had not, received at least one dose of HPV vaccine.

Methods

Clinical histories and HPV vaccination status were obtained from 363 participants eligible for HPV vaccination (Cervarix®) in the UK vaccination programme (born after 1 September 1990) attending GUM clinics in the North West of England. Using logistic regression, markers of sexual and non-sexual risk behaviours were compared between vaccinated and unvaccinated women.

Results

At least one dose of HPV vaccine had been received by 63.6% (n=231) of participants. Unvaccinated women demonstrated higher levels of risky behaviour than those who had undergone HPV vaccination. Unvaccinated women were significantly more likely to have had three or more partners in the last 6 months, attended the clinic with symptoms, not used a condom at first sexual intercourse, had anal intercourse with their last sexual contact, to have tested positive forChlamydia trachomatisdiagnosis at the clinic visit and to be a current smoker.

Conclusions

In the UK, where vaccine coverage is high, failure to initiate HPV vaccination amongst GUM attendees is a marker of high-risk behaviours. As a result, HPV vaccination status should be ascertained as part of an individual's clinical history by sexual health services to ensure advice and counselling is provided to those at greatest risk of HPV-associated disease.
Flow diverter device for the treatment of small middle cerebral artery aneurysms
Authors: Briganti Francesco , Delehaye Luigi , Leone Giuseppe , Sicignano Carmine , Buono Giuseppe , Marseglia Mariano , Caranci Ferdinando , Tortora Fabio , Maiuri Francesco
Published: January 2015

Purpose

Experience with the endovascular treatment of middle cerebral artery (MCA) aneurysms by flow diverter devices (FDD) is still limited. This study examines the results and complications of FDD for small aneurysms at this location.

Methods

From February 2010 to December 2013, 14 patients (10 women; mean age 59 years) with 15 small MCA aneurysms were treated with FDD. All procedures were performed with the Pipeline embolization device (PED).

Results

Complete occlusion was obtained in 12/15 aneurysms (80%) and partial occlusion in 3 (20%). Among 13 aneurysms with a side branch, this was patent at the angiographic control in 4 cases, showed decreased filling in 6, and was occluded in 3 (with neurological deficits in 2). All PEDs were patent at follow-up. Post-procedural ischemic complications occurred in 4 (27%) procedures with permanent neurological deficit (modified Rankin score 2) in 3 (21%). No early or delayed aneurysm rupture, no subarachnoid or intraparenchymal hemorrhage and no deaths occurred.

Conclusions

Endovascular treatment with FDD is a relatively safe treatment for small MCA aneurysms resulting in a high occlusion rate. The findings of this study suggest that complete occlusion after endovascular treatment with FDD can be delayed (>6 months). Ischemic complications may occur as early or delayed, particularly at clopidogrel interruption.