bluuebunny/crossref_metadata_2025 huggingface dataset:
The formation of Ca‐, Fe‐rich silicates in reduced and oxidized CV chondrites: The roles of impact‐modified porosity and permeability, and heterogeneous distribution of water ices
Authors: MacPherson Glenn J. , Krot Alexander N.
Published: June 2014

CV (Vigarano type) carbonaceous chondrites, comprising Allende‐like (CVoxA) and Bali‐like (CVoxB) oxidized and reduced (CVred) subgroups, experienced differing degrees of fluid‐assisted thermal and shock metamorphism. The abundance and speciation of secondary minerals produced during asteroidal alteration differ among the subgroups: (1) ferroan olivine and diopside–hedenbergite solid solution pyroxenes are common in all CVs; (2) nepheline and sodalite are abundant in CVoxA, rare in CVred, and absent in CVoxB; (3) phyllosilicates and nearly pure fayalite are common in CVoxB, rare in CVred, and virtually absent in CVoxA; (4) andradite, magnetite, and Fe‐Ni‐sulfides are common in oxidized CVs, but rare in reduced CVs; the latter contain kirschsteinite instead. Thus, a previously unrecognized correlation exists between meteorite bulk permeabilities and porosities with the speciation of the Ca‐, Fe‐rich silicates (pyroxenes, andradite, kirschsteinite) among the CVox and CVred meteorites. The extent of secondary mineralization was controlled by the distribution of water ices, permeability, and porosity, which in turn were controlled by impacts on the asteroidal parent body. More intense shock metamorphism in the region where the reduced CVs originated decreased their porosity and permeability while simultaneously expelling intergranular ices and fluids. The mineralogy, petrography, and bulk chemical compositions of both the reduced and oxidized CV chondrites indicate that mobile elements were redistributed between Ca,Al‐rich inclusions, dark inclusions, chondrules, and matrices only locally; there is no evidence for large‐scale (>several cm) fluid transport. Published 53Mn‐53Cr ages of secondary fayalite in CV, CO, and unequilibrated ordinary chondrites, and carbonates in CI, CM, and CR chondrites are consistent with aqueous alteration initiated by heating of water ice‐bearing asteroids by decay of 26Al, not shock metamorphism.
Characterization of weathering and heterogeneous mineral phase distribution in brachinite Northwest Africa 4872
Authors: Hyde Brendt C. , Day James M. D. , Tait Kimberly T. , Ash Richard D. , Holdsworth David W. , Moser Desmond E.
Published: June 2014

Terrestrial weathering of hot desert achondrite meteorite finds and heterogeneous phase distributions in meteorites can complicate interpretation of petrological and geochemical information regarding parent‐body processes. For example, understanding the effects of weathering is important for establishing chalcophile and siderophile element distributions within sulfide and metal phases in meteorites. Heterogeneous mineral phase distribution in relatively coarsely grained meteorites can also lead to uncertainties relating to compositional representativeness. Here, we investigate the weathering and high‐density (e.g., sulfide, spinel, Fe‐oxide) phase distribution in sections of ultramafic achondrite meteorite Northwest Africa (NWA) 4872. NWA 4872 is an olivine‐rich brachinite (Fo63.6 ± 0.5) with subsidiary pyroxene (Fs9.7 ± 0.1Wo46.3 ± 0.2), Cr‐spinel (Cr# = 70.3 ± 1.1), and weathered sulfide and metal. Raman mapping confirms that weathering has redistributed sulfur from primary troilite, resulting in the formation of Fe‐oxide (‐hydroxide) and marcasite (FeS2). From Raman mapping, NWA 4872 is composed of olivine (89%), Ca‐rich pyroxene (0.4%), and Cr‐spinel (1.1%), with approximately 7% oxidized metal and sulfide and 2.3% marcasite‐dominated sulfide. Microcomputed tomography (micro‐CT) observations reveal high‐density regions, demonstrating heterogeneities in mineral distribution. Precision cutting of the largest high‐density region revealed a single 2 mm Cr‐spinel grain. Despite the weathering in NWA 4872, rare earth element (REE) abundances of pyroxene determined by laser‐ablation inductively coupled plasma mass spectrometry (LA‐ICP‐MS) indicate negligible modification of these elements in this mineral phase. The REE abundances of mineral grains in NWA 4872 are consistent with formation of the meteorite as the residuum of the partial melting process that occurred on its parent body. LA‐ICP‐MS analyses of sulfide and alteration products demonstrate the mobility of Re and/or Os; however, highly siderophile element (HSE) abundance patterns remain faithful recorders of processes acting on the brachinite parent body(ies). Detailed study of weathering and phase distribution offers a powerful tool for assessing the effects of low‐temperature alteration and for identifying robust evidence for parent‐body processes.
Plastic deformation of olivine‐rich diogenites and implications for mantle processes on the diogenite parent body
Authors: Tkalcec Beverley J. , Brenker Frank E.
Published: June 2014

Numerous petrologic and geochemical studies so far on the howardite, eucrite, and diogenite (HED) meteorites have produced various crystallization scenarios for their parent body, believed to be the differentiated asteroid 4 Vesta. Structural analyses of diogenites can reveal important insights into postcrystallization deformation on the parent body. Recently published results (Tkalcec et al. ) of structural analysis on the olivine‐rich diogenite NWA 5480 reveal that it underwent solid‐state plastic deformation, although not at the base of a magma chamber. Dynamic mantle downwelling has been proposed as a plausible deformation mechanism (Tkalcec et al. ). The purpose of this study is to investigate whether the plastic deformation found in NWA 5480 is an isolated case. We expand the structural analysis on NWA 5480 and extend it to NWA 5784 and MIL 07001,6, two other samples of rare olivine‐rich diogenites, using electron‐backscattered‐diffraction (EBSD) techniques. Our EBSD results show that the diogenites analyzed in this study underwent solid‐state plastic deformation, confirming that the observed deformation of NWA 5480 was not an isolated case on the diogenite parent body. The lattice‐preferred orientations (LPOs) of olivine in NWA 5784 and NWA 5480 are clearly distinct from that typical for cumulate rocks at the base of magma chambers, indicating a different stress environment and a different deformation mechanism. The LPO of olivine in MIL 07001 is less conclusive. The structural results of this study suggest that plastic deformation occurred on the diogenite parent body at high temperatures (1273 < T ≤ 1573 K) in the solid state, i.e., after crystallization of the diogenites themselves, in a dynamic environment with active stress fields.
Impact of 6% hydroxyethyl starch 130/0.42 and 4% gelatin on renal function in a pediatric animal model
Authors: Witt Lars , Glage Silke , Schulz Katharina , Lichtinghagen Ralf , Simann Arne , Pape Lars , Sümpelmann Robert
Published: June 2014

Objectives

Artificial colloids, frequently used to prevent hemorrhagic shock in children, may induce serious renal side effects in critically ill adult patients. The impact of perioperative colloid infusion on the renal function in adults and children remains unclear.

Aim

To determine the impact of single doses of artificial colloids on renal function tests, we conducted an experimental animal study. We hypothesized that neither the infusion of moderate doses of 6% hydroxyethyl starch (HES) nor of 4% gelatin (GEL) would have a serious impact on the renal function of healthy piglets.

Methods

Fifteen sedated piglets were randomly assigned to receive an infusion of either 20 ml·kg−1 HES or GEL or a balanced electrolyte solution (BS, control group) over 30 min. Before and 7 days after infusion, serum and urine renal function tests were recorded and renal biopsies were taken.

Results

Serum and urine renal function tests (e.g., creatinine, urea, cystatin C, and neutrophil gelatinase‐associated lipocalin) were within normal ranges, and a microscopic examination of the renal tissue in all groups revealed no major alterations such as tubular necrosis, interstitial bleeding, interstitial inflammation, or vacuoles.

Conclusions

In this pediatric animal model, the infusion of moderate doses of artificial colloids was not found to have any relevant impact on renal function. Further clinical investigations are necessary to provide a conclusive assessment of the risk for renal impairment after HES and GEL administration during major pediatric surgery.
Multiepisodic evaporite sedimentation as an indicator of palaeogeographical evolution in foreland basins (South‐eastern Pyrenean basin, Early–Middle Eocene)
Authors: Carrillo Emili , Rosell Laura , Ortí Federico
Published: June 2014

Extensive deposition of marine evaporites occurred during the Early–Middle Eocene in the South‐eastern Pyrenean basin (north‐east Spain). This study integrates stratigraphic and geochemical analyses of subsurface data (oil wells, seismic profiles and gravity data) together with field surveys to characterize this sedimentation in the foredeep and adjacent platform. Four major evaporite units were identified. The oldest was the Serrat Evaporites unit, with a platform‐slope‐basin configuration. Thick salina and sabkha sulphates accumulated on the platform, whereas resedimented and gravity‐derived sulphates were deposited on the slope, and salt and sulphates were deposited in the deep basin. In the subsequent unit (Vallfogona evaporites), thin sulphates formed on the platform, whereas very thick siliciclastic turbidites accumulated in the foredeep. However, some clastic gypsum coming from the platform (gypsarenites and gypsum olistoliths) was intercalated in these turbidites. The following unit, the Beuda Gypsum Formation developed in a sulphate platform‐basin configuration, where the topography of the depositional surface had become smooth. The youngest unit, the Besalú Gypsum, formed in a shallow setting. This small unit provides the last evidence of marine influence in a residual basin. Sulphur and oxygen isotope compositions are consistent with a marine origin for all evaporites. However, δ34S and δ18O values also suggest that, except for the oldest unit (Serrat Evaporites), there was some sulphate recycling from the older into the younger units. The South‐eastern Pyrenean basin constitutes a fine example of a foreland basin that underwent multiepisodic evaporitic sedimentation. In the basin, depositional factors evolved with time under a structural control. Decreasing complexity is observed in the lithofacies, as well as in the depositional models, together with a diminishing thickness of the evaporite units.
In Sickness and in Health: The Role of TRAPP and Associated Proteins in Disease
Authors: Brunet Stephanie , Sacher Michael
Published: June 2014

Transport protein particle (TRAPP) represents a series of related protein complexes that function in specific stages of inter‐organelle traffic. They share a core of subunits that can activate the GTPase Rab1 through a guanine nucleotide exchange factor (GEF) activity and are distinguished by ‘accessory’ subunits giving each complex its distinct function. The subunits are ubiquitously expressed and, thus, mutations in TRAPP subunits would be expected to be embryonic lethal. However, since its discovery, a number of subunits have been found to be mutated in several diverse human disorders suggesting that some of these subunits may have cell‐ or tissue‐specific functions. Here we review the current state of knowledge with respect to TRAPP subunit mutations in human disease. We suggest ideas to explain their tissue‐specific phenotypes and present avenues for future investigation.
The value of area‐based analyses of donation patterns for recruitment strategies
Authors: James Adelbert B. , Josephson Cassandra D. , Shaz Beth H. , Schreiber George B. , Hillyer Christopher D. , Roback John D.
Published: June 2014

Background

Lack of ready access to a donation site may be a potential barrier to or influence the frequency of blood donations. In this study, we applied geographic analysis to blood donor behavior and use of different donation sites.

Study Design and Methods

The study population consisted of blood donors who gave whole blood in Georgia between 2004 and 2008. Zip code, city, and county of donor's residence were matched with the addresses of their donation sites. Donors were dichotomized as either nonmetro Atlanta or metro Atlanta residents. Six donation site categories were defined: donation within the same or a different zip code, within the same or a different city, and within the same or a different county. Logistic regression was used to compare donations by zip code, city, and county.

Results

The study population consisted of 402,692 blood donors who donated 1,147,442 whole blood units between 2004 and 2008, more than half of whom (56.4%) resided in the metro Atlanta area. The majority of donors were white (75.0%) and female (55.7%). In nonmetro Atlanta, repeat donors were more likely to have donated at fixed sites (p < 0.001). In metro Atlanta, repeat donors were more likely to have donated at a mobile site than at a fixed site (p < 0.001).

Conclusion

Geographic and demographic differences in blood donation patterns exist. The locations of donor residences and blood donation sites influence donor behaviors. Understanding the geographic influence on donation patterns provides an important tool for optimizing donor recruitment strategies.
A safe therapeutic apheresis protocol in paediatric patients weighing 11 to 25 kg
Authors: Maitta R. W. , Vasovic L. V. , Mohandas K. , Music‐Aplenc L. , Bonzon‐Adelson A. , Uehlinger J.
Published: June 2014

Background and Objectives

Erythrocytapheresis and leukapheresis (LPE) of small children are logistically complex and many centres are reluctant to perform these procedures. In children, both sickle cell and leukaemic emergencies demand prompt action to prevent additional morbidity but detailed protocols for small children are lacking, and often are performed using guidelines shown to work in larger patients. We report a 3‐year experience with children weighing 11–25 kg at a large academic medical centre.

Materials and Methods

All patients were treated with the COBE® Spectra apheresis system; circuit was primed with blood not adjusted for haematocrit and anticoagulant citrate dextrose A was used as anticoagulation. Procedures were performed in the paediatric intensive care unit by apheresis nursing staff.

Results

Twenty‐five apheresis procedures in 19 patients were performed; 17 of 19 patients presented with sickle cell‐related acute complications and two (2/19) with newly diagnosed acute leukaemia and hyperleucocytosis. None of the patients required medications during the procedures. Vital signs and clinical condition remained stable and did not worsen during or postapheresis. One patient had a delayed haemolytic transfusion reaction 1 week posterythrocytapheresis as he developed alloantibodies as a result of the procedure. All sickle cell patients achieved a target haematocrit of 21–30% and Haemoglobin A of ≥68%. Both leukaemia patients who underwent LPE had no further signs of leukostasis and achieved marked reductions in leucocyte counts.

Conclusions

Apheresis of children weighing 11–25 kg can be safely performed without increased morbidity. We outline a protocol that can be used to perform apheresis with minimal complications.
Going With the Flow: Enhancing Stochastic Switching Rates in Multigyre Systems
Authors: Heckman Christoffer R. , Ani Hsieh M. , Schwartz Ira B.
Published: June 2014

A control strategy is employed that modifies the stochastic escape times from one basin of attraction to another in a model of a double-gyre flow. The system studied captures the behavior of a large class of fluid flows that circulate and have multiple almost invariant sets. In the presence of noise, a particle in one gyre may randomly switch to an adjacent gyre due to a rare large fluctuation. We show that large fluctuation theory may be applied for controlling autonomous agents in a stochastic environment, in fact leveraging the stochasticity to the advantage of switching between regions of interest and concluding that patterns may be broken or held over time as the result of noise. We demonstrate that a controller can effectively manipulate the probability of a large fluctuation; this demonstrates the potential of optimal control strategies that work in combination with the endemic stochastic environment. To demonstrate this, stochastic simulations and numerical continuation are employed to tie together experimental findings with predictions.
Concentration-Dependent Chemical Expansion in Lithium-Ion Battery Cathode Particles
Authors: Malavé Veruska , Berger J. R. , Martin P. A.
Published: June 2014

In this work, the effect of the concentration-dependent chemical-expansion coefficient, β, on the chemo-elastic field in lithium-ion cathode particles is examined. To accomplish this, an isotropic linear-elastic model is developed for a single idealistic particle subjected to potentiostatic-discharge and charge conditions. It is shown that β can be a key parameter in demarcating the chemo-stress–strain state of the cathode material undergoing nonlinear volumetric strains. As an example, such strains develop in the hexagonal-to-monoclinic-phase region of LixCoO2 (0.37 ≤ x ≤ 0.55) and, subsequently, the corresponding β is a linear function of concentration. Previous studies have assumed a constant value for β. Findings suggest that the composition-generated chemo-elastic field that is based on a linear-β dramatically affects both the interdiffusion and the mechanical behavior of the LixCoO2 cathode particle. Because the chemo-elastic phenomena emanate in a reciprocal fashion, the resulting linear β-based hydrostatic-stress gradients significantly aid the diffusion of lithium. Thus, diffusion is accelerated in either electrochemical process that the cathode material undergoes.
An Area-Average Correlation for Oil-Jet Cooling of Automotive Pistons
Authors: Easter J. , Jarrett C. , Pespisa C. , Liu Y. C. , Alkidas A. C. , Guessous L. , Sangeorzan B. P.
Published: June 2014

Laboratory tests were performed to measure cooling rates of an impinging oil-jet on the underside of an automotive piston as functions of oil nozzle-to-piston surface spacing, oil pressure, oil temperature, and piston temperature. Based on these results, area-average Nusselt number correlations were derived for a Reynolds number range of 100–4500, a Prandtl number range of 90–750, and a nozzle-to-piston surface spacing range over 73–160 mm, which are within the ranges expected for oil-jet cooling of automotive pistons.
Periodic Impulsive Fault Feature Extraction of Rotating Machinery Using Dual-Tree Rational Dilation Complex Wavelet Transform
Authors: Zhang ChunLin , Li Bing , Chen BinQiang , Cao HongRui , Zi YanYang , He ZhengJia
Published: June 2014

Fault diagnosis of rotating machinery is very important to guarantee the safety of manufacturing. Periodic impulsive fault features commonly appear in vibration measurements when local defects occur in the key components like rolling bearings and gearboxes. To extract the periodic impulses embedded in strong background noise, wavelet transform (WT) is suitable and has been widely used in analyzing these nonstationary signals. However, a few limitations like shift-variance and fixed frequency partition manner of the dyadic WT would weaken its effectiveness in engineering application. Compared with dyadic WT, the dual-tree rational dilation complex wavelet transform (DT-RADWT) enjoys attractive properties of better shift-invariance, flexible time-frequency (TF) partition manner, and tunable oscillatory nature of the bases. In this article, an impulsive fault features extraction technique based on the DT-RADWT is proposed. In the routine of the proposed method, the optimal DT-RADWT basis is constructed dynamically and adaptively based on the input signal. Additionally, the sensitive wavelet subband is chosen using kurtosis maximization principle to reveal the potential weak fault features. The proposed method is applied on engineering applications for defects detection of the rolling bearing and gearbox. The results show that the proposed method performs better in extracting the fault features than dyadic WT and empirical mode decomposition (EMD), especially when the incipient fault features are embedded in the frequency transition bands of the dyadic WT.
Design of a Clutch–Spring Knee Exoskeleton for Running
Authors: Elliott Grant , Marecki Andrew , Herr Hugh
Published: June 2014

Because the leg is known to exhibit springlike behavior during the stance phase of running, several exoskeletons have attempted to place external springs in parallel with some or all of the leg during stance, but these designs have failed to permit natural kinematics during swing. To this end, a parallel-elastic exoskeleton is presented that introduces a clutch to disengage the parallel leg-spring and thereby not constrain swing-phase movements of the biological leg. A custom interference clutch with integrated planetary gear transmission, made necessary by the requirement for high holding torque but low mass, is presented and shown to withstand up to 190 N·m at 1.8 deg resolution with a mass of only 710 g. A suitable control strategy for locking the clutch at peak knee extension is also presented, where only an onboard rate gyroscope and exoskeletal joint encoder are employed as sensory inputs. Exoskeletal electromechanics, sensing, and control are shown to achieve design critieria necessary to emulate biological knee stiffness behaviors in running.
Interplay Between the Oxidoreductase PDIA6 and microRNA-322 Controls the Response to Disrupted Endoplasmic Reticulum Calcium Homeostasis
Authors: Groenendyk Jody , Peng Zhenling , Dudek Elzbieta , Fan Xiao , Mizianty Marcin J. , Dufey Estefanie , Urra Hery , Sepulveda Denisse , Rojas-Rivera Diego , Lim Yunki , Kim Do Han , Baretta Kayla , Srikanth Sonal , Gwack Yousang , Ahnn Joohong , Kaufman Randal J. , Lee Sun-Kyung , Hetz Claudio , Kurgan Lukasz , Michalak Marek
Published: June 2014

Depletion of Ca
2+
in the endoplasmic reticulum favors activation of a stress response involving IRE1α.
T Cell Receptor–Dependent Activation of mTOR Signaling in T Cells Is Mediated by Carma1 and MALT1, But Not Bcl10
Authors: Hamilton Kristia S. , Phong Binh , Corey Catherine , Cheng Jing , Gorentla Balachandra , Zhong Xiaoping , Shiva Sruti , Kane Lawrence P.
Published: June 2014

By shifting the constituents of signalosomes, T cells may stimulate distinct pathways in response to antigens.
How Cells Haul Down Their “Eat Me” Flags
Authors: Hurtley Stella M.
Published: June 2014

An enzyme maintains the asymmetrical distribution of a surface phospholipid during programmed cell death.
Allowing Calcium to Leak Across a Membrane
Authors: Vinson Valda K.
Published: June 2014

pH sensing regulates calcium flow through a bacterial membrane channel that is a homolog of a human antiapoptotic protein.
Emergence of VIM-2 and IMP-15 Carbapenemases and Inactivation of
oprD
Gene in Carbapenem-Resistant Pseudomonas aeruginosa Clinical Isolates from Lebanon
Authors: Al Bayssari Charbel , Diene Seydina M. , Loucif Lotfi , Gupta Sushim Kumar , Dabboussi Fouad , Mallat Hassan , Hamze Monzer , Rolain Jean-Marc
Published: June 2014

We report here the emergence of VIM-2 and IMP-15 carbapenemases in a series of clinical isolates of carbapenem-resistant
Pseudomonas aeruginosa
in Lebanon. We also describe the disruption of the
oprD
gene by either mutations or insertion sequence (IS) elements ISPa
1328
and ISPre
2
isoform. Our study reemphasizes a rapid dissemination of the VIM-2 carbapenemase-encoding gene in clinical isolates of
P. aeruginosa
in the Mediterranean basin.
Electrospun Solid Dispersions of Maraviroc for Rapid Intravaginal Preexposure Prophylaxis of HIV
Authors: Ball Cameron , Woodrow Kim A.
Published: June 2014

The development of topical anti-human immunodeficiency virus (HIV) microbicides may provide women with strategies to protect themselves against sexual HIV transmission. Pericoital drug delivery systems intended for use immediately before sex, such as microbicide gels, must deliver high drug doses for maximal effectiveness. The goal of achieving a high antiretroviral dose is complicated by the need to simultaneously retain the dose and quickly release drug compounds into the tissue. For drugs with limited solubility in vaginal gels, increasing the gel volume to increase the dose can result in leakage. While solid dosage forms like films and tablets increase retention, they often require more than 15 min to fully dissolve, potentially increasing the risk of inducing epithelial abrasions during sex. Here, we demonstrate that water-soluble electrospun fibers, with their high surface area-to-volume ratio and ability to disperse antiretrovirals, can serve as an alternative solid dosage form for microbicides requiring both high drug loading and rapid hydration. We formulated maraviroc at up to 28 wt% into electrospun solid dispersions made from either polyvinylpyrrolidone or poly(ethylene oxide) nanofibers or microfibers and investigated the role of drug loading, distribution, and crystallinity in determining drug release rates into aqueous media. We show here that water-soluble electrospun materials can rapidly release maraviroc upon contact with moisture and that drug delivery is faster (less than 6 min under sink conditions) when maraviroc is electrospun in polyvinylpyrrolidone fibers containing an excipient wetting agent. These materials offer an alternative dosage form to current pericoital microbicides.
Comparative Genomics of an IncA/C Multidrug Resistance Plasmid from Escherichia coli and Klebsiella Isolates from Intensive Care Unit Patients and the Utility of Whole-Genome Sequencing in Health Care Settings
Authors: Hazen Tracy H. , Zhao LiCheng , Boutin Mallory A. , Stancil Angela , Robinson Gwen , Harris Anthony D. , Rasko David A. , Johnson J. Kristie
Published: June 2014

The IncA/C plasmids have been implicated for their role in the dissemination of β-lactamases, including gene variants that confer resistance to expanded-spectrum cephalosporins, which are often the treatment of last resort against multidrug-resistant, hospital-associated pathogens. A
bla
FOX-5
gene was detected in 14
Escherichia coli
and 16
Klebsiella
isolates that were cultured from perianal swabs of patients admitted to an intensive care unit (ICU) of the University of Maryland Medical Center (UMMC) in Baltimore, MD, over a span of 3 years. Four of the FOX-encoding isolates were obtained from subsequent samples of patients that were initially negative for an AmpC β-lactamase upon admission to the ICU, suggesting that the AmpC β-lactamase-encoding plasmid was acquired while the patient was in the ICU. The genomes of five
E. coli
isolates and six
Klebsiella
isolates containing
bla
FOX-5
were selected for sequencing based on their plasmid profiles. An ∼167-kb IncA/C plasmid encoding the FOX-5 β-lactamase, a CARB-2 β-lactamase, additional antimicrobial resistance genes, and heavy metal resistance genes was identified. Another FOX-5-encoding IncA/C plasmid that was nearly identical except for a variable region associated with the resistance genes was also identified. To our knowledge, these plasmids represent the first FOX-5-encoding plasmids sequenced. We used comparative genomics to describe the genetic diversity of a plasmid encoding a FOX-5 β-lactamase relative to the whole-genome diversity of 11
E. coli
and
Klebsiella
isolates that carry this plasmid. Our findings demonstrate the utility of whole-genome sequencing for tracking of plasmid and antibiotic resistance gene distribution in health care settings.
Highly Sulfated K5 Escherichia coli Polysaccharide Derivatives Inhibit Respiratory Syncytial Virus Infectivity in Cell Lines and Human Tracheal-Bronchial Histocultures
Authors: Cagno Valeria , Donalisio Manuela , Civra Andrea , Volante Marco , Veccelli Elena , Oreste Pasqua , Rusnati Marco , Lembo David
Published: June 2014

Respiratory syncytial virus (RSV) exploits cell surface heparan sulfate proteoglycans (HSPGs) as attachment receptors. The interaction between RSV and HSPGs thus presents an attractive target for the development of novel inhibitors of RSV infection. In this study, selective chemical modification of the
Escherichia coli
K5 capsular polysaccharide was used to generate a collection of sulfated K5 derivatives with a backbone structure that mimics the heparin/heparan sulfate biosynthetic precursor. The screening of a series of N-sulfated (K5-NS), O-sulfated (K5-OS), and N,O-sulfated (K5-N,OS) derivatives with different degrees of sulfation revealed the highly sulfated K5 derivatives K5-N,OS(H) and K5-OS(H) to be inhibitors of RSV. Their 50% inhibitory concentrations were between 1.07 nM and 3.81 nM in two different cell lines, and no evidence of cytotoxicity was observed. Inhibition of RSV infection was maintained in binding and attachment assays but not in preattachment assays. Moreover, antiviral activity was also evident when the K5 derivatives were added postinfection, both in cell-to-cell spread and viral yield reduction assays. Finally, both K5-N,OS(H) and K5-OS(H) prevented RSV infection in human-derived tracheal/bronchial epithelial cells cultured to form a pseudostratified, highly differentiated model of the epithelial tissue of the human respiratory tract. Together, these features put K5-N,OS(H) and K5-OS(H) forward as attractive candidates for further development as RSV inhibitors.
Fatty Acid Synthesis and Pyruvate Metabolism Pathways Remain Active in Dihydroartemisinin-Induced Dormant Ring Stages of Plasmodium falciparum
Authors: Chen Nanhua , LaCrue Alexis N. , Teuscher Franka , Waters Norman C. , Gatton Michelle L. , Kyle Dennis E. , Cheng Qin
Published: June 2014

Artemisinin (ART)-based combination therapy (ACT) is used as the first-line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action, there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART-induced ring-stage dormancy and recovery have been implicated as possible causes of recrudescence; however, little is known about the characteristics of dormant parasites, including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways in
P. falciparum
during dihydroartemisinin (DHA)-induced dormancy and recovery. Transcription analysis showed an immediate downregulation for 10 genes following exposure to DHA but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly of genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also maintained. Additions of inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively, following DHA treatment. Our results demonstrate that most metabolic pathways are downregulated in DHA-induced dormant parasites. In contrast, fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment.
His224 Alters the R2 Drug Binding Site and Phe218 Influences the Catalytic Efficiency of the Metallo-β-Lactamase VIM-7
Authors: Leiros Hanna-Kirsti S. , Skagseth Susann , Edvardsen Kine Susann Waade , Lorentzen Marit Sjo , Bjerga Gro Elin Kjæreng , Leiros Ingar , Samuelsen Ørjan
Published: June 2014

Metallo-β-lactamases (MBLs) are the causative mechanism for resistance to β-lactams, including carbapenems, in many Gram-negative pathogenic bacteria. One important family of MBLs is the Verona integron-encoded MBLs (VIM). In this study, the importance of residues Asp120, Phe218, and His224 in the most divergent VIM variant, VIM-7, was investigated to better understand the roles of these residues in VIM enzymes through mutations, enzyme kinetics, crystal structures, thermostability, and docking experiments. The tVIM-7-D120A mutant with a tobacco etch virus (TEV) cleavage site was enzymatically inactive, and its structure showed the presence of only the Zn1 ion. The mutant was less thermostable, with a melting temperature (

T
m

) of 48.5°C, compared to 55.3°C for the wild-type tVIM-7. In the F218Y mutant, a hydrogen bonding cluster was established involving residues Asn70, Asp84, and Arg121. The tVIM-7-F218Y mutant had enhanced activity compared to wild-type tVIM-7, and a slightly higher

T
m

(57.1°C) was observed, most likely due to the hydrogen bonding cluster. Furthermore, the introduction of two additional hydrogen bonds adjacent to the active site in the tVIM-7-H224Y mutant gave a higher thermostability (

T
m

, 62.9°C) and increased enzymatic activity compared to those of the wild-type tVIM-7. Docking of ceftazidime in to the active site of tVIM-7, tVIM-7-H224Y, and VIM-7-F218Y revealed that the side-chain conformations of residue 224 and Arg228 in the L3 loop and Tyr67 in the L1 loop all influence possible substrate binding conformations. In conclusion, the residue composition of the L3 loop, as shown with the single H224Y mutation, is important for activity particularly toward the positively charged cephalosporins like cefepime and ceftazidime.
Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis
Authors: Liu Ping , Mould Diane R.
Published: June 2014

To assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC
0–12
] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).
SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors
Authors: Ballana Ester , Badia Roger , Terradas Gerard , Torres-Torronteras Javier , Ruiz Alba , Pauls Eduardo , Riveira-Muñoz Eva , Clotet Bonaventura , Martí Ramon , Esté José A.
Published: June 2014

Sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase recently recognized as an antiviral factor that acts by depleting dNTP availability for viral reverse transcriptase (RT). SAMHD1 restriction is counteracted by the human immunodeficiency virus type 2 (HIV-2) accessory protein Vpx, which targets SAMHD1 for proteosomal degradation, resulting in an increased availability of dNTPs and consequently enhanced viral replication. Nucleoside reverse transcriptase inhibitors (NRTI), one of the most common agents used in antiretroviral therapy, compete with intracellular dNTPs as the substrate for viral RT. Consequently, SAMHD1 activity may be influencing NRTI efficacy in inhibiting viral replication. Here, a panel of different RT inhibitors was analyzed for their different antiviral efficacy depending on SAMHD1. Antiviral potency was measured for all the inhibitors in transformed cell lines and primary monocyte-derived macrophages and CD4
+
T cells infected with HIV-1 with or without Vpx. No changes in sensitivity to non-NRTI or the integrase inhibitor raltegravir were observed, but for NRTI, sensitivity significantly changed only in the case of the thymidine analogs (AZT and d4T). The addition of exogenous thymidine mimicked the change in viral sensitivity observed after Vpx-mediated SAMHD1 degradation, pointing toward a differential effect of SAMHD1 activity on thymidine. Accordingly, sensitivity to AZT was also reduced in CD4
+
T cells infected with HIV-2 compared to infection with the HIV-2ΔVpx strain. In conclusion, reduction of SAMHD1 levels significantly decreases HIV sensitivity to thymidine but not other nucleotide RT analog inhibitors in both macrophages and lymphocytes.
Structure-Activity Relationship Study of the Plant-Derived Decapeptide OSIP108 Inhibiting Candida albicans Biofilm Formation
Authors: Delattin Nicolas , De Brucker Katrijn , Craik David J. , Cheneval Olivier , De Coninck Barbara , Cammue Bruno P. A. , Thevissen Karin
Published: June 2014

We performed a structure-activity relationship study of the antibiofilm plant-derived decapeptide OSIP108. Introduction of positively charged amino acids R, H, and K resulted in an up-to-5-fold-increased antibiofilm activity against
Candida albicans
compared to native OSIP108, whereas replacement of R9 resulted in complete abolishment of its antibiofilm activity. By combining the most promising amino acid substitutions, we found that the double-substituted OSIP108 analogue Q6R/G7K had an 8-fold-increased antibiofilm activity.
Substrate Binding Protein SBP2 of a Putative ABC Transporter as a Novel Vaccine Antigen of Moraxella catarrhalis
Authors: Otsuka Taketo , Kirkham Charmaine , Johnson Antoinette , Jones Megan M. , Murphy Timothy F.
Published: June 2014

Moraxella catarrhalis
is a common respiratory tract pathogen that causes otitis media in children and infections in adults with chronic obstructive pulmonary disease. Since the introduction of the pneumococcal conjugate vaccines with/without protein D of nontypeable
Haemophilus influenzae
,
M. catarrhalis
has become a high-priority pathogen in otitis media. For the development of antibacterial vaccines and therapies, substrate binding proteins of ATP-binding cassette transporters are important targets. In this study, we identified and characterized a substrate binding protein, SBP2, of
M. catarrhalis
. Among 30 clinical isolates tested, the
sbp2
gene sequence was highly conserved. In 2 different analyses (whole-cell enzyme-linked immunosorbent assay and flow cytometry), polyclonal antibodies raised to recombinant SBP2 demonstrated that SBP2 expresses epitopes on the bacterial surface of the wild type but not the
sbp2
mutant. Mice immunized with recombinant SBP2 showed significantly enhanced clearance of
M. catarrhalis
from the lung compared to that in the control group at both 25-μg and 50-μg doses (
P
< 0.001). We conclude that SBP2 is a novel, attractive candidate as a vaccine antigen against
M. catarrhalis
.
Involvement of Enterococcus faecalis Small RNAs in Stress Response and Virulence
Authors: Michaux Charlotte , Hartke Axel , Martini Cecilia , Reiss Swantje , Albrecht Dirk , Budin-Verneuil Aurélie , Sanguinetti Maurizio , Engelmann Susanne , Hain Torsten , Verneuil Nicolas , Giard Jean-Christophe
Published: June 2014

Candidate small RNAs (sRNAs) have recently been identified in
Enterococcus faecalis
, a Gram-positive opportunistic pathogen, and six of these candidate sRNAs with unknown functions were selected for a functional study. Deletion mutants and complemented strains were constructed, and their virulence was tested. We were unable to obtain the
ef0869-0870
mutant, likely due to an essential role, and the
ef0820-0821
sRNA seemed not to be involved in virulence. In contrast, the mutant lacking
ef0408-0409
sRNA, homologous to the RNAII component of the toxin-antitoxin system, appeared more virulent and more able to colonize mouse organs. The three other mutants showed reduced virulence. In addition, we checked the responses of these mutant strains to several stresses encountered in the gastrointestinal tract or during the infection process. In parallel, the activities of the sRNA promoters were measured using transcriptional fusion constructions. To attempt to identify the regulons of these candidate sRNAs, proteomics profiles of the mutant strains were compared with that of the wild type. This showed that the selected sRNAs controlled the expression of proteins involved in diverse cellular processes and the stress response. The combined data highlight the roles of certain candidate sRNAs in the adaptation of
E. faecalis
to environmental changes and in the complex transition process from a commensal to a pathogen.
CcpA Is Important for Growth and Virulence of Enterococcus faecium
Authors: Somarajan Sudha R. , Roh Jung H. , Singh Kavindra V. , Weinstock George M. , Murray Barbara E.
Published: June 2014

The collagen adhesin Acm was the first virulence determinant reported to be important for the pathogenesis of
Enterococcus faecium
in a rat infective endocarditis model. We had previously reported that there was a slight growth delay associated with
acm
allelic replacement (
cat
) mutant strain TX6051 used in that study. Recently, we generated a nonpolar markerless
acm
deletion mutant and did not observe a delay in growth. We therefore performed comparative genome sequence analysis of wild-type strain TX82 and TX6051 and found a single mutation, a nonsense mutation in the
ccpA
gene of TX6051. After correcting this mutation, the growth defect of TX6051 was abolished, implicating a role for CcpA in the growth of
E. faecium
. To confirm this, we created a
ccpA
deletion mutant of TX82, which also exhibited a slight delay in growth. Furthermore, the
ccpA
deletion mutant was attenuated (
P
= 0.0024) in a mixed-inoculum (TX82 plus TX82 Δ
ccpA
) rat endocarditis model and also in an
in vitro
competitive growth assay; a
ccpA
-complemented strain showed neither reduced growth nor reduced virulence. We also found attenuation in the endocarditis model with the new
acm
deletion mutant although not as great as that previously observed with TX6051 carrying the
ccpA
mutation. Taken together, our data confirm the role of Acm in the pathogenesis of endocarditis. We also show that CcpA affects the growth of
E. faecium
, that an intact
ccpA
gene is important for full virulence, and that a
ccpA
mutation was partly responsible for the highly attenuated phenotype of TX6051.
GneZ, a UDP-GlcNAc 2-Epimerase, Is Required for S-Layer Assembly and Vegetative Growth of Bacillus anthracis
Authors: Wang Ya-Ting , Missiakas Dominique , Schneewind Olaf
Published: June 2014

Bacillus anthracis
, the causative agent of anthrax, forms an S-layer atop its peptidoglycan envelope and displays S-layer proteins and
Bacillus
S-layer-associated (BSL) proteins with specific functions to support cell separation of vegetative bacilli and growth in infected mammalian hosts. S-layer and BSL proteins bind via the S-layer homology (SLH) domain to the pyruvylated secondary cell wall polysaccharide (SCWP) with the repeat structure [→4)-β-ManNAc-(1→4)-β-GlcNAc-(1→6)-α-GlcNAc-(1→]

n

, where α-GlcNAc and β-GlcNAc are substituted with two and one galactosyl residues, respectively.
B. anthracis
gneY
(BAS5048) and
gneZ
(BAS5117) encode nearly identical UDP-GlcNAc 2-epimerase enzymes that catalyze the reversible conversion of UDP-GlcNAc and UDP-ManNAc. UDP-GlcNAc 2-epimerase enzymes have been shown to be required for the attachment of the phage lysin PlyG with the bacterial envelope and for bacterial growth. Here, we asked whether
gneY
and
gneZ
are required for the synthesis of the pyruvylated SCWP and for S-layer assembly. We show that
gneZ
, but not
gneY
, is required for
B. anthracis
vegetative growth, rod cell shape, S-layer assembly, and synthesis of pyruvylated SCWP. Nevertheless, inducible expression of
gneY
alleviated all the defects associated with the
gneZ
mutant. In contrast to vegetative growth, neither germination of
B. anthracis
spores nor the formation of spores in mother cells required UDP-GlcNAc 2-epimerase activity.
Thoracic vertebral osteomyelitis: an unusual complication of Crohn's disease
Authors: Ajayi Olushola , Mayooran Nithiananthan , Iqbal Nasir
Published: June 2014

Vertebral osteomyelitis complicating Crohn's disease is a rare occurrence and mostly occurred in patients with Crohn's disease complicated by an abscess or fistulising disease. We report a case of thoracic vertebral osteomyelitis, occurring in a refractory Crohn's disease without contiguous abscess or fistula with the bowel.
Tophaceous calcium pyrophosphate dihydrate deposition disease of the knee mimicking an aggressive soft tissue tumour
Authors: Watura Christopher , Saifuddin Asif
Published: June 2014

Calcium pyrophosphate crystal deposition disease (CPPD), previously pseudogout, is the second most common crystal arthropathy after gout. There is increased radiographic prevalence associated with age, trauma and several metabolic disorders. Tophaceous CPPD (T-CPPD) is a rare form of CPPD which, though non-neoplastic, mimics a bone or soft tissue malignancy. T-CPPD usually presents as a mass in the temporomandibular joint and occasionally in the paraspinal tissues, but rarely in the joints of the extremities. We present an exceptionally rare case of T-CPPD that was subtle on plain radiography, presenting as a soft tissue mass in the knee joint.
Where's the ulcer? Spontaneous bleeding from Zenker's diverticulum
Authors: Sardana Nitin , Wallace Dustin , Agrawal Radheshyam , Aoun Elie
Published: June 2014

An 89-year-old man with a history of coronary artery disease status post coronary artery bypass grafting and atrial fibrillation on aspirin and warfarin, presented to the emergency department with a symptom of haemoptysis. He reported a history of dysphagia for 3 months prior to presentation, but had yet to seek medical attention. On presentation, he was hypotensive and tachycardic with a haemoglobin of 6.6 g/dL and an International Normalised Ratio (INR) of 3.9. Esophagogastroduodenoscopy was performed and showed active bleeding from Zenker's diverticulum. The patient's INR was reversed with fresh frozen plasma and his anaemia was treated with packed red blood cells. The bleeding stopped after reversal of his INR. A barium swallow confirmed a 9 cm Zenker's diverticulum. The patient had a diverticulectomy and cricopharyngeal myotomy. Histology showed mild chronic inflammation of the mucosa, but no ulceration. The patient was discharged without any further bleeding episodes.