bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the Essen Rotary as a new technique for bacterial swabs: results of a prospective controlled clinical investigation in 50 patients with chronic leg ulcers
Authors: Al Ghazal Philipp , Körber Andreas , Klode Joachim , Schmid Ernst N , Buer Jan , Dissemond Joachim
Published: July 2012

Most chronic wounds are colonised with different microorganisms, especially problematic bacteria like methicillin‐resistantStaphylococcus aureus(MRSA), which represent an increasing therapeutic challenge in the modern wound therapy regimen. Therefore, it is essential to specify the bacteria in wounds for an individual‐specific treatment. In most patients, an exemplary bacterial swab is taken from the centre of the wound surface. This so‐called Levine technique is propagated currently as the gold standard. The aim of our clinical investigation was to compare the results of different swab techniques to the new established Essen Rotary. In this monocentric prospective investigation, 50 patients with chronic leg ulcers were examined consecutively. The results of our clinical study show that bacteria are heterogeneously spread on wound surfaces. The analysis of the semiquantitative measured results showed that the Essen Rotary could detect significant more bacteria with a total amount of 111 bacteria (P= 0·049) compared to usual swab techniques. Considerably, only the Essen Rotary identified five compared to three MRSA‐patients detected by other techniques. The Essen Rotary is an efficient, economic and uncomplicated modification of bacteriological swab techniques which detects significant more bacteria compared to other conventional swab techniques. Therefore, the Essen Rotary may become the new gold standard in routinely taken bacteriological swabs especially for MRSA screenings in patients with chronic leg ulcers.
Integrated pest management concepts for red imported fire ants Solenopsis invicta (Hymenoptera: Formicidae)
Authors: Drees Bastiaan M. , Calixto Alejandro A. , Nester Paul R.
Published: July 2012

Management of imported fire ant species has evolved since their accidental introduction into the United States and currently uses integrated pest management concepts to design, implement, and evaluate suppression programs. Although eradication is the management goal in certain isolated infestation sites, localized goals vary dramatically in larger infestations where reinvasion of treated areas is likely. These goals are influenced by regulatory policies, medical liabilities, ecological impact, and/or economic considerations. Tactics employed in fire ant management programs presented here include cultural and biological control options along with judicious use of site‐specific insecticide products. In addition, program design considerations that include management goal(s), action level(s), ant form (monogyne or polygyne), presence of nontarget ant species, size of treatment area, seasonality, implementation cost, and environmental impact are also presented. Optimally, elegant IPM programs are target specific, threshold driven, environmentally friendly and cost‐effective.
Effects of Clarification and Storage on Anthocyanins and Color of Pomegranate Juice Concentrates
Authors: Turfan Özge , Türkyilmaz Meltem , Yemİş Oktay , Özkan Mehmet
Published: July 2012

Whole pomegranates with rinds were processed into juice and then concentrate. Effects of cold clarification and storage temperatures (−23C, 5C, 12C and 20C) on anthocyanins (ACNs), ACN composition and color were determined. Major ACNs in pomegranate juice concentrate (PJC) were identified as cyanidin‐3,5‐diglucoside (47.9%), delphinidin‐3,5‐diglucoside (23.2%) and cyanidin‐3‐glucoside (18.5%). Diglucosides were more stable than monoglucosides during storage. ACN degradation and polymeric color formation were fitted to first‐order reaction models. Higher storage temperatures increased the rate of ACN degradation and polymeric color formation in PJCs. Good correlation (r = −0.988) was found between ACN degradation and polymeric color formation during storage. Rate of ACN degradation and polymeric color formation were slower in the PJC obtained from unclarified juice than PJC obtained from clarified juice during storage.

Practical Applications

There has been great interest in pomegranates and their products for their potential health benefits due to their impressive antioxidative properties, which are highly correlated with their polyphenol content, including tannins and ACNs. During pressing of pomegranates, polyphenols especially high molecular weight tannins present in the rinds pass to the juice. And excessive polyphenols cause haze and sediment formation, astringent, taste and color loss. This is serious industrial problem in the production of clear pomegranate juice. Attractive red‐violet color of pomegranate products is due to their ACN contents. However, ACNs are unstable and susceptible to degradation leading to a brownish color during juice processing and storage. Results of this study showed that clarification with gelatin as well as high storage temperatures adversely affected the ACNs of pomegranate juice concentrates (PJCs). Therefore, PJC should be produced from unclarified juice and frozen‐stored. The reconstituted juice should then be cold‐clarified right before marketing.
Tangling the web of legal parenthood: legal responses to the use of known donors in lesbian parenting arrangements
Authors: Smith Leanne
Published: July 2012

This paper explores cases involving disputes between lesbian parents and known donors with whom informal insemination arrangements were made. It observes that the current legal framework for recognising parents following assisted reproduction is incapable of dealing adequately with known donors, notwithstanding a host of recent developments in the law relating to lesbian parenting. As a result, the case-law exhibits judicial uncertainty and inconsistency about the extent of the recognition to which known donors should be entitled. In spite of the difficulties posed by using known donors, the paper argues that there is a strong case for finding an appropriate way of accommodating them within the legal framework for recognising parents. It explores some of the possible legal responses and highlights their potential advantages and disadvantages from theoretical and practical perspectives.
Personal Sun Exposure and Serum 25‐hydroxy Vitamin D Concentrations
Authors: Nair‐Shalliker Visalini , Clements Mark , Fenech Michael , Armstrong Bruce K
Published: July 2012

Solar ultraviolet‐B radiation (UVB) is essential for epidermal vitamin D production. We aimed to quantitate the relationship between personal solar UV exposure and serum 25hydroxy vitamin D (25[OH]D) concentration. Blood was collected for 25(OH)D analysis in 207 South Australian adults aged 27–61 years. At the time of blood collection, each participant completed a questionnaire, which included a calendar for recall of sun exposure in the preceding 16 weeks. We examined the association between solar UV exposure and serum 25(OH)D graphically from smoothed scatter plots, and modeled it using multiple linear regression, with age, sex and body mass index as covariates. Estimated erythemal solar UV exposure in the 6 weeks before blood collection best predicted serum 25(OH)D concentrations. Serum 25(OH)D rose with increasing personal solar UV exposure to a maximum of about 89 nmol L−1 at an estimated mean weekly solar erythemal UV exposure of about 1230 mJ cm−2. The maximum was the same after accounting for clothing coverage and was reached at an estimated whole body equivalent exposure to ambient UV of ca 700 mJ cm−2. These results suggest that an average maximum serum 25(OH)D of ca 89 nmol L−1 is achieved from sun exposure in a healthy Australian adult population.
Quantitative proteomic approaches in biomarker discovery of inflammatory bowel disease
Authors: Han Na‐Young , Kim Eun Hee , Choi Joon , Lee Hookeun , Hahm Ki‐Baik
Published: July 2012

Proteomics offers considerable opportunities for either enhancing our biological understanding or discovering biomarkers, blood and biopsied specimen‐based proteomic approaches, provide reproducible and quantitative tools that can complement clinical assessments and aid clinicians in the diagnosis and treatment of inflammatory bowel disease (IBD). Sometimes a differential diagnosis of Crohn's disease (CD) and ulcerative colitis (UC) and the prediction of treatment response can be deduced by finding meaningful biomarkers, for which the central platform for proteomics is tandem mass spectrometry (MS/MS). A range of workflows are available for protein (or peptide) separation prior to MS/MS as well as bioinformatics analysis to achieve protein identification, for which two‐dimensional electrophoresis (2‐DE) and subsequent mass spectrometry (MS), liquid chromatography‐MS, difference gel electrophoresis following 2‐DE, isobaric tags for relative and absolute quantification (iTRAQ), stable isotope labeling by amino acids and label‐free quantification are under development. In this article, the current status and perspective of these advanced proteomic technologies are introduced, with examples of recent biomarkers focused on the diagnosis, treatment response, prognosis of IBD, and even colitis‐associated carcinogenesis in both animal models and human patients.
The Sexualisation of Culture?
Authors: Gill Rosalind
Published: July 2012

This article examines contemporary debates about the ‘sexualisation of culture’. It sets out the context for claims that Western societies are becoming more sexualised and it explores a number of competing perspectives about sexualisation. It then looks in more detail at the nature of claims about sexualisation as they emerge from the different disciplinary perspectives of Psychology and Media and Cultural Studies, contrasting the strengths and weaknesses of each, and raising criticisms of both. In a final discussion section, the article considers the usefulness or otherwise of the notion of ‘sexualisation’ as analytic category and points to the need to go beyond polarised positions. It advocates a psychosocial approach that takes seriously differences and power in considering the contemporary proliferation of ‘sexualised’ images, practices and media.
Simultaneous Infection of Pigs and People with Triple‐Reassortant Swine Influenza Virus H1N1 at a U.S. County Fair
Authors: Killian M. L. , Swenson S. L. , Vincent A. L. , Landgraf J. G. , Shu B. , Lindstrom S. , Xu X. , Klimov A. , Zhang Y. , Bowman A. S.
Published: July 2012

Influenza‐like illness was noted in people and pigs in attendance at an Ohio county fair in August 2007. The morbidity rate in swine approached 100% within 1–2 days of initial clinical signs being recognized, and approximately two dozen people developed influenza‐like illness. Triple‐reassortant swine H1N1 influenza viruses were identified in both pigs and people at the fair. The identified viruses (A/Sw/OH/511445/2007, A/Ohio/01/2007, and A/Ohio/02/2007) were similar to H1N1 swine influenza viruses currently found in the U.S. swine population. This case illustrates the possibility of transmission of swine influenza in settings where there is close human/swine interaction.
INVESTIGATING TAX DISTORTIONS: AN APPLIED MODEL OF PETROLEUM EXPLORATION AND EXTRACTION DECISIONS
Authors: BLAKE ANDON J.
Published: July 2012

AbstractA numerical model is proposed for the testing of distortions caused by petroleum fiscal systems on the exploration and extraction activities of a profit‐maximizing firm. Traditional models have not been capable of testing for the distortions caused by the complex tax structures most often used by governments. Two tax combinations, as well as certain other taxes, are analyzed for distortions in the model. The model is parameterized using generic data because specific jurisdictions are not considered. The distortions due to rentals and royalties are as expected by theory. Property taxes show a new distortion result where production tilting is ambiguous.
MODELING INDIVIDUAL TREE MORTALITY RATES USING MARGINAL AND RANDOM EFFECTS REGRESSION MODELS
Authors: MA ZHIHAI , PENG CHANGHUI , LI WEIZHONG , ZHU QIUAN , WANG WEIFENG , SONG XINZHANG , LIU JIANWEI
Published: July 2012

Abstract Developing models to predict tree mortality using data from long‐term repeated measurement data sets can be difficult and challenging due to the nature of mortality as well as the effects of dependence on observations. Marginal (population‐averaged) generalized estimating equations (GEE) and random effects (subject‐specific) models offer two possible ways to overcome these effects. For this study, standard logistic, marginal logistic based on the GEE approach, and random logistic regression models were fitted and compared. In addition, four model evaluation statistics were calculated by means of K‐fold cross‐valuation. They include the mean prediction error, the mean absolute prediction error, the variance of prediction error, and the mean square error. Results from this study suggest that the random effects model produced the smallest evaluation statistics among the three models. Although marginal logistic regression accommodated for correlations between observations, it did not provide noticeable improvements of model performance compared to the standard logistic regression model that assumed impendence. This study indicates that the random effects model was able to increase the overall accuracy of mortality modeling. Moreover, it was able to ascertain correlation derived from the hierarchal data structure as well as serial correlation generated through repeated measurements.
NATURAL RESOURCE MODELING: ALLOWING FOR INCONSTANT PROBABILITY OF DETECTION AND FREQUENCY MEASURES OF VIOLATION WITHIN DYNAMIC DETERRENCE FISHERY MODELS
Authors: ABUSIN SANA , HASSAN RASHID , HERTZLER GREG
Published: July 2012

Abstract.  The dynamic deterrence model (DDM) represents an analytical framework widely used for analyzing compliance with fishery regulations aiming for sustainable fishery management. However, applications of the DDM have so far been limited to the case of constant probability of detection that assumes independence of the length of time to detection. This paper modifies the DDM to allow for more flexible and broader specification by introducing, for the first time, two important variables to the supply of offences function, namely evasion activity and enforcement efforts and accommodating inconstant probability of detection specifications. Determinants of probability of detection are specified and important potential extensions of the modified DDM are discussed in this paper. The relative magnitude of the effects of each of these determinants on probability of detection, however, remains an important empirical question that requires further investigation for prioritization of policy actions.
A geometric approach to Orlov’s theorem
Authors: Shipman Ian
Published: July 2012

A famous theorem of D. Orlov describes the derived bounded category of coherent sheaves on projective hypersurfaces in terms of an algebraic construction called graded matrix factorizations. In this article, I implement a proposal of E. Segal to prove Orlov’s theorem in the Calabi–Yau setting using a globalization of the category of graded matrix factorizations (graded D-branes). Let X⊂ℙ be a projective hypersurface. Segal has already established an equivalence between Orlov’s category of graded matrix factorizations and the category of graded D-branes on the canonical bundle Kℙ to ℙ. To complete the picture, I give an equivalence between the homotopy category of graded D-branes on Kℙ and Dbcoh(X). This can be achieved directly, as well as by deforming Kℙ to the normal bundle of X⊂Kℙ and invoking a global version of Knörrer periodicity. We also discuss an equivalence between graded D-branes on a general smooth quasiprojective variety and on the formal neighborhood of the singular locus of the zero fiber of the potential.
Maskless fabrication of selectively sized silicon nanostructures for solar cell application
Authors: Dou Bingfei , Jia Rui , Li Haofeng , Chen Chen , Meng Yanlong , Ding Wuchang , Liu Xinyu , Ye Tianchun , Wang Yunfeng
Published: July 2012

A two-step maskless method was used to synthesize silicon nanostructures. In the first step, silver nanoparticles were formed through rapid thermal annealing of silver thin films. The temperature, duration of annealing, and initial thickness of the silver film jointly determined the distribution and diameter of silver particles. In the next step, silicon nanostructures were created using silver catalyzed etching in HF/H2O2. The experiment confirmed that the final sizes of the nanostructures corresponded to the diameters of the silver particles. Further, silicon nanostructure-textured solar cells were manufactured and tested. The surface-reflection ratio of the cells can be decreased to 5% in the 300–1000 nm wavelength range. The current-voltage and quantum efficiency measurements also reveal that silicon nanostructure-textured solar cells exhibit considerable light trapping enhancement. The results also indicate that effective passivation and electrode contact are important for those cells.
Dislocation-Driven Deformations in Graphene
Authors: Warner Jamie H. , Margine Elena Roxana , Mukai Masaki , Robertson Alexander W. , Giustino Feliciano , Kirkland Angus I.
Published: July 2012

Moving Dislocations

The mechanical properties of crystalline materials are limited by the presence and motion of defects caused by extra or missing atoms in the crystal lattice. Plastic deformation of a material causes these defects, known as dislocations, to move and multiply. Much is known about the motion of dislocations in three dimensions but less so in two.

Warner
et al.

(p.
209
; see the Perspective by

Bonilla and Carpio

) used graphene as a model material to track dislocation dynamics in real time. The strain fields in the graphene sheet were mapped, which suggests that the dislocation motion is connected to the stretching, rotating, and breaking of individual carbon bonds.
Complementary Phosphorylation Sites in the Adaptor Protein SLP-76 Promote Synergistic Activation of Natural Killer Cells
Authors: Kim Hun Sik , Long Eric O.
Published: July 2012

Targeted tyrosine phosphorylation of an adaptor protein is required for the synergistic activation of natural killer cells by distinct pairs of receptors.
Differential Regulation by Cyclic Nucleotides of the CNGA4 and CNGB1b Subunits in Olfactory Cyclic Nucleotide–Gated Channels
Authors: Nache Vasilica , Zimmer Thomas , Wongsamitkul Nisa , Schmauder Ralf , Kusch Jana , Reinhardt Lisa , Bönigk Wolfgang , Seifert Reinhard , Biskup Christoph , Schwede Frank , Benndorf Klaus
Published: July 2012

Different subunits of olfactory CNG channels enable specific regulation of channel activity by cAMP or cGMP.
Response to Comment on “A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation”: Building a Model of the mTOR Signaling Network with a Potentially Faulty Tool
Authors: Dalle Pezze Piero , Sonntag Annika G. , Shanley Daryl P. , Thedieck Kathrin
Published: July 2012

Dalle Pezze
et al
. respond to criticisms regarding the specificity of phosphorylation of Ser
2481
of mTOR as a specific readout of mTORC2 activity.
Comment on “A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation”: Building a Model of the mTOR Signaling Network with a Potentially Faulty Tool
Authors: Manning Brendan D.
Published: July 2012

Manning questions whether the biochemical readout used to test the network models is sufficiently specific.
Another Selective Path to Destruction
Authors: Foley John F.
Published: July 2012

Selective autophagy of Bcl10 inhibits T cell receptor–dependent activation of the transcription factor NF-κB.
Human Cytomegalovirus Inhibition by Cardiac Glycosides: Evidence for Involvement of the hERG Gene
Authors: Kapoor Arun , Cai Hongyi , Forman Michael , He Ran , Shamay Meir , Arav-Boger Ravit
Published: July 2012

Infection with human cytomegalovirus (HCMV) continues to be a major threat for pregnant women and the immunocompromised population. Although several anti-HCMV therapies are available, the development of new anti-HCMV agents is highly desired. There is growing interest in identifying compounds that might inhibit HCMV by modulating the cellular milieu. Interest in cardiac glycosides (CG), used in patients with congestive heart failure, has increased because of their established anticancer and their suggested antiviral activities. We report that the several CG—digoxin, digitoxin, and ouabain—are potent inhibitors of HCMV at nM concentrations. HCMV inhibition occurred prior to DNA replication, but following binding to its cellular receptors. The levels of immediate early, early, and late viral proteins and cellular NF-κB were significantly reduced in CG-treated cells. The activity of CG in infected cells correlated with the expression of the potassium channel gene, hERG. CMV infection upregulated hERG, whereas CG significantly downregulated its expression. Infection with mouse CMV upregulated mouse ERG (mERG), but treatment with CG did not inhibit virus replication or mERG transcription. These findings suggest that CG may inhibit HCMV by modulating human cellular targets associated with hERG and that these compounds should be studied for their antiviral activities.
Safety and Pharmacokinetics of the Anti-Orthopoxvirus Compound ST-246 following a Single Daily Oral Dose for 14 Days in Human Volunteers
Authors: Chinsangaram Jarasvech , Honeychurch Kady M. , Tyavanagimatt Shanthakumar R. , Leeds Janet M. , Bolken Tove' C. , Jones Kevin F. , Jordan Robert , Marbury Thomas , Ruckle Jon , Mee-Lee Denis , Ross Eric , Lichtenstein Israel , Pickens Margaret , Corrado Michael , Clarke Jean M. , Frimm Annie M. , Hruby Dennis E.
Published: July 2012

ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (
C
max
) and relative exposure for each dosing interval (AUC
τ
) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application.
Role of Oxidative Stress in Persister Tolerance
Authors: Wu Yanxia , Vulić Marin , Keren Iris , Lewis Kim
Published: July 2012

Persisters are dormant phenotypic variants of regular cells that are tolerant to antibiotics and play an important role in recalcitrance of chronic infections to therapy. Persisters can be produced stochastically in a population untreated with antibiotics. At the same time, a deterministic component of persister formation has also been documented in a population of cells with DNA damaged by fluoroquinolone treatment. Expression of the SOS response under these conditions induces formation of persisters by increasing expression of the TisB toxin. This suggests that other stress responses may also contribute to persister formation. Of particular interest is oxidative stress that pathogens encounter during infection. Activated macrophages produce reactive oxygen and nitrogen species which induce the SoxRS and OxyR regulons. Genes controlled by these regulons deactivate the oxidants and promote repair. We examined the ability of oxidative stress induced by paraquat (PQ) to affect persister formation. Preincubation of cells with PQ produced a dramatic increase in the number of persisters surviving challenge with fluoroquinolone antibiotics. PQ did not affect killing by kanamycin or ampicillin. Persisters in a culture treated with PQ that survived a challenge with a fluoroquinolone were also highly tolerant to other antibiotics. PQ induces SoxRS, which in turn induces expression of the AcrAB-TolC multidrug-resistant (MDR) pump. Fluoroquinolones are extruded by this MDR pump, and the effect of PQ on antibiotic tolerance was largely abolished in a mutant that was defective in the pump. It appears that PQ, acting through AcrAB-TolC, reduces the concentration of fluoroquinolones in the cells. This allows a larger fraction of cells to become persisters in the presence of a fluoroquinolone. Analysis of a
lexA3
mutant indeed showed a dependence of persister induction under these conditions on SOS. These findings show that induction of a classical resistance mechanism, MDR efflux, by oxidative stress leads to an increase in multidrug-tolerant persister cells.
Compared to Subcutaneous Tenofovir, Oral Tenofovir Disoproxyl Fumarate Administration Preferentially Concentrates the Drug into Gut-Associated Lymphoid Cells in Simian Immunodeficiency Virus-Infected Macaques
Authors: Van Rompay Koen K. A. , Babusis Darius , Abbott Zachary , Geng Yongzhi , Jayashankar Kartika , Johnson Jeffrey A. , Lipscomb Jonathan , Heneine Walid , Abel Kristina , Ray Adrian S.
Published: July 2012

To compare tissue-based pharmacokinetics and efficacy of oral tenofovir disoproxyl fumarate (TDF) versus subcutaneous tenofovir (TFV), macaques were treated for 2 weeks starting 1 week after simian immunodeficiency virus inoculation. Despite lower plasma TFV levels in the oral TDF arm, similar TFV diphosphate levels and antiviral activities were measured in lymphoid cells of most tissues. In intestinal tissues, however, oral TDF resulted in higher active drug levels, associated with lower virus levels and better immune preservation.
Feasibility of a Fixed-Dose Regimen of Pyrazinamide and Its Impact on Systemic Drug Exposure and Liver Safety in Patients with Tuberculosis
Authors: Sahota Tarjinder , Della Pasqua Oscar
Published: July 2012

Historically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [
C
max
]), the time above the MIC (
t
> MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents.
Pharmacological Characterization, Structural Studies, and
In Vivo
Activities of Anti-Chagas Disease Lead Compounds Derived from Tipifarnib
Authors: Buckner Frederick S. , Bahia Maria Terezinha , Suryadevara Praveen Kumar , White Karen L. , Shackleford David M. , Chennamaneni Naveen Kumar , Hulverson Matthew A. , Laydbak Joy U. , Chatelain Eric , Scandale Ivan , Verlinde Christophe L. M. J. , Charman Susan A. , Lepesheva Galina I. , Gelb Michael H.
Published: July 2012

Chagas disease, caused by the protozoan pathogen
Trypanosoma cruzi
, remains a challenging infection due to the unavailability of safe and efficacious drugs. Inhibitors of the trypanosome sterol 14α-demethylase enzyme (CYP51), including azole antifungal drugs, are promising candidates for development as anti-Chagas disease drugs. Posaconazole is under clinical investigation for Chagas disease, although the high cost of this drug may limit its widespread use. We have previously reported that the human protein farnesyltransferase (PFT) inhibitor tipifarnib has potent anti-
T. cruzi
activity by inhibiting the CYP51 enzyme. Furthermore, we have developed analogs that minimize the PFT-inhibitory activity and enhance the CYP51 inhibition. In this paper, we describe the efficacy of the lead tipifarnib analog compared to that of posaconazole in a murine model of
T. cruzi
infection. The plasma exposure profiles for each compound following a single oral dose in mice and estimated exposure parameters after repeated twice-daily dosing for 20 days are also presented. The lead tipifarnib analog had potent suppressive activity on parasitemia in mice but was unsuccessful at curing mice, whereas posaconazole as well as benznidazole cured 3 of 5 and 4 of 6 mice, respectively. The efficacy results are consistent with posaconazole having substantially higher predicted exposure than that of the tipifarnib analog after repeat twice-daily administration. Further changes to the tipifarnib analogs to reduce plasma clearance are therefore likely to be important. A crystal structure of a trypanosomal CYP51 bound to a tipifarnib analog is reported here and provides new insights to guide structure-based drug design for further optimized compounds.
Evaluation of Clinical Outcomes in Patients with Bloodstream Infections Due to Gram-Negative Bacteria According to Carbapenem MIC Stratification
Authors: Esterly John S. , Wagner Jamie , McLaughlin Milena M. , Postelnick Michael J. , Qi Chao , Scheetz Marc H.
Published: July 2012

Predictive modeling suggests that actual carbapenem MIC results are more predictive of clinical patient outcomes than categorical classification of the MIC as susceptible, intermediate, or resistant. Some have speculated that current CLSI guidelines' suggested thresholds are too high and that clinical success is more likely if the MIC value is ≤1 mg/liter for certain organisms. Patients treated with carbapenems and with positive blood cultures for
Pseudomonas aeruginosa
,
Acinetobacter baumannii
, or extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria were considered for evaluation in this clinical retrospective cohort study. Relevant patient demographics and microbiologic variables were collected, including carbapenem MIC. The primary objective was to define a risk-adjusted all-cause hospital mortality breakpoint for carbapenem MICs. Secondarily, we sought to determine if a similar breakpoint existed for indirect outcomes (e.g., time to mortality and length of stay [LOS] postinfection for survivors). Seventy-one patients met the criteria for study inclusion. Overall, 52 patients survived, and 19 died. Classification and regression tree (CART) analysis determined a split of organism MIC between 2 and 4 mg/liter and predicted differences in mortality (16.1% versus 76.9%;
P
< 0.01). Logistic regression controlling for confounders identified each imipenem MIC doubling dilution as increasing the probability of death 2-fold (adjusted odds ratio [aOR] 2.0; 95% confidence interval [CI], 1.3 to 3.2). Secondary outcomes were similar between groups. This study revealed that patients with organisms that had a MIC of ≥4 mg/liter had worse outcomes than patients whose isolates had a MIC of ≤2 mg/liter, even after adjustment for confounding variables. We recommend additional clinical studies to better understand the susceptibility breakpoint for carbapenems.
Role of RelA and SpoT in Burkholderia pseudomallei Virulence and Immunity
Authors: Müller Claudia M. , Conejero Laura , Spink Natasha , Wand Matthew E. , Bancroft Gregory J. , Titball Richard W.
Published: July 2012

Burkholderia pseudomallei
is a Gram-negative soil bacterium and the causative agent of melioidosis, a disease of humans and animals. It is also listed as a category B bioterrorism threat agent by the U.S. Centers for Disease Control and Prevention, and there is currently no melioidosis vaccine available. Small modified nucleotides such as the hyperphosphorylated guanosine molecules ppGpp and pppGpp play an important role as signaling molecules in prokaryotes. They mediate a global stress response under starvation conditions and have been implicated in the regulation of virulence and survival factors in many bacterial species. In this study, we created a
relA spoT
double mutant in
B. pseudomallei
strain K96243, which lacks (p)ppGpp-synthesizing enzymes, and investigated its phenotype
in vitro
and
in vivo
. The
B. pseudomallei
Δ
relA
Δ
spoT
mutant displayed a defect in stationary-phase survival and intracellular replication in murine macrophages. Moreover, the mutant was attenuated in the
Galleria mellonella
insect model and in both acute and chronic mouse models of melioidosis. Vaccination of mice with the Δ
relA
Δ
spoT
mutant resulted in partial protection against infection with wild-type
B. pseudomallei
. In summary, (p)ppGpp signaling appears to represent an essential component of the regulatory network governing virulence gene expression and stress adaptation in
B. pseudomallei
, and the Δ
relA
Δ
spoT
mutant may be a promising live-attenuated vaccine candidate.
Natural History of Inhalation Melioidosis in Rhesus Macaques (Macaca mulatta) and African Green Monkeys (Chlorocebus aethiops)
Authors: Yeager John J. , Facemire Paul , Dabisch Paul A. , Robinson Camenzind G. , Nyakiti David , Beck Katie , Baker Reese , Pitt M. Louise M.
Published: July 2012

Burkholderia pseudomallei, the causative agent of melioidosis, is recognized as a serious health threat due to its involvement in septic and pulmonary infections in areas of endemicity and is recognized by the Centers for Disease Control and Prevention as a category B biothreat agent. An animal model is desirable to evaluate the pathogenesis of melioidosis and medical countermeasures. A model system that represents human melioidosis infections is essential in this process. A group of 10 rhesus macaques (RMs) and 10 African green monkeys (AGMs) was exposed to aerosolizedB. pseudomallei1026b. The first clinical signs were fever developing 24 to 40 h postexposure followed by leukocytosis resulting from a high percentage of neutrophils. Dyspnea manifested 2 to 4 days postexposure. In the AGMs, an increase in interleukin 1β (IL-1β), IL-6, IL-8, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) was observed. In the RMs, IL-1β, IL-6, and TNF-α increased. All the RMs and AGMs had various degrees of bronchopneumonia, with inflammation consisting of numerous neutrophils and a moderate number of macrophages. Both the RMs and the AGMs appear to develop a melioidosis infection that closely resembles that seen in acute human melioidosis. However, for an evaluation of medical countermeasures, AGMs appear to be a more appropriate model.
Campylobacter jejuni Translocation across Intestinal Epithelial Cells Is Facilitated by Ganglioside-Like Lipooligosaccharide Structures
Authors: Louwen Rogier , Nieuwenhuis Edward E. S. , van Marrewijk Leonie , Horst-Kreft Deborah , de Ruiter Lilian , Heikema Astrid P. , van Wamel Willem J. B. , Wagenaar Jaap A. , Endtz Hubert P. , Samsom Janneke , van Baarlen Peter , Akhmanova Anna , van Belkum Alex
Published: July 2012

Translocation across intestinal epithelial cells is an established pathogenic feature of the zoonotic bacterial species
Campylobacter jejuni
. The number of
C. jejuni
virulence factors known to be involved in translocation is limited. In the present study, we investigated whether sialylation of
C. jejuni
lipooligosaccharide (LOS) structures, generating human nerve ganglioside mimics, is important for intestinal epithelial translocation. We here show that
C. jejuni
isolates expressing ganglioside-like LOS bound in larger numbers to the Caco-2 intestinal epithelial cells than
C. jejuni
isolates lacking such structures. Next, we found that ganglioside-like LOS facilitated endocytosis of bacteria into Caco-2 cells, as visualized by quantitative microscopy using the early and late endosomal markers early endosome-associated protein 1 (EEA1), Rab5, and lysosome-associated membrane protein 1 (LAMP-1). This increased endocytosis was associated with larger numbers of surviving and translocating bacteria. Next, we found that two different intestinal epithelial cell lines (Caco-2 and T84) responded with an elevated secretion of the T-cell attractant CXCL10 to infection by ganglioside-like LOS-expressing
C. jejuni
isolates. We conclude that
C. jejuni
translocation across Caco-2 cells is facilitated by ganglioside-like LOS, which is of clinical relevance since
C. jejuni
ganglioside-like LOS-expressing isolates are linked with severe gastroenteritis and bloody stools in
C. jejuni
-infected patients.
Brake fluid toxicity feigning brain death
Authors: Nahrir Shahpar , Sinha Shobhit , Siddiqui Khurram A
Published: July 2012

Brake fluid (glycol-based) toxicity is known to have a protean of central and peripheral nervous system manifestations. The principal component of this household poison is ethylene glycol. Toxic effect is generally attributed to peri-vascular deposition of calcium oxalate crystals in various tissues. However, clinical features resembling brain death have rarely been reported. We report a case of brake fluid toxicity simulating brain death in a 21-year-old healthy man who ingested it as a recreational agent.
A spontaneous coronary arterial dissection associated with a calcineurin inhibitor: Figure 1
Authors: Mallon Dermot Henry , McKenzie Daniel , Dayer Mark
Published: July 2012

We present the case of a 55-year-old lady presenting 5 months after a liver transplant with acute coronary syndrome. She was on maintenance-dose tacrolimus. An angiogram diagnosed a spontaneous coronary artery dissection, which was successfully stented. This is the third case in the literature associating a calcineurin inhibitor with a spontaneous coronary arterial dissection. The detrimental effect of calcineurin inhibitors on vasculature is well recognised. This report highlights their potentially serious side-effects. It should be appreciated that calcineurin inhibitors have the potential to cause or contribute to this rare vascular phenomenon and the diagnosis should therefore be considered in those taking such drugs.
Recent changes in climate and permafrost temperatures at forested and polar desert sites in northern Canada1This article is one of a series of papers published in this CJES Special Issue on the theme ofFundamental and applied research on permafrost in Canada.
Authors: Smith Sharon L. , Throop Jennifer , Lewkowicz Antoni G.
Published: July 2012

Climate and ground temperature records up to 30 years in length from permafrost monitoring sites in a polar desert at Alert, Nunavut, and a boreal forest at Table Mountain, Northwest Territories, were analyzed by season and year to assess the ground thermal response to recent climate warming. Methods were developed to standardize incomplete ground temperature data sets and to hindcast air temperatures for comparative analysis. The timing and magnitude of climate warming varied, beginning in the 1960s in the Mackenzie Valley and the 1970s in the High Arctic. Ground temperature increases occurred in both regions but varied in magnitude and timing in relation to the external forcing and permafrost conditions. Significant increases in winter air temperatures in both regions appear to be largely responsible for recent increases in ground temperature, particularly at the polar desert sites where snow cover is minimal.
Nonperturbative time-dependent density functional theory (TDDFT) and time-dependent electron localization function (TDELF) study of the ionization of OCS and CS2 with ultrashort intense laser pulses — Orientational effects
Authors: Penka Emmanuel Fowe , Bandrauk André Dieter
Published: July 2012

The nonlinear nonperturbative response of OCS and CS2 to ultrashort (few cycles) intense laser pulses was studied numerically by time-dependent density functional theory (TDDFT) methods to understand molecular ionization as a function of laser–molecule orientation. A time-dependent electron localization function(TDELF) was used to visualize the nonlinear nonperturbative electron transfer occurring during the laser pulse. It was found that, for intensities I > 3.5 × 1014 W/cm2, the inner shell Kohn–Sham (KS) molecular orbitals contribute significantly to the ionization, whereas for the intensity I < 3.5 × 1014 W/cm2, the highest occupied molecular orbital (HOMO) shows the dominant response to the field. In general, the ionization rate maxima correspond to the alignment of maximum KS orbital densities with the laser pulse polarization instead of orbital ionization potentials (IP). These findings are corroborated through analysis of the TDELF images, where the ionization occurs from the lone pair or bond regions of the corresponding molecules.
CLASS NUMBERS VIA 3-ISOGENIES AND ELLIPTIC SURFACES
Authors: McLEMAN CAM , MOODY DUSTIN
Published: July 2012

We show that a character sum attached to a family of 3-isogenies defined on the fibers of a certain elliptic surface over 𝔽p relates to the class number of the quadratic imaginary number field [Formula: see text]. In this sense, this provides a higher-dimensional analog of some recent class number formulas associated to 2-isogenies of elliptic curves.
Mean field equilibria of dynamic auctions with learning
Authors: Iyer Krishnamurthy , Johari Ramesh , Sundararajan Mukund
Published: July 2012

We study learning in a dynamic setting where identical copies of a good are sold over time through a sequence of second price auctions. Each agent in the market has an
unknown
independent private valuation which determines the distribution of the reward she obtains from the good; for example, in sponsored search settings, advertisers may initially be unsure of the value of a click. Though the induced dynamic game is complex, we simplify analysis of the market using an approximation methodology known as
mean field equilibrium
(MFE). The methodology assumes that agents optimize only with respect to long run average estimates of the distribution of other players' bids. We show a remarkable fact: in a mean field equilibrium, the agent has an optimal strategy where she bids truthfully according to a
conjoint valuation
. The conjoint valuation is the sum of her current expected valuation, together with an overbid amount that is exactly the expected marginal benefit to one additional observation about her true private valuation. Under mild conditions on the model, we show that an MFE exists, and that it is a good approximation to a
rational
agent's behavior as the number of agents increases. We conclude by discussing the implications of the auction format and design on the auctioneer's revenue. In particular, we establish a dynamic version of the revenue equivalence theorem, and discuss optimal selection of reserve prices in dynamic auctions.
Security and network effects
Authors: Vorobeychik Yevgeniy
Published: July 2012

Security, like many other complex decisions, is generally approached with a divide-and-conquer mindset. Consequences of security failures, however, can rarely be completely localized: an explosion or a fire at one building can affect neighboring structures, a debt crisis in Greece resonates throughout the tightly connected European and US financial markets, and a breach of security at one computer can facilitate access to others on the same network. It is thus crucial to view security holistically, and devise security strategies that explicitly account for interdependencies between valuable assets. Here we provide an overview of two recent approaches to security with network effects. The first approach takes a centralized perspective, attempting to compute an optimal security configuration for all interdependent assets. This approach explicitly accounts for an intelligent adversary optimally attacking one of the assets. The second approach studies the impact of decentralized decision making when local failures can propagate in complex ways through the entire system, but assumes that initial failures are random.
Strategyproof classification
Authors: Meir Reshef , Rosenschein Jeffrey S.
Published: July 2012

Experts reporting the labels used by a learning algorithm cannot always be assumed to be truthful. We describe recent advances in the design and analysis of strategyproof mechanisms for binary classification, and their relation to other mechanism design problems.
Contingency exigency
Authors: Reeves Daniel
Published: July 2012

Lawyers and debt collectors are classic examples of people you hire on contingency. The idea is to hire someone with payment contingent on the fruits of their labor. You don't pay them if you don't win, i.e., if you yourself don't get paid. And if you luck out, they share in the windfall.
Rationing problems in bipartite networks
Authors: Moulin Herve J. , Sethuraman Jay
Published: July 2012

The standard theory of rationing problems is extended to the bipartite context. The focus is on
consistency
, a compelling rationality property of fair division methods in the standard setting.
Multitier Programming in Hop
Authors: Serrano Manuel , Berry Gérard
Published: July 2012

The Web is becoming the richest platform on which to create computer applications. Its power comes from three elements: (1) modern Web browsers enable highly sophisticated GUIs with 3D, multimedia, fancy typesetting, etc.; (2) calling existing services through Web APIs makes it possible to develop sophisticated applications from independently available components; and (3) open data availability allows applications to access a wide set of information that was unreachable or that simply did not exist before. The combination of these three elements has already given birth to revolutionary applications such as Google Maps, radio podcasts, and social networks.