bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Hierarchical Cascade of Second Messengers Regulates Pseudomonas aeruginosa Surface Behaviors
Authors: Luo Yun , Zhao Kun , Baker Amy E. , Kuchma Sherry L. , Coggan Kimberly A. , Wolfgang Matthew C. , Wong Gerard C. L. , O’Toole George A. 
Published: January 2015

ABSTRACT

Biofilms are surface-attached multicellular communities. Using single-cell tracking microscopy, we showed that a
pilY1
mutant of
Pseudomonas aeruginosa
is defective in early biofilm formation. We leveraged the observation that PilY1 protein levels increase on a surface to perform a genetic screen to identify mutants altered in surface-grown expression of this protein. Based on our genetic studies, we found that soon after initiating surface growth, cyclic AMP (cAMP) levels increase, dependent on PilJ, a chemoreceptor-like protein of the Pil-Chp complex, and the type IV pilus (TFP). cAMP and its receptor protein Vfr, together with the FimS-AlgR two-component system (TCS), upregulate the expression of PilY1 upon surface growth. FimS and PilJ interact, suggesting a mechanism by which Pil-Chp can regulate FimS function. The subsequent secretion of PilY1 is dependent on the TFP assembly system; thus, PilY1 is not deployed until the pilus is assembled, allowing an ordered signaling cascade. Cell surface-associated PilY1 in turn signals through the TFP alignment complex PilMNOP and the diguanylate cyclase SadC to activate downstream cyclic di-GMP (c-di-GMP) production, thereby repressing swarming motility. Overall, our data support a model whereby P. aeruginosa senses the surface through the Pil-Chp chemotaxis-like complex, TFP, and PilY1 to regulate cAMP and c-di-GMP production, thereby employing a hierarchical regulatory cascade of second messengers to coordinate its program of surface behaviors.

IMPORTANCE
Biofilms are surface-attached multicellular communities. Here, we show that a stepwise regulatory circuit, involving ordered signaling via two different second messengers, is required for
Pseudomonas aeruginosa
to control early events in cell-surface interactions. We propose that our studies have uncovered a multilayered “surface-sensing” system that allows P. aeruginosa to effectively coordinate its surface-associated behaviors
.
Understanding how cells transition into the biofilm state on a surface may provide new approaches to prevent formation of these communities.
Therapeutic guidelines for prescribing antibiotics in neonates should be evidence-based: a French national survey
Authors: Leroux Stéphanie , Zhao Wei , Bétrémieux Pierre , Pladys Patrick , Saliba Elie , Jacqz-Aigrain Evelyne 
Published: January 2015

ObjectiveThis survey aims to describe and analyse the dosage regimens of antibiotics in French neonatal intensive care units (NICUs).MethodsSenior doctors from 56 French NICUs were contacted by telephone and/or email to provide their local guidelines for antibiotic therapy.Results44 (79%) NICUs agreed to participate in this survey. In total, 444 dosage regimens were identified in French NICUs for 41 antibiotics. The number of different dosage regimens varied from 1 to 32 per drug (mean 9, SD 7.8). 37% of intravenous dosage regimens used a unique mg/kg dose from preterm to full-term neonates. Doses and/or dosing intervals varied significantly for 12 antibiotics (amikacin, gentamicin, netilmicin, tobramycin, vancomycin administered as continuous infusion, ceftazidime, cloxacillin, oxacillin, penicillin G, imipenem/cilastatin, clindamycin and metronidazole). Among these antibiotics, 6 were used in more than 70% of local guidelines and had significant variations in (1) maintenance daily doses for amikacin, imipenem/cilastatin, ceftazidime and metronidazole; (2) loading doses for continuous infusion of vancomycin; and (3) dosing intervals for gentamicin and amikacin.ConclusionsA considerable inter-centre variability of dosage regimens of antibiotics exists in French NICUs. Developmental pharmacokinetic–pharmacodynamic studies are essential for the evaluation of antibiotics in order to establish evidence-based dosage regimens for effective and safe administration in neonates.
Prevalence of severe childhood obesity in England: 2006–2013
Authors: Ells Louisa J , Hancock Caroline , Copley Vicky R , Mead Emma , Dinsdale Hywell , Kinra Sanjay , Viner Russell M , Rutter Harry 
Published: January 2015

BackgroundInternational evidence shows that severe paediatric obesity results in an increased risk of ill health and may require specialised weight management strategies, yet there remains a lack of data on the extent of the problem.ObjectiveTo examine the prevalence of severe obesity in children aged 4–5 and 10–11 years, attending English schools between 2006/2007 and 2012/2013.DesignA retrospective analysis of National Child Measurement Programme (NCMP) data.SettingMaintained schools in England.ParticipantsAll children aged 4–5 and 10–11 years included in the NCMP dataset.Main outcome measuresPrevalence of severe childhood obesity, defined using the 99.6th centile of the British 1990 (UK90) growth reference for body mass index (BMI), analysed by sex, geography, ethnic group and deprivation.ResultsThe key findings show that in 2012/2013, severe obesity (BMI ≥UK90 99.6th centile) was found in 1.9% of girls and 2.3% of boys aged 4–5 years, and 2.9% of girls and 3.9% of boys aged 10–11 years. Severe obesity prevalence varies geographically and is more prevalent in children from deprived areas, and among those from black ethnic groups.ConclusionsThe findings from this study should help to raise awareness of the prevalence of severe obesity and support the provision of adequate treatment and prevention services both to support children who are already severely obese and reduce the prevalence of extreme weight in the future.
Comparison of Nottingham Prognostic Index and Adjuvant Online prognostic tools in young women with breast cancer: review of a single-institution experience
Authors: Hearne Benjamin Joseph , Teare M Dawn , Butt Mohammad , Donaldson Leslie 
Published: January 2015

ObjectiveAccurately predicting the prognosis of young patients with breast cancer (<40 years) is uncertain since the literature suggests they have a higher mortality and that age is an independent risk factor. In this cohort study we considered two prognostic tools; Nottingham Prognostic Index and Adjuvant Online (Adjuvant!), in a group of young patients, comparing their predicted prognosis with their actual survival.SettingNorth East EnglandParticipantsData was prospectively collected from the breast unit at a Hospital in Grimsby between January 1998 and December 2007. A cohort of 102 young patients with primary breast cancer was identified and actual survival data was recorded. The Nottingham Prognostic Index and Adjuvant! scores were calculated and used to estimate 10-year survival probabilities. Pearson's correlation coefficient was used to demonstrate the association between the Nottingham Prognostic Index and Adjuvant! scores. A constant yearly hazard rate was assumed to generate 10-year cumulative survival curves using the Nottingham Prognostic Index and Adjuvant! predictions.ResultsActual 10-year survival for the 92 patients who underwent potentially curative surgery for invasive cancer was 77.2% (CI 68.6% to 85.8%). There was no significant difference between the actual survival and the Nottingham Prognostic Index and Adjuvant! 10-year estimated survival, which was 77.3% (CI 74.4% to 80.2%) and 82.1% (CI 79.1% to 85.1%), respectively. The Nottingham Prognostic Index and Adjuvant! results demonstrated strong correlation and both predicted cumulative survival curves accurately reflected the actual survival in young patients.ConclusionsThe Nottingham Prognostic Index and Adjuvant! are widely used to predict survival in patients with breast cancer. In this study no statistically significant difference was shown between the predicted prognosis and actual survival of a group of young patients with breast cancer.
Trends in antimicrobial resistance in equine bacterial isolates: 1999–2012
Authors: Johns I. C. , Adams E.‐L. 
Published: January 2015

This study aimed to identify changing antimicrobial resistance patterns in isolates commonly obtained from equine clinical submissions. Laboratory records from 1999 to 2012 were searched for equine samples from which Escherichia coli or Streptococcus species was isolated. Susceptibility to enrofloxacin, ceftiofur, gentamicin, penicillin G, trimethoprim sulfamethoxazole (TMPS) and tetracyclines was noted. Isolates were divided into those identified between 1999 and 2004 (Early) and between 2007 and 2012 (Late). The proportion of isolates resistant to each antimicrobial and multiple drug‐resistant (MDR) isolates (≥3 antimicrobial classes) was compared between time periods. There were 464 isolates identified (242 Early; 222 Late). A significant increase in the percentage of E coli isolates resistant to ceftiofur (7.3–22.7 per cent, P=0.002), gentamicin (28.5–53.9 per cent, P<0.001), tetracyclines (48.4–74.2 per cent, P=0.002) and MDR (26.6–49.4 per cent, P=0.007) was identified. There was a significant increase over time in the percentage of all streptococcal species resistant to enrofloxacin, ranging from 0 per cent (Early) up to 63 per cent (Late) depending on species. For Streptococcus zooepidemicus, resistance over time to tetracyclines and MDR increased. There was also a decrease in the proportion of S zooepidemicus resistant to TMPS over time. An increase in resistance over time of common equine pathogens to a number of commonly used antimicrobials supports the responsible use of antimicrobials.
Raft Refloated
Authors: Howard Heidi , Schwarzkopf Malte , Madhavapeddy Anil , Crowcroft Jon 
Published: January 2015

The Paxos algorithm is famously difficult to reason about and even more so to implement, despite having been synonymous with distributed consensus for over a decade. The recently proposed Raft protocol lays claim to being a new, understandable consensus algorithm, improving on Paxos without making compromises in performance or correctness.
In this study, we repeat the Raft authors' performance analysis. We developed a clean-slate implementation of the Raft protocol and built an event-driven simulation framework for prototyping it on experimental topologies. We propose several optimizations to the Raft protocol and demonstrate their effectiveness under contention. Finally, we empirically validate the correctness of the Raft protocol invariants and evaluate Raft's understandability claims.
Treatment of Invasive Brain Tumors Using a Chain-like Nanoparticle
Authors: Peiris Pubudu M. , Abramowski Aaron , Mcginnity James , Doolittle Elizabeth , Toy Randall , Gopalakrishnan Ramamurthy , Shah Shruti , Bauer Lisa , Ghaghada Ketan B. , Hoimes Christopher , Brady-Kalnay Susann M. , Basilion James P. , Griswold Mark A. , Karathanasis Efstathios 
Published: January 2015

Abstract
Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood–tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment. Cancer Res; 75(7); 1356–65. ©2015 AACR.
Emergence of Drug Tolerance in Cancer Cell Populations: An Evolutionary Outcome of Selection, Nongenetic Instability, and Stress-Induced Adaptation
Authors: Chisholm Rebecca H. , Lorenzi Tommaso , Lorz Alexander , Larsen Annette K. , Almeida Luís Neves de , Escargueil Alexandre , Clairambault Jean 
Published: January 2015

Abstract
In recent experiments on isogenetic cancer cell lines, it was observed that exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells, which display markers associated with stem cell–like cancer cells. After a period of time, some of the surviving cells were observed to change their phenotype to resume normal proliferation and eventually repopulate the sample. Furthermore, the drug-tolerant cells could be drug resensitized following drug washout. Here, we propose a theoretical mechanism for the transient emergence of such drug tolerance. In this framework, we formulate an individual-based model and an integro-differential equation model of reversible phenotypic evolution in a cell population exposed to cytotoxic drugs. The outcomes of both models suggest that nongenetic instability, stress-induced adaptation, selection, and the interplay between these mechanisms can push an actively proliferating cell population to transition into a weakly proliferative and drug-tolerant state. Hence, the cell population experiences much less stress in the presence of the drugs and, in the long run, reacquires a proliferative phenotype, due to phenotypic fluctuations and selection pressure. These mechanisms can also reverse epigenetic drug tolerance following drug washout. Our study highlights how the transient appearance of the weakly proliferative and drug-tolerant cells is related to the use of high-dose therapy. Furthermore, we show how stem-like characteristics can act to stabilize the transient, weakly proliferative, and drug-tolerant subpopulation for a longer time window. Finally, using our models as in silico laboratories, we propose new testable hypotheses that could help uncover general principles underlying the emergence of cancer drug tolerance. Cancer Res; 75(6); 930–9. ©2015 AACR.
Plumbagin Inhibits Prostate Carcinogenesis in Intact and Castrated PTEN Knockout Mice via Targeting PKCϵ, Stat3, and Epithelial-to-Mesenchymal Transition Markers
Authors: Hafeez Bilal Bin , Fischer Joseph W. , Singh Ashok , Zhong Weixiong , Mustafa Ala , Meske Louise , Sheikhani Mohammad Ozair , Verma Ajit Kumar 
Published: January 2015

Abstract
Prostate cancer continues to remain the most common cancer and the second leading cause of cancer-related deaths in American males. The Pten deletions and/or mutations are frequently observed in both primary prostate cancers and metastatic prostate tissue samples. Pten deletion in prostate epithelium in mice results in prostatic intraepithelial neoplasia (PIN), followed by progression to invasive adenocarcinoma. The Pten conditional knockout mice [(Pten-loxp/loxp:PB-Cre4+) (Pten-KO)] provide a unique preclinical model to evaluate agents for efficacy for both the prevention and treatment of prostate cancer. We present here for the first time that dietary plumbagin, a medicinal plant–derived naphthoquinone (200 or 500 ppm) inhibits tumor development in intact as well as castrated Pten-KO mice. Plumbagin has shown no signs of toxicity at either of these doses. Plumbagin treatment resulted in a decrease expression of PKCϵ, AKT, Stat3, and COX2 compared with the control mice. Plumbagin treatment also inhibited the expression of vimentin and slug, the markers of epithelial-to-mesenchymal transition (EMT) in prostate tumors. In summary, the results indicate that dietary plumbagin inhibits growth of both primary and castration-resistant prostate cancer (CRPC) in Pten-KO mice, possibly via inhibition of PKCϵ, Stat3, AKT, and EMT markers (vimentin and slug), which are linked to the induction and progression of prostate cancer. Cancer Prev Res; 8(5); 375–86. ©2015 AACR.
Three Steps to Breaking Immune Tolerance to Lymphoma: A Microparticle Approach
Authors: Makkouk Amani , Joshi Vijaya B. , Lemke Caitlin D. , Wongrakpanich Amaraporn , Olivier Alicia K. , Blackwell Sue E. , Salem Aliasger K. , Weiner George J. 
Published: January 2015

Abstract
In situ immunization aims at generating antitumor immune responses through manipulating the tumor microenvironment. On the basis of recent advances in the understanding of antitumor immunity, we designed a three-step approach to in situ immunization to lymphoma: (i) inducing immunogenic tumor cell death with the chemotherapeutic drug doxorubicin. Doxorubicin enhances the expression of “eat-me” signals by dying tumor cells, facilitating their phagocytosis by dendritic cells (DC). Because of the vesicant activity of doxorubicin, microparticles made of biodegradable polymer poly(lactide-co-glycolide) or PLGA can safely deliver doxorubicin intratumorally and are effective vaccine adjuvants, (ii) enhancing T-cell activation using anti-OX40 and (iii) sustaining T-cell responses by checkpoint blockade using anti–CTLA-4. In vitro, doxorubicin microparticles were less cytotoxic to DCs than to B lymphoma cells, did not require internalization by tumor cells, and significantly enhanced phagocytosis of tumor cells by DCs as compared with soluble doxorubicin. In mice, this three-step therapy induced CD4- and CD8-dependent systemic immune responses that enhanced T-cell infiltration into distant tumors, leading to their eradication and significantly improving survival. Our findings demonstrate that systemic antitumor immune responses can be generated locally by three-step therapy and merit further investigation as an immunotherapy for patients with lymphoma. Cancer Immunol Res; 3(4); 389–98. ©2015 AACR.
Isolated MCA Disease in Patients Without Significant Atherosclerotic Risk Factors
Authors: Ahn Sung-Ho , Lee Jookyung , Kim Yeon-Jung , Kwon Sun U. , Lee Deokhee , Jung Seung-Chai , Kang Dong-Wha , Kim Jong S. 
Published: January 2015

Background and Purpose—
Diagnosis of intracranial artery atherosclerosis remains often uncertain. The high-resolution magnetic resonance imaging (HR-MRI) enables vessel wall assessment for more precise diagnoses. The aim of the present study was to investigate the etiologies of middle cerebral artery steno-occlusive disease in young adult patients with few atherosclerotic risk factors using HR-MRI.

Methods—
We prospectively studied patients who visited a tertiary hospital in Seoul, Korea, and had (1) unilateral middle cerebral artery disease (≥50% stenosis or occlusion), (2) were ≤55 years old and had no or minimal (≤1) atherosclerotic risk factors. We excluded patients with a confirmed diagnosis of Moyamoya disease, vasculitis, or dissection and those having emboligenic sources. A presumptive diagnosis was made based on HR-MRI findings, and patients were categorized as HR-athero (atherosclerotic disease), HR-MMD (Moyamoya disease), HR-dissection, or HR-vasculitis.

Results—

Among 95 patients analyzed, 26 (27.4%) had HR-athero who were more often male (
P
=0.004), smokers (
P
=0.018), and had focal stenosis (
P
=0.003) than others. As compared with the HR-athero patients, 29 HR-MMD patients were more often female (
P
<0.001) and more often had occlusive lesions (
P
=0.001) and nonfocal stenosis (
P
<0.001). The 22 HR-dissection patients tended to have hypertension less often, and the 13 HR-vasculitis patients were younger (
P
=0.004) and tended to have nonfocal stenosis.

Conclusions—
In our cohort of young patients with minimal risk factors, atherosclerosis seems to be an uncommon pathology of middle cerebral artery stenosis. HR-MRI aids us to make a more reliable diagnosis.
Verification of the New Nonhydrostatic Multiscale Model on the B Grid (NMMB): A View on Global Predictability of Surface Parameters
Authors: Müller Mathias D. , Janjic Zavisa 
Published: January 2015

AbstractA global verification of temperature, dewpoint temperature, and wind speed for the new Nonhydrostatic Multiscale Model on the B Grid (NMMB) is computed for a 3-yr period (2010–12) using over 9000 weather stations. The raw model forecasts, as well as bias-removed MOS forecasts, are analyzed and compared to NOAA’s operational GFS. In comparison to the GFS, the NMMB forecasts of temperature, dewpoint temperature, and wind speed are about 10% better, even though the NMMB is run at much coarser resolution and does not yet have its own data assimilation system. However, as a result of several changes in the GFS during the 3-yr period, the MOS computations for GFS are not optimal. Using unbiased MOS forecasts, the global distribution of spatial predictability can be analyzed. Clear spatial patterns emerge, which are partly dependent on the variable. For temperature, the best forecasts can be made for small islands and coastlines, and a clear gradient of decreasing skill with increasing distance from the sea is visible on the continents. For wind speed, this pattern is almost reversed. Dewpoint temperature shows the largest patterns, mainly controlled by the humidity of the climate. Combining temperature, wind speed, and dewpoint temperature in a gross predictability index reveals a clear large-scale pattern. Remarkably, smaller-scale features like mountain ranges are not readily apparent in the bias-free predictability pattern, indicating that the spatial pattern of the gross predictability is controlled at the very large scales.
Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry
Authors: Hughes Andrew T , Milan Anna M , Davison Andrew S , Christensen Peter , Ross Gordon , Gallagher James A , Dutton John J , Ranganath Lakshminarayan R 
Published: January 2015

Background Alkaptonuria is a rare debilitating autosomal recessive disorder of tyrosine metabolism, where deficiency of homogentisate 1,2-dioxygenase results in increased homogentisic acid. Homogentisic acid is deposited as an ochronotic pigment in connective tissues, especially cartilage, leading to a severe early onset form of osteoarthritis, increased renal and prostatic stone formation and hardening of heart vessels. Treatment with the orphan drug, nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase has been shown to reduce urinary excretion of homogentisic acid. Method A reverse phase liquid chromatography tandem mass spectrometry method has been developed to simultaneously analyse serum homogentisic acid, tyrosine and nitisinone. Using matrix-matched calibration standards, two product ion transitions were identified for each compound (homogentisic acid, tyrosine, nitisinone) and their respective isotopically labelled internal standards (13C6-homogentisic acid, d2-tyrosine, 13C6-nitisinone). Results Intrabatch accuracy was 94–108% for homogentisic acid, 95–109% for tyrosine and 89–106% for nitisinone; interbatch accuracy (n = 20) was 88–108% for homogentisic acid, 91–104% for tyrosine and 88–103% for nitisinone. Precision, both intra- and interbatch were <12% for homogentisic acid and tyrosine, and <10% for nitisinone. Matrix effects observed with acidified serum were normalized by the internal standard (<10% coefficient of variation). Homogentisic acid, tyrosine and nitisinone proved stable after 24 h at room temp, three freeze–thaw cycles and 24 h at 4℃. The assay was linear to 500μmol/L homogentisic acid, 2000μmol/L tyrosine and 10μmol/L nitisinone; increased range was not required for clinical samples and no carryover was observed. Conclusions The method developed and validated shows good precision, accuracy and linearity appropriate for the monitoring of alkaptonuria patients, pre- and post-nitisinone therapy.