bluuebunny/crossref_metadata_2025 huggingface dataset:
Shortcomings of prosthodontic rehabilitation of patients living in long‐term care facilities
Authors: Steinmassl P.‐A. , Steinmassl O. , Kraus G. , Dumfahrt H. , Grunert I.
Published: October 2015

Removable dentures are a non‐invasive, cost‐effective prosthodontic solution for the reduced dentition. Their intended purpose is the rehabilitation of harmonious oral function and aesthetics on a long‐term basis. The prevalence of removable dentures among patients of advanced age is high and the quality of the dentures is often poor. The aim of this study was to find the most important shortcomings of removable dentures and address the main targets for improving the quality of prosthodontic rehabilitation. The records from dental check‐ups in Austrian residential homes were analysed retrospectively. Dental anamnesis questionnaires and data from the clinical examinations of 105 denture wearers were analysed. The functional condition and retention of 192 dentures had been assessed, as well as the impact of the dentures on the intra‐oral tissues. Insufficient denture retention was very common, particularly in the lower jaw (56·0%). Problems with the masticatory function were reported by 26.7% of the denture wearers, 11·4% were dissatisfied with the denture aesthetics, and 4·8% had difficulties with phonetics. Traumatic ulcers were found in 18·1%. Cracks, broken pieces (6·3%) or missing denture teeth (2·1%) were rare. It may be assumed that the findings of the present study also apply to a great percentage of community‐dwelling seniors. The most important issues in prosthodontic rehabilitation with removable dentures are denture retention and masticatory function. Regular dental check‐ups, denture adjustment and, when necessary, relining can maintain the primary denture quality and prevent damages of the oral tissues caused by ill‐fitting dentures.
Supporting the Whole Child Through Coordinated Policies, Processes, and Practices
Authors: Murray Sharon D. , Hurley James , Ahmed Shannon R.
Published: October 2015

BACKGROUND

The Whole School, Whole Community, Whole Child (WSCC) model provides a framework for promoting greater alignment, integration, and collaboration between health and education across the school setting and improving students' cognitive, physical, social, and emotional development. By providing a learning environment that ensures each student is emotionally and physically healthy, safe, actively engaged, supported, and challenged, the WSCC model presents a framework for school systems to evaluate, streamline, implement, and sustain policies, processes, and practices.

METHODS

This article examines the essential roles of the school district and of schools in aligning, developing, and implementing policy, processes, and practices to create optimal learning environments that support the whole child.

RESULTS

Three key factors advance efforts to align policies, processes, and practices. These include hiring a coordinator at the district and school levels, having collaborative teams address health and learning at the district and school levels, and using data to make decisions and build health outcomes into school and district accountability systems.

CONCLUSIONS

These key factors provide a road map for successfully implementing WSCC. More research is needed to determine the extent that coordinators, collaborative teams, and the inclusion of health indicators in accountability systems impact student health and learning.
Lessons Learned From the Whole Child and Coordinated School Health Approaches
Authors: Rasberry Catherine N. , Slade Sean , Lohrmann David K. , Valois Robert F.
Published: October 2015

BACKGROUND

The new Whole School, Whole Community, Whole Child (WSCC) model, designed to depict links between health and learning, is founded on concepts of coordinated school health (CSH) and a whole child approach to education.

METHODS

The existing literature, including scientific articles and key publications from national agencies and organizations, was reviewed and synthesized to describe (1) the historical context for CSH and a whole child approach, and (2) lessons learned from the implementation and evaluation of these approaches.

RESULTS

The literature revealed that interventions conducted in the context of CSH can improve health‐related and academic outcomes, as well as policies, programs, or partnerships. Several structural elements and processes have proved useful for implementing CSH and a whole child approach in schools, including use of school health coordinators, school‐level and district‐level councils or teams; systematic assessment and planning; strong leadership and administrative support, particularly from school principals; integration of health‐related goals into school improvement plans; and strong community collaborations.

CONCLUSIONS

Lessons learned from years of experience with CSH and the whole child approaches have applicability for developing a better understanding of the WSCC model as well as maximizing and documenting its potential for impacting both health and education outcomes.
How the Whole School, Whole Community, Whole Child Model Works: Creating Greater Alignment, Integration, and Collaboration Between Health and Education
Authors: Chiang Rachelle Johnsson , Meagher Whitney , Slade Sean
Published: October 2015

BACKGROUND

The Whole School, Whole Community, Whole Child (WSCC) model calls for greater collaboration across the community, school, and health sectors to meet the needs and support the full potential of each child. This article reports on how 3 states and 2 local school districts have implemented aspects of the WSCC model through collaboration, leadership and policy creation, alignment, and implementation.

METHODS

We searched state health and education department websites, local school district websites, state legislative databases, and sources of peer‐reviewed and gray literature to identify materials demonstrating adoption and implementation of coordinated school health, the WSCC model, and associated policies and practices in identified states and districts. We conducted informal interviews in each state and district to reinforce the document review.

RESULTS

States and local school districts have been able to strategically increase collaboration, integration, and alignment of health and education through the adoption and implementation of policy and practice supporting the WSCC model. Successful utilization of the WSCC model has led to substantial positive changes in school health environments, policies, and practices.

CONCLUSIONS

Collaboration among health and education sectors to integrate and align services may lead to improved efficiencies and better health and education outcomes for students.
Diagnosing appendicitis: What works, what does not and where to go from here?
Authors: Craig Simon , Dalton Sarah
Published: October 2015

Although acute appendicitis is the most common reason for emergency abdominal surgery in children, diagnosis is far from straightforward. Delays in diagnosis can result in significant complications, whereas over‐diagnosis can result in costly inter‐hospital transfers and unnecessary surgery. This article aims to describe current evidence‐based assessment of children with possible appendicitis presenting to the emergency department. We provide an overview of the literature relating to the various available diagnostic approaches, including the application of history, examination, pathology tests, imaging, and clinical decision rules.
A combined morphological, ultrastructural, molecular, and biochemical study of the peculiar family Gomontiellaceae (Oscillatoriales) reveals a new cylindrospermopsin‐producing clade of cyanobacteria
Authors: Bohunická Markéta , Mareš Jan , Hrouzek Pavel , Urajová Petra , Lukeš Martin , Šmarda Jan , Komárek Jiří , Gaysina Lira A. , Strunecký Otakar
Published: October 2015

Members of the morphologically unusual cyanobacterial family Gomontiellaceae were studied using a polyphasic approach. Cultured strains of Hormoscilla pringsheimii, Starria zimbabweënsis, Crinalium magnum, and Crinalium epipsammum were thoroughly examined, and the type specimen of the family, Gomontiella subtubulosa, was investigated. The results of morphological observations using both light microscopy and transmission electron microscopy were consistent with previous reports and provided evidence for the unique morphological and ultrastructural traits of this family. Analysis of the 16S rRNA gene confirmed the monophyletic origin of non‐marine repre‐sentatives of genera traditionally classified into this family. The family was phylogenetically placed among other groups of filamentous cyanobacterial taxa. The presence of cellulose in the cell wall was analyzed and confirmed in all cultured Gomontiellaceae members using Fourier transform infrared spectroscopy and fluorescence microscopy. Evaluation of toxins produced by the studied strains revealed the hepatotoxin cylindrospermopsin (CYN) in available strains of the genus Hormoscilla. Production of this compound in both Hormoscilla strains was detected using high‐performance liquid chromatography in tandem with high resolution mass spectrometry and confirmed by positive PCR amplification of the cyrJ gene from the CYN biosynthetic cluster. To our knowledge, this is the first report of CYN production by soil cyanobacteria, establishing a previously unreported CYN‐producing lineage. This study indicates that cyanobacteria of the family Gomontiellaceae form a separate but coherent cluster defined by numerous intriguing morphological, ultrastructural, and biochemical features, and exhibiting a toxic potential worthy of further investigation.
Soybean Oil Volume Fraction Effects on the Rheology Characteristics and Gelation Behavior of Glucono‐δ‐Lactone and Calcium Sulfate‐Induced Tofu Gels
Authors: Nicole Murekatete , Caimeng Zhang , Joseph Hategekimana , Eric Karangwa , Yufei Hua
Published: October 2015

The effects soybean oil volume fraction on the rheological characteristics and gelation behavior of acid and salt‐induced soft tofu‐type gels was investigated. High oil volume fraction resulted in lower gel point temperature and shorter gelation time (tgel) while G′ at the gel point increased as the oil volume fraction in the gels increased. A power law relationship tgel, gel point temperature and oil concentration was found and also the plot of G′ versus oil concentration fitted well in the model: G′∼CA. The exponent “A” was positive in salt‐induced gels but negative in acid‐induced gels. This gelation behavior trend was demonstrated by estimating the composite gel shear modulus, which showed that, in salt‐induced gels the stiffness of the oil droplets was higher than the one of the gel matrix while it was the opposite in acid‐induced gels. Furthermore, the weak gel model was used to analyze and describe the network extension and its strength.

Practical Applications

In this comparative study, soybean oil volume fraction effects on the rheological characteristics and gelation behavior of acid and salt‐induced soft tofu‐type gels was established. Different coagulation temperatures and coagulants were used. The study gives new insights on the protein‐to‐oil droplets interactions during gelation at different pHs in a tofu gel like product. The better understanding of the gelation mechanism, small and large scale deformations of soy protein gels with additional oil, is industrially relevant, as it will help in better process line design, monitoring and quality control which would potentially lead to the development of novel soy‐based and dairy free cheeses products. Additionally, the parameters and conditions used were closely related to the ones used during soft silken tofu making, therefore, ensuring the process implementation much easier.
Pharmacokinetics and pharmacodynamics of gamithromycin in pulmonary epithelial lining fluid in naturally occurring bovine respiratory disease in multisource commingled feedlot cattle
Authors: DeDonder K. D. , Apley M. D. , Li M. , Gehring R. , Harhay D. M. , Lubbers B. V. , White B. J. , Capik S. F. , KuKanich B. , Riviere J. E. , Tessman R. K.
Published: October 2015

The objectives of this study were to determine (i) whether an association exists between individual pharmacokinetic parameters and treatment outcome when feeder cattle were diagnosed with bovine respiratory disease (BRD) and treated with gamithromycin (Zactran®) at the label dose and (ii) whether there was a stronger association between treatment outcome and gamithromycin concentration in plasma or in the pulmonary epithelial lining fluid (PELF) effect compartment. The study design was a prospective, blinded, randomized clinical trial utilizing three groups of 60 (362–592 lb) steers/bulls randomly allocated within origin to sham injection or gamithromycin mass medication. Cattle were evaluated daily for signs of BRD by a veterinarian blinded to treatment. Animals meeting the BRD case definition were enrolled and allocated to a sample collection scheme consisting of samples for bacterial isolation (bronchoalveolar lavage fluid and nasopharyngeal swabs) and gamithromycin concentration determination (PELF and plasma). Gamithromycin susceptibility of M. haemolytica (n = 287) and P. multocida (n = 257) were determined using broth microdilution with frozen panels containing gamithromycin at concentrations from 0.03 to 16 μg/mL. A two‐compartment plasma pharmacokinetic model with an additional compartment for gamithromycin in PELF was developed using rich data sets from published and unpublished studies. The sparse data from our study were then fit to this model using nonlinear mixed effects modeling to estimate individual parameter values. The resulting parameter estimates were used to simulate full time–concentration profiles for each animal in this study. These profiles were analyzed using noncompartmental methods so that PK/PD indices (AUC24/MIC, AUC∞/MIC, CMAX/MIC) could be calculated for plasma and PELF (also T>MIC) for each individual. The calculated PK/PD indices were indicative that for both M. haemolytica and P. multocida a higher drug exposure in terms of concentration, and duration of exposure relative to the MIC of the target pathogen, was favorable to a successful case outcome. A significant association was found between treatment success and PELF AUC0–24/MIC for P. multocida. The calves in this study demonstrated an increased clearance and volume of distribution in plasma as compared to the healthy calves in two previously published reports. Ultimately, the findings from this study indicate that higher PK/PD indices were predictive of positive treatment outcomes.
Factors Affecting Grammatical and Lexical Complexity of Long‐Term L2 Speakers’ Oral Proficiency
Authors: Lahmann Cornelia , Steinkrauss Rasmus , Schmid Monika S.
Published: October 2015

There remains considerable disagreement about which factors drive second language (L2) ultimate attainment. Age of onset (AO) appears to be a robust factor, lending support to theories of maturational constraints on L2 acquisition. The present study is an investigation of factors that influence grammatical and lexical complexity at the stage of L2 ultimate attainment. Grammatical and lexical complexity were assessed in 102 spontaneous oral interviews. Interviewees’ AOs ranged from 7 to 17 years old. Multifactorial analyses yielded consistently significant effects of gender and level of education for grammatical and lexical complexity. Additionally, native language use at work was a significant predictor for lexical complexity; conversely, AO did not emerge as a significant factor. We conclude that grammatical and lexical complexity at the stage of L2 ultimate attainment is the result of a complex interplay of variables that are general to language learning and performance rather than L2 specific.

Open Practices

This article has been awarded an Open Materials badge. All materials are publicly accessible in the IRIS digital repository at http://www.iris‐database.org. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki.
Silencing Nicotiana attenuata LHY and ZTL alters circadian rhythms in flowers
Authors: Yon Felipe , Joo Youngsung , Cortés Llorca Lucas , Rothe Eva , Baldwin Ian T. , Kim Sang‐Gyu
Published: October 2015

The rhythmic opening/closing and volatile emissions of flowers are known to attract pollinators at specific times. That these rhythms are maintained under constant light or dark conditions suggests a circadian clock involvement. Although a forward and reverse genetic approach has led to the identification of core circadian clock components in Arabidopsis thaliana, the involvement of these clock components in floral rhythms has remained untested, probably because of the weak diurnal rhythms in A. thaliana flowers.

Here, we addressed the role of these core clock components in the flowers of the wild tobacco Nicotiana attenuata, whose flowers open at night, emit benzyl acetone (BA) scents and move vertically through a 140° arc.

We first measured N. attenuata floral rhythms under constant light conditions. The results suggest that the circadian clock controls flower opening, BA emission and pedicel movement, but not flower closing.

We generated transgenic N. attenuata lines silenced in the homologous genes of Arabidopsis LATE ELONGATED HYPOCOTYL (LHY) and ZEITLUPE (ZTL), which are known to be core clock components. Silencing NaLHY and NaZTL strongly altered floral rhythms in different ways, indicating that conserved clock components in N. attenuata coordinate these floral rhythms.
Childhood obesity as a predictor of morbidity in adulthood: a systematic review and meta‐analysis
Authors: Llewellyn A. , Simmonds M. , Owen C. G. , Woolacott N.
Published: October 2015

Obese children are at higher risk of being obese as adults, and adult obesity is associated with an increased risk of morbidity. This systematic review and meta‐analysis investigates the ability of childhood body mass index (BMI) to predict obesity‐related morbidities in adulthood. Thirty‐seven studies were included. High childhood BMI was associated with an increased incidence of adult diabetes (OR 1.70; 95% CI 1.30–2.22), coronary heart disease (CHD) (OR 1.20; 95% CI 1.10–1.31) and a range of cancers, but not stroke or breast cancer. The accuracy of childhood BMI when predicting any adult morbidity was low. Only 31% of future diabetes and 22% of future hypertension and CHD occurred in children aged 12 or over classified as being overweight or obese. Only 20% of all adult cancers occurred in children classified as being overweight or obese. Childhood obesity is associated with moderately increased risks of adult obesity‐related morbidity, but the increase in risk is not large enough for childhood BMI to be a good predictor of the incidence of adult morbidities. This is because the majority of adult obesity‐related morbidity occurs in adults who were of healthy weight in childhood. Therefore, targeting obesity reduction solely at obese or overweight children may not substantially reduce the overall burden of obesity‐related disease in adulthood.
Emerging Hubs in Plant Light and Temperature Signaling
Authors: Lorenzo Christian D. , Sanchez‐Lamas Maximiliano , Antonietti Mariana S. , Cerdán Pablo D.
Published: October 2015

Due to their nature as sessile organisms, plants must accurately sense their surroundings and then translate this information into efficient acclimation responses to maximize development. Light and temperature are two major stimuli that provide immediate cues regarding energy availability, daylength, proximity of other species and seasonal changes. Both cues are sensed by complex systems and the integration of these signals is of very high value to properly respond to environmental changes without being disguised by random changes. For instance a cold day has a different significance if it occurs during the illuminated phase of the day or during the night, or when days are shortening during the fall instead of a long‐day in spring. Here, we summarize recent advances in the nature of signaling components that operate as connectors of light and temperature signaling, with emphasis on the emerging hubs. Despite the nature of the thermosensors is still in its infancy compared to an important body of knowledge about plant sensory photoreceptors, the interaction of both types of signaling will not only bring clues of how plants integrate environmental information, but also will help in leading research in the nature of the thermosensors themselves.
Business as a Collaborative Partner: Understanding Firms’ Sociopolitical Support for Policy Formation
Authors: Kim Younsung , Darnall Nicole
Published: October 2015

While many scholars have discussed the merits of collaborative governance, especially for addressing complicated modern policy challenges, the literature has paid less attention to how business can serve as an effective collaborative partner during the formation of mandatory policies and regulations. Drawing on scholarship in the management sciences and combining it with literature in public administration and public policy, the authors elaborate on four distinct types of business responses to proposed regulations based on degrees of political activity and social responsiveness: defensive, reactive, proactive, and anticipatory. They then characterize the reasons why proactive firms are more likely to be valuable collaborative partners with policy makers and public managers: their engagement may avoid costly stalemates that frequently hinder policy making and help develop cost‐effective, flexible policy approaches to complex social problems.
Composite Estimating Equation Method for the Accelerated Failure Time Model with Length‐biased Sampling Data
Authors: Qiu Zhiping , Qin Jing , Zhou Yong
Published: October 2015

Length‐biased sampling data are often encountered in the studies of economics, industrial reliability, epidemiology, genetics and cancer screening. The complication of this type of data is due to the fact that the observed lifetimes suffer from left truncation and right censoring, where the left truncation variable has a uniform distribution. In the Cox proportional hazards model, Huang & Qin (Journal of the American Statistical Association, 107, 2012, p. 107) proposed a composite partial likelihood method which not only has the simplicity of the popular partial likelihood estimator, but also can be easily performed by the standard statistical software. The accelerated failure time model has become a useful alternative to the Cox proportional hazards model. In this paper, by using the composite partial likelihood technique, we study this model with length‐biased sampling data. The proposed method has a very simple form and is robust when the assumption that the censoring time is independent of the covariate is violated. To ease the difficulty of calculations when solving the non‐smooth estimating equation, we use a kernel smoothed estimation method (Heller;Journal of the American Statistical Association, 102, 2007, p. 552). Large sample results and a re‐sampling method for the variance estimation are discussed. Some simulation studies are conducted to compare the performance of the proposed method with other existing methods. A real data set is used for illustration.
Sex Ratio Effects on Marital Formation and Dissolution, 1980–2000
Authors: Dollar Cindy Brooks
Published: October 2015

Although marriage market characteristics are often used to explain in–out marriage transitions, Guttentag and Secord's sex ratio thesis provides a unique theoretical framework by which to elucidate marriage and divorce. The theory emphasizes the availability of “opposite” sex partners as an important factor, but hypothesized outcomes assume a gendered marriage market whereby males are more socioeconomically powerful than females. Using geographically standardized census tract data (N = 65,443), I examine the theory empirically across three decennial time points. After establishing that males, on average, hold a disproportionate amount of socioeconomic power, I conduct cross‐sectional regression analyses of marriage and divorce from 1980 to 2000. Results partially support the theory. While female marriage is consistently related to sex ratios as expected, sex ratios influence male marriage as expected only in some time periods and female and male divorce do not operate as expected in any time point. The findings imply that marriage entry and dissolution have distinctive causal mechanisms, suggesting the need for further theorization and research.
The phylogeny of stiletto flies (Diptera: Therevidae)
Authors: WINTERTON SHAUN L. , HARDY NATE B. , GAIMARI STEPHEN D. , HAUSER MARTIN , HILL HILARY N. , HOLSTON KEVIN C. , IRWIN MICHAEL E. , LAMBKIN CHRISTINE L. , METZ MARK A. , TURCO FEDERICA , WEBB DONALD , YANG LONGLONG , YEATES DAVID K. , WIEGMANN BRIAN M.
Published: October 2015

The therevoid clade represents a group of four families (Apsilocephalidae, Evocoidae, Scenopinidae and Therevidae) of lower brachyceran Diptera in the superfamily Asiloidea. The largest of these families is that of the stiletto flies (Therevidae). A large‐scale (i.e. supermatrix) phylogeny of Therevidae is presented based on DNA sequence data from seven genetic loci (16S, 18S and 28S ribosomal DNA and four protein‐encoding genes: elongation factor 1‐alpha, triose phosphate isomerase, short‐wavelength rhodopsin and the CPSase region of carbamoyl‐phosphate synthase‐aspartate transcarbamoylase‐dihydroorotase). Results are presented from Bayesian phylogenetic analyses of approximately 8.7 kb of sequence data for 204 taxa representing all subfamilies and genus groups of Therevidae. Our results strongly support the sister‐group relationship between Therevidae and Scenopinidae, with Apsilocephalidae as sister to Evocoidae. Previous estimates of stiletto fly phylogeny based on morphology or DNA sequence data, or supertree analysis, have failed to find significant support for relationships among subfamilies. We report for the first time strong support for the placement of the subfamily Phycinae as sister to the remaining Therevidae, originating during the Mid Cretaceous. As in previous studies, the sister‐group relationship between the species‐rich subfamilies Agapophytinae and Therevinae is strongly supported. Agapophytinae are recovered as monophyletic, inclusive of the Taenogera group. Therevinae comprise the bulk of the species richness in the family and appear to be a relatively recent and rapid radiation originating in the southern hemisphere (Australia + Antarctica + South America) during the Late Cretaceous. Genus groups are defined for all subfamilies based on these results.
Full‐length nucleotide sequences of 30 common SLC44A2 alleles encoding human neutrophil antigen‐3
Authors: Chen Qing , Srivastava Kshitij , Ardinski Stefanie C. , Lam Kevin , Huvard Michael J. , Schmid Pirmin , Flegel Willy A.
Published: October 2015

BACKGROUND

Human neutrophil antigen‐3a (HNA‐3a) alloantibodies can cause severe transfusion‐related acute lung injury. The frequencies of the single‐nucleotide polymorphisms (SNPs) indicative of the two clinically relevant HNA‐3a/b antigens are known in many populations. In this study, we determined the full‐length nucleotide sequence of common SLC44A2 alleles encoding the choline transporter–like protein‐2 that harbors HNA‐3a/b antigens.

STUDY DESIGN AND METHODS

A method was devised to determine the full‐length coding sequence (CDS) and adjacent intron sequences from genomic DNA by eight polymerase chain reaction amplifications covering all 22 SLC44A2 exons. Samples from 200 African American, 96 Caucasian, two Hispanic, and four Asian blood donors were analyzed. We developed a decision tree to determine alleles (confirmed haplotypes) from the genotype data.

RESULTS

A total of 10 SNPs were detected in the SLC44A2 CDS. The noncoding sequences harbored an additional 28 SNPs (one in the 5′‐untranslated region [UTR]; 23 in the introns; and four in the 3′‐UTR). No SNP indicative of a nonfunctional allele was detected. The nucleotide sequences for 30 SLC44A2 alleles (haplotypes) were confirmed. There may be 66 haplotypes among the 604 chromosomes screened.

CONCLUSIONS

We found 38 SNPs, including one novel SNP, in 8192 nucleotides covering the CDS of the SLC44A2 gene among 302 blood donors. Population frequencies of these SNPs were established for African Americans and Caucasians. Because alleles encoding HNA‐3b are more common than non‐functional SLC44A2 alleles, we confirmed our previous postulate that African American donors are less likely to form HNA‐3a antibodies compared to Caucasians.
Unilateral ventral strabismus in an aquarium Silver Arowana (Osteoglossum bicirrhosum)
Authors: Chow Derek W.Y. , Westermeyer Hans D. , Fernando Nimal , Hoey Seamus , Dubielzig Richard R.
Published: October 2015

An adult silver arowana (Osteoglossum bicirrhosum) presented with a 2‐month history of acute onset ventral strabismus of the right eye associated with a cystic structure overlying the dorsal aspect of the globe. Aspiration of the cyst, removal of redundant conjunctival tissue, and apposition of the surgical edges of the conjunctiva did not correct the strabismus. Magnetic resonance imaging of the head and histopathology of the eye did not reveal significant differences between affected and unaffected eyes except for a more posterior dorsal rectus muscle insertion site in the affected eye. This case report documents and describes a syndrome well known among arowana hobbyists as ‘drop eye’.
Putting it all on pigmentation: Heuristics of a bold and stochastic cell fate decision
Authors: Xing Jianhua , Lee Robin E. C.
Published: October 2015

Aberrant epithelial-to-mesenchymal transition may mediate the conversion of
Xenopus
melanocytes to a hyperproliferative and invasive state.
Proteostasis trumps YAP in colon cancer
Authors: Avril Tony , Chevet Eric
Published: October 2015

Proteotoxic drugs may selectively kill cancer cells.
Science Signaling
Podcast for 6 October 2015: Hippo signaling in T cells
Authors: Tang Fengyuan , VanHook Annalisa M.
Published: October 2015

The kinases NDR1 and NDR2 mediate Hippo signaling in thymocyte migration.
Omic profiling of melanoma evolution
Authors: Prabakaran Sudhakaran
Published: October 2015

Integrated “omic” analyses reveal pathways to drug resistance for melanoma.
Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy
Authors: Kim Aryun , Kutschke Amy , Ehmann David E. , Patey Sara A. , Crandon Jared L. , Gorseth Elise , Miller Alita A. , McLaughlin Robert E. , Blinn Christina M. , Chen April , Nayar Asha S. , Dangel Brian , Tsai Andy S. , Rooney Michael T. , Murphy-Benenato Kerry E. , Eakin Ann E. , Nicolau David P.
Published: October 2015

The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in
Pseudomonas aeruginosa
by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (
fT
>MIC). To closer emulate the conditions of the
in vivo
model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake:
piuA
,
piuC
,
pirR
,
fecI
, and
pvdS
. Against four
P. aeruginosa
isolates, SMC-3176 displayed predictable efficacy corresponding to the
fT
>MIC using the MIC in CDMHB (
R
2
= 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for
P. aeruginosa
isolate JJ 4-36, as the
in vivo
responses were inconsistent with
fT
>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which
in vivo
failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in
P. aeruginosa
due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial
in vivo
testing is warranted for compounds using the siderophore approach to thoroughly screen for this
in vitro-in vivo
disconnect in
P. aeruginosa
.
Parenteral Administration of Capsule Depolymerase EnvD Prevents Lethal Inhalation Anthrax Infection
Authors: Negus David , Vipond Julia , Hatch Graham J. , Rayner Emma L. , Taylor Peter W.
Published: October 2015

Left untreated, inhalation anthrax is usually fatal. Vegetative forms of
Bacillus anthracis
survive in blood and tissues during infection due to elaboration of a protective poly-γ-
d
-glutamic acid (PDGA) capsule that permits uncontrolled bacterial growth
in vivo
, eventually leading to overwhelming bacillosis and death. As a measure to counter threats from multidrug-resistant strains, we are evaluating the prophylactic and therapeutic potential of the PDGA depolymerase EnvD, a stable and potent enzyme which rapidly and selectively removes the capsule from the surface of vegetative cells. Repeated intravenous administration of 10 mg/kg recombinant EnvD (rEnvD) to mice infected with lethal doses of
B. anthracis
Ames spores by inhalation prevented the emergence of symptoms of anthrax and death; all animals survived the 5-day treatment period, and 70% survived to the end of the 14-day observation period. In contrast to results in sham-treated animals, the lungs and spleen of rEnvD-dosed animals were free of gross pathological changes. We conclude that rEnvD has potential as an agent to prevent the emergence of inhalation anthrax in infected animals and is likely to be effective against drug-resistant forms of the pathogen.
Raltegravir Pharmacokinetics in Patients on Asunaprevir-Daclatasvir
Authors: Barrail-Tran Aurélie , Vincent Corine , Furlan Valérie , Rosa Isabelle , Rosenthal Eric , Cheret Antoine , Molina Jean-Michel , Taburet Anne-Marie , Piroth Lionel ,   for the ANRS HC30 QUADRIH Study Group
Published: October 2015

Raltegravir pharmacokinetics was studied in 20 patients included in the ANRS HC30 QUADRIH Study before and after addition of anti-hepatitis C virus (anti-HCV) quadritherapy, including pegylated-interferon–ribavirin and asunaprevir plus daclatasvir. Raltegravir pharmacokinetic parameters remained unchanged whether administered on or off anti-HCV therapy. In addition, concentrations of raltegravir, asunaprevir, and daclatasvir were not affected by liver cirrhosis. These data suggest that in human immunodeficiency virus (HIV)-HCV-coinfected patients, whether cirrhotic or not, asunaprevir and daclatasvir could be administered safely with raltegravir.
Roflumilast, a Type 4 Phosphodiesterase Inhibitor, Shows Promising Adjunctive, Host-Directed Therapeutic Activity in a Mouse Model of Tuberculosis
Authors: Maiga Mariama C. , Ahidjo Bintou Ahmadou , Maiga Mamoudou , Bishai William R.
Published: October 2015

With phosphodiesterase inhibitors (PDE-Is) showing significant promise in shortening tuberculosis treatment, we assessed the effect of roflumilast, an FDA-approved type 4 PDE-I, in both acute and chronic murine models of tuberculosis. Alone, roflumilast had no effect on lung bacillary burden and mortality. However, when roflumilast was used in combination with isoniazid, a reduction in lung bacillary burden was observed. These data suggest that roflumilast may be a good candidate for tuberculosis host-directed therapy (HDT).
Helicobacter pylori Adaptation
In Vivo
in Response to a High-Salt Diet
Authors: Loh John T. , Gaddy Jennifer A. , Algood Holly M. Scott , Gaudieri Silvana , Mallal Simon , Cover Timothy L.
Published: October 2015

Helicobacter pylori
exhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification of
H. pylori
is influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) on
H. pylori
diversification within a host. We analyzed
H. pylori
strains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high-salt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation in
fur
(
fur-R88H
). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress in
H. pylori
-infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection of
H. pylori
strains that are most fit for growth in this environment.
Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages
Authors: Carrasco Sebastian E. , Troxell Bryan , Yang Youyun , Brandt Stephanie L. , Li Hongxia , Sandusky George E. , Condon Keith W. , Serezani C. Henrique , Yang X. Frank
Published: October 2015

Outer surface protein C (OspC) is one of the major lipoproteins expressed on the surface ofBorrelia burgdorferiduring tick feeding and the early phase of mammalian infection. OspC is required forB. burgdorferito establish infection in both immunocompetent and SCID mice and has been proposed to facilitate evasion of innate immune defenses. However, the exact biological function of OspC remains elusive. In this study, we showed that theospC-deficient spirochete could not establish infection in NOD-scid IL2rγnullmice that lack B cells, T cells, NK cells, and lytic complement. TheospCmutant also could not establish infection in anti-Ly6G-treated SCID and C3H/HeN mice (depletion of neutrophils). However, depletion of mononuclear phagocytes at the skin site of inoculation in SCID and C3H/HeN mice allowed theospCmutant to establish infectionin vivo. In phagocyte-depleted mice, theospCmutant was able to colonize the joints and triggered neutrophilia during dissemination. Furthermore, we found that phagocytosis of green fluorescent protein (GFP)-expressingospCmutant spirochetes by murine peritoneal macrophages and human THP-1 macrophage-like cells, but not in PMN-HL60, was significantly higher than parental wild-typeB. burgdorferistrains, suggesting that OspC has an antiphagocytic property. In addition, overproduction of OspC in spirochetes also decreased the uptake of spirochetes by murine peritoneal macrophages. Together, our findings provide evidence that mononuclear phagocytes play a key role in clearance of theospCmutant and that OspC promotes spirochetes' evasion of macrophages during early Lyme borreliosis.
Expression of wild-type p53 is not compatible with continued growth of p53-negative tumor cells.
Authors: Johnson P , Gray D , Mowat M , Benchimol S
Published: October 2015

Inactivation of the cellular p53 gene is a common feature of Friend virus-induced murine erythroleukemia cell lines and may represent a necessary step in the progression of this disease. As well, frequent loss or mutation of p53 alleles in diverse human tumors is consistent with the view of p53 as a tumor suppressor gene. To examine the significance of p53 gene inactivation in tumorigenesis, we have attempted to express transfected wild-type p53 in three p53-negative tumor cell lines: murine DP16-1 Friend erythroleukemia cells, human K562 cells, and SKOV-3 cells. We found that aberrant p53 proteins, which differ from wild-type p53 by a single amino acid substitution, were expressed stably in these cells, whereas wild-type p53 expression was not tolerated. The inability of p53-negative tumor cell lines to support long-term expression of wild-type p53 protein is consistent with the view that p53 is a tumor suppressor gene.
Binding of the transcription factor EBP-80 mediates the methylation response of an intracisternal A-particle long terminal repeat promoter.
Authors: Falzon M , Kuff E L
Published: October 2015

Intracisternal A-particle (IAP) expression in mouse cells has been correlated with hypomethylation of HhaI and HpaII sites in proviral long terminal repeats (LTRs). In a previous study, in vitro methylation of three HhaI sites in the U3 region of the LTR from the cloned genomic IAP element, MIA14, was shown to inhibit promoter activity in vivo. In this study, we found by site-directed mutagenesis that the two more downstream HhaI sites within this LTR were responsible for the methylation effects on promoter activity in vivo; methylation of the other (5') HhaI site, which lies within a putative SP1 binding domain, did not affect promoter activity. Methylation of the HhaI sites also inhibited promoter activity of the LTR in a cell-free transcription system. Exonuclease III footprinting demonstrated methylation-induced changes in protein binding over the region encompassing the downstream HhaI site, designated the Enh2 domain. The protein that interacts specifically with this domain, EBP-80, was characterized in a previous study (M. Falzon and E. L. Kuff, J. Biol. Chem. 264:21915-21922, 1989). We show here that the presence of methylcytosine in the HhaI site within the Enh2 domain inhibited binding of EBP-80 in vitro. The methylated MIA14 LTR construct was much less responsive to added EBP-80 in an in vitro transcription system than was the unmethylated construct. These data suggest that CpG methylation within the Enh2 domain may exert its effect on transcription in vivo by altering the interaction between EBP-80 and its cognate DNA sequence.
trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors.
Authors: Middlemas D S , Lindberg R A , Hunter T
Published: October 2015

We have screened an adult rat cerebellar cDNA library in search of novel protein tyrosine-kinase (PTK) cDNAs. A cDNA for a putative PTK, trkB, was cloned, and its sequence indicates that it is likely to be derived from a gene for a ligand-regulated receptor closely related to the human trk oncogene. Northern (RNA) analysis showed that the trkB gene is expressed predominantly in the brain and that trkB expresses multiple mRNAs, ranging from 0.7 to 9 kb. Hybridization of cerebral mRNAs with a variety of probes indicates that there are mRNAs encoding truncated trkB receptors. Two additional types of cDNA were isolated, and their sequences are predicted to encode two distinct C-terminally truncated receptors which have the complete extracellular region and transmembrane domain, but which differ in their short cytoplasmic tails.
Mutational analysis of the functional domains of yeast K1 killer toxin.
Authors: Zhu H , Bussey H
Published: October 2015

To determine the functional domains of K1 killer toxin, we analyzed the phenotypes of a set of mutations throughout regions encoding the alpha- and beta-toxin subunits that allow secretion of mutant toxins. A range of techniques have been used to examine the ability of mutant toxins to bind to beta-glucan cell wall receptor and to form lethal ion channels. Our results indicate that both the alpha and beta subunits are involved in beta-glucan receptor binding. Defects in ion channel formation and toxin immunity are confined to the hydrophobic alpha subunit of the toxin.
Activin-A binding and biochemical effects in osteoblast-enriched cultures from fetal-rat parietal bone.
Authors: Centrella M , McCarthy T L , Canalis E
Published: October 2015

Activin, a disulfide-linked polypeptide dimer first isolated from gonadal tissue extracts, has amino acid sequence and structural homology with transforming growth factor beta (TGF beta). Along with other activities, TGF beta regulates replication and differentiation and interacts with a defined set of binding sites on isolated bone cells. To determine if activin shares these properties, recombinant human activin-A (A-chain homodimer) was examined in osteoblast-enriched cultures obtained from fetal-rat parietal bone. After 23 h of treatment, 60 to 6,000 pM activin-A increased the rate of [3H]thymidine incorporation into DNA 1.5- to 4.0-fold, and at 600 to 6,000 pM, it enhanced the rate of [3H]proline incorporation into collagen and noncollagen protein by up to 1.7-fold. Like earlier studies with TGF beta in primary osteoblast-enriched cultures, the stimulatory effects of activin-A on DNA and protein synthesis were opposed by parathyroid hormone, and the influence of activin-A on collagen synthesis was independent of cell replication. Binding studies with 125I-activin-A indicated approximately 8,000 high-affinity (Kd = 0.4 nM) and 300,000 low-affinity (Kd = 40 to 50 nM) binding sites per cell. Polyacrylamide gel analysis revealed 125I-activin-A-binding complexes of Mr greater than 200,000 and 73,000 which did not appear to correspond to primary TGF beta-binding sites. These results indicate that activin-A produces TGF beta-like effects in bone and that some of these effects may be mediated, at least in part, by distinct activin receptors on bone cells.
Phosphorylation and activation of epidermal growth factor receptors in cells transformed by the src oncogene.
Authors: Wasilenko W J , Payne D M , Fitzgerald D L , Weber M J
Published: October 2015

Because functionally significant substrates for the tyrosyl protein kinase activity of pp60v-src are likely to include membrane-associated proteins involved in normal growth control, we have tested the hypothesis that pp60v-src could phosphorylate and alter the signaling activity of transmembrane growth factor receptors. We have found that the epidermal growth factor (EGF) receptor becomes constitutively phosphorylated on tyrosine in cells transformed by the src oncogene and in addition displays elevated levels of phosphoserine and phosphothreonine. High-performance liquid chromatography phosphopeptide mapping revealed two predominant sites of tyrosine phosphorylation, both of which differed from the major sites of receptor autophosphorylation; thus, the src-induced phosphorylation is unlikely to occur via an autocrine mechanism. To determine whether pp60v-src altered the signaling activity of the EGF receptor, we analyzed the tyrosine phosphorylation of phospholipase C-gamma, since phosphorylation of this enzyme occurs in response to activation of the EGF receptor but not in response to pp60v-src alone. We found that in cells coexpressing pp60v-src and the EGF receptor, phospholipase C-gamma was constitutively phosphorylated, a result we interpret as indicating that the signaling activity of the EGF receptor was altered in the src-transformed cells. These findings suggest that pp60v-src-induced alterations in phosphorylation and function of growth regulatory receptors could play an important role in generating the phenotypic changes associated with malignant transformation.