bluuebunny/crossref_metadata_2025 huggingface dataset:
Hsc70 chaperone activity underlies Trio GEF function in axon growth and guidance induced by netrin-1
Authors: DeGeer Jonathan , Kaplan Andrew , Mattar Pierre , Morabito Morgane , Stochaj Ursula , Kennedy Timothy E. , Debant Anne , Cayouette Michel , Fournier Alyson E. , Lamarche-Vane Nathalie
Published: August 2015

During development, netrin-1 is both an attractive and repulsive axon guidance cue and mediates its attractive function through the receptor Deleted in Colorectal Cancer (DCC). The activation of Rho guanosine triphosphatases within the extending growth cone facilitates the dynamic reorganization of the cytoskeleton required to drive axon extension. The Rac1 guanine nucleotide exchange factor (GEF) Trio is essential for netrin-1–induced axon outgrowth and guidance. Here, we identify the molecular chaperone heat shock cognate protein 70 (Hsc70) as a novel Trio regulator. Hsc70 dynamically associated with the N-terminal region and Rac1 GEF domain of Trio. Whereas Hsc70 expression supported Trio-dependent Rac1 activation, adenosine triphosphatase–deficient Hsc70 (D10N) abrogated Trio Rac1 GEF activity and netrin-1–induced Rac1 activation. Hsc70 was required for netrin-1–mediated axon growth and attraction in vitro, whereas Hsc70 activity supported callosal projections and radial neuronal migration in the embryonic neocortex. These findings demonstrate that Hsc70 chaperone activity is required for Rac1 activation by Trio and this function underlies netrin-1/DCC-dependent axon outgrowth and guidance.
Nick Lane: Unearthing the first cellular innovations
Authors: Powell Kendall
Published: August 2015

Lane’s unorthodox career stalks the origins of complex eukaryotic life.
Integrins mediate mechanical compression–induced endothelium-dependent vasodilation through endothelial nitric oxide pathway
Authors: Lu Xiao , Kassab Ghassan S.
Published: August 2015

Cardiac and skeletal muscle contraction lead to compression of intramuscular arterioles, which, in turn, leads to their vasodilation (a process that may enhance blood flow during muscle activity). Although endothelium-derived nitric oxide (NO) has been implicated in compression-induced vasodilation, the mechanism whereby arterial compression elicits NO production is unclear. We cannulated isolated swine (n = 39) myocardial (n = 69) and skeletal muscle (n = 60) arteriole segments and exposed them to cyclic transmural pressure generated by either intraluminal or extraluminal pressure pulses to simulate compression in contracting muscle. We found that the vasodilation elicited by internal or external pressure pulses was equivalent; moreover, vasodilation in response to pressure depended on changes in arteriole diameter. Agonist-induced endothelium-dependent and -independent vasodilation was used to verify endothelial and vascular smooth muscle cell viability. Vasodilation in response to cyclic changes in transmural pressure was smaller than that elicited by pharmacological activation of the NO signaling pathway. It was attenuated by inhibition of NO synthase and by mechanical removal of the endothelium. Stemming from previous observations that endothelial integrin is implicated in vasodilation in response to shear stress, we found that function-blocking integrin α5β1 or αvβ3 antibodies attenuated cyclic compression–induced vasodilation and NOx (NO−2 and NO−3) production, as did an RGD peptide that competitively inhibits ligand binding to some integrins. We therefore conclude that integrin plays a role in cyclic compression–induced endothelial NO production and thereby in the vasodilation of small arteries during cyclic transmural pressure loading.
BS-SNPer: SNP calling in bisulfite-seq data
Authors: Gao Shengjie , Zou Dan , Mao Likai , Liu Huayu , Song Pengfei , Chen Youguo , Zhao Shancen , Gao Changduo , Li Xiangchun , Gao Zhibo , Fang Xiaodong , Yang Huanming , Ørntoft Torben F. , Sørensen Karina D. , Bolund Lars
Published: August 2015

Summary: Sodium bisulfite conversion followed by sequencing (BS-Seq, such as whole genome bisulfite sequencing or reduced representation bisulfite sequencing) has become popular for studying human epigenetic profiles. Identifying single nucleotide polymorphisms (SNPs) is important for quantification of methylation levels and for study of allele-specific epigenetic events such as imprinting. However, SNP calling in such data is complex and time consuming. Here, we present an ultrafast and memory-efficient package named BS-SNPer for the exploration of SNP sites from BS-Seq data. Compared with Bis-SNP, a popular BS-Seq specific SNP caller, BS-SNPer is over 100 times faster and uses less memory. BS-SNPer also offers higher sensitivity and specificity compared with existing methods.

Availability and implementation: BS-SNPer is written in C++ and Perl, and is freely available at https://github.com/hellbelly/BS-Snper.

Contact: bolund@biomed.au.dk, kdso@clin.au.dk or orntoft@ki.au.dk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Comparisons of the Efficacy and Safety of Finasteride and Dutasteride for Benign Prostatic Hyperplasia: A Network Meta-Analysis
Authors: Yin Ting , Qiao Zhanbing , Li You , Li Dezhi , Jiang Min , An Chao , Wang Fen , Zuo Minghuan , Hu Kaiwen , Li Quanwang
Published: August 2015

The purpose of this study was to determine the efficacy and safety of dutasteride compared with finasteride, used for the treatment of benign prostatic hyperplasia (BPH). Pertinent studies were identified by searching of PubMed and Web of Science. The random effect model was used to combine the results. Both direct comparison using traditional meta-analysis method and indirect comparison using network meta-analysis method were performed. Twenty-one articles involving a total of 29,094 patients were included in this network meta-analysis. Pooled data demonstrated a significantly reduction in International Prostate Symptom Score in the dutasteride group compared with finasteride group [weighted mean difference (WMD) = −1.80, 95% confidence interval (CI), −2.90 to −0.11]. The treatment effects of dutasteride compared with finasteride were not significant in peak urinary flow (Q
max) (WMD = 0.76, 95% CI, −0.67 to 2.00) and total prostate volume (WMD = −7.6, 95% CI, −21 to 6.6). Also, there is no significant association between dutasteride and finasteride of the safety for the treatment of BPH. Our results suggested that there were no statistically significant differences in the treatment of symptomatic BPH among dutasteride compared with finasteride except that dutasteride can improve BPH symptoms measured by International Prostate Symptom Score.
DNA-metabarcoding uncovers the diversity of soil-inhabiting fungi in the tropical island of Puerto Rico
Authors: Urbina Hector , Scofield Douglas G. , Cafaro Matias , Rosling Anna
Published: August 2015

Soil fungal communities in tropical regions remain poorly understood. In order to increase the knowledge of diversity of soil-inhabiting fungi, we extracted total DNA from top-organic soil collected in seven localities dominated by four major ecosystems in the tropical island of Puerto Rico. In order to comprehensively characterize the fungal community, we PCR-amplified the internal transcribed spacer 2 (ITS2) fungal barcode using newly designed degenerated primers and varying annealing temperatures to minimize primer bias. Sequencing results, obtained using Ion Torrent technology, comprised a total of 566,613 sequences after quality filtering. These sequences were clustered into 4,140 molecular operational taxonomic units (MOTUs) after removing low frequency sequences and rarefaction to account for differences in read depth between samples. Our results demonstrate that soil fungal communities in Puerto Rico are structured by ecosystem. Ascomycota, followed by Basidiomycota, dominates the diversity of fungi in soil. Amongst Ascomycota, the recently described soil-inhabiting class Archaeorhizomycetes was present in all localities, and taxa in Archaeorhizomycetes were among the most commonly observed MOTUs. The Basidiomycota community was dominated by soil decomposers and ectomycorrhizal fungi with a distribution strongly affected by local variation to a greater degree than Ascomycota
Modeling of Start-Up From Engine-Off Conditions Using High Fidelity Turbofan Engine Simulations
Authors: Bretschneider Stefan , Reed John
Published: August 2015

Engine models are widely used to simulate the engine behavior at steady state and transient operating conditions over the full flight envelope. Within the engine development process such simulations are used to support component design, evaluate engine performance, operability and test data, as well as to develop and optimize the engine controls. Recent developments have raised interest in the modeling of start-up processes of turbofan engines in order to support the definition of sufficient engine control laws. This implies that simulations are started at a condition where the engine shafts are static and temperatures and pressures are equal to ambient. During start-up the engine can only be operated transiently through the sub-sub-idle region (near zero speed) using a starter torque. The activity presented here was targeted to support the development of industrial-standard high-fidelity turbofan engine models capable of simulating start-up, shutdown or windmilling operation. Within the three previously mentioned cases starting from an engine-off condition, ground start from zero-speed is the most challenging in terms of physical and numerical modeling. For this reason, this paper concentrates on that case only. Zero mass flow and speed at the beginning of the simulation impose a set of special problems that do not exist in standard simulations: the modeling of a static engine-off condition, the modeling of static friction, and the modeling of reverse flows. The requirement to support an existing industrial model development process also made it necessary to apply the same quality of physical modeling to start-up simulations as would be the case for above-idle engine simulations. The physical effects present during engine start are discussed and modeling solutions are presented. Finally, results of a dry crank simulation are presented and discussed, illustrating that the expected effects are present and that the simulation is capable of predicting the correct trends.
Low-Emission, Liquid Fuel Combustion System for Conventional and Alternative Fuels Developed by the Scaling Analysis
Authors: Niguse Yonas , Agrawal Ajay
Published: August 2015

The objective of this study is to develop a theoretical basis for scalability considerations and design of a large-scale combustor utilizing flow blurring (FB) atomization. FB atomization is a recently discovered twin-fluid atomization concept, reported to produce fine spray of liquids with wide range of viscosities. Previously, we have developed and investigated a small-scale swirl-stabilized combustor of 7-kWth capacity. Spray measurements have shown that the FB injector's atomization capability is superior when compared to other techniques, such as air blast atomization. However, despite these favorable results, scalability of the FB injector and associated combustor design has never been explored for large capacity; for example, for gas turbine applications. In this study, a number of dimensionless scaling parameters that affect the processes of atomization, fuel–air mixing, and combustion are analyzed, and scaling criteria for the different components of the combustion system are selected. Constant velocity criterion is used to scale key geometric components of the system. Scaling of the nonlinear dimensions and complex geometries, such as swirler vanes and internal parts of the injector is undertaken through phenomenological analysis of the flow processes associated with the scaled component. A scaled-up 60-kWth capacity combustor with FB injector is developed and investigated for combustion performance using diesel and vegetable oil (VO) (soybean oil) as fuels. Results show that the scaled-up injector's performance is comparable to the smaller scale system in terms of flame quality, emission levels, and static flame stability. Visual flame images at different atomizing air-to-liquid ratio by mass (ALR) show mainly blue flames, especially for ALR > 2.8. Emission measurements show a general trend of lower CO and NOx levels at higher ALRs, replicating the performance of the small-scale combustion system. Flame liftoff height at different ALRs is similar for both scales. The scaled-up combustor with FB injector preformed robustly with uncompromised stability for the range of firing rates (FRs) above 50% of the design capacity. Experimental results corroborate with the scaling methodology developed in this research.
NOx Behavior for Lean-Premixed Combustion of Alternative Gaseous Fuels
Authors: Boyd Fackler K. , Karalus Megan , Novosselov Igor , Kramlich John , Malte Philip , Vijlee Shazib
Published: August 2015

Gaseous fuels other than pipeline natural gas are of interest in high-intensity premixed combustors (e.g., lean-premixed gas turbine combustors) as a means of broadening the range of potential fuel resources and increasing the utilization of alternative fuel gases. An area of key interest is the change in emissions that accompanies the replacement of a fuel. The work reported here is an experimental and modeling effort aimed at determining the changes in NOx emission that accompany the use of alternative fuels. Controlling oxides of nitrogen (NOx) from combustion sources is essential in nonattainment areas. Lean-premixed combustion eliminates most of the thermal NOx emission but is still subject to small, although significant amounts of NOx formed by the complexities of free radical chemistry in the turbulent flames of most combustion systems. Understanding these small amounts of NOx, and how their formation is altered by fuel composition, is the objective of this paper. We explore how NOx is formed in high-intensity, lean-premixed flames of alternative gaseous fuels. This is based on laboratory experiments and interpretation by chemical reactor modeling. Methane is used as the reference fuel. Combustion temperature is maintained the same for all fuels so that the effect of fuel composition on NOx can be studied without the complicating influence of changing temperature. Also the combustion reactor residence time is maintained nearly constant. When methane containing nitrogen and carbon dioxide (e.g., landfill gas) is burned, NOx increases because the fuel/air ratio is enriched to maintain combustion temperature. When fuels of increasing C/H ratio are burned leading to higher levels of carbon monoxide (CO) in the flame, or when the fuel contains CO, the free radicals made as the CO oxidizes cause the NOx to increase. In these cases, the change from high-methane natural gas to alternative gaseous fuel causes the NOx to increase. However, when hydrogen is added to the methane, the NOx may increase or decrease, depending on the combustor wall heat loss. In our work, in which combustor wall heat loss is present, hydrogen addition deceases the NOx. This observation is compared to the literature. Additionally, minimum NOx emission is examined by comparing the present results to the findings of Leonard and Stegmaier.
Vowel coarticulation: Landmark statistics measure vowel aggression
Authors: Chen Wei-rong , Chang Yueh-chin , Iskarous Khalil
Published: August 2015

Regression analysis and mutual information have been used to measure the degree of dependence between a consonant and a vowel, and this has been used to identify the invariance of consonant place and to quantify the coarticulatory resistance of consonants [e.g., Fowler (1994). Percept. Psychophys. 55, 597–610]. This paper presents the first application of this approach to measure coarticulatory properties of vowels, using regression analysis and mutual information on articulatory data of CV syllables produced by seven Taiwan Mandarin speakers. The results show that vowel /i/ shares the most information with the preceding consonant among vowels for the tongue body, whereas vowels /a/ and /u/ are not significantly different from each other in that respect. For the lip articulator, the degree of information sharing for vowels is in the progression: /u/ > /i/ > /a/. Based on the CV model theory of gestural coordination (C-V in-phase relation) and the present results, this study proposes that landmark statistics for vowels reflect the degree of vowel aggression and that V-to-C effect is dominant over C-to-V effect in C-V coarticulation.
The Anatomy of the Sports Scandal: An Outline for a Theoretical Contextualization
Authors: Storm Rasmus K. , Wagner Ulrik
Published: August 2015

Sports scandals are often discussed in the media and research literature without any deeper reflection on their specificities or development. As the economic and political significance of sport seem to grow in correlation with the development of globalization and new social media, the call for a sociological understanding of the downsides of sport becomes imperative. By deploying a communication-theory framework supplemented with insights from discourse theory, this article aims to develop a theoretical model of the sports scandal. It presents a 5-step model encompassing initial steps of transgression, followed by a publicly observed dislocation destabilizing the social order, which subsequently results in moral communication, environmental pressure for appropriate action, and, finally, an institutional solution.
A Critical Discourse Analysis of espnW: Divergent Dialogues and Postfeminist Conceptions of Female Fans and Female Athletes
Authors: Wolter Sarah
Published: August 2015

espnW is ESPN, Inc.’s, first entity targeted at female fans and female athletes. espnW portrays female athletes as competent sportswomen and serious competitors as measured by quantitative analysis of photographs and articles on the site. A more critical look at the discourse, however, reveals 2 major themes. First, divergent dialogues are used in espnW articles to reify relations of power and privilege for male athletes. Divergent dialogues appear in articles on espnW in the forms of descriptive language used for female athletes, mention of nonsporting topics that have little or nothing to do with athleticism, and direct references to physical/personality attributes. Second, positioning espnW as “additive content” to ESPN for female fans relies on ideas of natural sexual difference and choice. If the institution of sport is defined by masculinity and partially upheld by traditional sports journalism, women are excluded.
Online Communities Among International Masters Gymnastics Participants: A Uses and Gratifications Analysis
Authors: Geurin-Eagleman Andrea N.
Published: August 2015

Masters sport participation is continually increasing, and although much research has uncovered masters participation motives, it has been noted that an understanding of community among masters athletes was also necessary. Online communities of sport participants have been examined only minimally, with research uncovering correlations between new-media use and sport-participation frequency. Using uses and gratifications theory, this study sought to examine masters gymnastics participants to develop a better understanding of athletes’ use of online communities in relation to their sport participation and examine differences in online community use based on demographics. Online survey results from 164 international participants revealed they used new media primarily for fanship, information, and technical knowledge, and online masters gymnastics communities were most often extensions of in-person training groups and communities. These findings and their implications are discussed in the article.
Relationship Between Dietary Factors and Bodily Iron Status Among Japanese Collegiate Elite Female Rhythmic Gymnasts
Authors: Kokubo Yuki , Yokoyama Yuri , Kisara Kumiko , Ohira Yoshiko , Sunami Ayaka , Yoshizaki Takahiro , Tada Yuki , Ishizaki Sakuko , Hida Azumi , Kawano Yukari
Published: August 2015

This cross-sectional study explored the prevalence of iron deficiency (ID) and associations between dietary factors and incidence of ID in female rhythmic gymnasts during preseason periods. Participants were 60 elite collegiate rhythmic gymnasts (18.1 ± 0.3 years [M ± SD]) who were recruited every August over the course of 8 years. Participants were divided into 2 groups according to the presence or absence of ID. Presence of ID was defined either by ferritin less than 12 µg/L or percentage of transferrin saturation less than 16%. Anthropometric and hematologic data, as well as dietary intake, which was estimated via a semiquantitative food frequency questionnaire, were compared. ID was noted in 48.3% of participants. No significant group-dependent differences were observed in physical characteristics, red blood cell counts, hemoglobin, hematocrit, haptoglobin, or erythropoietin concentrations. The ID group had a significantly lower total iron-binding capacity; serum-free iron; percentage of transferrin saturation; ferritin; and intake of protein, fat, zinc, vitamin B2, vitamin B6, beans, and eggs but not iron or vitamin C. The recommended dietary allowance for intake of protein, iron, zinc, and various vitamins was not met by 30%, 90%, 70%, and 22%–87% of all participants, respectively. Multiple logistic analysis showed that protein intake was significantly associated with the incidence of ID (odds ratio = 0.814, 95% confidence interval [0.669, 0.990], p = .039). Participants in the preseason’s weight-loss periods showed a tendency toward insufficient nutrient intake and were at a high risk for ID, particularly because of lower protein intake.
Fractal circuit sensors enable rapid quantification of biomarkers for donor lung assessment for transplantation
Authors: Sage Andrew T. , Besant Justin D. , Mahmoudian Laili , Poudineh Mahla , Bai Xiaohui , Zamel Ricardo , Hsin Michael , Sargent Edward H. , Cypel Marcelo , Liu Mingyao , Keshavjee Shaf , Kelley Shana O.
Published: August 2015

Microchip sensors enable rapid, molecular-level profiling of donated lungs for transplant assessment.
Development of a Novel Plasmid-Free Thymidine Producer by Reprogramming Nucleotide Metabolic Pathways
Authors: Kim Jin-Sook , Jeong Min-Kyung , Koo Bong-Seong , Lee Hyeon-Cheol
Published: August 2015

A novel thymidine-producing strain of
Escherichia coli
was prepared by genome recombineering. Eleven genes were deleted by replacement with an expression cassette, and 7 genes were integrated into the genome. The resulting strain,
E. coli
HLT013, showed a high thymidine yield with a low deoxyuridine content. DNA microarrays were then used to compare the gene expression profiles of HLT013 and its isogenic parent strain. Based on microarray analysis, the
pyr
biosynthesis genes and 10 additional genes were selected and then expressed in HLT013 to find reasonable candidates for enhancing thymidine yield. Among these, phage shock protein A (PspA) showed positive effects on thymidine production by diminishing redox stress. Thus, we integrated
pspA
into the HLT013 genome, resulting in
E. coli
strain HLT026, which produced 13.2 g/liter thymidine for 120 h with fed-batch fermentation. Here, we also provide a basis for new testable hypotheses regarding the enhancement of thymidine productivity and the attainment of a more complete understanding of nucleotide metabolism in bacteria.
Strains of the Harmful Cyanobacterium Microcystis aeruginosa Differ in Gene Expression and Activity of Inorganic Carbon Uptake Systems at Elevated CO
2
Levels
Authors: Sandrini Giovanni , Jakupovic Dennis , Matthijs Hans C. P. , Huisman Jef
Published: August 2015

Cyanobacteria are generally assumed to be effective competitors at low CO
2
levels because of their efficient CO
2
-concentrating mechanism (CCM), and yet how bloom-forming cyanobacteria respond to rising CO
2
concentrations is less clear. Here, we investigate changes in CCM gene expression at ambient CO
2
(400 ppm) and elevated CO
2
(1,100 ppm) in six strains of the harmful cyanobacterium
Microcystis
. All strains downregulated
cmpA
encoding the high-affinity bicarbonate uptake system BCT1, whereas both the low- and high-affinity CO
2
uptake genes were expressed constitutively. Four strains downregulated the bicarbonate uptake genes
bicA
and/or
sbtA
, whereas two strains showed constitutive expression of the
bicA
-
sbtA
operon. In one of the latter strains, a transposon insert in
bicA
caused low
bicA
and
sbtA
transcript levels, which made this strain solely dependent on BCT1 for bicarbonate uptake. Activity measurements of the inorganic carbon (C
i
) uptake systems confirmed the CCM gene expression results. Interestingly, genes encoding the RuBisCO enzyme, structural carboxysome components, and carbonic anhydrases were not regulated. Hence,
Microcystis
mainly regulates the initial uptake of inorganic carbon, which might be an effective strategy for a species experiencing strongly fluctuating C
i
concentrations. Our results show that CCM gene regulation of
Microcystis
varies among strains. The observed genetic and phenotypic variation in CCM responses may offer an important template for natural selection, leading to major changes in the genetic composition of harmful cyanobacterial blooms at elevated CO
2
.
γ-Resorcylate Catabolic-Pathway Genes in the Soil Actinomycete Rhodococcus jostii RHA1
Authors: Kasai Daisuke , Araki Naoto , Motoi Kota , Yoshikawa Shota , Iino Toju , Imai Shunsuke , Masai Eiji , Fukuda Masao
Published: August 2015

TheRhodococcus jostiiRHA1 gene cluster required for γ-resorcylate (GRA) catabolism was characterized. The cluster includestsdA,tsdB,tsdC,tsdD,tsdR,tsdT, andtsdX, which encode GRA decarboxylase, resorcinol 4-hydroxylase, hydroxyquinol 1,2-dioxygenase, maleylacetate reductase, an IclR-type regulator, a major facilitator superfamily transporter, and a putative hydrolase, respectively. ThetsdAgene conferred GRA decarboxylase activity onEscherichia coli. Purified TsdB oxidized NADH in the presence of resorcinol, suggesting thattsdBencodes a unique NADH-specific single-component resorcinol 4-hydroxylase. Mutations in eithertsdAortsdBresulted in growth deficiency on GRA. ThetsdCandtsdDgenes conferred hydroxyquinol 1,2-dioxygenase and maleylacetate reductase activities, respectively, onE. coli. Inactivation oftsdTsignificantly retarded the growth of RHA1 on GRA. The growth retardation was partially suppressed under acidic conditions, suggesting the involvement oftsdTin GRA uptake. Reverse transcription-PCR analysis revealed that thetsdgenes constitute three transcriptional units, thetsdBADCandtsdTXoperons andtsdR. Transcription of thetsdBADCandtsdTXoperons was induced during growth on GRA. Inactivation oftsdRderepressed transcription of thetsdBADCandtsdTXoperons in the absence of GRA, suggesting thattsdgene transcription is negatively regulated by thetsdR-encoded regulator. Binding of TsdR to thetsdR-tsdBandtsdT-tsdRintergenic regions was inhibited by the addition of GRA, indicating that GRA interacts with TsdR as an effector molecule.
A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18INK4cTo Promote Reactivation from Latency
Authors: Williams Lisa M. , Niemeyer Brian F. , Franklin David S. , Clambey Eric T. , van Dyk Linda F.
Published: August 2015

Gammaherpesviruses (GHVs) carry homologs of cellular genes, including those encoding a viral cyclin that promotes reactivation from latent infection. The viral cyclin has reduced sensitivity to host cyclin-dependent kinase inhibitorsin vitro; however, thein vivosignificance of this is unclear. Here, we tested the genetic requirement for the viral cyclin in mice that lack the host inhibitors p27Kip1and p18INK4c, two cyclin-dependent kinase inhibitors known to be important in regulating B cell proliferation and differentiation. While the viral cyclin was essential for reactivation in wild-type mice, strikingly, it was dispensable for reactivation in mice lacking p27Kip1and p18INK4c. Further analysis revealed that genetic ablation of only p18INK4calleviated the requirement for the viral cyclin for reactivation from latency. p18INK4cregulated reactivation in a dose-dependent manner so that the viral cyclin was dispensable in p18INK4cheterozygous mice. Finally, treatment of wild-type cells with the cytokine BAFF, a known attenuator of p18INK4cfunction in B lymphocytes, was also able to bypass the requirement for the viral cyclin in reactivation. These data show that the gammaherpesvirus viral cyclin functions specifically to bypass the cyclin-dependent kinase inhibitor p18INK4c, revealing an unanticipated specificity between a GHV cyclin and a single cyclin-dependent kinase inhibitor.

IMPORTANCEThe gammaherpesviruses (GHVs) cause lifelong infection and can cause chronic inflammatory diseases and cancer, especially in immunosuppressed individuals. Many GHVs encode a conserved viral cyclin that is required for infection and disease. While a common property of the viral cyclins is that they resist inhibition by normal cellular mechanisms, it remains unclear how important it is that the GHVs resist this inhibition. We used a mouse GHV that either contained or lacked a viral cyclin to test whether the viral cyclin lost importance when these inhibitory pathways were removed. These studies revealed that the viral cyclin was required for optimal function in normal mice but that it was no longer required following removal or reduced function of a single cellular inhibitor. These data define a very specific role for the viral cyclin in bypassing one cellular inhibitor and point to new methods to intervene with viral cyclins.
Equine Herpesvirus Type 1 Enhances Viral Replication in CD172a
+
Monocytic Cells upon Adhesion to Endothelial Cells
Authors: Laval Kathlyn , Favoreel Herman W. , Poelaert Katrien C. K. , Van Cleemput Jolien , Nauwynck Hans J.
Published: August 2015

Equine herpesvirus type 1 (EHV-1) is a main cause of respiratory disease, abortion, and encephalomyelopathy in horses. Monocytic cells (CD172a
+
) are the main carrier cells of EHV-1 during primary infection and are proposed to serve as a “Trojan horse” to facilitate the dissemination of EHV-1 to target organs. However, the mechanism by which EHV-1 is transferred from CD172a
+
cells to endothelial cells (EC) remains unclear. The aim of this study was to investigate EHV-1 transmission between these two cell types. We hypothesized that EHV-1 employs specific strategies to promote the adhesion of infected CD172a
+
cells to EC to facilitate EHV-1 spread. Here, we demonstrated that EHV-1 infection of CD172a
+
cells resulted in a 3- to 5-fold increase in adhesion to EC. Antibody blocking experiments indicated that α
4
β
1
, α
L
β
2
, and α
V
β
3
integrins mediated adhesion of infected CD172a
+
cells to EC. We showed that integrin-mediated phosphatidylinositol 3-kinase (PI3K) and ERK/MAPK signaling pathways were involved in EHV-1-induced CD172a
+
cell adhesion at early times of infection. EHV-1 replication was enhanced in adherent CD172a
+
cells, which correlates with the production of tumor necrosis factor alpha (TNF-α). In the presence of neutralizing antibodies, approximately 20% of infected CD172a
+
cells transferred cytoplasmic material to uninfected EC and 0.01% of infected CD172a
+
cells transmitted infectious virus to neighboring cells. Our results demonstrated that EHV-1 infection induces adhesion of CD172a
+
cells to EC, which enhances viral replication, but that transfer of viral material from CD172a
+
cells to EC is a very specific and rare event. These findings give new insights into the complex pathogenesis of EHV-1.

IMPORTANCE
Equine herpesvirus type 1 (EHV-1) is a highly prevalent pathogen worldwide, causing frequent outbreaks of abortion and myeloencephalopathy, even in vaccinated horses. After primary replication in the respiratory tract, EHV-1 disseminates via cell-associated viremia in peripheral blood mononuclear cells (PBMC) and subsequently infects the endothelial cells (EC) of the pregnant uterus or central nervous system, leading in some cases to abortion and/or neurological disorders. Recently, we demonstrated that CD172a
+
monocytic carrier cells serve as a “Trojan horse” to facilitate EHV-1 spread from blood to target organs. Here, we investigated the mechanism underlying the transmission of EHV-1 from CD172a
+
cells to EC. We demonstrated that EHV-1 infection induces cellular changes in CD172a
+
cells, promoting their adhesion to EC. We found that both cell-to-cell contacts and the secretion of soluble factors by EC activate EHV-1 replication in CD172a
+
cells. This facilitates transfer of cytoplasmic viral material to EC, resulting mainly in a nonproductive infection. Our findings give new insights into how EHV-1 may spread to EC of target organs in vaccinated horses.
Herpesvirus saimiri MicroRNAs Preferentially Target Host Cell Cycle Regulators
Authors: Guo Yang Eric , Oei Theresa , Steitz Joan A.
Published: August 2015

In latently infected marmoset T cells,
Herpesvirus saimiri
(HVS) expresses six microRNAs (known as miR-HSURs [
H. saimiri
U-rich RNAs]). The viral miR-HSURs are processed from chimeric primary transcripts, each containing a noncoding U-rich RNA (HSUR) and a pre-miRNA hairpin. To uncover the functions of miR-HSURs, we identified mRNA targets in infected cells using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP). HITS-CLIP revealed hundreds of robust Argonaute (Ago) binding sites mediated by miR-HSURs that map to the host genome but few in the HVS genome. Gene ontology analysis showed that several pathways regulating the cell cycle are enriched among cellular targets of miR-HSURs. Interestingly, miR-HSUR4-3p represses expression of the p300 transcriptional coactivator by binding the open reading frame of its mRNA. miR-HSUR5-3p directly regulates BiP, an endoplasmic reticulum (ER)-localized chaperone facilitating maturation of major histocompatibility complex class I (MHC-I) and the antiviral response. miR-HSUR5-3p also robustly downregulates WEE1, a key negative regulator of cell cycle progression, leading to reduced phosphorylation of its substrate, cyclin-dependent kinase (Cdk1). Consistently, inhibition of miR-HSUR5-3p in HVS-infected cells decreases their proliferation. Together, our results shed light on the roles of viral miRNAs in cellular transformation and viral latency.

IMPORTANCE
Viruses express miRNAs during various stages of infection, suggesting that viral miRNAs play critical roles in the viral life cycle. Compared to protein-coding genes, the functions of viral miRNAs are not well understood. This is because it has been challenging to identify their mRNA targets. Here, we focused on the functions of the recently discovered HVS miRNAs, called miR-HSURs. HVS is an oncogenic gammaherpesvirus that causes acute T-cell lymphomas and leukemias in New World primates and transforms human T cells. A better understanding of HVS biology will help advance our knowledge of virus-induced oncogenesis. Because numerous cellular miRNAs play crucial roles in cancer, viral miRNAs from the highly oncogenic HVS might also be important for transformation. Here, we found that the miR-HSURs preferentially modulate expression of host cell cycle regulators, as well as antiviral response factors. Our work provides further insight into the functions of herpesviral miRNAs in virus-induced oncogenesis and latency.
Two siblings with fatalChromobacterium violaceumsepsis linked to drinking water
Authors: Al Khalifa Salman Mohammed , Al Khaldi Turki , Alqahtani Manaf Mohammed , Al Ansari Ahmed Mohamed
Published: August 2015

Chromobacterium violaceumis a Gram-negative organism found in water and soil.C. violaceumis not usually pathogenic in humans; only approximately 150 human cases have been reported worldwide.C. violaceumbacteraemia progresses rapidly, leading to fatal sepsis on dissemination to multiple organs within a short time. We describe two cases of fatal septicaemia caused byC. violaceumin siblings. Our initial impression was that these cases were associated with an undiagnosed immunodeficiency in the siblings. However, detailed patient histories revealed a potential underlying immunodeficiency in only one patient. These findings prompted us to investigate possible environmental exposure. We identifiedC. violaceumin filtered water that was sold to the family at a nearby store. This discovery led to a public health alert and closer scrutiny of similar stores by the Ministry of Health.
A randomized controlled trial comparing treatment with oral agents and basal insulin in elderly patients with type 2 diabetes in long-term care facilities
Authors: Pasquel Francisco J , Powell Winter , Peng Limin , Johnson Theodore M , Sadeghi-Yarandi Shadi , Newton Christopher , Smiley Dawn , Toyoshima Marcos T , Aram Pedram , Umpierrez Guillermo E
Published: August 2015

Background

Managing hyperglycemia and diabetes is challenging in geriatric patients admitted to long-term care (LTC) facilities.

Methods

This randomized control trial enrolled patients with type 2 diabetes (T2D) with blood glucose (BG) >180 mg/dL or glycated hemoglobin >7.5% to receive low-dose basal insulin (glargine, starting dose 0.1 U/kg/day) or oral antidiabetic drug (OAD) therapy as per primary care provider discretion for 26 weeks. Both groups received supplemental rapid-acting insulin before meals for BG >200 mg/dL. Primary end point was difference in glycemic control as measured by fasting and mean daily glucose concentration between groups.

Results

A total of 150 patients (age: 79±8 years, body mass index: 30.1±6.5 kg/m2, duration of diabetes mellitus: 8.2±5.1 years, randomization BG: 194±97 mg/dL) were randomized to basal insulin (n=75) and OAD therapy (n=75). There were no differences in the mean fasting BG (131±27 mg/dL vs 123±23 mg/dL, p=0.06) between insulin and OAD groups, but patients treated with insulin had greater mean daily BG (163±39 mg/dL vs 138±27 mg/dL, p<0.001) compared to those treated with OADs. There were no differences in the rate of hypoglycemia (<70 mg/dL) between insulin (27%) and OAD (31%) groups, p=0.58. In addition, there were no differences in the number of hospital complications, emergency room visits, and mortality between treatment groups.

Conclusions

The results of this randomized study indicate that elderly patients with T2D in LTC facilities exhibited similar glycemic control, hypoglycemic events and complications when treated with either basal insulin or with oral antidiabetic drugs.

Trial registration number

ClinicalTrials.gov Identifier:NCT01131052.
Socioeconomic inequalities in functional somatic symptoms by social and material conditions at four life course periods in Sweden: a decomposition analysis
Authors: San Sebastian Miguel , Hammarström Anne , Gustafsson Per E
Published: August 2015

Objective

Socioeconomic inequalities in health are deemed a worldwide public health problem, but current research is lacking on key points including determinants of socioeconomic differences in health, and not the least variations of these determinants over the life course. Using a 26-year prospective Swedish community-based cohort, we aim at decomposing socioeconomic inequalities in functional somatic symptoms by social and material life circumstances, at 4 periods of the life course.

Design

Repeated cross-sectional study.

Setting

Participants came from the Northern Swedish Cohort (n=1001), who completed questionnaires about occupational class, social and material living conditions, and symptoms at ages 16, 21, 30 and 42. Socioeconomic inequalities were estimated and decomposed using the Blinder-Oaxaca decomposition analysis.

Results

Inequalities in symptoms between blue-collar and white-collar socioeconomic groups increased along the life course in the sample. In the decomposition analysis, a high proportion of the gap between socioeconomic groups could be explained by social and material living conditions at ages 16 (84% explained), 30 (45%) and 42 (68%), but not at age 21. Specific social (parental illness at age 16 and violence at ages 30 and 42) and material (parental unemployment at age 16, and own unemployment and financial strain at ages 30 and 42) factors contributed jointly to the health gaps.

Conclusions

Socioeconomic inequalities in functional somatic symptoms increased along the life course in this Swedish cohort. A considerable portion of the social gaps in health was explained by concurrent social and material conditions, and the importance of specific adversities was dependent on the life course stage. Our findings suggest that socioeconomic inequalities in functional somatic symptoms may be reduced by addressing both social and material living conditions of disadvantaged families, and also that the life course stage needs to be taken into consideration.
Feasibility and acceptability of advance care planning in elderly Italian and Greek speaking patients as compared to English-speaking patients: an Australian cross-sectional study
Authors: Detering Karen , Sutton Elizabeth , Fraser Scott , Wallis Kasey , Silvester William , Mawren Daveena , Whiteside Kathryn
Published: August 2015

Objectives

To assess the feasibility and acceptability of facilitated advance care planning (ACP) discussions in elderly Italian and Greek-speaking inpatients compared to English-speaking inpatients.

Design, setting and participants

This cross-sectional study with convenience sampling was conducted in Melbourne, Australia, and recruited hospital inpatients with medical decision-making capacity, aged 65 years or above, who spoke Greek (25 patients), Italian (24 patients) or English (63 patients).

Intervention

Facilitated ACP was offered, aiming to assists patients to consider and discuss their goals, values, beliefs and future treatment wishes with their family and doctor; to help them consider how they would like healthcare decisions made in the future if they become unable to do this for themselves; and to complete advance care directives.

Main outcome measures

The completion of ACP discussions, their duration, advance care directive completion and utilisation of interpreters.

Results

Of 112 patients, 109 (97%) had at least one discussion, 63 (54%) completed advance care directives, either nominating a substitute decision-maker, documenting their wishes or both, and 76 (68%) included family in discussions. The median duration of discussions for all patients was slightly more than 1 h, over two visits. There were no differences between the Greek-speaking and the Italian-speaking patients, or between the Non-English speaking and the English-speaking patients in any of these measures. Only 14 non-English speaking patients, (30%) utilised interpreters, but when utilised, patients were much more likely (p<0.005) to complete advance care directives.

Conclusions

Facilitated ACP in elderly Italian and Greek-speaking patients is feasible, acceptable and is similar to that for English-speaking patients.
Floral development of Condylocarpon isthmicum (Apocynaceae)
Authors: Morokawa Rosemeri , Mayer Juliana Lischka Sampaio , Simões André Olmos , Kinoshita Luiza Sumiko
Published: August 2015

Apocynaceae is one of the largest families of angiosperms. Its representatives have flowers with relatively simple morphology, ranging from anthers free from the style head to more complex flowers in which the anthers are postgenitally united with the style head, forming a gynostegium, and those with a style head that is vertically differentiated into distinct functional regions. The aim of this study is to understand the morphology and secretory structures of Condylocarpon isthmicum (Vell.) A.DC. at different stages of development. This species, which is in the family Apocynaceae, has morphologically simple flowers. Flowers at four different stages of development were collected and processed for anatomical and histochemical analysis; floral anatomy was examined using light and scanning electron microscopy. The simplicity of the C. isthmicum flower morphology was contrasted with the complexity observed in the secretory structures at different stages of flower development. Four secretory structures were identified in this species: colleters, style head epidermal cells, nectariferous tissue, and an obturator. The colleters were observed in the bracts and bracteoles of the young inflorescences. The style head began the secretory phase in the pre-anthetic stage and remained in this phase until anthesis. The nectariferous tissue was secreted during anthesis, and the obturator was present only in post-anthetic flowers. We identified a nectary in the wall of the ovary, and we verified and described a new structure in the Apocynaceae, the obturator.
Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats
Authors: El-Kashef Dalia H. , El-Kenawi Asmaa E. , Rahim Mona Abdel , Suddek Ghada M. , Salem Hatem A.
Published: August 2015

The present study was designed to explore the possible protective effects of agmatine, a known nitric oxide (NO) synthase inhibitor, against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of agmatine on gentamicin-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was evaluated. Twenty-four male Wistar albino rats were randomly divided into 3 groups, namely control, gentamicin (100 mg/kg, i.p.), and gentamicin plus agmatine (40 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood and urine samples and kidneys were taken. Administration of agmatine significantly decreased kidney/body mass ratio, serum creatinine, lactate dehydrogenase (LDH), renal malondialdehyde (MDA), myeloperoxidase (MPO), NO, and tumor necrosis factor-alpha (TNF-α) while it significantly increased creatinine clearance and renal superoxide dismutase (SOD) activity when compared with the gentamicin-treated group. Additionally, agmatine ameliorated tissue morphology as evidenced by histological evaluation and reduced the responses of isolated bladder rings to ACh. Our study indicates that agmatine administration with gentamicin attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation, restoring NO level and inhibiting inflammatory mediators such as TNF-α.
Fast Algorithms for Local Similarity Queries in Two Sequences
Authors: Arslan Abdullah N.
Published: August 2015

In sequence comparison, finding local similarities in given strings is a very important well-known problem. In this work we introduce two local sequence similarity query problems, and present algorithms for them. Our algorithms use a data structure that supports constant time longest common extension queries. This data structure is created only once, and in time linear in the size of the input strings. After this step all subsequent local similarity queries can be answered very fast. Existing algorithms take significantly more time in answering these queries.