bluuebunny/crossref_metadata_2025 huggingface dataset:
Responses of sex steroid hormones to different intensities of exercise in endurance athletes
Authors: Sato Koji , Iemitsu Motoyuki , Katayama Keisho , Ishida Koji , Kanao Yoji , Saito Mitsuru
Published: October 2015

New Findings

What is the central question of this study?

What is the effect of different exercise intensities on sex steroid hormone concentrations in individuals with different degrees of physical fitness?

What is the main finding and its importance?

In endurance athletes, serum concentrations of sex steroid hormones increased only with high‐intensity exercise. Moreover, different responses of sex steroid hormone secretions were induced by different exercise intensities in individuals with low and high levels of physical fitness.

Previous studies have shown that acute exercise elevates sex steroid hormone concentrations in rodents and that sprint exercise increases circulating testosterone in healthy young men. However, the effect of different exercise intensities on sex steroid hormone responses at different levels of physical fitness is still unclear. In this study, we compared circulating sex steroid hormone responses at different exercise intensities in athletes and non‐athletes. Eight male endurance athletes and 11 non‐athletes performed two 15 min sessions of submaximal exercise at 40 and 70% peak oxygen uptake (), respectively, and exercised at 90% until exhaustion. Venous blood samples were collected during the last minute of each submaximal exercise session and immediately after exhaustion. Acute exercise at 40, 70 and 90% induced significant increases in serum dehydroepiandrosterone (DHEA) and free testosterone concentrations in non‐athletes. On the contrary, only 90% exercise led to an increase in serum DHEA and free testosterone concentrations in athletes. Serum 5α‐dihydrotestosterone concentrations increased with 90% exercise in both athletes and non‐athletes. Additionally, serum estradiol concentrations were significantly increased at moderate and high exercise intensities in both athletes and non‐athletes. These results indicate that in endurance athletes, serum sex steroid hormone concentrations, especially serum DHEA and 5α‐dihydrotestosterone concentrations, increased only with high‐intensity exercise, suggesting that different responses of sex steroid hormone secretion are induced by different exercise intensities in individuals with low and high levels of physical fitness. In athletes, therefore, high‐intensity exercise may be required to increase circulating sex steroid hormone concentrations.
Individualistic sensitivities and exposure to climate change explain variation in species’ distribution and abundance changes
Authors: Palmer Georgina , Hill Jane K. , Brereton Tom M. , Brooks David R. , Chapman Jason W. , Fox Richard , Oliver Tom H. , Thomas Chris D.
Published: October 2015

Analysis of butterfly and moth species shows that responses to climate change may be more predictable than previously recognized.
Epidermal devices for noninvasive, precise, and continuous mapping of macrovascular and microvascular blood flow
Authors: Webb R. Chad , Ma Yinji , Krishnan Siddharth , Li Yuhang , Yoon Stephen , Guo Xiaogang , Feng Xue , Shi Yan , Seidel Miles , Cho Nam Heon , Kurniawan Jonas , Ahad James , Sheth Niral , Kim Joseph , Taylor VI James G. , Darlington Tom , Chang Ken , Huang Weizhong , Ayers Joshua , Gruebele Alexander , Pielak Rafal M. , Slepian Marvin J. , Huang Yonggang , Gorbach Alexander M. , Rogers John A.
Published: October 2015

Advances in ultrathin, skin-like electronics lead to wearable devices for continuous, noninvasive blood flow monitoring.
A surface code quantum computer in silicon
Authors: Hill Charles D. , Peretz Eldad , Hile Samuel J. , House Matthew G. , Fuechsle Martin , Rogge Sven , Simmons Michelle Y. , Hollenberg Lloyd C. L.
Published: October 2015

A scalable shared-control architecture for silicon-based quantum computing using topological quantum error correction.
Spectrometer-free vibrational imaging by retrieving stimulated Raman signal from highly scattered photons
Authors: Liao Chien-Sheng , Wang Pu , Wang Ping , Li Junjie , Lee Hyeon Jeong , Eakins Gregory , Cheng Ji-Xin
Published: October 2015

Vibrational imaging reveals vitamin E distribution on mouse skin in vivo and captures human breast cancer tissues in situ.
Lunar impact basins revealed by Gravity Recovery and Interior Laboratory measurements
Authors: Neumann Gregory A. , Zuber Maria T. , Wieczorek Mark A. , Head James W. , Baker David M. H. , Solomon Sean C. , Smith David E. , Lemoine Frank G. , Mazarico Erwan , Sabaka Terence J. , Goossens Sander J. , Melosh H. Jay , Phillips Roger J. , Asmar Sami W. , Konopliv Alexander S. , Williams James G. , Sori Michael M. , Soderblom Jason M. , Miljković Katarina , Andrews-Hanna Jeffrey C. , Nimmo Francis , Kiefer Walter S.
Published: October 2015

New gravity measurements greatly improve the Moon’s preserved impact basin inventory.
Carbyne with finite length: The one-dimensional
sp
carbon
Authors: Pan Bitao , Xiao Jun , Li Jiling , Liu Pu , Wang Chengxin , Yang Guowei
Published: October 2015

Carbyne with one-dimensional
sp
-hybridized carbon atoms is synthesized under ambient conditions in the laboratory.
A Branch Point of Streptomyces Sulfur Amino Acid Metabolism Controls the Production of Albomycin
Authors: Kulkarni Aditya , Zeng Yu , Zhou Wei , Van Lanen Steven , Zhang Weiwen , Chen Shawn
Published: October 2015

Albomycin (ABM), also known as grisein, is a sulfur-containing metabolite produced by
Streptomyces griseus
ATCC 700974. Genes predicted to be involved in the biosynthesis of ABM and ABM-like molecules are found in the genomes of other actinomycetes. ABM has potent antibacterial activity, and as a result, many attempts have been made to develop ABM into a drug since the last century. Although the productivity of
S. griseus
can be increased with random mutagenesis methods, understanding of
Streptomyces
sulfur amino acid (SAA) metabolism, which supplies a precursor for ABM biosynthesis, could lead to improved and stable production. We previously characterized the gene cluster (
abm
) in the genome-sequenced
S. griseus
strain and proposed that the sulfur atom of ABM is derived from either cysteine (Cys) or homocysteine (Hcy). The gene product, AbmD, appears to be an important link between primary and secondary sulfur metabolic pathways. Here, we show that propargylglycine or iron supplementation in growth media increased ABM production by significantly changing the relative concentrations of intracellular Cys and Hcy. An SAA metabolic network of
S. griseus
was constructed. Pathways toward increasing Hcy were shown to positively impact ABM production. The
abmD
gene and five genes that increased the Hcy/Cys ratio were assembled downstream of
hrdB
p promoter sequences and integrated into the chromosome for overexpression. The ABM titer of one engineered strain, SCAK3, in a chemically defined medium was consistently improved to levels ∼400% of the wild type. Finally, we analyzed the production and growth of SCAK3 in shake flasks for further process development.
Diversity of Pseudomonas Genomes, Including Populus-Associated Isolates, as Revealed by Comparative Genome Analysis
Authors: Jun Se-Ran , Wassenaar Trudy M. , Nookaew Intawat , Hauser Loren , Wanchai Visanu , Land Miriam , Timm Collin M. , Lu Tse-Yuan S. , Schadt Christopher W. , Doktycz Mitchel J. , Pelletier Dale A. , Ussery David W.
Published: October 2015

The
Pseudomonas
genus contains a metabolically versatile group of organisms that are known to occupy numerous ecological niches, including the rhizosphere and endosphere of many plants. Their diversity influences the phylogenetic diversity and heterogeneity of these communities. On the basis of average amino acid identity, comparative genome analysis of >1,000
Pseudomonas
genomes, including 21
Pseudomonas
strains isolated from the roots of native
Populus deltoides
(eastern cottonwood) trees resulted in consistent and robust genomic clusters with phylogenetic homogeneity. All
Pseudomonas aeruginosa
genomes clustered together, and these were clearly distinct from other
Pseudomonas
species groups on the basis of pangenome and core genome analyses. In contrast, the genomes of
Pseudomonas fluorescens
were organized into 20 distinct genomic clusters, representing enormous diversity and heterogeneity. Most of our 21
Populus
-associated isolates formed three distinct subgroups within the major
P. fluorescens
group, supported by pathway profile analysis, while two isolates were more closely related to
Pseudomonas chlororaphis
and
Pseudomonas putida
. Genes specific to
Populus
-associated subgroups were identified. Genes specific to subgroup 1 include several sensory systems that act in two-component signal transduction, a TonB-dependent receptor, and a phosphorelay sensor. Genes specific to subgroup 2 contain hypothetical genes, and genes specific to subgroup 3 were annotated with hydrolase activity. This study justifies the need to sequence multiple isolates, especially from
P. fluorescens
, which displays the most genetic variation, in order to study functional capabilities from a pangenomic perspective. This information will prove useful when choosing
Pseudomonas
strains for use to promote growth and increase disease resistance in plants.
Genetic Diversity of Clostridium sporogenes PA 3679 Isolates Obtained from Different Sources as Resolved by Pulsed-Field Gel Electrophoresis and High-Throughput Sequencing
Authors: Schill Kristin M. , Wang Yun , Butler Robert R. , Pombert Jean-François , Reddy N. Rukma , Skinner Guy E. , Larkin John W.
Published: October 2015

Clostridium sporogenes
PA 3679 is a nonpathogenic, nontoxic model organism for proteolytic
Clostridium botulinum
used in the validation of conventional thermal food processes due to its ability to produce highly heat-resistant endospores. Because of its public safety importance, the uncertain taxonomic classification and genetic diversity of PA 3679 are concerns. Therefore, isolates of
C. sporogenes
PA 3679 were obtained from various sources and characterized using pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing. The phylogenetic relatedness and genetic variability were assessed based on 16S rRNA gene sequencing and whole-genome single nucleotide polymorphism (SNP) analysis. All
C. sporogenes
PA 3679 isolates were categorized into two clades (clade I containing ATCC 7955 NCA3679 isolates 1961-2, 1990, and 2007 and clade II containing PA 3679 isolates NFL, UW, FDA, and Campbell and ATCC 7955 NCA3679 isolate 1961-4). The 16S maximum likelihood (ML) tree clustered both clades within proteolytic
C. botulinum
strains, with clade I forming a distinct cluster with other
C. sporogenes
non-PA 3679 strains. SNP analysis revealed that clade I isolates were more similar to the genomic reference PA 3679 (NCTC8594) genome (GenBank accession number
AGAH00000000.1
) than clade II isolates were. The genomic reference
C. sporogenes
PA 3679 (NCTC8594) genome and clade I
C. sporogenes
isolates were genetically distinct from those obtained from other sources (University of Wisconsin, National Food Laboratory, U.S. Food and Drug Administration, and Campbell's Soup Company). Thermal destruction studies revealed that clade I isolates were more sensitive to high temperature than clade II isolates were. Considering the widespread use of
C. sporogenes
PA 3679 and its genetic information in numerous studies, the accurate identification and genetic characterization of
C. sporogenes
PA 3679 are of critical importance.
Mechanisms of Inactivation by High-Voltage Atmospheric Cold Plasma Differ for Escherichia coli and Staphylococcus aureus
Authors: Han L. , Patil S. , Boehm D. , Milosavljević V. , Cullen P. J. , Bourke P.
Published: October 2015

Atmospheric cold plasma (ACP) is a promising nonthermal technology effective against a wide range of pathogenic microorganisms. Reactive oxygen species (ROS) play a crucial inactivation role when air or other oxygen-containing gases are used. With strong oxidative stress, cells can be damaged by lipid peroxidation, enzyme inactivation, and DNA cleavage. Identification of ROS and an understanding of their role are important for advancing ACP applications for a range of complex microbiological issues. In this study, the inactivation efficacy of in-package high-voltage (80 kV [root mean square]) ACP (HVACP) and the role of intracellular ROS were investigated. Two mechanisms of inactivation were observed in which reactive species were found to either react primarily with the cell envelope or damage intracellular components.
Escherichia coli
was inactivated mainly by cell leakage and low-level DNA damage. Conversely,
Staphylococcus aureus
was mainly inactivated by intracellular damage, with significantly higher levels of intracellular ROS observed and little envelope damage. However, for both bacteria studied, increasing treatment time had a positive effect on the intracellular ROS levels generated.
Ex Vivo
Application of Secreted Metabolites Produced by Soil-Inhabiting Bacillus spp. Efficiently Controls Foliar Diseases Caused by Alternaria spp
Authors: Ali Gul Shad , El-Sayed Ashraf S. A. , Patel Jaimin S. , Green Kari B. , Ali Mohammad , Brennan Mary , Norman David
Published: October 2015

Bacterial biological control agents (BCAs) are largely used as live products to control plant pathogens. However, due to variable environmental and ecological factors, live BCAs usually fail to produce desirable results against foliar pathogens. In this study, we investigated the potential of cell-free culture filtrates of 12 different bacterial BCAs isolated from flower beds for controlling foliar diseases caused by
Alternaria
spp.
In vitro
studies showed that culture filtrates from two isolates belonging to
Bacillus subtilis
and
Bacillus amyloliquefaciens
displayed strong efficacy and potencies against
Alternaria
spp. The antimicrobial activity of the culture filtrate of these two biological control agents was effective over a wider range of pH (3.0 to 9.0) and was not affected by autoclaving or proteolysis. Comparative liquid chromatography-mass spectrometry (LC-MS) analyses showed that a complex mixture of cyclic lipopeptides, primarily of the fengycin A and fengycin B families, was significantly higher in these two BCAs than inactive
Bacillus
spp. Interaction studies with mixtures of culture filtrates of these two species revealed additive activity, suggesting that they produce similar products, which was confirmed by LC-tandem MS analyses. In
in planta
pre- and postinoculation trials, foliar application of culture filtrates of
B. subtilis
reduced lesion sizes and lesion frequencies caused by
Alternaria alternata
by 68 to 81%. Taken together, our studies suggest that instead of live bacteria, culture filtrates of
B. subtilis
and
B. amyloliquefaciens
can be applied either individually or in combination for controlling foliar diseases caused by
Alternaria
species.
Genus-Specific Primers for Study of Fusarium Communities in Field Samples
Authors: Karlsson Ida , Edel-Hermann Véronique , Gautheron Nadine , Durling Mikael Brandström , Kolseth Anna-Karin , Steinberg Christian , Persson Paula , Friberg Hanna
Published: October 2015

Fusariumis a large and diverse genus of fungi of great agricultural and economic importance, containing many plant pathogens and mycotoxin producers. To date, high-throughput sequencing ofFusariumcommunities has been limited by the lack of genus-specific primers targeting regions with high discriminatory power at the species level. In the present study, we evaluated twoFusarium-specific primer pairs targeting translation elongation factor 1 (TEF1). We also present the new primer pair Fa+7/Ra+6. MockFusariumcommunities reflecting phylogenetic diversity were used to evaluate the accuracy of the primers in reflecting the relative abundance of the species. TEF1 amplicons were subjected to 454 high-throughput sequencing to characterizeFusariumcommunities. Field samples from soil and wheat kernels were included to test the method on more-complex material. For kernel samples, a single PCR was sufficient, while for soil samples, nested PCR was necessary. The newly developed primer pairs Fa+7/Ra+6 and Fa/Ra accurately reflectedFusariumspecies composition in mock DNA communities. In field samples, 47Fusariumoperational taxonomic units were identified, with the highestFusariumdiversity in soil. TheFusariumcommunity in soil was dominated by members of theFusarium incarnatum-Fusarium equisetispecies complex, contradicting findings in previous studies. The method was successfully applied to analyzeFusariumcommunities in soil and plant material and can facilitate further studies ofFusariumecology.
Influence of Iron on Production of the Antibacterial Compound Tropodithietic Acid and Its Noninhibitory Analog in Phaeobacter inhibens
Authors: D'Alvise Paul W. , Phippen Christopher B. W. , Nielsen Kristian F. , Gram Lone
Published: October 2015

Tropodithietic acid (TDA) is an antibacterial compound produced by some
Phaeobacter
and
Ruegeria
spp. of the
Roseobacter
clade. TDA production is studied in marine broth or agar since antibacterial activity in other media is not observed. The purpose of this study was to determine how TDA production is influenced by substrate components. High concentrations of ferric citrate, as present in marine broth, or other iron sources were required for production of antibacterially active TDA. However, when supernatants of noninhibitory, low-iron cultures of
Phaeobacter inhibens
were acidified, antibacterial activity was detected in a bioassay. The absence of TDA in nonacidified cultures and the presence of TDA in acidified cultures were verified by liquid chromatography–high-resolution mass spectrometry. A noninhibitory TDA analog (pre-TDA) was produced by
P. inhibens
,
Ruegeria mobilis
F1926, and
Phaeobacter
sp. strain 27-4 under low-iron concentrations and was instantaneously converted to TDA when pH was lowered. Production of TDA in the presence of Fe
3+
coincides with formation of a dark brown substance, which could be precipitated by acid addition. From this brown pigment TDA could be liberated slowly with aqueous ammonia, and both direct-infusion mass spectrometry and elemental analysis indicated a [Fe
III
(TDA)
2
]

x

complex. The pigment could also be produced by precipitation of pure TDA with FeCl
3
. Our results raise questions about how biologically active TDA is produced in natural marine settings where iron is typically limited and whether the affinity of TDA to iron points to a physiological or ecological function of TDA other than as an antibacterial compound.
Novel Alginate Lyase (Aly5) from a Polysaccharide-Degrading Marine Bacterium, Flammeovirga sp. Strain MY04: Effects of Module Truncation on Biochemical Characteristics, Alginate Degradation Patterns, and Oligosaccharide-Yielding Properties
Authors: Han Wenjun , Gu Jingyan , Cheng Yuanyuan , Liu Huihui , Li Yuezhong , Li Fuchuan
Published: October 2015

Alginate lyases are important tools for oligosaccharide preparation, medical treatment, and energy bioconversion. Numerous alginate lyases have been elucidated. However, relatively little is known about their substrate degradation patterns and product-yielding properties, which is a limit to wider enzymatic applications and further enzyme improvements. Herein, we report the characterization and module truncation of Aly5, the first alginate lyase obtained from the polysaccharide-degrading bacterium
Flammeovirga
. Aly5 is a 566-amino-acid protein and belongs to a novel branch of the polysaccharide lyase 7 (PL7) superfamily. The protein rAly5 is an endolytic enzyme of alginate and associated oligosaccharides. It prefers guluronate (G) to mannuronate (M). Its smallest substrate is an unsaturated pentasaccharide, and its minimum product is an unsaturated disaccharide. The final alginate digests contain unsaturated oligosaccharides that generally range from disaccharides to heptasaccharides, with the tetrasaccharide fraction constituting the highest mass concentration. The disaccharide products are identified as ΔG units. While interestingly, the tri- and tetrasaccharide fractions each contain higher proportions of ΔG to ΔM ends, the larger final products contain only ΔM ends, which constitute a novel oligosaccharide-yielding property of guluronate lyases. The deletion of the noncatalytic region of Aly5 does not alter its M/G preference but significantly decreases the enzymatic activity and enzyme stability. Notably, the truncated protein accumulates large final oligosaccharide products but yields fewer small final products than Aly5, which are codetermined by its M/G preference to and size enlargement of degradable oligosaccharides. This study provides novel enzymatic properties and catalytic mechanisms of a guluronate lyase for potential uses and improvements.
Improving Detection of IV Infiltrates in Neonates
Authors: Driscoll, MD Colleen , Langer Melissa , Burke Susan , El Metwally, MD Dina
Published: October 2015

Neonates and infants in the neonatal intensive care unit suffer significant morbidity when intravenous (IV) catheters infiltrate. The underreporting of adverse events through hospital voluntary reporting systems, such as ours, can complicate the monitoring of low incidence events, like IV infiltrates. Based on severe cases of IV infiltrates observed in our neonatal intensive care unit, we attempted to improve the detection of all infiltrates and reduce the incidence of Stage 4 infiltrates.

We developed, and initiated the use of, an evidence-based guideline for the improved surveillance, prevention, and management of IV infiltrates, with corresponding educational interventions for faculty and staff. We instituted the use of a checklist for compliance with guidelines, and as a mechanism of surveillance.

The baseline incidence rate of IV infiltrates, determined by the voluntary reporting system, was 5 per 1000 line days. Following initiation of the guidelines and checklist, the IV infiltrate rate increased to 9 per 1000 line days. In most months, the detection of IV infiltrates was improved by use of the checklist. During the post-intervention period the rate of Stage 4 infiltrates, as measured by usage of nitroglycerin ointment, was significantly reduced.

In conclusion, the detection of IV infiltrates was improved following our quality improvement interventions. Further, use of an evidence-based guideline for managing infiltrates may reduce the most severe infiltrate injuries.
Assessing the utility of an online registry for patients monitoring their own warfarin therapy
Authors: McCahon Deborah , Baker Jennifer M , Murray Ellen T , Fitzmaurice David A
Published: October 2015

Aims

To evaluate the utility of an online self-report registry for patient self-monitoring and self-management (PSM) of warfarin therapy.

Methods

A prospective observational study of UK-based patients undertaking PSM and recording their international normalised ratio (INR) data via an online registry. Consenting participants recorded INR test dates, results and warfarin dosages using the online registry for a period of 12 months. Participants reported demographic data, disease characteristics and treatment-related adverse events and provided feedback via a survey. Data accuracy was assessed through comparison of INR results recorded online with results stored on 19 INR testing devices. Percentage time spent within therapeutic time in range (TTR) was also examined.

Results

Eighty-seven per cent (39/45) completed the study period. Age ranged from 26 to 83 years, 44% had undertaken PSM for >5 years. Sixty-six per cent (25/38) reported that the registry was easy to navigate and use. Forty-two participants contributed a total of 1669 INR results. Agreement between self-reported INR results and source INR data was high (99%). Mean TTR was 76% (SD 18.58) with 83% having >60% TTR.

Conclusions

Findings suggest that an online PSM registry is feasible, accurate and acceptable to patients. These findings require confirmation in a larger cohort of PSM patients. An online self-report registry could provide a valuable resource for gathering real world evidence of clinical effectiveness and safety of these developing models of care.
The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy
Authors: Zhang Jimmy , Nadtochiy Sergiy M. , Urciuoli William R. , Brookes Paul S.
Published: October 2015

Mitochondrial quality control mechanisms have been implicated in protection against cardiac ischemia-reperfusion (IR) injury. Previously, cloxyquin (5-chloroquinolin-8-ol) was identified via phenotypic screening as a cardioprotective compound. Herein, cloxyquin was identified as a mitochondrial uncoupler in both isolated heart mitochondria and adult cardiomyocytes. Additionally, cardiomyocytes isolated from transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein light chain 3 showed increased autophagosome formation with cloxyquin treatment. The autophagy inhibitor chloroquine abolished cloxyquin-induced cardioprotection in both cellular and perfused heart (Langendorff) models of IR injury. Finally, in an in vivo murine left anterior descending coronary artery occlusion model of IR injury, cloxyquin significantly reduced infarct size from 31.4 ± 3.4% to 16.1 ± 2.2%. In conclusion, the cardioprotective compound cloxyquin simultaneously uncoupled mitochondria and induced autophagy. Importantly, autophagy appears to be required for cloxyquin-induced cardioprotection.
Induction and regulation of murine emphysema by elastin peptides
Authors: Sellami Mehdi , Meghraoui-Kheddar Aïda , Terryn Christine , Fichel Caroline , Bouland Nicole , Diebold Marie-Daniele , Guenounou Moncef , Héry-Huynh Stéphanie , Le Naour Richard
Published: October 2015

Emphysema is the major component of chronic obstructive pulmonary disease (COPD). During emphysema, elastin breakdown in the lung tissue originates from the release of large amounts of elastase by inflammatory cells. Elevated levels of elastin-derived peptides (EP) reflect massive pulmonary elastin breakdown in COPD patients. Only the EP containing the GXXPG conformational motif with a type VIII β-turn are elastin receptor ligands inducing biological activities. In addition, the COOH-terminal glycine residue of the GXXPG motif seems a prerequisite to the biological activity. In this study, we endotracheally instilled C57BL/6J mice with GXXPG EP and/or COOH-terminal glycine deleted-EP whose sequences were designed by molecular dynamics and docking simulations. We investigated their effect on all criteria associated with the progression of murine emphysema. Bronchoalveolar lavages were recovered to analyze cell profiles by flow cytometry and lungs were prepared to allow morphological and histological analysis by immunostaining and confocal microscopy. We observed that exposure of mice to EP elicited hallmark features of emphysema with inflammatory cell accumulation associated with increased matrix metalloproteinases and desmosine expression and of remodeling of parenchymal tissue. We also identified an inactive COOH-terminal glycine deleted-EP that retains its binding-activity to EBP and that is able to inhibit the in vitro and in vivo activities of emphysema-inducing EP. This study demonstrates that EP are key actors in the development of emphysema and that they represent pharmacological targets for an alternative treatment of emphysema based on the identification of EP analogous antagonists by molecular modeling studies.
Systemic interleukin-2 administration improves lung function and modulates chorioamnionitis-induced pulmonary inflammation in the ovine fetus
Authors: Willems Monique G. M. , Ophelders Daan R. M. G. , Nikiforou Maria , Jellema Reint K. , Butz Anke , Delhaas Tammo , Kramer Boris W. , Wolfs Tim G. A. M.
Published: October 2015

Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3+/CD3+ratio, which was associated with reduced CD3-positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1-positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL-6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis.
Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension
Authors: Afolayan Adeleye J. , Eis Annie , Alexander Maxwell , Michalkiewicz Teresa , Teng Ru-Jeng , Lakshminrusimha Satyan , Konduri Girija G.
Published: October 2015

Impaired vasodilation in persistent pulmonary hypertension of the newborn (PPHN) is characterized by mitochondrial dysfunction. We investigated the hypothesis that a decreased endothelial nitric oxide synthase level leads to impaired mitochondrial biogenesis and function in a lamb model of PPHN induced by prenatal ductus arteriosus constriction. We ventilated PPHN lambs with 100% O2alone or with inhaled nitric oxide (iNO). We treated pulmonary artery endothelial cells (PAECs) from normal and PPHN lambs with detaNONOate, an NO donor. We observed decreased mitochondrial (mt) DNA copy number, electron transport chain (ETC) complex subunit levels, and ATP levels in PAECs and lung tissue of PPHN fetal lambs at baseline compared with gestation matched controls. Phosphorylation of AMP-activated kinase (AMPK) and levels of peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) and sirtuin-1, which facilitate mitochondrial biogenesis, were decreased in PPHN. Ventilation with 100% O2was associated with larger decreases in ETC subunits in the lungs of PPHN lambs compared with unventilated PPHN lambs. iNO administration, which facilitated weaning of FiO2, partly restored mtDNA copy number, ETC subunit levels, and ATP levels. DetaNONOate increased eNOS phosphorylation and its interaction with heat shock protein 90 (HSP90); increased levels of superoxide dismutase 2 (SOD2) mRNA, protein, and activity; and decreased the mitochondrial superoxide levels in PPHN-PAECs. Knockdown of eNOS decreased ETC protein levels in control PAECs. We conclude that ventilation with 100% O2amplifies oxidative stress and mitochondrial dysfunction in PPHN, which are partly improved by iNO and weaning of oxygen.
Risk Stratification Using Human Papillomavirus Testing among Women with Equivocally Abnormal Cytology: Results from a State-Wide Surveillance Program
Authors: Gage Julia C. , Hunt William C. , Schiffman Mark , Katki Hormuzd A. , Cheung Li C. , Cuzick Jack , Myers Orrin , Castle Philip E. , Wheeler Cosette M.
Published: October 2015

Background: Clinical guidelines for cervical cancer screening have incorporated comparative risks of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) for various screening outcomes to determine management. Few cohorts are large enough to distinguish CIN3+ risks among women with minor abnormalities versus negative cytology because of low incidence. The New Mexico Human Papillomavirus (HPV) Pap Registry offers a unique opportunity to evaluate cervical cancer screening in a diverse population across a broad-spectrum of health service delivery.

Methods: Kaplan–Meier and logistic–Weibull survival models were used to estimate cumulative risks of CIN3+ among women ages 21 to 64 who were screened in New Mexico between 2007 and 2011 with negative, equivocal or mildly abnormal cytology, that is, atypical squamous cells of undetermined significance (ASC-US; with or without HPV triage), or low-grade squamous intraepithelial lesions (LSIL).

Results: We identified 452,045 women meeting the selection criteria. The 3-year CIN3+ risks for women with negative, ASC-US, and LSIL cytology were 0.30%, 2.6%, and 5.2%, respectively. HPV triage of ASC-US stratified 3-year CIN3+ risks were 0.72% for HPV-negative and 7.7% for HPV-positive. Risks tended to decline after age 30 for all screening results.

Conclusions: In this state-wide population-based cohort, cytology and HPV triage of ASC-US stratified women's CIN3+ risk into similar patterns observed previously, suggesting the validity of screening guidelines for diverse populations in the United States. Absolute risk estimates should be compared across other large populations.

Impact: Strategies for HPV triage of ASC-US derived from clinical trials are upheld in large clinical practice settings and across diverse screening populations in the United States. Cancer Epidemiol Biomarkers Prev; 25(1); 36–42. ©2015 AACR.
Molecular Pathways: Fatty Acid Synthase
Authors: Jones Suzanne F. , Infante Jeffrey R.
Published: October 2015

Therapies that target tumor metabolism represent a new horizon in anticancer therapies. In particular, cancer cells are dependent on the generation of lipids, which are essential for cell membrane synthesis, modification of proteins, and localization of many oncogenic signal transduction enzymes. Because fatty acids are the building blocks of these important lipids, fatty acid synthase (FASN) emerges as a unique oncologic target. FASN inhibitors are being studied preclinically and beginning to transition to first-in-human trials. Early generation FASN inhibitors have been studied preclinically but were limited by their pharmacologic properties and side-effect profiles. A new generation of molecules, including GSK2194069, JNJ-54302833, IPI-9119, and TVB-2640, are in development, but only TVB-2640 has moved into the clinic. FASN inhibition, either alone or in combination, holds promise as a novel therapeutic approach for patients with cancer. Clin Cancer Res; 21(24); 5434–8. ©2015 AACR.
Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy
Authors: Zhai Lijie , Spranger Stefani , Binder David C. , Gritsina Galina , Lauing Kristen L. , Giles Francis J. , Wainwright Derek A.
Published: October 2015

Indoleamine 2, 3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2, 3-dioxygenase (TDO) comprise a family of enzymes that catalyze the first- and rate-limiting step associated with the catabolic conversion of tryptophan (Trp) into kynurenine (Kyn). Through subsequent enzymatic and spontaneous reactions, Kyn is further converted into the energetic substrates, NAD+ and ATP, to fuel cellular metabolic functions. Coincidently, the depletion of Trp and accumulation of Kyn has been demonstrated to induce effector T-cell apoptosis/dysfunction and immunosuppressive regulatory T-cell induction, respectively. Similar to other immune checkpoints, IDO1 and TDO are suggested to be important targets for immunotherapeutic intervention. This is represented by the recent growth of efforts to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression. Inhibitors currently in clinical trials, INCB024360, GDC-0919, indoximod, and an IDO1 peptide-based vaccine, are being evaluated for their efficacy against a wide range of cancers including melanoma, glioblastoma, non–small cell lung, pancreatic, and/or breast cancer, as well as metastatic disease. Despite the rapid development of potent clinical grade inhibitors, strategic questions remain. Here, we review the state of the literature with respect to current therapeutic inhibitors of tryptophan catabolism, evaluation of those efforts preclinically and clinically, compensatory changes that occur with therapeutic targeting, as well as newly recognized signaling features that raise critical questions to the field. Given the rapidly evolving interest in determining how IDO1/TDO, and to an unknown extent, IDO2, can be targeted for increasing cancer immunotherapeutic efficacy, we present a brief but comprehensive analysis that addresses critical questions, while highlighting the mechanics that remain to be explored. Clin Cancer Res; 21(24); 5427–33. ©2015 AACR.
Functional Genomics Analysis of Big Data Identifies Novel Peroxisome Proliferator–Activated Receptor γ Target Single Nucleotide Polymorphisms Showing Association With Cardiometabolic Outcomes
Authors: Richardson Kris , Schnitzler Gavin R. , Lai Chao-Qiang , Ordovas Jose M.
Published: October 2015

Background—

Cardiovascular disease and type 2 diabetes mellitus represent overlapping diseases where a large portion of the variation attributable to genetics remains unexplained. An important player in their pathogenesis is peroxisome proliferator–activated receptor γ (PPARγ) that is involved in lipid and glucose metabolism and maintenance of metabolic homeostasis. We used a functional genomics methodology to interrogate human chromatin immunoprecipitation-sequencing, genome-wide association studies, and expression quantitative trait locus data to inform selection of candidate functional single nucleotide polymorphisms (SNPs) falling in PPARγ motifs.

Methods and Results—

We derived 27 328 chromatin immunoprecipitation-sequencing peaks for PPARγ in human adipocytes through meta-analysis of 3 data sets. The PPARγ consensus motif showed greatest enrichment and mapped to 8637 peaks. We identified 146 SNPs in these motifs. This number was significantly less than would be expected by chance, and Inference of Natural Selection from Interspersed Genomically coHerent elemenTs analysis indicated that these motifs are under weak negative selection. A screen of these SNPs against genome-wide association studies for cardiometabolic traits revealed significant enrichment with 16 SNPs. A screen against the MuTHER expression quantitative trait locus data revealed 8 of these were significantly associated with altered gene expression in human adipose, more than would be expected by chance. Several SNPs fall close, or are linked by expression quantitative trait locus to lipid-metabolism loci including CYP26A1.

Conclusions—

We demonstrated the use of functional genomics to identify SNPs of potential function. Specifically, that SNPs within PPARγ motifs that bind PPARγ in adipocytes are significantly associated with cardiometabolic disease and with the regulation of transcription in adipose. This method may be used to uncover functional SNPs that do not reach significance thresholds in the agnostic approach of genome-wide association studies.
Hypertrophic Cardiomyopathy in Children, Adolescents, and Young Adults Associated With Low Cardiovascular Mortality With Contemporary Management Strategies
Authors: Maron Barry J. , Rowin Ethan J. , Casey Susan A. , Lesser John R. , Garberich Ross F. , McGriff Deepa M. , Maron Martin S.
Published: October 2015

Background—

Youthful age has been considered the time of greatest risk for patients with hypertrophic cardiomyopathy (HCM), largely because of the possibility of sudden death. The last 2 decades have witnessed more reliable identification of at-risk patients and utilization of implantable cardioverter-defibrillators for prevention of sudden death, and other contemporary treatment options. Whether such management advances have significantly altered the considerable mortality rate for young HCM patients remains unresolved.

Methods and Results—

We studied long-term outcome in 474 consecutive HCM patients between 7 and 29 years of age presenting at 2 referral institutions. Over 7.1±5.1 years of follow-up (6.0 [3.0, 10.0]), 452 patients (95%) survived, with 95% experiencing no or mild symptoms. HCM-related death occurred in 18 patients (3%; 0.54%/y): arrhythmic sudden death (n=12), progressive heart failure and heart transplant complications (n=5), or postoperatively (n=1). In contrast, aborted life-threatening events occurred in 63 other high-risk patients (13%) with implantable cardioverter-defibrillator interventions for ventricular tachyarrhythmias (n=31), resuscitated out-of-hospital cardiac arrest (n=20), or heart transplant for advanced heart failure (n=12), 1.8%/y, 3-fold higher than HCM mortality. Five- and 10-year survival (considering only HCM deaths) was high (97% and 94%, respectively), virtually identical to that reported in middle-aged adult HCM patients (98% and 94%,
P
=0.23).

Conclusions—

In a large hospital-based cohort of young HCM patients, representing an age group considered at greatest risk, low mortality rates can be achieved with the application of contemporary cardiovascular treatment strategies, largely because of reliable identification of high-risk patients who benefited from implantable cardioverter-defibrillators for sudden death prevention, thereby creating the opportunity for extended longevity and good quality of life.
Transvenous Implantable Cardioverter‐Defibrillator (ICD) Lead Performance: A Meta‐Analysis of Observational Studies
Authors: Providência Rui , Kramer Daniel B. , Pimenta Dominic , Babu Girish G. , Hatfield Laura A. , Ioannou Adam , Novak Jan , Hauser Robert G. , Lambiase Pier D.
Published: October 2015

Background

Despite the widespread use of implantable cardioverter‐defibrillators (
ICD
s) in clinical practice, concerns exist regarding
ICD
lead durability. The performance of specific lead designs and factors determining this in large populations need clarification.

Methods and Results

The Medline, Embase, and Cochrane Collaboration databases were searched for studies including ≥2 of the most commonly implanted leads. The Mantel‐Haenszel random‐effects model was used. Seventeen studies were selected, including a total of 49 871 patients—5538 implanted with Durata (St. Jude Medical Inc), 10 605 with Endotak Reliance (Boston Scientific), 16 119 with Sprint Quattro (Medtronic Corp), 11 709 with Sprint Fidelis (Medtronic Corp), and 5900 with Riata (St. Jude Medical Inc)—with follow‐up of 136 509 lead‐years. Although the Durata lead presented a numerically higher rate, no statistically significant differences in the mean incidence of lead failure (0.29%–0.45% per year) were observed in comparison of the 3 nonrecalled leads. A higher event rate was documented with the Riata (1.0% per‐year increase) and Sprint Fidelis (>2.0% per‐year increase) leads compared with nonrecalled leads. An indication of increased incidence of Durata lead failure versus Sprint Quattro and Endotak Reliance leads was observed in 1 of 3 included studies, allowing for comparison of purely electrical lead failure, but this requires further evaluation.

Conclusions

Endotak Reliance (8F), Sprint Quattro (8F), and Durata (7F) leads displayed low annual incidence of failure; however, long‐term follow‐up data are still scarce. More data are needed to clarify the performance and safety of the Durata lead.
Direct-to-consumer Genetic Testing: Changes in the eu Regulatory Landscape
Authors: Slokenberga Santa
Published: October 2015

Rapid advances in genomics and technology have rendered genetic testing services easily accessible to consumers over the Internet in the form of direct-to-consumer genetic testing. In the eu, the ivd Directive has been animadverted for its inability to tackle the challenges direct-to-consumer genetic testing has posed. Currently, the eu legislation is in a transition state. It is thus, timely to assess, to what extent the proposed ivd Regulation is intended to address the performance requirements and utility of direct-to-consumer genetic tests, which are made available to consumers within the eu over the Internet, and discuss the developments vis-à-vis the ivd Directive. To compare with the ivd Directive, the ivd Regulation presents a major shift in how direct-to-consumer genetic testing is treated in the eu. It remains unclear, whether and how the eu requirements can be applied beyond the eu market.
uk’s Legalisation of Mitochondrial Donation in ivf Treatment: A Challenge to the International Community or a Promotion of Life-saving Medical Innovation to Be Followed by Others?
Authors: Varvaštian Samvel
Published: October 2015

Mitochondrial dna diseases are rare genetic disorders, which can have a devastating effect on the patients’ health and well-being. There is no cure for such diseases, although recent experiments suggest that there may be a way to prevent them by genetically altering the eggs or embryos through a procedure known as mitochondrial donation. However, such a procedure not only raises serious safety and ethical concerns, but legal challenges as well, since it involves germline gene modification, which until recently was not legal in the uk or elsewhere. In February 2015, the British Parliament amended the relevant legislation to allow such a procedure, making the uk the first state to openly challenge the global policy on germline gene modification. The article presents the scientific background to the procedure and discusses the regulatory challenges brought by the first case of its legalisation.
Encountering Challenges with the eu Regulation on Advance Therapy Medical Products
Authors: Mansnérus Juli
Published: October 2015

This article aims at analysing how well the Advanced Therapy Medical Product Regulation (ec) No. 1394/2007 (atmp Regulation) meets the needs of small and medium-sized enterprises (smes), academia and public tissue establishments developing advanced therapy medical products (atmps). Benefits and shortcomings of the atmp Regulation are identified, and possible amendments are proposed to accelerate the translation of research into advanced therapies and to facilitate the commercialisation of atmps whilst ensuring safety. It was set up as a lex specialis to ensure the free movement of atmps within the eu in order to facilitate their access to the internal market and to foster the competitiveness of European pharmaceutical companies, while guaranteeing the highest level protection of public health. Since the adoption of the atmp Regulation in late 2008, only 5 atmps have been granted marketing authorisations thus far. Hence, there is a need to analyse whether the atmp Regulation meets its objectives.
Making the Most of Multiple Measures
Authors: Saperstein Aliya , Kizer Jessica M. , Penner Andrew M.
Published: October 2015

The majority of social science research uses a single measure of race when investigating racial inequality. However, a growing body of work demonstrates that race shapes the life chances of individuals in multiple ways, related not only to how people self-identify but also to how others perceive them. As multiple measures of race are increasingly collected and used in survey research, it becomes important to consider the best methods of leveraging such data. We present four analytical approaches for incorporating two different dimensions of race in the same study and illustrate their use with data from the U.S. National Longitudinal Study of Adolescent to Adult Health. The approaches range from tests of specific hypotheses to the most exploratory description of how different measures of race relate to social inequality. Although each approach has its strengths and weaknesses, by accounting for the multidimensionality of race, they all allow for more nuanced patterns of advantage and disadvantage than standard single-measure methods.