bluuebunny/crossref_metadata_2025 huggingface dataset:
Resource Letter SPE-1: Single-Photon Experiments in the Undergraduate Laboratory
Authors: Galvez Enrique J.
Published: October 2014

This Resource Letter lists undergraduate-laboratory adaptations of landmark optical experiments on the fundamentals of quantum physics. Journal articles and websites give technical details of the adaptations, which offer students unique hands-on access to testing fundamental concepts and predictions of quantum mechanics. A selection of the original research articles that led to the implementations is included. These developments have motivated a rethinking of the way quantum mechanics is taught, so this Resource Letter also lists textbooks that provide these new approaches.
Antarctic role in Northern Hemisphere glaciation
Authors: Woodard Stella C. , Rosenthal Yair , Miller Kenneth G. , Wright James D. , Chiu Beverly K. , Lawrence Kira T.
Published: October 2014

Earth’s climate underwent a major transition from the warmth of the late Pliocene, when global surface temperatures were ~2° to 3°C higher than today, to extensive Northern Hemisphere glaciation (NHG) ~2.73 million years ago (Ma). We show that North Pacific deep waters were substantially colder (4°C) and probably fresher than the North Atlantic Deep Water before the intensification of NHG. At ~2.73 Ma, the Atlantic-Pacific temperature gradient was reduced to <1°C, suggesting the initiation of stronger heat transfer from the North Atlantic to the deep Pacific. We posit that increased glaciation of Antarctica, deduced from the 21 ± 10–meter sea-level fall from 3.15 to 2.75 Ma, and the development of a strong polar halocline fundamentally altered deep ocean circulation, which enhanced interhemispheric heat and salt transport, thereby contributing to NHG.
Genome Sequence Analysis of the Biogenic Amine-Producing Strain Lactococcus lactis subsp.
cremoris
CECT 8666 (Formerly GE2-14)
Authors: Ladero Victor , del Rio Beatriz , Linares Daniel M. , Fernandez Maria , Mayo Baltasar , Martin M. Cruz , Alvarez Miguel A.
Published: October 2014

We here report a 2,801,031-bp annotated draft assembly for the
Lactococcus lactis
subsp.
cremoris
GE2-14 genome. This dairy strain produces the biogenic amine putrescine. This sequence may help identify the mechanisms regulating putrescine biosynthesis and throw light on ways to reduce its presence in fermented foods.
Cost-utility of transcatheter aortic valve implantation for inoperable patients with severe aortic stenosis treated by medical management: a UK cost-utility analysis based on patient-level data from the ADVANCE study
Authors: Brecker Stephen , Mealing Stuart , Padhiar Amie , Eaton James , Sculpher Mark , Busca Rachele , Bosmans Johan , Gerckens Ulrich J , Wenaweser Peter , Tamburino Corrado , Bleiziffer Sabine , Piazza Nicolo , Moat Neil , Linke Axel
Published: October 2014

Objective

To use patient-level data from the ADVANCE study to evaluate the cost-effectiveness of transcatheter aortic valve implantation (TAVI) compared to medical management (MM) in patients with severe aortic stenosis from the perspective of the UK NHS.

Methods

A published decision-analytic model was adapted to include information on TAVI from the ADVANCE study. Patient-level data informed the choice as well as the form of mathematical functions that were used to model all-cause mortality, health-related quality of life and hospitalisations. TAVI-related resource use protocols were based on the ADVANCE study. MM was modelled on publicly available information from the PARTNER-B study. The outcome measures were incremental cost-effectiveness ratios (ICERs) estimated at a range of time horizons with benefits expressed as quality-adjusted life-years (QALY). Extensive sensitivity/subgroup analyses were undertaken to explore the impact of uncertainty in key clinical areas.

Results

Using a 5-year time horizon, the ICER for the comparison of all ADVANCE to all PARTNER-B patients was £13 943 per QALY gained. For the subset of ADVANCE patients classified as high risk (Logistic EuroSCORE >20%) the ICER was £17 718 per QALY gained). The ICER was below £30 000 per QALY gained in all sensitivity analyses relating to choice of MM data source and alternative modelling approaches for key parameters. When the time horizon was extended to 10 years, all ICERs generated in all analyses were below £20 000 per QALY gained.

Conclusion

TAVI is highly likely to be a cost-effective treatment for patients with severe aortic stenosis.
Stereoselective suppressive effects of protopanaxadiol epimers on UV-B-induced reactive oxygen species and matrix metalloproteinase-2 in human dermal keratinocytes
Authors: Oh Sun-Joo , Lee Sihyeong , Kho Ye Eun , Kim Kyunghoon , Jin Chang Duck , Lim Chang-Jin
Published: October 2014

This study aimed to assess the skin-related anti-photoaging activities of the 2 epimeric forms of protopanaxadiol (PPD), 20(S)-PPD and 20(R)-PPD, in cultured human keratinocytes (HaCaT cells). The anti-photoaging activity was evaluated by analyzing the levels of reactive oxygen species (ROS) and matrix metalloproteinases (MMPs), as well as cell viability for HaCaT cells under UV-B irradiation. The activities for MMP-2 and -1 in conditioned medium were determined using gelatin zymography, and MMP-2 protein in the conditioned medium was detected using Western blot analysis. 20(S)-PPD, but not 20(R)-PPD, suppressed UV-B-induced ROS elevation. Neither of the epimers, at the concentrations used, exhibited cytotoxicity, irrespective of UV-B irradiation. 20(S)-PPD, but not 20(R)-PPD, exhibited an inhibitory effect on UV-B-induced MMP-2 activity and expression in HaCaT cells. In brief, only 20(S)-PPD, a major metabolic product of PPD-type ginsenosides, inhibits UV-B-induced ROS and MMP-2 elevation, implying its stereospecific anti-photoaging activity on the skin.
Recent developments in the study of insect flight
Authors: Hedrick Tyson L. , Combes Stacey A. , Miller Laura A.
Published: October 2014

Here we review recent contributions to the study of insect flight, in particular those brought about by advances in experimental techniques. We focus particularly on the following areas: wing flexibility and deformation, the physiology and biophysics of asynchronous insect flight muscle, the aerodynamics of flight, and stability and maneuverability. This recent research reveals the importance of wing flexibility to insect flight, provides a detailed model of how asynchronous flight muscle functions and how it may have evolved, synthesizes many recent studies of insect flight aerodynamics into a broad-reaching summary of unsteady flight aerodynamics, and highlights new insights into the sources of flight stability in insects. The focus on experimental techniques and recently developed apparatus shows how these advancements have occurred and point the way towards future experiments.
Lp estimates for the $\bar\partial$-equation on a class of infinite type domains
Authors: Ha Ly Kim , Khanh Tran Vu , Raich Andrew
Published: October 2014

We prove Lp estimates, 1 ≤ p ≤ ∞, for solutions to the Cauchy–Riemann equations [Formula: see text] on a class of infinite type domains in ℂ2. The domains under consideration are a class of convex ellipsoids, and we show that if ϕ is a [Formula: see text]-closed (0, 1)-form with coefficients in Lp and u is the Henkin kernel solution to [Formula: see text], then ‖u‖p ≤ C‖ϕ‖p where the constant C is independent of ϕ. In particular, we prove L1 estimates and obtain Lp estimates by interpolation.
Document Representation with Statistical Word Senses in Cross-Lingual Document Clustering
Authors: Tang Guoyu , Xia Yunqing , Cambria Erik , Jin Peng , Zheng Thomas Fang
Published: October 2014

Cross-lingual document clustering is the task of automatically organizing a large collection of multi-lingual documents into a few clusters, depending on their content or topic. It is well known that language barrier and translation ambiguity are two challenging issues for cross-lingual document representation. To this end, we propose to represent cross-lingual documents through statistical word senses, which are automatically discovered from a parallel corpus through a novel cross-lingual word sense induction model and a sense clustering method. In particular, the former consists in a sense-based vector space model and the latter leverages on a sense-based latent Dirichlet allocation. Evaluation on the benchmarking datasets shows that the proposed models outperform two state-of-the-art methods for cross-lingual document clustering.
Computing homology invariants of Legendrian knots
Authors: Casey Emily E. , Henry Michael B.
Published: October 2014

The Chekanov–Eliashberg differential graded algebra of a Legendrian knot L is a rich source of Legendrian knot invariants, as is the theory of generating families. The set P(L) of homology groups of augmentations of the Chekanov–Eliashberg algebra is an invariant, as is a count of objects from the theory of generating families called graded normal rulings. This paper gives two results demonstrating the usefulness of computing the homology group of an augmentation using a combinatorial interpretation of a generating family called a Morse complex sequence (MCS). First, we show that if the projection of L to the xz-plane has exactly 4 cusps, then |P(L)| ≤ 1. Second, we show that two augmentations associated to the same graded normal ruling by the many-to-one map between augmentations and graded normal rulings defined by Ng and Sabloff [The correspondence between augmentations and rulings for Legendrian knots, Pacific J. Math.224(1) (2006) 141–150] need not have isomorphic homology groups.
Stability Prediction in High-Speed Milling Process Considering the Milling Force Coefficients Dependent on the Spindle Speed
Authors: Wen Kunlong , Qi Houjun , Jin Gang
Published: October 2014

In order to further research the chatter vibration in high-speed milling, in this paper, a new regenerative chatter vibration model, considering the effect of milling force coefficients dependent on the spindle speed (MFCDSS) on the stability of high-speed milling process is proposed, and then milling stability lobe diagram is obtained, based on full-discretization method (FDM). The variable tendency of the stability of milling system is analyzed by comparisons in case of different radial immersion ratios in low-speed and high-speed milling regions, respectively. It is found that great stability predicting differences occur, especially in high-speed region when the MFCDSS is considered. This model can further supplement the theory of stability of high-speed milling process, it has certain engineering guidance significance in the selection of high-speed milling parameters.
Super-Lie n-algebra extensions, higher WZW models and super-p-branes with tensor multiplet fields
Authors: Fiorenza Domenico , Sati Hisham , Schreiber Urs
Published: October 2014

We formalize higher-dimensional and higher gauge WZW-type sigma-model local prequantum field theory, and discuss its rationalized/perturbative description in (super-)Lie n-algebra homotopy theory (the true home of the "FDA"-language used in the supergravity literature). We show generally how the intersection laws for such higher WZW-type σ-model branes (open brane ending on background brane) are encoded precisely in (super-)L∞-extension theory and how the resulting "extended (super-)space-times" formalize spacetimes containing σ-model brane condensates. As an application we prove in Lie n-algebra homotopy theory that the complete super-p-brane spectrum of superstring/M-theory is realized this way, including the pure σ-model branes (the "old brane scan") but also the branes with tensor multiplet worldvolume fields, notably the D-branes and the M5-brane. For instance the degree-0 piece of the higher symmetry algebra of 11-dimensional (11D) spacetime with an M2-brane condensate turns out to be the "M-theory super-Lie algebra". We also observe that in this formulation there is a simple formal proof of the fact that type IIA spacetime with a D0-brane condensate is the 11D sugra/M-theory spacetime, and of (prequantum) S-duality for type IIB string theory. Finally we give the non-perturbative description of all this by higher WZW-type σ-models on higher super-orbispaces with higher WZW terms in stacky differential cohomology.
Comparison of photovoltaic performance of TiO2 nanoparticles based thin films via different routes
Authors: Ji Yajun
Published: October 2014

Well crystallized TiO 2 nanoparticles were prepared by hydrothermal and sol–gel routes, respectively. The morphologies, structures, crystallinity and optical properties of resulted TiO 2 nanoparticles-based thin films via the two methods were examined by field emission scanning electron microscope (FE-SEM), transmission electron microscope (TEM), X-ray diffractometer (XRD) and reflectance spectra. In addition, comparison of photovoltaic performance of TiO 2 nanoparticles-based thin films by the two methods was performed. It is found that the maximum energy conversion efficiency of 4.06% was achieved based on the obtained electrode via hydrothermal, which is much better than that of the sol–gels route. The uniform film structure with improved dye absorption capability, increased diffused reflectance property and relatively low charge recombination rates for injected electrons are believed to be responsible to the superior photoelectrochemical properties of dye-sensitized solar cells (DSSC) via hydrothermal route.
Welcome from the new SIGCAS committee
Authors: Goldweber Michael
Published: October 2014

An introduction and welcome from the incoming SIGCAS Executive Committee.
A synthesized definition of computer ethics
Authors: Hall Brian R.
Published: October 2014

Computing ethics is a complex area of study that is of significant importance to the computing community and global society. However, research and education in computing ethics are difficult due to the diverse meanings of ethics. This paper presents details of a content analysis study that analyzed definitions of computer ethics. The purpose of this study was to educe and present the meaning of computing ethics, resulting in a thematic definition of computing ethics for use in education and research. This paper presents definition themes that emerged: interdisciplinary, collaboration, scholars and professionals, methodically study, practically affect, contributions and costs, computing artifacts, and global society. The results of this study can assist computing ethicists with research, aid computing educators with curriculum development, and provide a theoretical frame for relating ethics to computing. This exploration demonstrates that groups within the computing community can find common ground, even on such a difficult and complex matter as ethics.
MicroRNA Polymorphisms and Risk of Colorectal Cancer
Authors: Schmit Stephanie L. , Gollub Jeremy , Shapero Michael H. , Huang Shu-Chen , Rennert Hedy S. , Finn Andrea , Rennert Gad , Gruber Stephen B.
Published: October 2014

Background: miRNAs act as post-transcriptional regulators of gene expression. Genetic variation in miRNA-encoding sequences or their corresponding binding sites may affect the fidelity of the miRNA–mRNA interaction and subsequently alter the risk of cancer development.

Methods: This study expanded the search for miRNA-related polymorphisms contributing to the etiology of colorectal cancer across the genome using a novel platform, the Axiom miRNA Target Site Genotyping Array (237,858 markers). After quality control, the study included 596 cases and 429 controls from the Molecular Epidemiology of Colorectal Cancer study, a population-based case–control study of colorectal cancer in northern Israel. The association between each marker and colorectal cancer status was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and two principal components.

Results: Twenty-three markers had P values less than 5.0E−04, and the most statistically significant association involved rs2985 (chr6:34845648; intronic of UHRF1BP1; OR = 0.66; P = 3.7E−05). Furthermore, this study replicated a previously published risk locus, rs1051690, in the 3′-untranslated region of the insulin receptor gene INSR (OR = 1.38; P = 0.03), with strong evidence of differences in INSR gene expression by genotype.

Conclusions: This study is the first to examine associations between genetic variation in miRNA target sites and colorectal cancer using a genome-wide approach. Functional studies to identify allele-specific effects on miRNA binding are needed to confirm the regulatory capacity of genetic variation to influence risk of colorectal cancer.

Impact: This study demonstrates the potential for an miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization. Cancer Epidemiol Biomarkers Prev; 24(1); 65–72. ©2014 AACR.
Do Environmental Factors Modify the Genetic Risk of Prostate Cancer?
Authors: Loeb Stacy , Peskoe Sarah B. , Joshu Corinne E. , Huang Wen-Yi , Hayes Richard B. , Carter H. Ballentine , Isaacs William B. , Platz Elizabeth A.
Published: October 2014

Background: Many SNPs influence prostate cancer risk. To what extent genetic risk can be reduced by environmental factors is unknown.

Methods: We evaluated effect modification by environmental factors of the association between susceptibility SNPs and prostate cancer in 1,230 incident prostate cancer cases and 1,361 controls, all white and similar ages, nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Trial. Genetic risk scores were calculated as number of risk alleles for 20 validated SNPs. We estimated the association between higher genetic risk (≥12 SNPs) and prostate cancer within environmental factor strata and tested for interaction.

Results: Men with ≥12 risk alleles had 1.98, 2.04, and 1.91 times the odds of total, advanced, and nonadvanced prostate cancer, respectively. These associations were attenuated with the use of selenium supplements, aspirin, ibuprofen, and higher vegetable intake. For selenium, the attenuation was most striking for advanced prostate cancer: compared with <12 alleles and no selenium, the OR for ≥12 alleles was 2.06 [95% confidence interval (CI), 1.67–2.55] in nonusers and 0.99 (0.38–2.58) in users (Pinteraction = 0.031). Aspirin had the most marked attenuation for nonadvanced prostate cancer: compared with <12 alleles and nonusers, the OR for ≥12 alleles was 2.25 (1.69–3.00) in nonusers and 1.70 (1.25–2.32) in users (Pinteraction = 0.009). This pattern was similar for ibuprofen (Pinteraction = 0.023) and vegetables (Pinteraction = 0.010).

Conclusions: This study suggests that selenium supplements may reduce genetic risk of advanced prostate cancer, whereas aspirin, ibuprofen, and vegetables may reduce genetic risk of nonadvanced prostate cancer.

Impact: The effect of genetic factors on prostate cancer risk may vary by lifestyle interventions. Cancer Epidemiol Biomarkers Prev; 24(1); 213–20. ©2014 AACR.
Predictors of Posttreatment Drinking Outcomes in Patients with Alcohol Dependence
Authors: Flórez Gerardo , Saiz Pilar A. , García-Portilla Paz , De Cos Francisco J. , Dapía Sonia , Álvarez Sandra , Nogueiras Luis , Bobes Julio
Published: October 2014

Aim: This cohort study examined how predictors of alcohol dependence treatment outcomes work together over time by comparing pretreatment and posttreatment predictors. Methods: A sample of 274 alcohol-dependent patients was recruited and assessed at baseline, 6 months after treatment initiation (end of the active intervention phase), and 18 months after treatment initiation (end of the 12-month research follow-up phase). At each assessment point, the participants completed a battery of standardized tests [European Addiction Severity Index (EuropASI), Obsessive Compulsive Drinking Scale (OCDS), Alcohol Timeline Followback (TLFB), Fagerström, and International Personality Disorder Examination (IPDE)] that measured symptom severity and consequences; biological markers of alcohol consumption were also tested at each assessment point. A sequential strategy with univariate and multivariate analyses was used to identify how pretreatment and posttreatment predictors influence outcomes up to 1 year after treatment. Results: Pretreatment variables had less predictive power than posttreatment ones. OCDS scores and biological markers of alcohol consumption were the most significant variables for the prediction of posttreatment outcomes. Prior pharmacotherapy treatment and relapse prevention interventions were also associated with posttreatment outcomes. Conclusions: The findings highlight the positive impact of pharmacotherapy during the first 6 months after treatment initiation and of relapse prevention during the first year after treatment and how posttreatment predictors are more important than pretreatment predictors.
Blood Levels of the Heavy Metal, Lead, and Caries in Children Aged 24-72 Months: NHANES III
Authors: Wiener R. Constance , Long D. Leann , Jurevic Richard J.
Published: October 2014

Lead remains a significant pollutant. It has acute toxic and chronic effects on many tissues and accumulates in teeth and bones. The researchers for this study investigated the association of blood lead levels with the extent/severity of caries as measured by the number of decayed/filled teeth of children aged 24-72 months using data from NHANES III (the Third National Health and Nutrition Examination Survey), accounting for the excess zero caries in the analysis and using less than 2 µg/dl as the reference blood lead level (n = 3,127). Zero-inflated negative binomial regression models indicated unadjusted extent/severity mean ratios of 1.79, 1.88 and 1.94 for the number of decayed/filled teeth in children whose blood lead levels were 2-5, 5-10 and >10 µg/dl, respectively, compared with children having <2 µg/dl blood lead levels. The results did not attenuate when other variables were added to the model for the 5-10 and >10 µg/dl levels of exposure. The adjusted extent/severity mean ratios were 1.84, 2.14 and 1.91, respectively, for the categories. This study indicated a strong association of blood lead levels with increasing numbers of carious teeth in children aged 24-72 months. These findings support other studies in an innovative analysis handling cases of children with no caries. The findings may inform caries risk assessment. © 2014 S. Karger AG, Basel
Identification of Novel Functional Null Allele of SLC26A4 Associated with Enlarged Vestibular Aqueduct and Its Possible Implication
Authors: Jang Jeong Hun , Jung Jinsei , Kim Ah Reum , Cho Young Mi , Kim Min Young , Lee Sang Yeon , Choi Jae Young , Lee Jun Ho , Choi Byung Yoon
Published: October 2014

Mutations in the SLC26A4 gene, which encodes pendrin, cause congenital hearing loss as a manifestation of Pendred syndrome (PS) with an iodide organification defect or nonsyndromic enlarged vestibular aqueduct (NSEVA, DFNB4). There have been reports of differences between PS and NSEVA, including their auditory phenotypes and molecular genetic bases. For appropriate genetic diagnosis and counseling, it is important to functionally characterize SLC26A4 variants. In this study, we identified and evaluated a novel null mutation of SLC26A4 and report our method of assessing the pathogenic potential of mutations in SLC26A4, one of the most frequent causative genes of deafness in humans. A 3-year-old female with progressive sensorineural hearing loss and her parents were recruited. They underwent clinical, audiological, radiological and genetic evaluations, which revealed that the female patient had an enlarged vestibular aqueduct and an incomplete partition type II anomaly in the cochlea bilaterally. Sanger sequencing of the SLC26A4 gene was also performed. For a confirmatory genetic diagnosis, we first characterized the anion/base exchange ability of mutant pendrin products in HEK 293 cells and, if necessary, evaluated whether the mutant pendrin traffics to the plasma membrane in COS-7 cells. We also expressed a null function mutant, p.H723R, and a previously documented polymorphism, p.P542R, as controls. The pure tone average was 66 dB HL in the right ear and 75 dB HL in the left ear. Sequencing of SLC26A4 revealed a known pathogenic mutation (p.H723R) and a novel missense variant (p.V510D) as a compound heterozygote. When we expressed the p.V510D mutant pendrin in mammalian cells, the rate constants for Cl-/HCO3- exchange were 10.96 ± 4.79% compared with those of wild-type pendrin. This figure was comparable to that of p.H723R, indicating p.V510D to be another pathogenic mutation with a null function. The p.V510D pendrin product was shown to be entrapped in the endoplasmic reticulum (ER) at 24-30 h after transfection, and not trafficked to the plasma membrane in COS-7 cells, suggesting retention in the ER and abnormal trafficking as the pathogenic mechanism. This was similar to p.H723R, which is a null function founder mutant in this population but is a candidate variant for future drug therapy to rescue the abnormal cell trafficking. Impaired cellular trafficking due to ER retention and abolished exchange activity of the newly detected p.V510D indicates the pathogenic potential of this variant. These missense variants may be good candidate variants for drug therapy if the intrinsic exchange activity is not damaged by the change.
The Use of MRI, CT and Lumbar Puncture in Dementia Diagnostics: Data from the SveDem Registry
Authors: Falahati Farshad , Fereshtehnejad Seyed-Mohammad , Religa Dorota , Wahlund Lars-Olof , Westman Eric , Eriksdotter Maria
Published: October 2014

Background/Aims: The use of structural brain imaging [computed tomography (CT)/magnetic resonance imaging (MRI)] and the analysis of cerebrospinal fluid biomarkers are included in the guidelines for the diagnosis of dementia. The influence of variables such as age, gender and disease severity on the use of MRI, CT and lumbar puncture (LP) for the differential diagnosis of dementia and the consonance with the recommendations of the Swedish national guidelines were investigated. Methods: From the National Swedish Dementia Registry (SveDem), 17,057 newly diagnosed dementia patients were included in our study, with the majority from specialist care units (90%). Results: In the diagnostic workup, a CT was performed in 87%, MRI in 16% and LP in 40% of the cases. Age (p < 0.001) and cognitive status (p < 0.001) significantly influenced the use of MRI, CT or LP. Older patients with severe dementia were often investigated with CT. LP and MRI were used more often when less common dementia disorders were suspected. Conclusion: Our findings indicate that age, severity of cognitive impairment and the type of dementia disorder suspected are determinants for the choice of CT, MRI or LP. The majority of the dementia workups in specialist care units follow the recommendations of the Swedish national guidelines where CT is performed as a basic workup, and MRI and LP are chosen when extended workup is needed. © 2014 S. Karger AG, Basel
The Single Nucleotide Polymorphism rs499765 Is Associated with Fibroblast Growth Factor 21 and Nonalcoholic Fatty Liver Disease in a Chinese Population with Normal Glucose Tolerance
Authors: Jiang Shan , Zhang Rong , Li Huating , Fang Qichen , Jiang Feng , Hou Xuhong , Hu Cheng , Jia Weiping
Published: October 2014

Background: Fibroblast growth factor 21 (FGF21) is a hormone involved in the metabolism of carbohydrates and lipids. Increased circulating FGF21 levels are closely associated with nonalcoholic fatty liver disease (NAFLD). However, the association between genetic variations of FGF21 and NAFLD remains unknown. In our study, we aimed to investigate the association of these genetic variations with serum FGF21 levels and NAFLD. Methods: We genotyped four single nucleotide polymorphisms (SNPs) in FGF21 and its flanking region in 340 nondiabetic subjects. NAFLD was defined as the presence of a specific abdominal ultrasonographic pattern. Serum FGF21 concentrations were measured using an enzyme-linked immunosorbent assay kit. Results: We found significant evidence of an association with NAFLD for rs499765 (p = 0.039). After adjusting for age and sex, the effect of rs499765 on NAFLD remained significant (p = 0.045). However, after adjusting for multiple comparisons, no association was found. Moreover, rs499765 was associated with serum FGF21 levels (p = 0.030). In addition, both rs2071699 and rs838136 showed an association with serum aspartate aminotransferase levels (p = 0.049 and p = 0.047, respectively). The SNP rs838136 also showed a correlation with serum alanine aminotransferase concentrations after adjustment for body mass index (p = 0.034). We also combined the minor group with the heterozygous genotype and observed that rs499765 had an effect on FGF21 (p = 0.031). Conclusion: The variant rs499765 adjacent to FGF21 is associated with serum FGF21 levels and NAFLD in a Chinese nondiabetic population. © 2014 S. Karger AG, Basel
Intravenous Immunoglobulin as Salvage Therapy in Refractory Pyoderma Gangrenosum: Report of a Case and Review of the Literature
Authors: Cafardi John , Sami Naveed
Published: October 2014

Pyoderma gangrenosum is a neutrophilic dermatosis that occurs both as a primary disorder as well as secondary to an underlying disease. Due to its low prevalence there are limited data on therapeutics, particularly in refractory cases. Here, we discuss a case successfully managed with intravenous immunoglobulin and review the supporting literature.
Induction of Sustained Hypercholesterolemia by Single Adeno-Associated Virus–Mediated Gene Transfer of Mutant hPCSK9
Authors: Roche-Molina Marta , Sanz-Rosa David , Cruz Francisco M. , García-Prieto Jaime , López Sergio , Abia Rocío , Muriana Francisco J.G. , Fuster Valentín , Ibáñez Borja , Bernal Juan A.
Published: October 2014

Objectives—

Patients with mutations in the proprotein convertase subtilisin/kexin type 9 (
PCSK9
) gene have hypercholesterolemia and are at high risk of adverse cardiovascular events. We aimed to stably express the pathological human D374Y gain-of-function mutant form of
PCSK9
(
PCSK9
DY
) in adult wild-type mice to generate a hyperlipidemic and proatherogenic animal model, achieved with a single systemic injection with adeno-associated virus (AAV).

Approach and Results—

We constructed an AAV-based vector to support targeted transfer of the
PCSK9
DY
gene to liver. After injection with 3.5×10
10
viral particles, mice in the C57BL/6J, 129/SvPasCrlf, or FVB/NCrl backgrounds developed long-term hyperlipidemia with a strong increase in serum low-density lipoprotein. Macroscopic and histological analysis showed atherosclerotic lesions in the aortas of AAV-
PCSK9
DY
mice fed a high-fat-diet. Advanced lesions in these high-fat-diet–fed mice also showed evidence of macrophage infiltration and fibrous cap formation. Hepatic AAV-
PCSK9
DY
infection did not result in liver damage or signs of immunologic response. We further tested the use of AAV-
PCSK9
DY
to study potential genetic interaction with the
ApoE
gene. Histological analysis of
ApoE
−/−
AAV-
PCSK9
DY
mice showed a synergistic response to
ApoE
deficiency, with aortic lesions twice as extensive in
ApoE
−/−
AAV-
PCSK9
DY
-transexpressing mice as in
ApoE
−/−
AAV-
Luc
controls without altering serum cholesterol levels.

Conclusions—

Single intravenous AAV-
PCSK9
DY
injection is a fast, easy, and cost-effective approach, resulting in rapid and long-term sustained hyperlipidemia and atherosclerosis. We demonstrate as a proof of concept the synergy between
PCSK9
DY
gain-of-function and
ApoE
deficiency. This methodology could allow testing of the genetic interaction of several mutations without the need for complex and time-consuming backcrosses.
Interleukin 17 Drives Vascular Inflammation, Endothelial Dysfunction, and Arterial Hypertension in Psoriasis-Like Skin Disease
Authors: Karbach Susanne , Croxford Andrew L. , Oelze Matthias , Schüler Rebecca , Minwegen Daniel , Wegner Joanna , Koukes Lija , Yogev Nir , Nikolaev Alexei , Reißig Sonja , Ullmann Alexander , Knorr Maike , Waldner Maximilian , Neurath Markus F. , Li Huige , Wu Zhixiong , Brochhausen Christoph , Scheller Jürgen , Rose-John Stefan , Piotrowski Carolin , Bechmann Ingo , Radsak Markus , Wild Philipp , Daiber Andreas , von Stebut Esther , Wenzel Philip , Waisman Ari , Münzel Thomas
Published: October 2014

Objective—

Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease.

Approach and Results—

Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A
ind/+
mice), associated with increased reactive oxygen species formation and circulating CD11b
+
inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A
ind/+
mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase
+
CD11b
+
GR1
+
F4/80
−
cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-α and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A
ind/+
mice.

Conclusions—

Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase
+
CD11b
+
GR1
+
F4/80
−
inflammatory cells. Depletion of the GR-1
+
immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A
ind/+
mice.
T-Cell Profile in Adipose Tissue Is Associated With Insulin Resistance and Systemic Inflammation in Humans
Authors: McLaughlin Tracey , Liu Li-Fen , Lamendola Cindy , Shen Lei , Morton John , Rivas Homero , Winer Daniel , Tolentino Lorna , Choi Okmi , Zhang Hong , Hui Yen Chng Melissa , Engleman Edgar
Published: October 2014

Objective—

The biological mechanisms linking obesity to insulin resistance have not been fully elucidated. We have shown that insulin resistance or glucose intolerance in diet-induced obese mice is related to a shift in the ratio of pro- and anti-inflammatory T cells in adipose tissue. We sought to test the hypothesis that the balance of T-cell phenotypes would be similarly related to insulin resistance in human obesity.

Approach and Results—

Healthy overweight or obese human subjects underwent adipose-tissue biopsies and quantification of insulin-mediated glucose disposal by the modified insulin suppression test. T-cell subsets were quantified by flow cytometry in visceral (VAT) and subcutaneous adipose tissue (SAT). Results showed that CD4 and CD8 T cells infiltrate both depots, with proinflammatory T-helper (Th)-1, Th17, and CD8 T cells, significantly more frequent in VAT as compared with SAT. T-cell profiles in SAT and VAT correlated significantly with one another and with peripheral blood. Th1 frequency in SAT and VAT correlated directly, whereas Th2 frequency in VAT correlated inversely, with plasma high-sensitivity C-reactive protein concentrations. Th2 in both depots and peripheral blood was inversely associated with systemic insulin resistance. Furthermore, Th1 in SAT correlated with plasma interleukin-6. Relative expression of associated cytokines, measured by real-time polymerase chain reaction, reflected flow cytometry results. Most notably, adipose tissue expression of anti-inflammatory interleukin-10 was inversely associated with insulin resistance.

Conclusions—

CD4 and CD8 T cells populate human adipose tissue and the relative frequency of Th1 and Th2 are highly associated with systemic inflammation and insulin resistance. These findings point to the adaptive immune system as a potential mediator between obesity and insulin resistance or inflammation. Identification of antigenic stimuli in adipose tissue may yield novel targets for treatment of obesity-associated metabolic disease.
Measurement of Endothelium-Dependent Vasodilation in Mice—Brief Report
Authors: Schuler Dominik , Sansone Roberto , Freudenberger Till , Rodriguez-Mateos Ana , Weber Gesine , Momma Tony Y. , Goy Christine , Altschmied Joachim , Haendeler Judith , Fischer Jens W. , Kelm Malte , Heiss Christian
Published: October 2014

Objective—

Endothelium-dependent, flow-mediated vasodilation after an increase in shear stress at the endothelial lining of conduit arteries during reactive hyperemia after ischemia is a fundamental principle of vascular physiology adapting blood flow to demand of supplied tissue. Flow-mediated vasodilation measurements have been performed in human studies and are of diagnostic and prognostic importance, but have been impossible because of technical limitations in transgenic mice to date, although these represent the most frequently used animal model in cardiovascular research.

Approach and Results—

Using high-frequency ultrasound, we visualized, quantified, and characterized for the first time endothelium-dependent dilation of the femoral artery after temporal ischemia of the lower part of the hindlimb and demonstrated that the signaling was almost exclusively dependent on stimulation of endothelial nitric oxide synthase, similar to acetylcholine, completely abolished after pharmacological or genetic inhibition of endothelial nitric oxide synthase and endothelial denudation, substantially impaired in mice of increasing age and cholesterol-fed ApoE knock outs and increased by the dietary polyphenol (−)-epicatechin. Intra- and interindividual variability were similar to the human methodology.

Conclusions—

The physiology of flow-mediated vasodilation in mice resembles that in humans underscoring the significance of this novel technology to noninvasively, serially, and reliably quantify flow-mediated vasodilation in transgenic mice.
Soluble Urokinase Plasminogen Activator Receptor Level Is an Independent Predictor of the Presence and Severity of Coronary Artery Disease and of Future Adverse Events
Authors: Eapen Danny J. , Manocha Pankaj , Ghasemzadeh Nima , Patel Riyaz S. , Al Kassem Hatem , Hammadah Muhammad , Veledar Emir , Le Ngoc‐Anh , Pielak Tomasz , Thorball Christian W. , Velegraki Aristea , Kremastinos Dimitrios T. , Lerakis Stamatios , Sperling Laurence , Quyyumi Arshed A.
Published: October 2014

Introduction

Soluble urokinase plasminogen activator receptor (suPAR) is an emerging inflammatory and immune biomarker. Whether suPAR level predicts the presence and the severity of coronary artery disease (CAD), and of incident death and myocardial infarction (MI) in subjects with suspected CAD, is unknown.

Methods and Results

We measured plasma suPAR levels in 3367 subjects (67% with CAD) recruited in the Emory Cardiovascular Biobank and followed them for adverse cardiovascular (CV) outcomes of death and MI over a mean 2.1±1.1 years. Presence of angiographic CAD (≥50% stenosis in ≥1 coronary artery) and its severity were quantitated using the Gensini score. Cox's proportional hazard survival and discrimination analyses were performed with models adjusted for established CV risk factors and C‐reactive protein levels. Elevated suPAR levels were independently associated with the presence of CAD (
P
<0.0001) and its severity (
P
<0.0001). A plasma suPAR level ≥3.5 ng/mL (cutoff by Youden's index) predicted future risk of MI (hazard ratio [HR]=3.2;
P
<0.0001), cardiac death (HR=2.62;
P
<0.0001), and the combined endpoint of death and MI (HR=1.9;
P
<0.0001), even after adjustment of covariates. The C‐statistic for a model based on traditional risk factors was improved from 0.72 to 0.74 (
P
=0.008) with the addition of suPAR.

Conclusion

Elevated levels of plasma suPAR are associated with the presence and severity of CAD and are independent predictors of death and MI in patients with suspected or known CAD.
Recombinant Milk Fat Globule–EGF Factor-8 Reduces Oxidative Stress via Integrin β3/Nuclear Factor Erythroid 2–Related Factor 2/Heme Oxygenase Pathway in Subarachnoid Hemorrhage Rats
Authors: Liu Fei , Hu Qin , Li Bo , Manaenko Anatol , Chen Yujie , Tang Junjia , Guo Zongduo , Tang Jiping , Zhang John H.
Published: October 2014

Background and Purpose—

Milk fat globule–EGF factor-8 (MFGE8) has been reported to be neuroprotective in ischemic stroke. However, the effects of MFGE8 in early brain injury after subarachnoid hemorrhage (SAH) have not been investigated. We investigated the role of MFGE8 in early brain injury and the potential mechanisms in antioxidation after SAH.

Methods—

Two dosages (1 μg and 3.3 μg) of recombinant human MFGE8 were injected intracerebroventricularly at 1.5 hours after SAH. SAH grades, neurological scores, and brain water content were measured at 24 and 72 hours. For mechanistic study, MFGE8 siRNA, integrin β3 siRNA, and heme oxygenase (HO) inhibitor SnPP IX were used for intervention. The oxidative stress and expression of MFGE8, integrin β3, HO-1, extracellular signal-regulated kinase, and nuclear factor erythroid 2–related factor 2 were measured by Western blots 24 hours after SAH.

Results—

The expression of MFGE8 and HO-1 increased and peaked 24 hours after SAH. Administration of recombinant human MFGE8 decreased brain water content and improved neurological functions both at 24 hours and at 72 hours after SAH. Recombinant human MFGE8 reduced oxidative stress and enhanced the expression of extracellular signal-regulated kinase, nuclear factor erythroid 2–related factor 2, and HO-1; and the effects were abolished by integrin β3 siRNA and HO inhibitor SnPP IX.

Conclusions—

Recombinant MFGE8 attenuated oxidative stress that may be mediated by integrin β3/nuclear factor erythroid 2–related factor 2/HO pathway after SAH. Recombinant MFGE8 may serve as an alternative treatment to ameliorate early brain injury for SAH patients.
The Political Decline of Traditional Ulama in Indonesia
Authors: Fealy Greg , Bush Robin
Published: October 2014

Political wisdom in Indonesia has long held that its large mass-based Muslim organizations, Nahdlatul Ulama (NU) and Muhammadiyah, are politically influential. Within the current democratizing environment ulama have faced many challenges to their social standing and it is our contention in this article that their socio-political role has been diminished in this environment. In order to gauge this situation, the Asia Foundation, working with Indonesian research organizations, conducted a nation-wide survey to explore the changing ways that these Muslim organizations wield political influence, especially at the local level. The survey results confirm that religious figures, or ulama, within NU and Muhammadiyah, do not wield the same kind of direct political influence as they have historically, but this article also highlights how these leaders are still important power brokers at the local level.
The Runaway to the Future
Authors: Dabbous Yasmine
Published: October 2014

Between 1920 and 2000, Lebanon’s national currency changed both in shape and form over six times, the last being during the post-civil war era of the 1990s. But despite their eventful chronicle, the country’s banknotes preserved the same oriental ornamentation and theme of cultural tourism. It was not until the 1990s, with the end of the civil war and the advent of a new non-feudal leadership, that the iconic character of the Lebanese pound changed completely. This paper explores the currency change using semiotic analysis developed by Barthes and Baudrillard in order to compare the currency designs of the 1960s and the 1990s. It proposes that the postwar replacement of national currency reflects, among other things, a conscious effort on the part of the new Lebanese leadership to change Lebanon’s national identity and slowly deemphasize sectarian tensions in the collective memory of its people. To achieve this objective, the postwar government resorted to postmodern banknotes, almost void of social and political meaning. However, as this paper argues, the effort to overcome the divisive issues of the war was attempted solely at the level of the simulacra. The new Lebanon—as reflected in the new currency—is void of history, sectarian tensions and divisive issues; it only exists on the banknotes.
Notes on Early Land Plants Today. 61. New synonyms and new combinations in Cephaloziaceae and Cephaloziellaceae (Marchantiophyta)
Authors: Vana Jiri , Söderström Lars , Hagborg Anders , Von Konrat Matt
Published: October 2014

Váňa et al. (2013) published some new combinations and synonyms of Cephaloziaceae and Cephaloziellaceae. In the present note some additional synonyms and combinations based on newly studied material, are presented.
Notes on Early Land Plants Today. 60. Circumscription of Gymnomitriaceae (Marchantiophyta)
Authors: Vana Jiri , Söderström Lars , Hagborg Anders , Von Konrat Matt
Published: October 2014

Gymnomitriaceae Klinggräff (1858: 16) was thoroughly treated by Váňa et al. (2010). Since the publication, a series of papers have shown that the circumscription of the family and genera within the family must be revised.
Ulyxes, a new Australopapuan mite genus associated with arboreal nests (Acari: Laelapidae)
Authors: SHAW MATTHEW D.
Published: October 2014

As part of a survey of mammal and bird nests, new species, new male stages, and some feeding observations have been collected from what was formerly called the Androlaelaps ulysses group. As many features of this group are consistently different from Androlaelaps, and also from Haemolaelaps where it was formerly placed, this group is here elevated to Ulyxes new genus, and U. autolycus, U. euryclea, and U. theoclymenus are described as new species.      This genus has a broad range of feeding behaviour spanning intranasal parasitism, nidicolous parasitism, and at least one species is a nidicolous predator. Its host range is broad; two new species are shown here to cohabit with parrots while most remaining species associate with mammals. In contrast to the variation in feeding behaviour, Ulyxes spp are associated with a narrow range of nest types, being confined to arboreal nests, usually tree hollows (rarely fallen logs), and on the parrot or mammal hosts that use them.          Ulyxes spp show a remarkable variability in male cheliceral development, which assorts according to feeding behaviour. There is a strong contrast between male chelicerae of predatory and parasitic species that has not been previously observed in such a compact dermanyssine genus. Previously male cheliceral morphology was thought to be conservative enough to provide diagnostic characters at suprageneric rank. For systematics, these findings complicate previous attempts to recognise male mouthparts as reliable features marking higher-level natural groups that include dermanyssoid vertebrate parasites. For evolutionary studies, this may be relevant in seeking examples of transitions to, or away from, parasitism.