bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronaviruses Resistant to a 3C-Like Protease Inhibitor Are Attenuated for Replication and Pathogenesis, Revealing a Low Genetic Barrier but High Fitness Cost of Resistance
Authors: Deng Xufang , StJohn Sarah E. , Osswald Heather L. , O'Brien Amornrat , Banach Bridget S. , Sleeman Katrina , Ghosh Arun K. , Mesecar Andrew D. , Baker Susan C.
Published: August 2014

Viral protease inhibitors are remarkably effective at blocking the replication of viruses such as human immunodeficiency virus and hepatitis C virus, but they inevitably lead to the selection of inhibitor-resistant mutants, which may contribute to ongoing disease. Protease inhibitors blocking the replication of coronavirus (CoV), including the causative agents of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), provide a promising foundation for the development of anticoronaviral therapeutics. However, the selection and consequences of inhibitor-resistant CoVs are unknown. In this study, we exploited the model coronavirus, mouse hepatitis virus (MHV), to investigate the genotype and phenotype of MHV quasispecies selected for resistance to a broad-spectrum CoV 3C-like protease (3CLpro) inhibitor. Clonal sequencing identified single or double mutations within the 3CLpro coding sequence of inhibitor-resistant virus. Using reverse genetics to generate isogenic viruses with mutant 3CLpros, we found that viruses encoding double-mutant 3CLpros are fully resistant to the inhibitor and exhibit a significant delay in proteolytic processing of the viral replicase polyprotein. The inhibitor-resistant viruses also exhibited postponed and reduced production of infectious virus particles. Biochemical analysis verified double-mutant 3CLpro enzyme as impaired for protease activity and exhibiting reduced sensitivity to the inhibitor and revealed a delayed kinetics of inhibitor hydrolysis and activity restoration. Furthermore, the inhibitor-resistant virus was shown to be highly attenuated in mice. Our study provides the first insight into the pathogenicity and mechanism of 3CLpro inhibitor-resistant CoV mutants, revealing a low genetic barrier but high fitness cost of resistance.

IMPORTANCE
RNA viruses are infamous for their ability to evolve in response to selective pressure, such as the presence of antiviral drugs. For coronaviruses such as the causative agent of Middle East respiratory syndrome (MERS), protease inhibitors have been developed and shown to block virus replication, but the consequences of selection of inhibitor-resistant mutants have not been studied. Here, we report the low genetic barrier and relatively high deleterious consequences of CoV resistance to a 3CLpro protease inhibitor in a coronavirus model system, mouse hepatitis virus (MHV). We found that although mutations that confer resistance arise quickly, the resistant viruses replicate slowly and do not cause lethal disease in mice. Overall, our study provides the first analysis of the low barrier but high cost of resistance to a CoV 3CLpro inhibitor, which will facilitate the further development of protease inhibitors as anti-coronavirus therapeutics.
Epstein-Barr Virus-Encoded Latent Membrane Protein 2A Promotes the Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma via Metastatic Tumor Antigen 1 and Mechanistic Target of Rapamycin Signaling Induction
Authors: Lin Zhe , Wan Xin , Jiang Runqiu , Deng Lei , Gao Yun , Tang Junwei , Yang Yu , Zhao Wei , Yan Xin , Yao Kun , Sun Beicheng , Chen Yun
Published: August 2014

Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) promotes the epithelial-mesenchymal transition (EMT) of nasopharyngeal carcinoma (NPC), thereby increasing tumor invasion. Recently, the dysregulation of metastatic tumor antigen 1 (MTA1) was found to enhance tumor metastasis in a variety of cancers. A molecular connection between these two proteins has been proposed but not firmly established. In this study, we reported the overexpression of MTA1 in 29/60 (48.3%) NPC patients, and the overexpression of MTA1 significantly correlated with tumor metastasis. The overexpression of MTA1 promoted EMT via the Wnt1 pathway and β-catenin activation. We demonstrated that LMP2A reinforces the expression of MTA1 via the mechanistic target of rapamycin (mTOR) pathway to promote EMT in NPC. Furthermore, by knocking down 4EBP1 in combination with the new mTOR inhibitor INK-128 treatment, we discovered that LMP2A expression activates the 4EBP1-eIF4E axis and increases the expression of MTA1 at the translational level partially independent of c-myc. These findings provided novel insights into the correlation between the LMP2A and MTA1 proteins and reveal a novel function of the 4EBP1-eIF4E axis in EMT of nasopharyngeal carcinoma.

IMPORTANCE
Prevention of the recurrence and metastasis of NPC is critical to achieving a successful NPC treatment. As we all know, EMT has a vital role in metastasis of malignancies. LMP2A, an oncoprotein of Epstein-Barr virus, a well-known NPC activator, induces EMT and has been proved to exert a promoting effect in tumor metastasis. Our study demonstrated that LMP2A could induce EMT by activating MTA1 at the translational level via activating mTOR signaling and the 4EBP1-eIF4E axis. Taken together, our findings bridge the gap between the NPC-specific cell surface molecule and the final phenotype of the NPC cells. Additionally, our findings indicate that LMP2A and mTOR will serve as targets for NPC therapy in the future.
An Eriophyid Mite-Transmitted Plant Virus Contains Eight Genomic RNA Segments with Unusual Heterogeneity in the Nucleocapsid Protein
Authors: Tatineni Satyanarayana , McMechan Anthony J. , Wosula Everlyne N. , Wegulo Stephen N. , Graybosch Robert A. , French Roy , Hein Gary L.
Published: August 2014

Eriophyid mite-transmitted, multipartite, negative-sense RNA plant viruses with membrane-bound spherical virions are classified in the genus
Emaravirus
. We report here that the eriophyid mite-transmitted
Wheat mosaic virus
(WMoV), an
Emaravirus
, contains eight genomic RNA segments, the most in a known negative-sense RNA plant virus. Remarkably, two RNA 3 consensus sequences, encoding the nucleocapsid protein, were found with 12.5% sequence divergence, while no heterogeneity was observed in the consensus sequences of additional genomic RNA segments. The RNA-dependent RNA polymerase, glycoprotein precursor, nucleocapsid, and P4 proteins of WMoV exhibited limited sequence homology with the orthologous proteins of other emaraviruses, while proteins encoded by additional genomic RNA segments displayed no significant homology with proteins reported in GenBank, suggesting that the genus
Emaravirus
evolved further with a divergent octapartite genome. Phylogenetic analyses revealed that WMoV formed an evolutionary link between members of the
Emaravirus
genus and the family
Bunyaviridae
. Furthermore, genomic-length virus- and virus-complementary (vc)-sense strands of all WMoV genomic RNAs accumulated asymmetrically in infected wheat, with 10- to 20-fold more virus-sense genomic RNAs than vc-sense RNAs. These data further confirm the octapartite negative-sense polarity of the WMoV genome. In WMoV-infected wheat, subgenomic-length mRNAs of vc sense were detected for genomic RNAs 3, 4, 7, and 8 but not for other RNA species, suggesting that the open reading frames present in the complementary sense of genomic RNAs are expressed through subgenomic- or near-genomic-length vc-sense mRNAs.

IMPORTANCE
Wheat mosaic virus
(WMoV), an
Emaravirus
, is the causal agent of High Plains disease of wheat and maize. In this study, we demonstrated that the genome of WMoV comprises eight negative-sense RNA segments with an unusual sequence polymorphism in an RNA encoding the nucleocapsid protein but not in the additional genomic RNA segments. WMoV proteins displayed weak or no homology with reported emaraviruses, suggesting that the genus
Emaravirus
further evolved with a divergent octapartite genome. The current study also examined the profile of WMoV RNA accumulation in wheat and provided evidence for the synthesis of subgenomic-length mRNAs of virus complementary sense. This is the first report to demonstrate that emaraviruses produce subgenomic-length mRNAs that are most likely utilized for genome expression. Importantly, this study facilitates the examination of gene functions and virus diversity and the development of effective diagnostic methods and management strategies for an economically important but poorly understood virus.
Cellular Visualization of Macrophage Pyroptosis and Interleukin-1β Release in a Viral Hemorrhagic Infection in Zebrafish Larvae
Authors: Varela Mónica , Romero Alejandro , Dios Sonia , van der Vaart Michiel , Figueras Antonio , Meijer Annemarie H. , Novoa Beatriz
Published: August 2014

Hemorrhagic viral diseases are distributed worldwide with important pathogens, such as dengue virus or hantaviruses. The lack of adequatein vivoinfection models has limited the research on viral pathogenesis and the current understanding of the underlying infection mechanisms. Although hemorrhages have been associated with the infection of endothelial cells, other cellular types could be the main targets for hemorrhagic viruses. Our objective was to take advantage of the use of zebrafish larvae in the study of viral hemorrhagic diseases, focusing on the interaction between viruses and host cells. Cellular processes, such as transendothelial migration of leukocytes, virus-induced pyroptosis of macrophages. and interleukin-1β (Il-1β) release, could be observed in individual cells, providing a deeper knowledge of the immune mechanisms implicated in the disease. Furthermore, the application of these techniques to other pathogens will improve the current knowledge of host-pathogen interactions and increase the potential for the discovery of new therapeutic targets.

IMPORTANCEPathogenic mechanisms of hemorrhagic viruses are diverse, and most of the research regarding interactions between viruses and host cells has been performed in cell lines that might not be major targets during natural infections. Thus, viral pathogenesis research has been limited because of the lack of adequatein vivoinfection models. The understanding of the relative pathogenic roles of the viral agent and the host response to the infection is crucial. This will be facilitated by the establishment ofin vivoinfection models using organisms such as zebrafish, which allows the study of the diseases in the context of a complete individual. The use of this animal model with other pathogens could improve the current knowledge on host-pathogen interactions and increase the potential for the discovery of new therapeutic targets against diverse viral diseases.
Multidetector CT angiography influences the choice of treatment for blunt carotid artery injury
Authors: Beliaev Andrei M , Civil Ian
Published: August 2014

A 43-year-old woman presented with a 2 h history of left neck pain after striking her neck against a marble bench while playing with her son. The patient was screened for blunt cerebrovascular injury (BCVI) and a left carotid bruit was identified. Subsequently, she underwent multidetector CT angiography (MCTA) of the aortic arch and neck vessels, which demonstrated a flow-limiting dissection of the left common carotid artery (CCA). The patient was started on heparin infusion and underwent an emergency operation. At surgery, a circumferential intimal dissection was excised and the arteriotomy defect closed with an autologous venous patch. This case emphasises the importance of adequately examining patients with direct injury to the neck, screening relevant patients for BCVI and investigating them with MCTA that influences the choice of a treatment option.
A rare case of acute hepatitis induced by use of Babchi seeds as an Ayurvedic remedy for vitiligo
Authors: Smith Deborah Ann , MacDonald Stewart
Published: August 2014

This case highlights that hepatitis is a potential side effect of Babchi seeds, an Ayurvedic remedy used to treat vitiligo. The patient, a 52-year-old Indian woman, presented with a 1 week history of jaundice, vomiting, pruritus and abdominal pain. Progressive deterioration in liver function prompted a liver biopsy which was consistent with the diagnosis of a drug-induced hepatitis. The hepatitis resolved after withdrawal of its use. A PubMed search found no previous UK cases and only two cases have been reported globally. This potentially serious side effect of a widely available substance is not acknowledged by manufacturers, and those purchasing the product are unaware of the risk of harm. To compound this risk, there is an absence of dosing advice or maximum recommended daily intake. It is important to ask about topical and oral herbal remedies in cases of acute jaundice as patients rarely perceive these preparations as ‘medications’.
Plasmablastic multiple myeloma following clear cell renal cell carcinoma
Authors: Padhi Somanath , Mokkappan Sudhagar , Varghese Renu G’ Boy , Veerappan Ilangovan
Published: August 2014

We aim to describe the clinicohaematological profile of an elderly male with plasmablastic multiple myeloma (MM) (IgG λ, International System Stage II) with an unfavourable outcome following chemotherapy. The serum interleukin-6 level was found to be markedly elevated (2464 pg/mL, reference; <50 pg/mL). Thirty-six months prior to MM diagnosis, he underwent left radical nephrectomy for a stage III (pT3N0M0) clear cell renal cell carcinoma (RCC, Fuhrman grade 2). The unique MM-RCC association, shared risk factors, myeloma pathobiology and clinical implications are discussed with a brief literature review.
Unicystic ameloblastoma with mural proliferation: conservative or surgical approach?
Authors: Samuel Soumi , Mistry Freddy K , Chopra Shilpa , Pillai Ajay
Published: August 2014

Ameloblastoma occurs in a wide variety of forms. Various forms of ameloblastomas have various treatment modalities ranging from a conservative approach to surgical resection with reconstruction. We report a case of unicystic ameloblastoma with mural proliferation in a 17-year-old girl, who presented with a swelling in the lower left jaw associated with dull aching pain and was managed initially by a conservative approach followed by surgical enucleation on recurrence.
Does general exercise training before and during pregnancy influence the pelvic floor “opening” and delivery outcome? A 3D/4D ultrasound study following nulliparous pregnant women from mid-pregnancy to childbirth
Authors: Bø Kari , Hilde Gunvor , Stær-Jensen Jette , Siafarikas Franziska , Tennfjord Merete Kolberg , Engh Marie Ellstrøm
Published: August 2014

Background

It has been suggested that women who are regular exercisers have a tighter pelvic floor and thereby have more difficulty during childbirth than non-exercising women. We investigated whether women exercising before and during pregnancy have a narrower levator hiatus (LH) area than their sedentary counterparts. We also studied whether regular exercise at gestational week 37 influences delivery outcome.

Methods

Cohort study of 274 nulliparous pregnant women assessed at mid-pregnancy and gestational week 37 by three-dimensional/four-dimensional transperineal ultrasonography of the LH area. Exercisers were defined as those exercising ≥30 min three times per week and non-exercisers as not exercising. Exercise data were collected via electronic questionnaire at mean gestational weeks 21 and 37. Labour and delivery outcomes were collected from the women's electronic medical birth records. Differences between exercisers and non-exercisers were analysed using independent sample t test or χ2test. p Value was set to ≤0.05.

Results

At gestational week 37, exercisers had a significantly larger LH area than non-exercisers at rest and during PFM contraction (mean difference −1.6 cm2(95% CI −3.0 to −0.3), p=0.02 and −1.1 cm2(95% CI −2.0 to −0.1), p=0.04, respectively). No significant differences were found between exercisers and non-exercisers at week 37 in any labour or delivery outcomes.

Conclusions

The results of the present study do not support the hypothesis that women exercising regularly before or during pregnancy have a narrower LH area or more complicated childbirths than non-exercising women.

Trial registration number

ClinicalTrials.gov:NCT01045135.
Cross-sectional survey of salt content in cheese: a major contributor to salt intake in the UK
Authors: Hashem Kawther M , He Feng J , Jenner Katharine H , MacGregor Graham A
Published: August 2014

Objective

To investigate the salt (sodium chloride) content in cheese sold in UK supermarkets.

Study design

We carried out a cross-sectional survey in 2012, including 612 cheeses available in UK supermarkets.

Methods

The salt content (g/100 g) was collected from product packaging and nutrient information panels of cheeses available in the top seven retailers.

Results

Salt content in cheese was high with a mean (±SD) of 1.7±0.58 g/100 g. There was a large variation in salt content between different types of cheeses and within the same type of cheese. On average, halloumi (2.71±0.34 g/100 g) and imported blue cheese (2.71±0.83 g/100 g) contained the highest amounts of salt and cottage cheese (0.55±0.14 g/100 g) contained the lowest amount of salt. Overall, among the 394 cheeses that had salt reduction targets, 84.5% have already met their respective Department of Health 2012 salt targets.

Cheddar and cheddar-style cheese is the most popular/biggest selling cheese in the UK and has the highest number of products in the analysis (N=250). On average, salt level was higher in branded compared with supermarket own brand cheddar and cheddar-style products (1.78±0.13 vs 1.72±0.14 g/100 g, p<0.01). Ninety per cent of supermarket own brand products met the 2012 target for cheddar and cheddar-style cheese compared with 73% of branded products (p=0.001).

Conclusions

Salt content in cheese in the UK is high. There is a wide variation in the salt content of different types of cheeses and even within the same type of cheese. Despite this, 84.5% of cheeses have already met their respective 2012 targets. These findings demonstrate that much larger reductions in the amount of salt added to cheese could be made and more challenging targets need to be set, so that the UK can continue to lead the world in salt reduction.
Genetic, clinical and pharmacological determinants of out-of-hospital cardiac arrest: rationale and outline of the AmsteRdam Resuscitation Studies (ARREST) registry
Authors: Blom M T , van Hoeijen D A , Bardai A , Berdowski J , Souverein P C , De Bruin M L , Koster R W , de Boer A , Tan H L
Published: August 2014

Introduction

Out-of-hospital cardiac arrest (OHCA) is a major public health problem. Recognising the complexity of the underlying causes of OHCA in the community, we aimed to establish the clinical, pharmacological, environmental and genetic factors and their interactions that may cause OHCA.

Methods and analysis

We set up a large-scale prospective community-based registry (AmsteRdam Resuscitation Studies, ARREST) in which we prospectively include all resuscitation attempts from OHCA in a large study region in the Netherlands in collaboration with Emergency Medical Services. Of all OHCA victims since June 2005, we prospectively collect medical history (through hospital and general practitioner), and current and previous medication use (through community pharmacy). In addition, we include DNA samples from OHCA victims with documented ventricular tachycardia/fibrillation during the resuscitation attempt since July 2007. Various study designs are employed to analyse the data of the ARREST registry, including case–control, cohort, case only and case-cross over designs.

Ethics and dissemination

We describe the rationale, outline and potential results of the ARREST registry. The design allows for a stable and reliable collection of multiple determinants of OHCA, while assuring that the patient, lay-caregiver or medical professional is not hindered in any way. Such comprehensive data collection is required to unravel the complex basis of OHCA. Results will be published in peer-reviewed journals and presented at relevant scientific symposia.
Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing
Authors: Granada Juan F , Stenoien Mark , Buszman Piotr P , Tellez Armando , Langanki Dan , Kaluza Greg L , Leon Martin B , Gray William , Jaff Michael R , Schwartz Robert S
Published: August 2014

Background

The efficacy of paclitaxel-coated balloons (PCB) for restenosis prevention has been demonstrated in humans. However, the mechanism of action for sustained drug retention and biological efficacy following single-time drug delivery is still unknown.

Methods and results

The pharmacokinetic profile and differences in drug concentration (vessel surface vs arterial wall) of two different paclitaxel coating formulations (3 µg/mm2) displaying opposite solubility characteristics (CC=crystalline vs AC=amorphous) were tested in vivo and compared with paclitaxel-eluting stents (PES). Also, the biological effect of both PCB formulations on vascular healing was tested in the porcine coronary injury model. One hour following balloon inflation, both formulations achieved similar arterial paclitaxel levels (CC=310 vs AC=245 ng/mg; p=NS). At 24 h, the CC maintained similar tissue concentrations, whereas the AC tissue levels declined by 99% (p<0.01). At this time point, arterial levels were 20-fold (CC) and 5-fold (AC) times higher compared to the PES group (p<0.05). At 28 days, arterial levels retained were 9.2% (CC) and 0.04% (AC, p<0.01) of the baseline levels. Paclitaxel concentration on the vessel surface was higher in the CC at 1 (CC=36.7% vs AC=13.1%, p<0.05) and 7 days (CC=38.4% vs AC=11%, p<0.05). In addition, the CC induced higher levels of neointimal inhibition, fibrin deposition and delayed healing compared with the AC group.

Conclusions

The presence of paclitaxel deposits on the vessel surface driving diffusion into the arterial tissue in a time-dependent fashion supports the mechanism of action of PCB. This specific pharmacokinetic behaviour influences the patterns of neointimal formation and healing.
Chronic heavy drinking and ischaemic heart disease: a systematic review and meta-analysis
Authors: Roerecke Michael , Rehm Jürgen
Published: August 2014

Previous meta-analyses have reported either a protective, neutral or detrimental association from chronic heavy drinking in relation to ischaemic heart disease (IHD). We investigated the potential for systematic error because of study design. Using MOOSE guidelines, studies were identified through MEDLINE, EMBASE and Web of Science up to end of March, 2014. Epidemiological studies reporting on chronic heavy drinking and IHD risk in population studies and samples of people with alcohol use disorder (AUD) were included. Random-effects meta-analysis was used to pool eligible studies. The I2statistic was used to assess heterogeneity across studies. In total, 34 observational studies with 110 570 chronic heavy drinkers and 3086 IHD events were identified. In population studies among men, the pooled risk for IHD incidence (fatal+non-fatal events) among chronic heavy drinkers (on average ≥60 g pure alcohol/day) in comparison to lifetime abstainers (n=11 studies) was relative risk (RR)=1.04 (95% CI 0.83 to 1.31, I2=54%). Few studies were available for women. In patients with AUD, the risk of IHD mortality in comparison to the general population was elevated with a RR=1.62 (95% CI 1.34 to 1.95, I2=81%) in men and RR=2.09 (95% CI 1.28 to 3.41, I2=67%) in women. There was a general lack of adjustment other than sex and age in studies among patients with AUD. There is no systematic evidence for a protective association from any type of chronic heavy drinking on IHD risk. Patients with AUD were at higher risk for IHD mortality, but better quality evidence is needed with regard to potential confounding.
Distribution of aquaporin genes and selection of individual reference genes for quantitative real-time RT-PCR analysis in multiple tissues of the mouse
Authors: Sakai Hiroyasu , Sato Ken , Kai Yuki , Shoji Tetsuro , Hasegawa Satoshi , Nishizaki Maiko , Sagara Atsunobu , Yamashita Akira , Narita Minoru
Published: August 2014

Aquaporins (AQPs) are a family of water-transporting proteins that are selectively expressed in epithelial, endothelial, and many other cell types of various tissues, where they play important physiological functions. However, the accurate distribution of AQP gene expression has not yet been examined in various tissues of the mouse. We first evaluated the tissue distribution of AQP gene expression using tongue, nasal epithelium, bronchus, trachea, lung, esophagus, stomach, ileum, transverse colon, liver, pancreas, whole blood, thigh muscle, spinal cord, brain, thoracic aorta, heart, kidney, thymus, spleen, skin, eye, and testis of the mouse. Furthermore, for a quantitative analysis, we selected appropriate reference genes for normalized qRT-PCR data in various tissues. The stability of the reference genes was assessed using NormFinder. The stably expressed genes identified in the present study were 18s rRNA. When 18s rRNA was used, as the best reference gene in the present study, the genes for AQPs 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, and 12 were notably expressed in the eye, lung, testis, eye, spinal cord, trachea, kidney, testis, testis, testis, testis, and pancreas. These results, regarding the distribution of AQPs, suggest that AQPs may be involved in various physiological and pathophysiological processes.
One-parameter model for the superworld
Authors: Li Tianjun , Maxin James A. , Nanopoulos Dimitri V. , Walker Joel W.
Published: August 2014

We review the No-Scale ℱ-SU(5) model with extra TeV-scale vector-like flippon multiplets and its associated collider phenomenology in the search for supersymmetry at the LHC. The model framework possesses the rather unique capacity to provide a light CP-even Higgs boson mass in the favored 124–126 GeV window while simultaneously retaining a testably light SUSY spectrum that is consistent with emerging low-statistics excesses beyond the Standard Model expectation in the ATLAS and CMS multijet data.
Division algebra representations of SO(4, 2)
Authors: Kincaid Joshua , Dray Tevian
Published: August 2014

Representations of SO (4, 2) are constructed using 4×4 and 2×2 matrices with elements in ℍ' ⊗ ℂ and the known isomorphism between the conformal group and SO (4, 2) is written explicitly in terms of the 4×4 representation. The Clifford algebra structure of SO (4, 2) is briefly discussed in this language, as is its relationship to other groups of physical interest.
PHOTOVOLTAIC SYSTEM WITH A DC–DC CONVERTER FED SHUNT ACTIVE FILTER FOR POWER QUALITY IMPROVEMENT USING ICos Φ ALGORITHM
Authors: VIJAYAKUMAR G. , ANITA R.
Published: August 2014

This paper presents an operation of photovoltaic (PV)-based shunt active filter (SAF) for significant energy conservation, harmonic mitigation and reactive power compensation. When the PV system generates excessive or equal power required to the load demand, then the coordinating logic disconnects the service grid from the load and with a consequent reduction of panel tariff and global warming gasses. The PV module is connected to the DC side of SAF through the DC–DC converter. Converter switch is controlled by fuzzy-based perturb & observe (P&O) maximum power point tracking (MPPT) algorithm and it eliminates the drawback in the conventional PV system. The reference currents are extracted by the fuzzy logic controller-based ICos Φ control strategy. This proposed PV-SAF, if connected at the terminals of a small industry or a home or a small enlightening institution can avoid the use of interruptible power supply and individual stabilizer. An emulation using MATLAB Simulink is presented to validate the advantage of the proposed system.
Many Unstable Particles from an Open Quantum System's Perspective
Authors: Smoliński Kordian Andrzej
Published: August 2014

We postulate a master equation, written in the language of creation and annihilation operators, as a candidate for unambiguous quantum mechanical description of unstable particles. We have found Kraus representation for the evolution driven by this master equation and study its properties. Both Schrödinger and Heisenberg picture of the system evolution are presented. We show that the resulting time evolution leads to exponential decay law. Moreover, we analyse mixing of particle flavours and show that it can lead to flavour oscillation phenomenon.
Synthesis and Characterization of Ag@C Core–Shell Structures
Authors: Zhao Daoli , Guo Xuefei , Wang Tingting , Zheng Yuchuan , Wang Linlin , Yang Qing
Published: August 2014

Ag @ C core–shell structures were prepared using hydrothermal methods by AgNO 3 reduction with ascorbic acid in the presence of polyacrylamide (PAM). Temperature plays a key role in the formation of the core–shell structures. The roles of reactants, surfactant concentrations and reaction time on the morphologies of core–shell nanoparticles were investigated in detail. This synthetic method is one-pot synthesis, which is fast, high-yield and environmental-friendly for fabrication of Ag @ C core–shell structures. The surface properties of core–shell Ag @ C nanoparticles were characterized by Raman spectroscopy.
Forehead versus forearm skin vascular responses at presyncope in humans
Authors: Gagnon Daniel , Matthew Brothers R. , Ganio Matthew S. , Hastings Jeffrey L. , Crandall Craig G.
Published: August 2014

Facial pallor is commonly observed at presyncope in humans, suggestive of reductions in facial skin blood flow (SkBF). Yet, cutaneous vasoconstriction is usually minimal at presyncope when measured at the forearm. We tested the hypothesis that reductions in forehead SkBF at presyncope are greater than in the forearm. Forehead and forearm SkBF (laser-Doppler) and blood pressure (Finometer or radial artery catheterization) were measured during lower body negative pressure (LBNP) to presyncope in 11 normothermic and 13 heat-stressed subjects (intestinal temperature increased ∼1.4°C). LBNP reduced mean arterial pressure from 91 ± 5 to 57 ± 7 mmHg during normothermia ( P ≤ 0.001) and from 82 ± 5 to 57 ± 7 mmHg during heat stress ( P ≤ 0.001). During normothermia, LBNP decreased forehead SkBF 55 ± 14% compared with 24 ± 11% at the forearm ( P = 0.002), while during heat stress LBNP decreased forehead SkBF 39 ± 11% compared with 28 ± 8% in the forearm ( P = 0.007). In both conditions, most (≥68%) of the decreases in SkBF were due to decreases in blood pressure. However, a greater contribution of actively mediated reductions in SkBF was observed at the forehead, relative to the forearm during normothermia (32 ± 13% vs. 11 ± 11%, P = 0.031) and heat stress (30 ± 13% vs. 10 ± 13%, P = 0.004). These data suggest that facial pallor at presyncope is due to a combination of passive decreases in forehead SkBF secondary to reductions in blood pressure and to active decreases in SkBF, the latter of which are relatively greater than in the forearm.
Novel antidiabetic nutrients identified by in vivo screening for gastric secretion and emptying regulation in rats
Authors: Jordi Josua , Herzog Brigitte , Lutz Thomas A. , Verrey François
Published: August 2014

Diabetes mellitus is a disease characterized by elevated blood glucose levels and represents a worldwide health issue. Postprandial hyperglycemia is considered a major predictor of diabetic complications, and its reduction represents a specific treatment target in Type 1 and 2 diabetes. Since postprandial glucose excursions depend to a large extent on gastric secretion and emptying, amylin and glucagon-like peptide 1 analogs are prescribed to reduce them. Although gastric function is considered mainly sensitive to ingested calories, its chemospecificity is not well understood. To identify ingestible nutrients reducing postprandial hyperglycemia, we applied intragastrically more than 40 individual nutrients at an isomolar dose to rats and quantified their impact on gastric secretion and emptying using a novel in vivo computed tomography imaging method. We identified l-tryptophan, l-arginine, l-cysteine, and l-lysine as the most potent modulators with effective strength comparable to a supraphysiological dose of amylin. Importantly, all identified candidates reduced postprandial glucose excursion within an oral glucose tolerance test in healthy and diabetic rats. This clinical beneficial effect originated predominantly from their impact on gastric function, as none of the candidates altered plasma glucose concentrations induced by intraperitoneal or intraduodenal glucose tolerance tests. Overall, these data demonstrate a remarkable chemospecificity of stomach function, unveil a strong role of the stomach for glycemic control and identifies nutrients with antidiabetic potential.
Nitric oxide and carbon monoxide antagonize TGF-β through ligand-independent internalization of TβR1/ALK5
Authors: Hovater Michael B. , Ying Wei-Zhong , Agarwal Anupam , Sanders Paul W.
Published: August 2014

Transforming growth factor (TGF)-β plays a central role in vascular homeostasis and in the pathology of vascular disease. There is a growing appreciation for the role of nitric oxide (NO) and carbon monoxide (CO) as highly diffusible, bioactive signaling molecules in the vasculature. We hypothesized that both NO and CO increase endocytosis of TGF-β receptor type 1 (TβR1) in vascular smooth muscle cells (VSMCs) through activation of dynamin-2, shielding cells from the effects of circulating TGF-β. In this study, primary cultures of VSMCs from Sprague-Dawley rats were treated with NO-releasing molecule 3 (a NO chemical donor), CO-releasing molecule 2 (a CO chemical donor), or control. NO and CO stimulated dynamin-2 activation in VSMCs. NO and CO promoted time- and dose-dependent endocytosis of TβR1. By decreasing TβR1 surface expression through this dynamin-2-dependent process, NO and CO diminished the effects of TGF-β on VSMCs. These findings help explain an important mechanism by which NO and CO signal in the vasculature by decreasing surface expression of TβR1 and the cellular response to TGF-β.
Encoding of social signals in all three electrosensory pathways ofEigenmannia virescens
Authors: Stöckl Anna , Sinz Fabian , Benda Jan , Grewe Jan
Published: August 2014

Extracting complementary features in parallel pathways is a widely used strategy for a robust representation of sensory signals. Weakly electric fish offer the rare opportunity to study complementary encoding of social signals in all of its electrosensory pathways. Electrosensory information is conveyed in three parallel pathways: two receptor types of the tuberous (active) system and one receptor type of the ampullary (passive) system. Modulations of the fish's own electric field are sensed by these receptors and used in navigation, prey detection, and communication. We studied the neuronal representation of electric communication signals (called chirps) in the ampullary and the two tuberous pathways of Eigenmannia virescens. We first characterized different kinds of chirps observed in behavioral experiments. Since Eigenmannia chirps simultaneously drive all three types of receptors, we studied their responses in in vivo electrophysiological recordings. Our results demonstrate that different electroreceptor types encode different aspects of the stimuli and each appears best suited to convey information about a certain chirp type. A decoding analysis of single neurons and small populations shows that this specialization leads to a complementary representation of information in the tuberous and ampullary receptors. This suggests that a potential readout mechanism should combine information provided by the parallel processing streams to improve chirp detectability.
Subtype-dependent postnatal development of direction- and orientation-selective retinal ganglion cells in mice
Authors: Chen Hui , Liu Xiaorong , Tian Ning
Published: August 2014

The direction-selective ganglion cells (DSGCs) and orientation-selective ganglion cells (OSGCs) encode the directional and the orientational information of a moving object, respectively. It is unclear how DSGCs and OSGCs mature in the mouse retina during postnatal development. Here we investigated the development of DSGCs and OSGCs after eye-opening. We show that 1) DSGCs and OSGCs are present at postnatal day 12 (P12), just before eye-opening; 2) the fractions of both DSGCs and OSGCs increase from P12 to P30; 3) the development of DSGCs and OSGCs is subtype dependent; and 4) direction and orientation selectivity are two separate features of retinal ganglion cells (RGCs) in the mouse retina. We classified RGCs into different functional subtypes based on their light response properties. Compared with P12, the direction and orientation selectivity of ON-OFF RGCs but not ON RGCs became stronger at P30. The tuning width of DSGCs for both ON and ON-OFF subtypes decreased with age. For OSGCs, we divided them into non-direction-selective (non-DS) OSGCs and direction-selective OSGCs (DS&OSGCs). For DS&OSGCs, we found that there was no correlation between the direction and orientation selectivity, and that the tuning width of both ON and ON-OFF subtypes remained unchanged with age. For non-DS OSGCs, the tuning width of ON but not ON-OFF subtype decreased with development. These findings provide a foundation to reveal the molecular and synaptic mechanisms underlying the development of the direction and orientation selectivity in the retina.
Rigorous 2D Model for Study of Pulsed and Monochromatic Waves Propagation Near the Earth’s Surface
Authors: Sautbekov Seil S. , Sirenko Yuriy K. , Yashina Nataliya P. , Vertiy Aleksey A.
Published: August 2014

A model problem considered in the paper allows solving rather complex 2D problems of the electromagnetic wave propagation with a required accuracy using conventional personal computers. The problems are of great importance for the theory and practical applications. The association of FDTD schemes with exact absorbing conditions makes up the basis for constructing models of the kind. This approach reduces the original open initial boundary value problems to the equivalent closed problems which can be solved numerically using the standard grid methods.
Trim32 Facilitates Degradation of MYCN on Spindle Poles and Induces Asymmetric Cell Division in Human Neuroblastoma Cells
Authors: Izumi Hideki , Kaneko Yasuhiko
Published: August 2014

Asymmetric cell division (ACD) is a physiologic process during development and tissue homeostasis. ACD produces two unequal daughter cells: one has stem/progenitor cell activity and the other has potential for differentiation. Recent studies showed that misregulation of the balance between self-renewal and differentiation by ACD may lead to tumorigenesis in Drosophila neuroblasts. However, it is still largely unknown whether human cancer stem–like cells exhibit ACD or not. Here, using human neuroblastoma cells as an ACD model, we found that MYCN accumulates at spindle poles by GSK-3β phosphorylation during mitosis. In parallel, the ACD-related ubiquitin ligase Trim32 was recruited to spindle poles by CDK1/cyclin B–mediated phosphorylation. Trim32 interacted with MYCN at spindle poles during mitosis, facilitating proteasomal degradation of MYCN at spindle poles and inducing ACD. Trim32 also suppressed sphere formation of neuroblastoma-initiating cells, suggesting that the mechanisms of ACD produce differentiated neuroblastoma cells that will eventually die. Thus, Trim32 is a positive regulator of ACD that acts against MYCN and should be considered as a tumor-suppressor candidate. Our findings offer novel insights into the mechanisms of ACD and clarify its contributions to human tumorigenesis. Cancer Res; 74(19); 5620–30. ©2014 AACR.
Prevalence and Correlates of Smoking and Cessation-Related Behavior among Survivors of Ten Cancers: Findings from a Nationwide Survey Nine Years after Diagnosis
Authors: Westmaas J. Lee , Alcaraz Kassandra I. , Berg Carla J. , Stein Kevin D.
Published: August 2014

Background: Smoking is detrimental to recovery and survival from cancer, but many cancer survivors continue to smoke. Information is lacking on smoking patterns of survivors many years after diagnosis and correlates of smoking status and patterns, likelihood of quitting, and intentions to quit.

Methods: Cross-sectional analyses were conducted among survivors of 10 cancers recruited by stratified random sampling from cancer registries in a nationwide, longitudinal, quality-of-life study (n = 2,938).

Results: Approximately 9 years after diagnosis, 9.3% of all survivors were current (past 30-day) smokers. Smoking prevalence was highest among survivors of bladder (17.2%), lung (14.9%), and ovarian (11.6%) cancers. Most current smokers (83%) smoked daily, averaging 14.7 cigarettes per day (cpd). Forty percent of daily smokers smoked more than 15 cpd. Nondaily smokers smoked a mean of 10.9 days in the last 30 days and averaged 5.7 cpd on smoking days. Current smoking was associated with younger age, lower education and income, and greater alcohol consumption. Quitting after diagnosis was associated with having a smoking-related cancer. Roughly, a third of current smokers intended to quit, 40% within the next month. The odds of intending to quit were lower if survivors were married, older, or smoked more.

Conclusions: This population-based study indicated that smoking can persist long after initial diagnosis and at high levels and identified characteristics associated with quitting and intentions to quit.

Impact: Findings can be used to identify survivors most at risk for continued smoking and to inform tailoring of cessation treatments for survivors. Cancer Epidemiol Biomarkers Prev; 23(9); 1783–92. ©2014 AACR.
ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents
Authors: Agnihotri Sameer , Burrell Kelly , Buczkowicz Pawel , Remke Marc , Golbourn Brian , Chornenkyy Yevgen , Gajadhar Aaron , Fernandez Nestor A. , Clarke Ian D. , Barszczyk Mark S. , Pajovic Sanja , Ternamian Christian , Head Renee , Sabha Nesrin , Sobol Robert W. , Taylor Michael D. , Rutka James T. , Jones Chris , Dirks Peter B. , Zadeh Gelareh , Hawkins Cynthia
Published: August 2014

Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity. Using an siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular, the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM), were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent–induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM–MPG axis will lead to improved treatment of alkylating agent–resistant tumors.

Significance: Inhibition of ATM and MPG-mediated BER cooperate to sensitize tumor cells to alkylating agents, impairing tumor growth in vitro and in vivo with no toxicity to normal cells, providing an ideal therapeutic window. Cancer Discov; 4(10); 1198–1213. ©2014 AACR.

See related commentary by Wick and Platten, p. 1120

This article is highlighted in the In This Issue feature, p. 1103
Urinoma following Kidney Biopsy: A Case Report
Authors: Limwattana Sorawan , Rianthavorn Pornpimol
Published: August 2014

Major complications of a percutaneous kidney biopsy are infrequent but warrant early detection and appropriate treatment. We herein report a patient who developed urinoma following kidney biopsy in the effort to emphasize the paramount importance for practitioners to recognize this complication. Prompt diagnosis and proper management of urinoma following kidney biopsy is prudent as delayed treatment may lead to abscess formation, hydronephrosis, obstructive uropathy and chronic kidney failure.
Increased Aggression, Improved Spatial Memory, and Reduced Anxiety-Like Behaviour in Adult Male Mice Exposed to Fluoxetine Early in Life
Authors: Kiryanova Veronika , Dyck Richard H.
Published: August 2014

Rationale: Fluoxetine (Flx; brand names Prozac, Sarafem, Rapiflux), a selective serotonin reuptake inhibitor, is prescribed for the treatment of depression in pregnant women; however, this commonly prescribed medication could affect fetal brain development as Flx crosses the placenta. The available data concerning the anatomical and behavioural consequences of perinatal exposure to Flx during early development on adult behaviour are limited and often contradictory. Objectives: To further delineate the long-term behavioural effects of altering 5-HT during development, we examined the effects of perinatal Flx exposure on the behaviour of male mice as adults. Methods: Dams were treated with approximately 25 mg/kg/day of Flx from embryonic day 15 to postnatal day 12, and the behaviour of the adult offspring was assessed. Results: We found that perinatal Flx exposure leads to increased aggression, improved spatial memory, and reduced anxiety-like behaviour. This exposure did not cause memory deficits, changes in sensory processing, or changes in gross motor function. Conclusions: Our results suggest that while perinatal exposure to Flx may have long-term effects on adult behaviour, these effects appear limited and not necessarily detrimental.
Management of Extreme Ametropia after Penetrating Keratoplasty: A Series of Surgical Procedures for High Myopia and Astigmatism
Authors: Valdez-Garcia Jorge E. , Cueto-Gómez Juan J. , Lozano-Ramírez Juan F. , Tamez-Peña Alejandro E.
Published: August 2014

A series of surgical interventions - relaxing corneal incisions, intraocular lens, and intrastromal rings - were used to correct a case of extreme ametropia in a thin cornea after a penetrating keratoplasty in an 18-year-old patient who presented with a -10.25 -8.50 × 120 preoperative refraction and 20/200 best-corrected visual acuity (BCVA). After a series of surgical procedures, the patient's BCVA in his left eye improved to 20/30 with +0.50 -1.00 × 170, the slit lamp examination showed no significant findings, and the patient's visual complaints disappeared. At the 1-year follow-up, the BCVA was 20/25, without visual complaints. The process of individualizing the surgical procedure in the present case was employed in an outcome-based approach, that is, the next surgical procedure was defined after the surgery and postoperative evaluation. The patient did not present complications during the follow-up period of 2.5 years.