bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening for Neuraminidase Inhibitor Resistance Markers among Avian Influenza Viruses of the N4, N5, N6, and N8 Neuraminidase Subtypes
Authors: Choi Won-Suk , Jeong Ju Hwan , Kwon Jin Jung , Ahn Su Jeong , Lloren Khristine Kaith S. , Kwon Hyeok-Il , Chae Hee Bok , Hwang Jungwon , Kim Myung Hee , Kim Chul-Joong , Webby Richard J. , Govorkova Elena A. , Choi Young Ki , Baek Yun Hee , Song Min-Suk 
Published: October 2017

ABSTRACTSeveral subtypes of avian influenza viruses (AIVs) are emerging as novel human pathogens, and the frequency of related infections has increased in recent years. Although neuraminidase (NA) inhibitors (NAIs) are the only class of antiviral drugs available for therapeutic intervention for AIV-infected patients, studies on NAI resistance among AIVs have been limited, and markers of resistance are poorly understood. Previously, we identified unique NAI resistance substitutions in AIVs of the N3, N7, and N9 NA subtypes. Here, we report profiles of NA substitutions that confer NAI resistance in AIVs of the N4, N5, N6, and N8 NA subtypes using gene-fragmented random mutagenesis. We generated libraries of mutant influenza viruses using reverse genetics (RG) and selected resistant variants in the presence of the NAIs oseltamivir carboxylate and zanamivir in MDCK cells. In addition, two substitutions, H274Y and R292K (N2 numbering), were introduced into each NA gene for comparison. We identified 37 amino acid substitutions within the NA gene, 16 of which (4 in N4, 4 in N5, 4 in N6, and 4 in N8) conferred resistance to NAIs (oseltamivir carboxylate, zanamivir, or peramivir) as determined using a fluorescence-based NA inhibition assay. Substitutions conferring NAI resistance were mainly categorized as either novel NA subtype specific (G/N147V/I, A246V, and I427L) or previously reported in other subtypes (E119A/D/V, Q136K, E276D, R292K, and R371K). Our results demonstrate that each NA subtype possesses unique NAI resistance markers, and knowledge of these substitutions in AIVs is important in facilitating antiviral susceptibility monitoring of NAI resistance in AIVs.IMPORTANCEThe frequency of human infections with avian influenza viruses (AIVs) has increased in recent years. Despite the availability of vaccines, neuraminidase inhibitors (NAIs), as the only available class of drugs for AIVs in humans, have been constantly used for treatment, leading to the inevitable emergence of drug-resistant variants. To screen for substitutions conferring NAI resistance in AIVs of N4, N5, N6, and N8 NA subtypes, random mutations within the target gene were generated, and resistant viruses were selected from mutant libraries in the presence of individual drugs. We identified 16 NA substitutions conferring NAI resistance in the tested AIV subtypes; some are novel and subtype specific, and others have been previously reported in other subtypes. Our findings will contribute to an increased and more comprehensive understanding of the mechanisms of NAI-induced inhibition of influenza virus and help lead to the development of drugs that bind to alternative interaction motifs.
Foamy Virus Vector Carries a Strong Insulator in Its Long Terminal Repeat Which Reduces Its Genotoxic Potential
Authors: Goodman Michael Aaron , Arumugam Paritha , Pillis Devin Marie , Loberg Anastacia , Nasimuzzaman Mohammed , Lynn Danielle , van der Loo Johannes Christiaan Maria , Dexheimer Phillip Joseph , Keddache Mehdi , Bauer Thomas Roy , Hickstein Dennis Durand , Russell David William , Malik Punam 
Published: October 2017

ABSTRACT

Strong viral enhancers in gammaretrovirus vectors have caused cellular proto-oncogene activation and leukemia, necessitating the use of cellular promoters in “enhancerless” self-inactivating integrating vectors. However, cellular promoters result in relatively low transgene expression, often leading to inadequate disease phenotype correction. Vectors derived from foamy virus, a nonpathogenic retrovirus, show higher preference for nongenic integrations than gammaretroviruses/lentiviruses and preferential integration near transcriptional start sites, like gammaretroviruses. We found that strong viral enhancers/promoters placed in foamy viral vectors caused extremely low immortalization of primary mouse hematopoietic stem/progenitor cells compared to analogous gammaretrovirus/lentivirus vectors carrying the same enhancers/promoters, an effect not explained solely by foamy virus' modest insertional site preference for nongenic regions compared to gammaretrovirus/lentivirus vectors. Using CRISPR/Cas9-mediated targeted insertion of analogous proviral sequences into the
LMO2
gene and then measuring
LMO2
expression, we demonstrate a sequence-specific effect of foamy virus, independent of insertional bias, contributing to reduced genotoxicity. We show that this effect is mediated by a 36-bp insulator located in the foamy virus long terminal repeat (LTR) that has high-affinity binding to the CCCTC-binding factor. Using our LMO2 activation assay,
LMO2
expression was significantly increased when this insulator was removed from foamy virus and significantly reduced when the insulator was inserted into the lentiviral LTR. Our results elucidate a mechanism underlying the low genotoxicity of foamy virus, identify a novel insulator, and support the use of foamy virus as a vector for gene therapy, especially when strong enhancers/promoters are required.

IMPORTANCE
Understanding the genotoxic potential of viral vectors is important in designing safe and efficacious vectors for gene therapy. Self-inactivating vectors devoid of viral long-terminal-repeat enhancers have proven safe; however, transgene expression from cellular promoters is often insufficient for full phenotypic correction. Foamy virus is an attractive vector for gene therapy. We found foamy virus vectors to be remarkably less genotoxic, well below what was expected from their integration site preferences. We demonstrate that the foamy virus long terminal repeats contain an insulator element that binds CCCTC-binding factor and reduces its insertional genotoxicity. Our study elucidates a mechanism behind the low genotoxic potential of foamy virus, identifies a unique insulator, and supports the use of foamy virus as a vector for gene therapy.
Viperin Targets Flavivirus Virulence by Inducing Assembly of Noninfectious Capsid Particles
Authors: Vonderstein Kirstin , Nilsson Emma , Hubel Philipp , Nygård Skalman Larsård , Upadhyay Arunkumar , Pasto Jenny , Pichlmair Andreas , Lundmark Richard , Överby Anna K. 
Published: October 2017

ABSTRACT
Efficient antiviral immunity requires interference with virus replication at multiple layers targeting diverse steps in the viral life cycle. We describe here a novel flavivirus inhibition mechanism that results in interferon-mediated obstruction of tick-borne encephalitis virus particle assembly and involves release of malfunctioning membrane-associated capsid (C) particles. This mechanism is controlled by the activity of the interferon-induced protein viperin, a broad-spectrum antiviral interferon-stimulated gene. Through analysis of the viperin-interactome, we identified the Golgi brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) as the cellular protein targeted by viperin. Viperin-induced antiviral activity, as well as C-particle release, was stimulated by GBF1 inhibition and knockdown and reduced by elevated levels of GBF1. Our results suggest that viperin targets flavivirus virulence by inducing the secretion of unproductive noninfectious virus particles via a GBF1-dependent mechanism. This as-yet-undescribed antiviral mechanism allows potential therapeutic intervention.

IMPORTANCE
The interferon response can target viral infection on almost every level; however, very little is known about the interference of flavivirus assembly. We show here that interferon, through the action of viperin, can disturb the assembly of tick-borne encephalitis virus. The viperin protein is highly induced after viral infection and exhibit broad-spectrum antiviral activity. However, the mechanism of action is still elusive and appears to vary between the different viruses, indicating that cellular targets utilized by several viruses might be involved. In this study, we show that viperin induces capsid particle release by interacting and inhibiting the function of the cellular protein Golgi brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1). GBF1 is a key protein in the cellular secretory pathway and is essential in the life cycle of many viruses, also targeted by viperin, implicating GBF1 as a novel putative drug target.
Asymmetrical accommodation in hyperopic anisometropic amblyopia
Authors: Toor Sonia , Horwood Anna M , Riddell Patricia 
Published: October 2017

Background/aimsTo investigate the presence of asymmetrical accommodation in hyperopic anisometropic amblyopia.MethodsAccommodation in each eye and binocular vergence were measured simultaneously using a PlusoptiX SO4 photorefractor in 26 children aged 4–8 years with hyperopic anisometropic amblyopia and 13 controls (group age-matched) while they viewed a detailed target moving in depth.ResultsWithout spectacles, only 5 (19%) anisometropes demonstrated symmetrical accommodation (within the 95% CI of the mean gain of the sound eye of the anisometropic group), whereas 21 (81%) demonstrated asymmetrical accommodation. Of those, 15 (58%) showed aniso-accommodation and 6 (23%) demonstrated ‘anti-accommodation’ (greater accommodation for distance than for near). In those with anti-accommodation, the response gain in the sound eye was (0.93±0.20) while that of the amblyopic eye showed a negative accommodation gain of (−0.44±0.23). Anti-accommodation resolved with spectacles. Vergence gains were typical in those with symmetrical and asymmetrical accommodation.ConclusionThe majority of hyperopic anisometropic amblyopes demonstrated non-consensual asymmetrical accommodation. Approximately one in four demonstrated anti-accommodation.
How does sevoflurane induction, followed by a ketamine maintenance infusion, affect intraocular pressure? Establishment of an anaesthetic protocol for paediatric glaucoma examinations under anaesthesia
Authors: van der Walt Jessica Gwendoline , Roodt Francois , Tinley Christopher 
Published: October 2017

Accurate measurement of intraocular pressure (IOP) is essential in paediatric glaucoma management. Children require serial measurements and examination under anaesthesia (EUA). Most anaesthetic agents reduce IOP, and the ideal time to measure IOP under anaesthesia is questionable.Study purposeTo determine the effect of sevoflurane induction, followed by intravenous ketamine infusion on IOP, in children undergoing EUA for glaucoma or suspected glaucoma, and to establish the earliest time point at which reliable, repeatable IOP measurements can be obtained under anaesthesia.MethodA prospective, descriptive study of IOP changes occurring in children requiring EUAs. A standardised anaesthetic protocol: sevoflurane induction, intravenous cannulation, 2 mg/kg intravenous ketamine bolus and 4 mg/kg/hour maintenance for 15 min. IOP measurements (taken supine with a Perkins applanation tonometer) and physiological variables were recorded.ResultsIOPs were measured in 25 children (50 eyes). Twenty-six eyes (52%) were glaucomatous. Mean patient age was 29 months (2–88 months). Physiological variables returned to baseline at 8 min, correlating with recorded sevoflurane elimination. Mean IOP after sevoflurane induction was 3.68 mm Hg lower than with ketamine maintenance at 15 min (95% CI 1.35 to 6.02 mm Hg) (p=0.002). Contrastingly, the difference in IOP between ketamine anaesthesia at 15 min and near wakefulness was 0.28 mm Hg (95% CI −2.23 to 2.79 mm Hg) (p=0.826).ConclusionSevoflurane’s IOP-lowering effect is reversed 15 min after the discontinuation of the inhalational gas, if anaesthesia is maintained with an intravenous ketamine infusion. IOP measurements appear to stabilise at this time point until the point of near wakefulness and may reflect awake values.
INFLUENCE OF TITANIUM TETRAISOPROPOXIDE CONCENTRATION ON THE ANTIBACTERIAL ACTIVITY OF TiO2 THIN FILMS
Authors: TAHA ALI A. , AL-JAWAD SELMA M. H. , SALIM MOHAMMED M. 
Published: October 2017

In this study, titanium dioxide thin films were successfully prepared via sol–gel method. Titanium tetraisopropoxide (TTIP) as a precursor solution was used to prepare different concentrations and deposited by spin coating. All prepared films were inspected by X-ray diffraction (XRD), atomic force microscopy (AFM) and scanning electron microscopy (SEM). XRD patterns show that all samples have anatase crystal structure. Transmittance spectra were measured by using UV-Vis spectrophotometer. The optical band gaps were 3.55, 3.62 and 3.78 eV for TTIP concentrations of 6, 6.3 and 6.6[Formula: see text]ml, respectively. Antibacterial activity of TiO2 films against S. aureus and E. coli was evaluated by international recognized test (JIS Z 2801). The test revealed incrementally increase in antibacterial activity of the films with TTIP concentrations activated by UV light.
SYNTHESIS OF NEW NITROBENZYLIDENE DERIVATIVES AND PYRROLE-BASED COPOLYMERS FOR DYE-SENSITIZED SOLAR CELLS: EFFECT OF SUBSTITUENT ON OPTO-ELECTRICAL PROPERTIES OF DIP-COATED THIN FILMS
Authors: REMIL ABDERRAHMANNE , MOUCHAAL YOUNES , REGUIG ABDELKARIM BENDOUKHA , TOUMI ABDERAHMANNE LAKHDAR , GHERRASS HAMOU , HACHEMAOUI AISHA , YAHIAOUI AHMED , KHELIL ABDELBACET 
Published: October 2017

The mastery of the optoelectronic properties of conjugated copolymers by substituting their radicals is a promising way for increasing the light absorption and charge career transport in the organic devices active layer. In this paper, we present the chemical synthesis of four different conjugated benzaldehyde derivatives and pyrrole-based copolymers (P–P:B) followed by their conception in thin films on glass substrates by dip coating root from a solution in dichloromethane. UV–Vis measurements showed absorption in good part of the visible region, with an optical gap around 2 eV. Morphological properties observed by scanning electron microscope of the four P–P:B based thin films illustrated homogenous and continuous surfaces with roughness and surface shape that can be modulated according to Nitrobenzylidene derivative that contains the copolymer. First oxidation ([Formula: see text]) and reduction ([Formula: see text]) potentials of synthetized copolymers have been estimated by cyclic voltammetry which led us to estimate the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), respectively. The HOMO and LUMO energy level diagram of P–P:B compared with the most commonly used organic materials as donor/acceptor couples showed a cascade shape, which allowed us to opt for organic solar cells based on multiple active layers in our aim to improve its performance.
PP2A Inactivation Mediated by PPP2R4 Haploinsufficiency Promotes Cancer Development
Authors: Sents Ward , Meeusen Bob , Kalev Petar , Radaelli Enrico , Sagaert Xavier , Miermans Eline , Haesen Dorien , Lambrecht Caroline , Dewerchin Mieke , Carmeliet Peter , Westermarck Jukka , Sablina Anna , Janssens Veerle 
Published: October 2017

Abstract
Protein phosphatase 2A (PP2A) complexes counteract many oncogenic kinase pathways. In cancer cells, PP2A function can be compromised by several mechanisms, including sporadic mutations in its scaffolding A and regulatory B subunits or more frequently through overexpression of cellular PP2A inhibitors. Here, we identify a novel genetic mechanism by which PP2A function is recurrently affected in human cancer, involving haploinsufficiency of PPP2R4, a gene encoding the cellular PP2A activator PTPA. Notably, up to 70% of cancer patients showed a heterozygous deletion or missense mutations in PPP2R4. Cancer-associated PTPA mutants exhibited decreased abilities to bind the PP2A-C subunit or activate PP2A and failed to reverse the tumorigenic phenotype induced by PTPA suppression, indicating they function as null alleles. In Ppp2r4 gene-trapped (gt) mice showing residual PTPA expression, total PP2A activity and methylation were reduced, selectively affecting specific PP2A holoenzymes. Both PTPAgt/gt and PTPA+/gt mice showed higher rates of spontaneous tumors, mainly hematologic malignancies and hepatocellular adenomas and carcinomas. These tumors exhibited increased c-Myc phosphorylation and increased Wnt or Hedgehog signaling. We observed a significant reduction in lifespan in PTPA+/gt mice compared with wild-type mice. In addition, chemical-induced skin carcinogenesis was accelerated in PTPA+/gt compared with wild-type mice. Our results provide evidence for PPP2R4 as a haploinsufficient tumor suppressor gene, defining a high-penetrance genetic mechanism for PP2A inhibition in human cancer. Cancer Res; 77(24); 6825–37. ©2017 AACR.
Cathepsin B Is Dispensable for Cellular Processing of Cathepsin B-Cleavable Antibody–Drug Conjugates
Authors: Caculitan Niña G. , dela Cruz Chuh Josefa , Ma Yong , Zhang Donglu , Kozak Katherine R. , Liu Yichin , Pillow Thomas H. , Sadowsky Jack , Cheung Tommy K. , Phung Qui , Haley Benjamin , Lee Byoung-Chul , Akita Robert W. , Sliwkowski Mark X. , Polson Andrew G. 
Published: October 2017

Abstract
Antibody–drug conjugates (ADC) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline [VC(S)] linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload. Mass spectrometry studies of payload release suggested that other cysteine cathepsins can cleave the VC(S) linker. Also, ADCs with a nonprotease-cleavable enantiomer, the VC(R) isomer, mediated effective cell killing with a cysteine-VC(R)-MMAE catabolite generated by lysosomal catabolism. Based on these observations, we altered the payload to a pyrrolo[2,1-c][1,4]benzodiazepine dimer (PBD) conjugate that requires linker cleavage in order to bind its DNA target. Unlike the VC-MMAE ADCs, the VC(S)-PBD ADC is at least 20-fold more cytotoxic than the VC(R)-PBD ADC. Our findings reveal that the VC(S) linker has multiple paths to produce active catabolites and that antibody and intracellular targets are more critical to ADC efficacy. These results suggest that protease-cleavable linkers are unlikely to increase the therapeutic index of ADCs and that resistance based on linker processing is improbable. Cancer Res; 77(24); 7027–37. ©2017 AACR.
cGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels
Authors: Frankenreiter Sandra , Bednarczyk Piotr , Kniess Angelina , Bork Nadja I. , Straubinger Julia , Koprowski Piotr , Wrzosek Antoni , Mohr Eva , Logan Angela , Murphy Michael P. , Gawaz Meinrad , Krieg Thomas , Szewczyk Adam , Nikolaev Viacheslav O. , Ruth Peter , Lukowski Robert 
Published: October 2017

Background:

The nitric oxide–sensitive guanylyl cyclase/cGMP-dependent protein kinase type I signaling pathway can afford protection against the ischemia/reperfusion injury that occurs during myocardial infarction. Reportedly, voltage and Ca
2+
-activated K
+
channels of the BK type are stimulated by cGMP/cGMP-dependent protein kinase type I, and recent ex vivo studies implicated that increased BK activity favors the survival of the myocardium at ischemia/reperfusion. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes or in other cardiac cell types.

Methods:
Gene-targeted mice with a cardiomyocyte- or smooth muscle cell–specific deletion of the BK (CMBK or SMBK knockouts) were subjected to the open-chest model of myocardial infarction. Infarct sizes of the conditional mutants were compared with litter-matched controls, global BK knockout, and wild-type mice. Cardiac damage was assessed after mechanical conditioning or pharmacological stimulation of the cGMP pathway and by using direct modulators of BK. Long-term outcome was studied with respect to heart functions and cardiac fibrosis in a chronic myocardial infarction model.

Results:
Global BK knockouts and CMBK knockouts, in contrast with SMBK knockouts, exhibited significantly larger infarct sizes compared with their respective controls. Ablation of CMBK resulted in higher serum levels of cardiac troponin I and elevated amounts of reactive oxygen species, lower phosphorylated extracellular receptor kinase and phosphorylated AKT levels and an increase in myocardial apoptosis. Moreover, CMBK was required to allow beneficial effects of both nitric oxide–sensitive guanylyl cyclase activation and inhibition of the cGMP-degrading phosphodiesterase-5, ischemic preconditioning, and postconditioning regimens. To this end, after 4 weeks of reperfusion, fibrotic tissue increased and myocardial strain echocardiography was significantly compromised in CMBK-deficient mice.

Conclusions:
Lack of CMBK channels renders the heart more susceptible to ischemia/reperfusion injury, whereas the pathological events elicited by ischemia/reperfusion do not involve BK in vascular smooth muscle cells. BK seems to permit the protective effects triggered by cinaciguat, riociguat, and different phosphodiesterase-5 inhibitors and beneficial actions of ischemic preconditioning and ischemic postconditioning by a mechanism stemming primarily from cardiomyocytes. This study establishes mitochondrial CMBK channels as a promising target for limiting acute cardiac damage and adverse long-term events that occur after myocardial infarction.
Evidence that Recent Warming is Reducing Upper Colorado River Flows
Authors: McCabe Gregory J. , Wolock David M. , Pederson Gregory T. , Woodhouse Connie A. , McAfee Stephanie 
Published: October 2017

Abstract
The upper Colorado River basin (UCRB) is one of the primary sources of water for the western United States, and increasing temperatures likely will elevate the risk of reduced water supply in the basin. Although variability in water-year precipitation explains more of the variability in water-year UCRB streamflow than water-year UCRB temperature, since the late 1980s, increases in temperature in the UCRB have caused a substantial reduction in UCRB runoff efficiency (the ratio of streamflow to precipitation). These reductions in flow because of increasing temperatures are the largest documented temperature-related reductions since record keeping began. Increases in UCRB temperature over the past three decades have resulted in a mean UCRB water-year streamflow departure of −1306 million m3 (or −7% of mean water-year streamflow). Additionally, warm-season (April through September) temperature has had a larger effect on variability in water-year UCRB streamflow than the cool-season (October through March) temperature. The greater contribution of warm-season temperature, relative to cool-season temperature, to variability of UCRB flow suggests that evaporation or snowmelt, rather than changes from snow to rain during the cool season, has driven recent reductions in UCRB flow. It is expected that as warming continues, the negative effects of temperature on water-year UCRB streamflow will become more evident and problematic.