julilili42/papers huggingface dataset:
Safety of tiotropium and olodaterol fixed-dose combination for COPD in patients on β-blockers
2015-09-01

<b>Introduction:</b> The TONADO studies (NCT01431274; NCT01431287) established the efficacy and safety of a new once-daily fixed-dose combination (FDC) with tiotropium (T), a long-acting muscarinic antagonist, and olodaterol (O), a long-acting β<sub>2</sub>-agonist, for the treatment of COPD. This <i>post hoc</i> analysis evaluates T+O safety in the subgroup of patients (pts) receiving β-blockers (BBs) in these studies. <b>Methods:</b> These were randomised, double-blind, parallel-group, 52-week, Phase III trials comparing T+O FDC (2.5/5 μg; 5/5 μg) with the monocomponents. Adverse events (AEs) and serious AEs (SAEs) were recorded and SAEs independently adjudicated. Pooled safety data from pts receiving BBs at baseline are presented. <b>Results:</b> 5162 pts were evaluable: 557 (10.8%) received BBs at baseline. Incidence of AEs was similar between pts receiving BBs and those not receiving BBs for both T+O FDCs (Table). A higher incidence of cardiac, general, musculoskeletal and vascular disorders was reported in pts taking BBs at baseline compared to pts not taking BBs at baseline. Within BB subgroups, frequency of AEs, including respiratory and cardiovascular AEs, was generally similar across treatment arms. <b>Conclusions:</b> Although the number of pts on BBs was relatively small, these data suggest no safety concerns with T+O FDCs in pts receiving BBs at baseline. These data support the use of T+O FDCs in pts receiving BBs. Funding: Boehringer Ingelheim.
Comparing sensitivity estimates from MLDS and forced-choice methods in a slant-from-texture experiment
2015-09-01

Maximum likelihood difference scaling (MLDS) is a method for the estimation of perceptual scales based on an equal-variance, Gaussian, signal detection model (Maloney & Yang, 2003). It has recently been shown that perceptual scales derived with MLDS allowed the prediction of near-threshold discrimination performance for the Watercolor effect (Devinck & Knoblauch, 2012). The use of MLDS-based scales to predict sensitivity is psychophysically attractive, because the MLDS scale estimation promises to require a comparatively small amount of data relative to classical forced-choice procedures, such as the method of constant stimulus. However, the relationship between estimates from MLDS and forced-choice procedures is not yet well characterized with respect to their bias and variability. It also remains to be tested whether their close correspondence applies to stimuli other than the Watercolor effect. Here, we studied these issues by comparing the MLDS and forced-choice methods in a slant-from-texture experiment. We used a 'polka dot' texture pattern which was slanted 0 to 80 deg away from fronto-parallel and viewed through a circular aperture (Rosas et al., 2004). We first obtained perceptual scales describing the relationship between physical and perceived slant using MLDS with the method of triads. Based on individual scales we measured slant discrimination thresholds at different performance levels (d'=0.5, 1 and 2) for four different standard slants using standard forced-choice procedures. We obtained a high correspondence between slant thresholds obtained from the two methods. The variability of the estimates, however, depended heavily on the amount of data for MLDS, somewhat questioning its efficiency. Furthermore, the correspondence between the two methods was reduced in the lower region of the MLDS scale. We conclude that MLDS scales can be used to estimate sensitivity, however, we would advise caution with respect to the generalizability of the correspondence between MLDS and forced-choice based sensitivity measures across experimental tasks. Meeting abstract presented at VSS 2015
Reproducibility of the Structural Brain Connectome Derived from Diffusion Tensor Imaging
2015-09-02

Anatomical factors and tractography approaches can influence the reproducibility of the structural connectome and should be factored in the interpretation of future studies. Our results demonstrate that connectome mapping is a largely reproducible technique, particularly as it relates to the geometry of network architecture measured by graph theory methods.
Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer
2015-09-02

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1 . Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P =1.86×10 −5 ), which was stronger for cancers of endometrioid subtype ( P =3.76×10 −6 ). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1 , and eQTL analysis found that rs79575945 was associated with expression of SYNE1 , a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1 , at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.
Modeling long-term uptake and re-volatilization of semi-volatile organic compounds (SVOCs) across the soil–atmosphere interface
2015-09-02

Soil-atmosphere exchange is important for the environmental fate and atmospheric transport of many semi-volatile organic compounds (SVOCs). This study focuses on modeling the vapor phase exchange of semi-volatile hydrophobic organic pollutants between soil and the atmosphere using the multicomponent reactive transport code MIN3P. MIN3P is typically applied to simulate aqueous and vapor phase transport and reaction processes in the subsurface. We extended the code to also include an atmospheric boundary layer where eddy diffusion takes place. The relevant processes and parameters affecting soil-atmosphere exchange were investigated in several 1-D model scenarios and at various time scales (from years to centuries). Phenanthrene was chosen as a model compound, but results apply for other hydrophobic organic compounds as well. Gaseous phenanthrene was assumed to be constantly supplied to the system during a pollution period and a subsequent regulation period (with a 50% decline in the emission rate). Our results indicate that long-term soil-atmosphere exchange of phenanthrene is controlled by the soil compartment - re-volatilization thus depends on soil properties. A sensitivity analysis showed that accumulation and transport in soils in the short term is dominated by diffusion, whereas in the long term groundwater recharge and biodegradation become relevant. As expected, sorption causes retardation and slows down transport and biodegradation. If atmospheric concentration is reduced (e.g. after environmental regulations), re-volatilization from soil to the atmosphere occurs only for a relatively short time period. Therefore, the model results demonstrate that soils generally are sinks for atmospheric pollutants. The atmospheric boundary layer is only relevant for time scales of less than one month. The extended MIN3P code can also be applied to simulate fluctuating concentrations in the atmosphere, for instance due to temperature changes in the topsoil.
‘We were taken by surprise’: body scanners, technology adjustment, and the eradication of failure
2015-09-02

This paper analyzes how body scanners were implemented at German airports in 2014 after failing a preliminary trial run in 2010–2011. The paper retraces how this initial failure became possible. It highlights the different ways of framing failure at both the political level and by experts and stakeholders from aviation security and the security industry. In both cases, although with reference to different claims (numbers and operational capacity on the one hand; surprise and privacy issues on the other hand), failure was conceived of as a dynamic and contingent process that did not necessarily demarcate the end of the line for body scanners. The diagnosis of failure as a non-terminal and preliminary state speaks to wider findings in critical security studies that highlight the role of technology as a self-referential driver within security politics, and the vested (economic) interests in the development and marketization of security technologies.
Phenobarbital inhibits calpain activity and expression in mouse hepatoma cells
2015-09-02

Abstract The antiepileptic drug phenobarbital (PB) exerts hepatic effects related to cell proliferation and tumorigenesis which are closely linked to the Wnt/β-catenin signaling pathway. This pathway is, amongst others, regulated by calpain proteases. We now identified PB as an inhibitor of Wnt/β-catenin signaling in mouse hepatoma cells. Further analyses revealed that PB inhibits calpain activity, an effect which is at least in parts mediated by a transcriptional regulation of calpain mRNA levels and which is furthermore independent of the constitutive androstane receptor, the known mediator of most effects of PB in liver cells.
How partnership between African and European entrepreneurs can support the UN post-2015 development agenda
2015-09-02

This article discusses how the private sector, and here specifically African–European partnerships between entrepreneurs, can assist to attain the development goals formulated by the United Nations’ Post-2015 Agenda for Sub-Saharan Africa. Drawing on meetings between African and European entrepreneurs convened on the initiative of H. E. Prof. Dr. Horst Kohler, former President of the Federal Republic of Germany and former Managing Director of the IMF, we will discuss the private sector's role for the UN development agenda in the African context from the perspectives of participants of these meetings. More specifically, we will outline the contribution of the business sector in Africa to the creation of employment, education, job opportunities and training for young people, ecological sustainability, economic diversification and a supportive climate for start-ups. However, to enable these contributions, entrepreneurs are calling for favorable policies, reliable institutions, access to financial services an...
Lack of protection from development of multiple melanomas by an injected melanocortin analogue in a combined high‐risk MC1R/CDKN2A genotype patient
2015-09-02

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Real-time imaging of cGMP signals in platelets
2015-09-02

Background cGMP plays an essential role in platelet aggregation. However, the intracellular cGMP concentrations and the spatiotemporal dynamics of cGMP signals in platelets during hemostasis and thrombosis are largely unknown. To visualize cGMP signals in vivo, we have generated so-called cGMP sensor knock-in mice [1]. A Cre recombinaseactivatable expression cassette encoding the fluorescence resonance energy transfer (FRET)-based cGMP sensor, cGi500, driven by the CAG promoter was integrated into the Rosa26 locus. Depending on the strategy to activate sensor expression, these mice can show either ubiquitous or tissue-specific sensor expression allowing for delineation of cGMP signaling in live cells in vitro and in vivo.
Cyclic GMP signaling and mitochondrial BK channels in cardioprotection against ischemia/reperfusion injury
2015-09-02

Background By studying hearts obtained from global BK-null mice (BK-KO) in an ex vivo Langendorff perfusion setup we and others previously found evidence for mitochondrial BK channels (mitoBKs) in cardiomyocytes as infarctlimiting factors [1,2]. It is well established that canonical BK channels usually present at the plasma membrane of cells are directly stimulated by the cyclic guanosine3’,5’-monophosphate (cGMP)/cGMP-dependent protein kinase type I pathway; however, it is unclear whether cardioprotection afforded by cardiomyocyte (CM) cGMP in vivo requires mitoBK.
Correlation of vascular smooth muscle cell phenotype and cGMP signalling
2015-09-02

The phenotypic modulation of vascular smooth muscle cells (VSMCs) is important during vascular development and disease states, such as restenosis and atherosclerosis. It has been suggested that cyclic guanosine monophosphate (cGMP) signalling might be involved in the dynamic changes of VSMC growth and phenotype. Cyclic GMP can be produced by various guanylyl cyclases (GCs). Soluble GC is activated by nitric oxide (NO), whereas the plasma membrane-associated GCs, GC-A and GC-B are stimulated by atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP), respectively. To elucidate the potential link between VSMC phenotype and cGMP signalling we isolated and cultured VSMCs from aortae of transgenic mice [R26-CAG-cGi500(L1)] expressing the fluorescence resonance energy transfer (FRET)-based cGMP sensor cGi500 ubiquitously. These cultures underwent different treatments, such as passaging or serum-starvation, to modulate the phenotype of VSMCs. Then the VSMCs were exposed to ANP, CNP, or the NO-releasing compound DEA/NO and intracellular cGMP transients were monitored in real-time at the single-cell level by FRET microscopy. In subsequent steps, the expression of marker proteins for VSMCs was assessed by immunofluorescence staining and correlated with the respective cGMP response of each individual cell. Interestingly, VSMC populations showed heterogeneous cGMP responses with respect to cGMP signals elicited by ANP compared to CNP and these differential responses correlated well with the expression of smooth muscle cell specific marker proteins. VSMCs with a stronger ANP response in comparison to CNP expressed high levels of α smooth muscle actin (α-SMA) and transgelin (SM22α), while cells with a stronger CNP response in comparison to ANP expressed low levels of α-SMA and SM22α. Shifting the VSMC phenotype towards a more contractile phenotype by serum-starvation increased the fraction of cells with strong α-SMA expression and preferential ANP responsiveness. In contrast, promoting the synthetic phenotype by passaging shifted the population towards cells with low α-SMA expression and preferential CNP responsiveness. In conclusion, the differential cGMP responses of VSMCs in culture appear to correlate with distinct phenotypes. Cells with strong responses to ANP exhibit features of differentiated/contractile VSMCs, whereas cells with strong responses to CNP exhibit features of dedifferentiated/synthetic VSMCs. In the future, cGMP imaging in normal and pathophysiologically remodelled vessels should elucidate the relevance of our in vitro findings for in vivo situations.
Differential role of NO-sensitive guanylyl cyclase isoforms NO-GC1 and NO-GC2 in auditory function in adult mice
2015-09-02

Background In the inner ear, elevated cyclic guanosine 3’-5’-monophospate (cGMP) levels were shown to have a sheltering role for cochlear hair cells and hearing function [1]. However, the individual roles of the two nitric oxide-sensitive guanylyl cyclase isoforms (NO-GC1 and NO-GC2) as cGMP generators in this protective effect are still unclear. The aim of this study was to investigate how the deletion of either one of the a-subunits of NO-GC (NO-GC1 KO or NO-GC2 KO) [2] or deletion of the b1-subunit of NO-GC (NO-GC KO), leading to global lack of NO-GC expression [3], affects hearing function, vulnerability to noise exposure and recovery from acoustic trauma in mice.
The role of particulate guanylyl cyclase B (GC-B) in auditory function in adult mice
2015-09-02

Background cGMP signaling triggered by the binding of C-type natriuretic peptide (CNP) to its receptor guanylyl cyclase B (GC-B; NPR2; NPRB) has been linked by genetic evidence to a remarkable variety of physiological functions like skeletal bone growth, female fertility, cardiac growth, fat metabolism and gastrointestinal function. For the nervous system it has been recently demonstrated that the CNP/GC-B/cGMP/cGMP-dependent protein kinase type I (cGKI) signaling pathway is essential for sensory axon branching at the dorsal root entry zone of the spinal cord and at the rhombomeres of the hindbrain during embryonic development [1]. Also in the auditory system, distinct auditory nerve fiber (ANF) types that differ in their discharge rate and sound sensitivity bifurcate in the cochlear nucleus (CN), sending collaterals to the anteroventral, posteroventral, and dorsal subdivisions. The lack of GC-B has been shown to lead to a central phenotype [2].
Comparative analysis of established and new biosensors for cyclic nucleotides
2015-09-02

BackgroundCyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) are versatile second messengers relevant to many physiological and pathophysiological conditions.Live-cell imaging of these cyclic nucleotides with biosensors allows to elucidate their levels and dynamics under close-to-native conditions.However, in order to monitor cGMP and cAMP signals in parallel in the same cell, the respective biosensors must be spectrally compatible.We have characterised some commonly used as well as novel "green" and "red" biosensors for cGMP and cAMP with regard to their sensitivity and specificity.
Cyclic GMP/cGMP-dependent protein kinase type I signaling and cysteine-rich LIM-only protein 4 in AngII/AT1R-induced heart hypertrophy and fibrosis
2015-09-02

Background Cardiac hypertrophy is an adaptive response of the heart to many cardio-vascular disorders including hypertension, infarction and defects of the valves. Elevated levels of cardiac cyclic guanosine-3',5'-monophosphate (cGMP) activate cGMP-dependent protein kinase I (cGKI), which reportedly exhibited either anti-fibrotic and anti-hypertrophic effects or did not change the cardiac remodeling response. Based on these conflicting results, we and others suggested that the ability of natriuretic peptides (NP) to oppose detrimental changes via cGMP/cGKI might be strongly influenced by the stress stimuli that actually trigger the harmful events i.e. Angiotensin II (Ang II) modulating multiple reno-vascular and cardiac functions via G q-coupled Ang II type 1 receptors (AT1Rs). It is the overall aim of this study to dissect the molecular details underlying the cross-talk between the NP/cGMP/cGKI pathway and AngII/AT1R signaling in the heart.
Thioredoxin f1 and NADPH-dependent thioredoxin reductase C have overlapping functions in regulating photosynthetic metabolism and plant growth in response to varying light conditions
2015-09-03

Two different thiol-redox-systems exist in plant chloroplasts, the ferredoxin-thioredoxin system, which depends of ferredoxin reduced by the photosynthetic electron-transport chain and, thus, of light, and the NADPH-dependent thioredoxin reductase C (NTRC) system, which relies on NADPH and thus may be linked to sugar metabolism in the dark. Previous studies suggested therefore that the two different systems may have different functions in plants. We now report that there is a previously unrecognized functional redundancy of thioredoxin-f1 and NTRC in regulating photosynthetic metabolism and growth. In Arabidopsis mutants, combined - but not single - deficiencies of thioredoxin-f1 and NTRC led to severe growth inhibition and perturbed light acclimation, accompanied by strong impairments of Calvin-Benson-cycle activity and starch accumulation. Light-activation of key-enzymes of these pathways, fructose-1,6-bisphosphatase and ADP-glucose pyrophosphorylase, was almost completely abolished. The subsequent increase in NADPH/NADP+ and ATP/ADP ratios led to increased nitrogen assimilation, NADP-malate dehydrogenase activation and light-vulnerability of photosystem I core-proteins. In an additional approach, reporter studies show that Trx f1 and NTRC proteins are both co-localized in the same chloroplast substructure. Results provide genetic evidence that light and NADPH dependent thiol-redox systems interact at the level of thioredoxin-f1 and NTRC to coordinately participate in the regulation of Calvin-Benson-cycle, starch metabolism and growth in response to varying light conditions.
Interference of Nitrite with Pyrite under Acidic Conditions: Implications for Studies of Chemolithotrophic Denitrification
2015-09-03

Chemolithotrophic denitrification coupled to pyrite oxidation is regarded a key process in the removal of nitrate in aquifers. A common product is nitrite, which is a strong oxidant under acidic conditions. Nitrite may thus interfere with Fe(II) during acidic extraction, a procedure typically used to quantify microbial pyrite oxidation, in overestimating Fe(III) production. We studied the reaction between pyrite (5-125 mM) and nitrite (40-2000 μM) at pH 0, 5.5, and 6.8 in the absence and presence of oxygen. Significant oxidation of pyrite was measured at pH 0 with a yield of 100 μM Fe(III) after 5 mM pyrite was incubated with 2000 μM nitrite for 24 h. Dissolved oxygen increased the rate at pH 0. No oxidation of pyrite was observed at pH 5.5 and 6.8. Our data imply a cyclic model for pyrite oxidation by Fe(III) on the basis of the oxidation of residual Fe(II) by NO and NO2. Interference by nitrite could be avoided if nitrite was removed from the pyrite suspensions through a washing procedure prior to acidic extraction. We conclude that such interferences should be considered in studies on microbially mediated pyrite oxidation with nitrate.