bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the QuantiFERON-TB Gold Plus and QuantiFERON-TB Gold In-Tube Interferon Gamma Release Assays in Patients at Risk for Tuberculosis and in Health Care Workers
Authors: Theel Elitza S. , Hilgart Heather , Breen-Lyles Margaret , McCoy Kevin , Flury Rhiannon , Breeher Laura E. , Wilson John , Sia Irene G. , Whitaker Jennifer A. , Clain Jeremy , Aksamit Timothy R. , Escalante Patricio 
Published: May 2018

ABSTRACT

The QuantiFERON-TB Gold Plus (QFT-Plus; Qiagen, Germantown, MD) interferon gamma release assay (IGRA) received FDA clearance in 2017 and will replace the prior version of the assay, the QFT-Gold In-Tube (QFT-GIT). Here, we compared performances of the QFT-Plus assay and the QFT-GIT version in a diverse patient population, including patients undergoing evaluation for or follow-up of latent tuberculosis infection (LTBI;
n
= 39) or active TB infection (
n
= 3), and in health care workers (HCWs;
n
= 119) at Mayo Clinic (Rochester, MN). Compared to the QFT-GIT, the QFT-Plus assay showed 91.2% (31/34) positive, 98.4% (124/126) negative, and 96.6% (156/161) overall qualitative agreement among the 161 enrolled subjects, with a Cohen's kappa value of 0.91 (excellent interrater agreement). Among the 28 patients diagnosed with LTBI at the time of enrollment, the QFT-GIT and QFT-Plus assays agreed in 24 (85.7%) patients; in all four discordant patients, the positivity of the QFT-GIT or QFT-Plus IGRA was associated with low-level interferon gamma (IFN-γ) reactivity, ranging from 0.36 IU/ml to 0.66 IU/ml. Additionally, we document a high degree of correlation between IFN-γ levels in the QFT-GIT TB antigen tube and each of the two QFT-Plus TB antigen tubes, as well as between the QFT-Plus TB1 and TB2 tubes (Pearson's correlation coefficients [
R
] > 0.95). Overall, we show comparable results between the QFT-GIT and QFT-Plus assays in our study population composed of subjects presenting with a diverse spectrum of TB infections. Our findings suggest that the necessary transition to the QFT-Plus assay will be associated with a minimal difference in assay performance characteristics.
Common and Distinct Capsid and Surface Protein Requirements for Secretion of Complete and Genome-Free Hepatitis B Virions
Authors: Ning Xiaojun , Luckenbaugh Laurie , Liu Kuancheng , Bruss Volker , Sureau Camille , Hu Jianming 
Published: May 2018

ABSTRACT
During the morphogenesis of hepatitis B virus (HBV), an enveloped virus, two types of virions are secreted: (i) a minor population of complete virions containing a mature nucleocapsid with the characteristic, partially double-stranded, relaxed circular DNA genome and (ii) a major population containing an empty capsid with no DNA or RNA (empty virions). Secretion of both types of virions requires interactions between the HBV capsid or core protein (HBc) and the viral surface or envelope proteins. We have studied the requirements from both HBc and envelope proteins for empty virion secretion in comparison with those for secretion of complete virions. Substitutions within the N-terminal domain of HBc that block secretion of DNA-containing virions reduced but did not prevent secretion of empty virions. The HBc C-terminal domain was not essential for empty virion secretion. Among the three viral envelope proteins, the smallest, S, alone was sufficient for empty virion secretion at a basal level. The largest protein, L, essential for complete virion secretion, was not required but could stimulate empty virion secretion. Also, substitutions in L that eliminated secretion of complete virions reduced but did not eliminate empty virion secretion. S mutations that blocked secretion of the hepatitis D virus (HDV), an HBV satellite, did not block secretion of either empty or complete HBV virions. Together, these results indicate that both common and distinct signals on empty capsids and mature nucleocapsids interact with the S and L proteins during the formation of complete and empty virions.

IMPORTANCE
Hepatitis B virus (HBV) is a major cause of severe liver diseases, including cirrhosis and cancer. In addition to the complete infectious virion particle, which contains an outer envelope layer and an interior capsid that, in turn, encloses a DNA genome, HBV-infected cells also secrete noninfectious, incomplete viral particles in large excess over the number of complete virions. In particular, the empty (or genome-free) virion shares with the complete virion the outer envelope and interior capsid but contains no genome. We have carried out a comparative study on the capsid and envelope requirements for the secretion of these two types of virion particles and uncovered both shared and distinct determinants on the capsid and envelope for their secretion. These results provide new information on HBV morphogenesis and have implications for efforts to develop empty HBV virions as novel biomarkers and a new generation of HBV vaccine.
Expression Levels of Glycoprotein O (gO) Vary between Strains of Human Cytomegalovirus, Influencing the Assembly of gH/gL Complexes and Virion Infectivity
Authors: Zhang Le , Zhou Momei , Stanton Richard , Kamil Jeremy , Ryckman Brent J. 
Published: May 2018

ABSTRACT

The tropism of human cytomegalovirus (HCMV) is influenced by the envelope glycoprotein complexes gH/gL/gO and gH/gL/UL128-131. During virion assembly, gO and the UL128-131 proteins compete for binding to gH/gL in the endoplasmic reticulum (ER). This assembly process clearly differs among strains, since Merlin (ME) virions contain abundant gH/gL/UL128-131 and little gH/gL/gO, whereas TR contains much higher levels of total gH/gL, mostly in the form of gH/gL/gO, but much lower levels of gH/gL/UL128-131 than ME. Remaining questions include (i) what are the mechanisms behind these assembly differences, and (ii) do differences reflect
in vitro
culture adaptations or natural genetic variations? Since the UL74(gO) open reading frame (ORF) differs in 25% of amino acids between TR and ME, we analyzed recombinant viruses in which the UL74(gO) ORF was swapped. TR virions were >40-fold more infectious than ME. Transcriptional repression of UL128-131 enhanced the infectivity of ME to the level of TR, despite still far lower levels of gH/gL/gO. Swapping the UL74(gO) ORF had no effect on either TR or ME. A quantitative immunoprecipitation approach revealed that gH/gL expression levels were within 4-fold between TR and ME, but the gO expression level was 20-fold lower for ME, which suggested differences in mRNA transcription, translation, or rapid ER-associated degradation of gO.
trans
-Complementation of gO expression during ME replication gave a 6-fold enhancement of infectivity beyond the 40-fold effect of UL128-131 repression alone. Overall, strain variations in the assembly of gH/gL complexes result from differences in the expression of gO and UL128-131, and selective advantages for reduced UL128-131 expression during fibroblast propagation are much stronger than those for higher gO expression.

IMPORTANCE
Specific genetic differences between independently isolated HCMV strains may result from purifying selection on
de novo
mutations arising during propagation in culture or random sampling among the diversity of genotypes present in clinical specimens. Results presented indicate that while reduced UL128-131 expression may confer a powerful selective advantage during cell-free propagation of HCMV in fibroblast cultures, selective pressures for increased gO expression are much weaker. Thus, variation in gO expression among independent strains may represent natural genotype variability present
in vivo
. This may have important implications for virus-host interactions, such as immune recognition, and underscores the value of studying molecular mechanisms of replication using multiple HCMV strains.
Basic lifestyle advice to individuals at high risk of type 2 diabetes: a 2-year population-based diabetes prevention study. The DE-PLAN intervention in the HUNT Study, Norway
Authors: Jølle Anne , Åsvold Bjørn Olav , Holmen Jostein , Carlsen Sven Magnus , Tuomilehto Jaakko , Bjørngaard Johan Håkon , Midthjell Kristian 
Published: May 2018

ObjectiveAmong individuals at high risk for diabetes identified through a population survey, we performed an intervention study with basic lifestyle advice aiming to prevent diabetes.Research design and methodsAmong 50 806 participants in the HUNT3 Survey (2006–2008), 5297 individuals with Finnish Diabetes Risc Score (FINDRISC ≥15 were invited to an oral glucose tolerance test (OGTT) and an education session with lifestyle advice, and 2634 (49.7%) attended. Among them, 2380 people without diabetes were included in the prevention study with repeated examinations and education sessions after 6, 12, and 24 months. We examined participation, diabetes incidence, glycemia, and adiposity during follow-up.ResultsOf 2380 participants, 1212 (50.9%) participated in ≥3 of the four examinations. Diabetes was detected in 3.5%, 3.1%, and 4.0% of individuals at the 6-month, 12-month, and 24-month examinations, respectively, indicating a 10.3% 2-year diabetes incidence. Mean (95% CI) increases from baseline to 2-year follow-up were 0.30 (0.29 to 0.32) percentage points (3.3 (3.2 to 3.5) mmol/mol) for Hemoglobin A1c, 0.13 (0.10 to 0.16) mmol/L for fasting serum-glucose, 0.46 (0.36 to 0.56) mmol/L for 2-hour OGTT s-glucose, 0.30 (0.19 to 0.40) kg/m2forbody mass index (BMI) (all p<0.001) and −0.5 (-0.9 to −0.2) cm for waist circumference (p=0.004), with broadly similar estimates by baseline age, sex, education, depressive symptoms, BMI, physical activity, and family history of diabetes. Only 206 (8.7%) participants had evidence of >5% weight loss during follow-up; their fasting and 2-hour s-glucose did not increase, and HbA1cincreased less than in other participants.ConclusionBasic lifestyle advice given to high-risk individuals during three group sessions with 6-month intervals was not effective in reducing 2-year diabetes risk.
Prevalence estimates and risk factors for early childhood wheeze across Europe: the EuroPrevall birth cohort
Authors: Selby Anna , Munro Alasdair , Grimshaw Kate E , Cornelius Victoria , Keil Thomas , Grabenhenrich Linus , Clausen Michael , Dubakiene Ruta , Fiocchi Alessandro , Kowalski Marek L , Papadopoulos Nikolaos G , Reche Marta , Sigurdardottir Sigurveig T , Sprikkelman Aline B , Xepapadaki Paraskevi , Mills E N Clare , Beyer Kirsten , Roberts Graham 
Published: May 2018

BackgroundPreschool wheeze is an important problem worldwide. No comparative population-based studies covering different countries have previously been undertaken.ObjectiveTo assess the prevalence of early childhood wheeze across Europe and evaluate risk factors focusing on food allergy, breast feeding and smoke exposure.MethodsInfants from nine countries were recruited into the EuroPrevall birth cohort. At 12 and 24 months, data on wheeze, allergic signs/symptoms, feeding, smoke exposure, infections and day care attendance were collected using questionnaires. Poisson regression was used to assess risk factors for wheeze.Results12 049 infants were recruited. Data from the second year of life were available in 8805 (73.1%). The prevalence of wheeze in the second year of life ranged from <2% in Lodz (Poland) and Vilnius (Lithuania) to 13.1% (95% CI 10.7% to 15.5%) in Southampton (UK) and 17.2% (95% CI 15.0% 19.5%) in Reykjavik (Iceland). In multivariable analysis, frequent lower respiratory tract infections in the first and second years of life (incidence rate ratio (IRR) 1.9 (95% CI 1.3 to 2.6) and 2.5 (95% CI 1.9 to3.4), respectively), postnatal maternal smoking (IRR 1.6, 95% CI 1.1 to 2.4), day care attendance (IRR 1.6, 95% CI 1.1 to 2.5) and male gender (IRR 1.3, 95% CI 1.0 to 1.7) were associated with wheeze. The strength of their association with wheeze differed between countries. Food allergy and breast feeding were not independently associated with wheeze.ConclusionThe prevalence of early childhood wheeze varied considerably across Europe. Lower respiratory tract infections, day care attendance, postnatal smoke exposure and male gender are important risk factors. Further research is needed to identify additional modifiable risk factors that may differ between countries.
Catchment-scale heterogeneity of flow and storage properties in a weathered/fractured hard rock aquifer from resistivity and magnetic resonance surveys: implications for groundwater flow paths and the distribution of residence times
Authors: Comte J.-C. , Ofterdinger U. , Legchenko A. , Caulfield J. , Cassidy R. , Mézquita González J. A. 
Published: May 2018

Abstract
Groundwater pathways and residence times are controlled by aquifer flow and storage properties, which, in weathered/fractured hard rock aquifers, are characterized by high spatial heterogeneity. Building on earlier work in a metamorphic aquifer in NW Ireland, new clay mineralogy and analyses of geophysical data provided high spatial resolution constraints on the variations in aquifer properties. Groundwater storage values derived from magnetic resonance sounding and electrical resistivity tomography were found to largely vary laterally and with depth, by orders of magnitude. The subsequent implementation of hillslope, two-dimensional numerical groundwater models showed that incorporating heterogeneity from geophysical data in model parametrization led to the best fit to observations compared with a reference model based on borehole data alone. Model simulations further revealed that (1) strong spatial heterogeneity produces deeper, longer groundwater flow paths and higher age mixing, in agreement with the mixed sub-modern/modern ages (mostly <50 years) provided by independent tritium data, and (2) areas with extensive weathering/fracturing are correlated with seepage zones of older groundwater resulting from changes in the flow directions and are likely to act as drainage structures for younger groundwater on a catchment or regional scale. Implications for groundwater resilience to climate extremes and surface pollution are discussed together with recommendations for further research.
Intraocular pressure and cardiovascular alterations investigated in artificial gravity as a countermeasure to spaceflight associated neuro-ocular syndrome
Authors: Anderson Allison P. , Butterfield Joseph S. , Subramanian Prem S. , Clark Torin K. 
Published: May 2018

Artificial gravity (AG) has been proposed as a countermeasure to spaceflight-associated neuro-ocular syndrome (SANS). The etiology of SANS is unknown but mimicking gravitational loading through AG may mitigate these negative adaptations. Seventeen subjects (nine men, eight women; 18–32 yr) were analyzed in four experimental conditions: 1) standing, 2) supine, 3) AG with the center of rotation at the eye (AGEC), and 4) AG with 2 Gs at the feet (AG2G). In both AG conditions, subjects were spun to produce 1 G at their center of mass. Data included self-administered intraocular pressure (IOP, Tono-pen AVIA, Depew, NY), heart rate (HR), and mean arterial blood pressure (MAP, Omron Series 10, Omron Healthcare, Kyoto, Japan). Data were analyzed with repeated measures ANOVAs with Tukey-Kramer corrections for multiple pairwise comparisons. IOP was 15.7 ± 1.4 mmHg (mean ± 95% confidence interval) standing, 18.8 ± 1.3 mmHg supine, 18.5 ± 1.7 mmHg in AGEC, and 17.5 ± 1.5 mmHg in AG2G. Postures showed a main effect [F(3,48) = 11.0, P < 0.0005], with standing significantly lower than supine ( P = 0.0009), AGEC ( P = 0.002), and AG2G (0.036). Supine, AGEC, and AG2G were not statistically different. HR and MAP were lower in supine compared with all other postures ( P = 0.002 to P < 0.0005), but there were no differences between standing, AGEC, and AG2G. IOP in supine and standing was consistent with previous studies, but contrary to our hypothesis, remained elevated in both AG conditions. Cardiovascular parameters and hydrostatic gradients determine IOP, which remain unchanged compared with standing. These results suggest additional influence on IOP from previously unconsidered factors. NEW & NOTEWORTHY This is the first study, to the authors’ knowledge, to measure intraocular pressure in short-radius centrifuge artificial gravity (AG), which has been proposed as a countermeasure to the spaceflight-associated neuro-ocular syndrome (SANS). If the etiology of SANS is related to intraocular pressure, these results have implications for whether or not short-radius AG can be used to prevent ocular changes relevant to it. Our results indicate this proposed countermeasure merits further investigation.
The Bohr/Haldane effect: a model-based uncovering of the full extent of its impact on O2delivery to and CO2removal from tissues
Authors: Malte Hans , Lykkeboe Gunnar 
Published: May 2018

For a century, the influence of the Bohr effect on the utilization of blood-borne oxygen has been deemed secondary to its influence on the uptake of carbon dioxide by the blood. Here, we show that the opposite is the case. Using a simple two-ligand, two-state formulation, we modeled the simultaneous oxygen and proton binding to hemoglobin, as well as the resulting acid-base changes of the surrounding solution. Blocking of the Bohr effect in this model system results in a dramatic increase in the oxygen affinity, as expressed by the oxygen partial pressure at half saturation, the P50. It also becomes clear that the P50and the Bohr factor (a measure of the size of the Bohr effect) are not independent but directly related. Thus, everything else being equal, varying the number of Bohr groups from 0 to 8 per tetramer results in an increase in the Bohr factor from 0 to −0.9 and an increase in P50from 6 to 46 mmHg at a constant Pco2of 40 mmHg. Therefore, changes in hemoglobin structure that lead to changes in the Bohr factor will inevitably also change hemoglobin oxygen affinity.NEW & NOTEWORTHY Using a mathematical model, we show that the Bohr effect has a more profound effect on gas exchange than is evident when comparing oxygen equilibrium curves measured in the laboratory at different constant values of Pco2or pH. Protons preloaded on the Bohr groups, as well as the protons taken up during oxygen unloading, dramatically decrease oxygen affinity of the physiological oxygen equilibrium curve. Therefore, the Bohr effect is instrumental in setting the oxygen affinity.
Antileukemic Efficacy of BET Inhibitor in a Preclinical Mouse Model of MLL-AF4+ Infant ALL
Authors: Bardini Michela , Trentin Luca , Rizzo Francesca , Vieri Margherita , Savino Angela M. , Garrido Castro Patricia , Fazio Grazia , Van Roon Eddy H.J. , Kerstjens Mark , Smithers Nicholas , Prinjha Rab K. , Te Kronnie Geertruy , Basso Giuseppe , Stam Ronald W. , Pieters Rob , Biondi Andrea , Cazzaniga Gianni 
Published: May 2018

Abstract
MLL-rearranged acute lymphoblastic leukemia (ALL) occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with MLL-rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy. Herein, we have investigated the effects of bromodomain and extra-terminal (BET) function abrogation in a preclinical mouse model of MLL-AF4+ infant ALL using the BET inhibitor I-BET151. We reported that I-BET151 is able to arrest the growth of MLL-AF4+ leukemic cells in vitro, by blocking cell division and rapidly inducing apoptosis. Treatment with I-BET151 in vivo impairs the leukemic engraftment of patient-derived primary samples and lower the disease burden in mice. I-BET151 affects the transcriptional profile of MLL-rearranged ALL through the deregulation of BRD4, HOXA7/HOXA9, and RUNX1 gene networks. Moreover, I-BET151 treatment sensitizes glucocorticoid-resistant MLL-rearranged cells to prednisolone in vitro and is more efficient when used in combination with HDAC inhibitors, both in vitro and in vivo. Given the aggressiveness of the disease, the failure of the current therapies and the lack of an ultimate cure, this study paves the way for the use of BET inhibitors to treat MLL-rearranged infant ALL for future clinical applications. Mol Cancer Ther; 17(8); 1705–16. ©2018 AACR.
Dicer in Macrophages Prevents Atherosclerosis by Promoting Mitochondrial Oxidative Metabolism
Authors: Wei Yuanyuan , Corbalán-Campos Judit , Gurung Rashmi , Natarelli Lucia , Zhu Mengyu , Exner Nicole , Erhard Florian , Greulich Franziska , Geißler Claudia , Uhlenhaut N. Henriette , Zimmer Ralf , Schober Andreas 
Published: May 2018

Background:
Alternative macrophage activation, which relies on mitochondrial oxidative metabolism, plays a central role in the resolution of inflammation and prevents atherosclerosis. Moreover, macrophages handle large amounts of cholesterol and triglycerides derived from the engulfed modified lipoproteins during atherosclerosis. Although several microRNAs regulate macrophage polarization, the role of the microRNA-generating enzyme Dicer in macrophage activation during atherosclerosis is unknown.

Methods:

To evaluate the role of Dicer in atherosclerosis,
Apoe
−/−
mice with or without macrophage-specific
Dicer
deletion were fed a high-fat diet for 12 weeks. Anti-argonaute 2 RNA immunoprecipitation chip and RNA deep sequencing combined with microRNA functional screening were performed in the
Dicer
wild-type and knockout bone marrow–derived macrophages to identify the individual microRNAs and the mRNA targets mediating the phenotypic effects of Dicer. The role of the identified individual microRNA and its target in atherosclerosis was determined by tail vein injection of the target site blockers in atherosclerotic
Apoe
−/−
mice.

Results:

We show that
Dicer
deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited whereas lipid-filled foam cell formation was exacerbated in
Dicer
-deficient macrophages as a result of impaired mitochondrial fatty acid oxidative metabolism. Rescue of microRNA (miR)-10a, let-7b, and miR-195a expression restored the oxidative metabolism in alternatively activated
Dicer
-deficient macrophages. Suppression of ligand-dependent nuclear receptor corepressor by miR-10a promoted fatty acid oxidation, which mediated the lipolytic and anti-inflammatory effect of Dicer. miR-10a expression was negatively correlated to the progression of atherosclerosis in humans. Blocking the interaction between ligand-dependent nuclear receptor corepressor and miR-10a by target site blockers aggravated atherosclerosis development in mice.

Conclusions:
Dicer plays an atheroprotective role by coordinately regulating the inflammatory response and lipid metabolism in macrophages through enhancing fatty acid–fueled mitochondrial respiration, suggesting that promoting Dicer/miR-10a–dependent metabolic reprogramming in macrophages has potential therapeutic implications to prevent atherosclerosis.