Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we showed interleukin-12 ...acting via the transcription factor STAT4 induced both
Il21 and
Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced the transcription factor T-bet. With ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed
Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh cell-like phenotype in the late phase of Th1 cell specification. Tfh-like cells were rapidly generated after
Toxoplasma gondii infection in mice, but T-bet constrained Tfh cell expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 cells share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh cell functionalities, promoting full Th1 cell differentiation.
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► STAT4 drives
Il21 and
Bcl6 genes to create a cell with Tfh and Th1 cell features ► IFN-γ and T-bet attenuates the Tfh cell-like phenotype at later stage of the specification ► The
Bcl6 locus remains accessible in fully polarized Th1 cells ► T-bet limits Tfh and germinal center B cell generation during
T. gondii infection
Blended learning combines online digital resources with traditional classroom activities and enables students to attain higher learning performance through well-defined interactive strategies ...involving online and traditional learning activities. Learning analytics is a conceptual framework and as a part of our Precision education used to analyze and predict students' performance and provide timely interventions based on student learning profiles. This study applied learning analytics and educational big data approaches for the early prediction of students' final academic performance in a blended Calculus course. Real data with 21 variables were collected from the proposed course, consisting of video-viewing behaviors, out-of-class practice behaviors, homework and quiz scores, and after-school tutoring. This study applied principal component regression to predict students' final academic performance. The experimental results show that students' final academic performance could be predicted when only one-third of the semester had elapsed. In addition, we identified seven critical factors that affect students' academic performance, consisting of four online factors and three traditional factors. The results showed that the blended data set combining online and traditional critical factors had the highest predictive performance.
We are proposing in this work a new model of ultraviolet (UV) damage for polymers and Polymer Matrix Composites (PMCs). Flat and sinusoidal polymer surfaces were numerically simulated for their UV ...damage as a function of UV intensity, surface topography, and exposure time. Experimentally determined UV degradation rates for a unidirectional glass/epoxy composite were used to predict numerically the local rates of material degradation on sinusoidal epoxy surfaces subjected to UV. This allowed us to show that UV damage on uneven polymer surfaces reduces their surface roughness making them planar and that the degradation rates are the largest at the tips of the local heights of the surfaces. This was subsequently verified experimentally by exposing neat epoxy specimens to UV in air at 80 °C for 1000 h and by precisely monitoring their surface topography as a function of time. It was found that the surface roughness of the epoxy was reduced by about 12.5% and that UV affected the local peaks on the surfaces of the specimens more than the valleys.
•Sinusoidal polymer surfaces were numerically simulated for UV damage.•UV intensity, surface topography, and exposure time were considered.•UV damage on polymer surfaces reduces their surface roughness.•This was subsequently verified experimentally.
Abstract
The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this ...heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesized to represent a measure of biological aging with a positive/negative residual signifying age acceleration (AA)/deceleration, respectively. The present study examines the associations of 4 epigenetic clocks—Horvath, Hannum, PhenoAge, GrimAge—with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA). HorvathAA and HannumAA were not predictive of health; PhenoAgeAA was associated with 4/9 outcomes (walking speed, frailty MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8/9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of walking speed, .polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.
Coronary artery calcium (CAC) is an established predictor of future major adverse atherosclerotic cardiovascular events in asymptomatic individuals. However, limited data exist as to how CAC compares ...with functional testing (FT) in estimating prognosis in symptomatic patients.
In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain (or dyspnea) and intermediate pretest probability for obstructive coronary artery disease were randomized to FT (exercise electrocardiography, nuclear stress, or stress echocardiography) or anatomic testing. We evaluated those who underwent CAC testing as part of the anatomic evaluation (n=4209) and compared that with results of FT (n=4602). We stratified CAC and FT results as normal or mildly, moderately, or severely abnormal (for CAC: 0, 1-99 Agatston score AS, 100-400 AS, and >400 AS, respectively; for FT: normal, mild=late positive treadmill, moderate=early positive treadmill or single-vessel ischemia, and severe=large ischemic region abnormality). The primary end point was all-cause death, myocardial infarction, or unstable angina hospitalization over a median follow-up of 26.1 months. Cox regression models were used to calculate hazard ratios (HRs) and C statistics to determine predictive and discriminatory values.
Overall, the distribution of normal or mildly, moderately, or severely abnormal test results was significantly different between FT and CAC (FT: normal, n=3588 78.0%; mild, n=432 9.4%; moderate, n=217 4.7%; severe, n=365 7.9%; CAC: normal, n=1457 34.6%; mild, n=1340 31.8%; moderate, n=772 18.3%; severe, n=640 15.2%;
<0.0001). Moderate and severe abnormalities in both arms robustly predicted events (moderate: CAC: HR, 3.14; 95% confidence interval, 1.81-5.44; and FT: HR, 2.65; 95% confidence interval, 1.46-4.83; severe: CAC: HR, 3.56; 95% confidence interval, 1.99-6.36; and FT: HR, 3.88; 95% confidence interval, 2.58-5.85). In the CAC arm, the majority of events (n=112 of 133, 84%) occurred in patients with any positive CAC test (score >0), whereas fewer than half of events occurred in patients with mildly, moderately, or severely abnormal FT (n=57 of 132, 43%;
<0.001). In contrast, any abnormality on FT was significantly more specific for predicting events (78.6% for FT versus 35.2% for CAC;
<0.001). Overall discriminatory ability in predicting the primary end point of mortality, nonfatal myocardial infarction, and unstable angina hospitalization was similar and fair for both CAC and FT (C statistic, 0.67 versus 0.64). Coronary computed tomographic angiography provided significantly better prognostic information compared with FT and CAC testing (C index, 0.72).
Among stable outpatients presenting with suspected coronary artery disease, most patients experiencing clinical events have measurable CAC at baseline, and fewer than half have any abnormalities on FT. However, an abnormal FT was more specific for cardiovascular events, leading to overall similarly modest discriminatory abilities of both tests.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01174550.
It was unknown whether plasma protein levels can be estimated based on DNA methylation (DNAm) levels, and if so, how the resulting surrogates can be consolidated into a powerful predictor of ...lifespan. We present here, seven DNAm-based estimators of plasma proteins including those of plasminogen activator inhibitor 1 (PAI-1) and growth differentiation factor 15. The resulting predictor of lifespan, DNAm GrimAge (in units of years), is a composite biomarker based on the seven DNAm surrogates and a DNAm-based estimator of smoking pack-years. Adjusting DNAm GrimAge for chronological age generated novel measure of epigenetic age acceleration,
.Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death (Cox regression P=2.0E-75), time-to-coronary heart disease (Cox P=6.2E-24), time-to-cancer (P= 1.3E-12), its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause (P=1.6E-12). AgeAccelGrim is strongly associated with a host of age-related conditions including comorbidity count (P=3.45E-17). Similarly, age-adjusted DNAm PAI-1 levels are associated with lifespan (P=5.4E-28), comorbidity count (P= 7.3E-56) and type 2 diabetes (P=2.0E-26). These DNAm-based biomarkers show the expected relationship with lifestyle factors including healthy diet and educational attainment.Overall, these epigenetic biomarkers are expected to find many applications including human anti-aging studies.
Summary
Background
The biological mechanisms of how prenatal smoke exposure leading to atopic disorders remain to be addressed. Whether prenatal smoke exposure affects DNA methylation leading to ...atopic disorders is not clear.
Objective
As most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure induces cord blood DNA methylation.
Methods
Methylation differences associated with smoke exposure were screened by Illumina Infinium 27K methylation arrays for 14 children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors was collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation‐dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen.
Results
Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p = 0.018). TSLP gene was further investigated in a larger sample of 150 children from the cohort who completed the follow‐up study. Methylation status of the TSLP 5′‐CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.17, 95% CI=1.63–6.19) and with AD (OR=2.32, 95% CI=1.06–5.11). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (r = −0.45, P = 0.001).
Conclusions & Clinical Relevance
The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation.
High-volume, hydraulic fracturing (HVHF) is widely applied for natural gas and oil production from shales, coals, or tight sandstone formations in the United States, Canada, and Australia, and is ...being widely considered by other countries with similar unconventional energy resources. Secure retention of fluids (natural gas, saline formation waters, oil, HVHF fluids) during and after well stimulation is important to prevent unintended environmental contamination, and release of greenhouse gases to the atmosphere. Here, we critically review state-of-the-art techniques and promising new approaches for identifying oil and gas production from unconventional reservoirs to resolve whether they are the source of fugitive methane and associated contaminants into shallow aquifers. We highlight future research needs and propose a phased program, from generic baseline to highly specific analyses, to inform HVHF and unconventional oil and gas production and impact assessment studies. These approaches may also be applied to broader subsurface exploration and development issues (e.g., groundwater resources), or new frontiers of low-carbon energy alternatives (e.g., subsurface H2 storage, nuclear waste isolation, geologic CO2 sequestration).
Noble gas radionuclides, including 81Kr (t1/2=229,000years), 85Kr (t1/2=10.8years), and 39Ar (t1/2=269years), possess nearly ideal chemical and physical properties for studies of earth and ...environmental processes. Recent advances in Atom Trap Trace Analysis (ATTA), a laser-based atom counting method, have enabled routine measurements of the radiokrypton isotopes, as well as the demonstration of the ability to measure 39Ar in environmental samples. Here we provide an overview of the ATTA technique, and a survey of recent progress made in several laboratories worldwide. We review the application of noble gas radionuclides in the geosciences and discuss how ATTA can help advance these fields, specifically: determination of groundwater residence times using 81Kr, 85Kr, and 39Ar; dating old glacial ice using 81Kr; and an 39Ar survey of the main water masses of the oceans, to study circulation pathways and estimate mean residence times. Other scientific questions involving a deeper circulation of fluids in the Earth's crust and mantle are also within the scope of future applications. We conclude that the geoscience community would greatly benefit from an ATTA facility dedicated to this field, with instrumentation for routine measurements, as well as for research on further development of ATTA methods.
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