Targeted methods for epigenetic age predictions in mice

Age-associated DNA methylation reflects aspect of biological aging-therefore epigenetic clocks for mice can elucidate how the aging process in this model organism is affected by specific treatments or genetic background. Initially, age-predictors for mice were trained for genome-wide DNA methylation profiles and we have recently described a targeted assay based on pyrosequencing of DNA methylation at only three age-associated genomic regions. Here, we established alternative approaches using droplet digital PCR (ddPCR) and barcoded bisulfite amplicon sequencing (BBA-seq). At individual CG dinucleotides (CpGs) the correlation of DNA methylation with chronological age was slightly higher for pyrosequencing and ddPCR as compared to BBA-seq. On the other hand, BBA-seq revealed that neighboring CpGs tend to be stochastically modified at murine age-associated regions. Furthermore, the binary sequel of methylated and non-methylated CpGs in individual reads can be used for single-read predictions, which may reflect heterogeneity in epigenetic aging. In comparison to C57BL/6 mice the single-read age-predictions using BBA-seq were also accelerated in the shorter-lived DBA/2 mice, and in C57BL/6 mice with a lifespan quantitative trait locus of DBA/2 mice. Taken together, we describe alternative targeted methods for epigenetic age predictions that provide new perspectives for aging-intervention studies in mice

Culture expansion of CAR T cells results in aberrant DNA methylation that is associated with adverse clinical outcome

Chimeric antigen receptor (CAR) T cells provide new perspectives for treatment of hematological malignancies. Manufacturing of these cellular products includes culture expansion procedures, which may affect cellular integrity and therapeutic outcome. In this study, we investigated culture-associated epigenetic changes in CAR T cells and found continuous gain of DNAm, particularly within genes that are relevant for T cell function. Hypermethylation in many genes, such as TCF7, RUNX1, and TOX, was reflected by transcriptional downregulation. 332 CG dinucleotides (CpGs) showed an almost linear gain in methylation with cell culture time, albeit neighboring CpGs were not coherently regulated on the same DNA strands. An epigenetic signature based on 14 of these culture-associated CpGs predicted cell culture time across various culture conditions. Notably, even in CAR T cell products of similar culture time higher DNAm levels at these CpGs were associated with significantly reduced long-term survival post transfusion. Our data demonstrate that cell culture expansion of CAR T cells evokes DNA hypermethylation at specific sites in the genome and the signature may also reflect loss of potential in CAR T cell products. Hence, reduced cultivation periods are beneficial to avoid dysfunctional methylation programs that seem to be associated with worse therapeutic outcome.This research was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation − 363055819/GRK2415; WA1706/11–1; WA 1706/12–2 within CRU344/417911533; WA1706/14–1; and SFB 1506/1); and the ForTra gGmbH für Forschungstransfer der Else Kröner-Fresenius-Stiftung. Furthermore, we thank CERCA Programme / Generalitat de Catalunya for institutional support. The research leading to these results has received funding from MCIN/AEI/10.13039/501100011033 and European Commission “Next GenerationEU”/PRTR (PDC2022–133476-I00); Ministry of Research and Universities of the Catalan Government (2021 PROD 00020); and the Cellex Foundation.Peer ReviewedPostprint (published version

Cross-cultural neuropsychological assessment in Europe:Position statement of the European Consortium on Cross-Cultural Neuropsychology (ECCroN)

Objective: Over the past decades European societies have become increasingly diverse. This diversity in culture, education, and language significantly impacts neuropsychological assessment. Although several initiatives are under way to overcome these barriers – e.g. newly developed and validated test batteries – there is a need for more collaboration in the development and implementation of neuropsychological tests, such as in the domains of social cognition and language. Method: To address these gaps in cross-cultural neuropsychological assessment in Europe, the European Consortium on Cross-Cultural Neuropsychology (ECCroN) was established in 2019. Results: ECCroN recommends taking a broad range of variables into account, such as linguistic factors, literacy, education, migration history, acculturation and other cultural factors. We advocate against race-based norms as a solution to the challenging interpretation of group differences on neuropsychological tests, and instead support the development, validation, and standardization of more widely applicable/cross-culturally applicable tests that take into account interindividual variability. Last, ECCroN advocates for an improvement in the clinical training of neuropsychologists in culturally sensitive neuropsychological assessment, and the development and implementation of guidelines for interpreter-mediated neuropsychological assessment in diverse populations in Europe. Conclusions: ECCroN may impact research and clinical practice by contributing to existing theoretical frameworks and by improving the assessment of diverse individuals across Europe through collaborations on test development, collection of normative data, cross-cultural clinical training, and interpreter-mediated assessment

The Vehicle, Fall 1993

Table of Contents 7/10ths SynthesisPeter F. Essigpage 5 Aug 1992 (My Small Catechism)Jon Montgomerypage 6 Chaos Is-J. Dylan McNeillpage 7 UntouchedTraci Williamspage 8 The JustificationJohn C. Carminepage 8 LincolnJon Montgomerypage 9 Untitled (Photo)Nicole Niemanpage 10 Park PoemJohn Brillhartpage 11 SmokeJulia Ann Canhampage 12 Warming the BenchAnn Moutraypage 12 Cereal KillerJay Harnackpage 13 The Dutiful SonsTom McGrathpage 14 UntitledCatherine DeGraafpage 17 7-up bottleWalt Howardpage 17 BreedDan Trutterpage 18 An Argument Against LoveTony Martinezpage 19 UntitledT. Scott Laniganpage 19 Glassblowers BallStephanie Franzenpage 20 Portrait of a Young GirlJohn C. Carminepage 20 Untitled (artwork)Dan Trutterpage 21 Death of a FriendLizabeth Kulkapage 22 Submission BluesMartin Paul Brittpage 23 To the Fourteen Year Old SuicideScott Langenpage 23 The Flabby PilgrimTom McGrathpage 24 The Fall of ImmortalityBrian Wheelerpage 25 Merging with AirThom Schnarrepage 26 UntitledCatherine DeGraafpage 27 Tree FishSandra Beauchamppage 28 Country SlumberJ. Dylan McNeillpage 29 Untitled (artwork)Dan Trutterpage 33 Authors\u27 Pagepage 34https://thekeep.eiu.edu/vehicle/1060/thumbnail.jp

Zum Zusammenhang von Geschlechterungleichheiten in Bildung, Beruf und Karriere : ein Ausblick

Ziel der folgenden Ausführungen im abschliessenden Teil dieses Sammelbands zur Entwicklung und Genese von geschlechtsspezifischen Bildungsungleichheiten ist es, den Blick zu öffnen in Richtung Berufsleben. Wie sind die verbesserten Bildungsmöglichkeiten von Frauen zu interpretieren? Ist es in den letzten Jahrzehnten gelungen, eines der grundlegendsten gesellschaftlichen Ungleichheitsverhältnisse zu beseitigen? Oder beginnt sich dieses sogar zu verkehren in eine gesellschaftliche Benachteiligung der Männer? Wir gehen bei unseren Überlegungen von der These aus, dass ein Abbau von Benachteiligungen der Frauen im Bildungssystem für sich genommen noch wenig aussagekräftig ist, wenn wir uns mit der klassischen soziologischen Frage der Persistenz bzw. des Wandels von gesellschaftlichen Ungleichheiten befassen wollen. Erst wenn die ganze Verknüpfung von Bildung und gesellschaftlicher Ungleichheit in den Blick genommen wird und sich dabei zeigt, dass Frauen ihre Bildungsgewinne auch in entsprechende Chancen im Beschäftigungssystem umsetzen können, sind ihre verbesserten Bildungschancen ein Gewinn für die Individuen und ein Fortschritt für die Gesellschaft – und erst dann könnten mögliche Bildungsvorteile von Frauen, wie sie in den vorliegenden Aufsätzen z.T. diagnostiziert werden, gar als neue gesellschaftliche Benachteiligungen von Männern skandalisiert werden

The radio source count at 93.2 GHz from observations of 9C sources using AMI and CARMA

We present results from follow-up observations of a sample of 80 radio sources, originally detected as part of the 15.2-GHz Ninth Cambridge (9C) survey. The observations were carried out, close to simultaneously, at two frequencies: 15.7 GHz, using the Arcminute Microkelvin Imager (AMI) Large Array, and 93.2 GHz, using the Combined Array for Research in Millimeter-wave Astronomy (CARMA). There is currently little direct information on the 90-GHz-band source count for S ≲ 1 Jy. However, we have used the measured 15.7-to-93.2-GHz spectral-index distribution and 9C source count to predict the differential source count at 93.2 GHz as 26 ± 4(S/Jy)^(−2.15) Jy^(−1) sr^(−1); our projection is estimated to be most accurate for 10 ≲ S ≲ 100 mJy. Our estimated differential count is more than twice the 90-GHz prediction made by Waldram et al.; we believe that this discrepancy is because the measured 43-GHz flux densities used in making their prediction were too low. Similarly, our prediction is significantly higher than that of Sadler et al. at 95 GHz. Since our spectral-index distribution is similar to the 20-to-95-GHz distribution measured by Sadler et al. and used in making their prediction, we believe that the difference is almost entirely attributable to the dissimilarity in the lower frequency counts used in making the estimates

DNA methylation changes during long-term in vitro cell culture are caused by epigenetic drift

Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes. We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated during long-term culture of mesenchymal stem cells (MSCs) and other cell types. Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development and without association to oligoclonal subpopulations. Circularized chromatin conformation capture (4C) revealed reproducible changes in nuclear organization between early and late passages, while there was no enriched interaction with other genomic regions that also harbor culture-associated DNAm changes. Chromatin immunoprecipitation of CTCF did not show significant differences during long-term culture of MSCs, however culture-associated hypermethylation was enriched at CTCF binding sites and hypomethylated CpGs were devoid of CTCF. Taken together, our results support the notion that DNAm changes during culture-expansion are not directly regulated by a targeted mechanism but rather resemble epigenetic drift

Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease

Background: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. Objectives: To assess effects of increasing PUFA intake on cardiovascular disease (CVD) and all-cause mortality in adults. Search method: We searched CENTRAL, MEDLINE and Embase to April 2017 and ClinicalTrials.com and World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. Selection criteria: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without CVD that assessed effects over ≥12 months. We included full-text, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, CVD mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. Data collection and analysis: Two authors independently screened titles/abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included studies for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. Main result: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Twelve included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA. Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 3.4% vs 3.3% in primary prevention, 11.7% vs 11.5% in secondary prevention, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 24 trials in 19290 participants), but probably reduces risk of CVD events from 5.8% to 4.9% in primary prevention, 23.3% to 20.8% in secondary prevention (RR 0.89, 95% CI 0.79 to 1.01, 20 trials in 17,073 participants), both moderate quality evidence. Increasing PUFA may reduce risk of CHD events from 13.4% to 7.1% primary prevention, 14.3% to 13.7% secondary prevention (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants), CHD death (5.2% to 4.4% primary prevention, 6.8% to 6.1% secondary prevention, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) and may slightly reduce stroke risk (2.1% to 1.5% primary prevention, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, I2 31%, 16 trials, 15,107 participants) all low quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality. Event outcomes were all downgraded for indirectness, as most events occurred in men in westernised countries. Increasing PUFA intake reduces total cholesterol (MD -0.12 mmol/L, 95% CI -0.23 to -0.02, I2 79%, 8072 participants, 26 trials) and probably decreases triglycerides (TG, MD -0.12 mmol/L, 95% CI -0.20 to -0.04, I2 50%, 3905 participants, 20 trials), but has little or no effect on HDL (MD -0.01 mmol/L, 95% CI -0.02 to 0.01, I2 0%, 4674 participants, 18 trials) and LDL (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, I2 44%, 3362 participants, 15 trials). Increasing PUFA probably causes slight weight gain (MD 0.76 kg, 95% CI 0.34 to 1.19, I2 59%, 7100 participants, 12 trials). Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. Authors' conclusions: Increasing PUFA intake probably reduces risk of CVD events, may reduce risk of CHD events and CHD mortality,and may slightly reduce stroke risk, but has little or no effect on all-cause or CVD mortality. The mechanism may be via lipid reduction, but increasing PUFA probably slightly increases weight

Notes for genera: basal clades of Fungi (including Aphelidiomycota, Basidiobolomycota, Blastocladiomycota, Calcarisporiellomycota, Caulochytriomycota, Chytridiomycota, Entomophthoromycota, Glomeromycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota, Mucoromycota, Neocallimastigomycota, Olpidiomycota, Rozellomycota and Zoopagomycota)

Compared to the higher fungi (Dikarya), taxonomic and evolutionary studies on the basal clades of fungi are fewer in number. Thus, the generic boundaries and higher ranks in the basal clades of fungi are poorly known. Recent DNA based taxonomic studies have provided reliable and accurate information. It is therefore necessary to compile all available information since basal clades genera lack updated checklists or outlines. Recently, Tedersoo et al. (MycoKeys 13:1--20, 2016) accepted Aphelidiomycota and Rozellomycota in Fungal clade. Thus, we regard both these phyla as members in Kingdom Fungi. We accept 16 phyla in basal clades viz. Aphelidiomycota, Basidiobolomycota, Blastocladiomycota, Calcarisporiellomycota, Caulochytriomycota, Chytridiomycota, Entomophthoromycota, Glomeromycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota, Mucoromycota, Neocallimastigomycota, Olpidiomycota, Rozellomycota and Zoopagomycota. Thus, 611 genera in 153 families, 43 orders and 18 classes are provided with details of classification, synonyms, life modes, distribution, recent literature and genomic data. Moreover, Catenariaceae Couch is proposed to be conserved, Cladochytriales Mozl.-Standr. is emended and the family Nephridiophagaceae is introduced