Publications by authors named "A Grafen"

54 Publications

Recurrence of atrial fibrillation after pulmonary vein isolation in dependence of arterial stiffness.

Neth Heart J 2021 Nov 24. Epub 2021 Nov 24.

First Department of Medicine-Cardiology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Arterial stiffness (AS) has emerged as a strong predictor of cardiovascular (CV) diseases. Although increased AS has been described as a predictor of atrial fibrillation (AF), its role as a risk marker for AF recurrence has not yet been elucidated.

Methods: Patients with AF who underwent pulmonary vein isolation (PVI) were included in this study. Presence of AS was evaluated by measuring aortic distensibility (AD) of the descending aorta by transoesophageal echocardiography.

Results: In total, 151 patients (mean ± standard deviation (SD) age 71.9 ± 9.8 years) were enrolled and followed for a median duration of 21 months (interquartile range 15.0-31.0). During follow-up, AF recurred in 94 (62.3%) patients. AF recurrence was seen more frequently in patients with permanent AF (27% vs 46%, p = 0.03) and in those who had undergone prior PVI (9% vs 23%, p = 0.02). AD was significantly reduced in patients with AF recurrence (mean ± SD 2.6 ± 2.3 vs 1.5 ± 0.7 × 10 mm Hg, p < 0.0001), as well as left atrial volume index (LAVI) (mean ± SD 29 ± 12 vs 44 ± 15 ml/m, p < 0.0001). Multivariable analysis revealed LAVI (odds ratio (OR) 2.9, 95% confidence interval (CI) 1.2-3.4) and AS (OR 3.6, 95% CI 2.8-4.1) as independent risk factors of AF recurrence.

Conclusion: Increased AS and left atrial size were independent predictors of AF recurrence after PVI. AD as surrogate marker of AS seemed to reflect the overall CV risk. In addition, AD was significantly correlated with left atrial size, which suggests that increased AS leads to atrial remodelling and thus to AF recurrence.

Trial Registration: German registry for clinical studies (DRKS), DRKS00019007.
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http://dx.doi.org/10.1007/s12471-021-01644-wDOI Listing
November 2021

A multifunctional mouse model to study the role of Samd3.

Eur J Immunol 2021 Oct 9. Epub 2021 Oct 9.

Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, Wurzburg, Germany.

The capacity to develop immunological memory is a hallmark of the adaptive immune system. To investigate the role of Samd3 for cellular immune responses and memory development, we generated a conditional knock-out mouse including a fluorescent reporter and a huDTR cassette for conditional depletion of Samd3-expressing cells. Samd3 expression was observed in NK cells and CD8 T cells, which are known for their specific function against intracellular pathogens like viruses. After acute viral infections, Samd3 expression was enriched within memory precursor cells and the frequency of Samd3-expressing cells increased during the progression into the memory phase. Similarly, during chronic viral infections, Samd3 expression was predominantly detected within precursors of exhausted CD8 T cells that are critical for viral control. At the functional level however, Samd3-deficient CD8 T cells were not compromised in the context of acute infection with Vaccinia virus or chronic infection with Lymphocytic choriomeningitis virus. Taken together, we describe a novel multifunctional mouse model to study the role of Samd3 and Samd3-expressing cells. We found that Samd3 is specifically expressed in NK cells, memory CD8 T cells, and precursor exhausted T cells during viral infections, while the molecular function of this enigmatic gene remains further unresolved.
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http://dx.doi.org/10.1002/eji.202149469DOI Listing
October 2021

Extending the range of additivity in using inclusive fitness.

Ecol Evol 2021 Mar 7;11(5):1970-1983. Epub 2021 Feb 7.

Department of Zoology Oxford University Oxford UK.

Inclusive fitness is a concept widely utilized by social biologists as the quantity organisms appear designed to maximize. However, inclusive fitness theory has long been criticized on the (uncontested) grounds that other quantities, such as offspring number, predict gene frequency changes accurately in a wider range of mathematical models. Here, we articulate a set of modeling assumptions that extend the range of scenarios in which inclusive fitness can be applied. We reanalyze recent formal analyses that searched for, but did not find, inclusive fitness maximization. We show (a) that previous models have not used Hamilton's definition of inclusive fitness, (b) a reinterpretation of Hamilton's definition that makes it usable in this context, and (c) that under the assumption of probabilistic mixing of phenotypes, inclusive fitness is indeed maximized in these models. We also show how to understand mathematically, and at an individual level, the definition of inclusive fitness, in an explicit population genetic model in which exact additivity is not assumed. We hope that in articulating these modeling assumptions and providing formal support for inclusive fitness maximization, we help bridge the gap between empiricists and theoreticians, which in some ways has been widening, demonstrating to mathematicians why biologists are content to use inclusive fitness, and offering one way to utilize inclusive fitness in general models of social behavior.
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http://dx.doi.org/10.1002/ece3.6935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920790PMC
March 2021

A simple completion of Fisher's fundamental theorem of natural selection.

Authors:
Alan Grafen

Ecol Evol 2021 Jan 27;11(2):735-742. Epub 2020 Dec 27.

Zoology Department Oxford University Oxford UK.

Fisher's fundamental theorem of natural selection shows that the part of the rate of change of mean fitness that is due to natural selection equals the additive genetic variance in fitness. Fisher embedded this result in a model of total fitness, adding terms for deterioration of the environment and density dependence. Here, a quantitative genetic version of this neglected model is derived that relaxes its assumptions that the additive genetic variance in fitness and the rate of deterioration of the environment do not change over time, allows population size to vary, and includes an input of mutational variance. The resulting formula for total rate of change in mean fitness contains two terms more than Fisher's original, representing the effects of stabilizing selection, on the one hand, and of mutational variance, on the other, making clear for the first time that the fundamental theorem deals only with natural selection that is directional (as opposed to stabilizing) on the underlying traits. In this model, the total (rather than just the additive) genetic variance increases mean fitness. The unstructured population allows an explanation of Fisher's concept of fitness as simply birth rate minus mortality rate, and building up to the definition in structured populations.
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http://dx.doi.org/10.1002/ece3.6918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820154PMC
January 2021

BATF3 programs CD8 T cell memory.

Nat Immunol 2020 11 28;21(11):1397-1407. Epub 2020 Sep 28.

Würzburg Institute of Systems Immunology, Max-Planck Research Group, University of Würzburg, Würzburg, Germany.

Antiviral CD8 T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells, which in turn are critical for optimal priming of CD8 T cells. Here we show that BATF3 was expressed transiently within the first days after T cell priming and had long-lasting T cell-intrinsic effects. T cells that lacked Batf3 showed normal expansion and differentiation, yet succumbed to an aggravated contraction and had a diminished memory response. Vice versa, BATF3 overexpression in CD8 T cells promoted their survival and transition to memory. Mechanistically, BATF3 regulated T cell apoptosis and longevity via the proapoptotic factor BIM. By programing CD8 T cell survival and memory, BATF3 is a promising molecule to optimize adoptive T cell therapy in patients.
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http://dx.doi.org/10.1038/s41590-020-0786-2DOI Listing
November 2020
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