0198: Global and regional echocardiographic strain to assess early phase of hypertrophic cardiomyopathy due to sarcomeric mutations

ObjectiveHypertrophic cardiomyopathy (HCM) is a genetic disease with delayed cardiac expression. Our objective was to characterize global and regional LV myocardial strain by two-dimensional imaging in sarcomeric HCM families and hypothesized that early systolic dysfunction, before hyper-trophic stage, may be diagnosed by this technique.Methods and resultsWe analyzed 81 adults: HCM patients with LV hypertrophy (LVH+, n=38), mutation carriers without LV hypertrophy (LVH/G+, n=20), and normal control subjects (n=23). We calculated global longitudinal strain (GLS), regional peak longitudinal strain and the Echo/TDI score (combination of 3 parameters about remodeling and pulse TDI). Age, sex ratio and body surface area were not significantly different between groups. Maximal 2D wall thickness of left ventricle was 10.1±1.6mm in LVH-/G+and not different from controls (9.9±1.2mm). We observed that LV GLS was not different in LVH-/G+as compared to controls (–21.6%±3.2 vs –23.5%±3.3) but was reduced in HCM patients (–15.3%±4.5) although a normal ejection fraction. Interestingly, regional peak longitudinal strain was similar in LVH-/G+and controls except antero-septo-basal segment strain that was decreased in LVH-/G+as compared to controls (–15.6%±7.2 vs –20.0%±3.9, p=0.025). A cut-off of –16% for abnormal strain of antero-septo-basal segment identified LVH-/G+subjects with a sensitivity of 47% and a specificity of 90%. The Echo/TDI score was different in LVH-/G+as compared to controls (p=0.0008) and sensitivity of previous defined cut-off was 83% for identification of LVH-/G+. All LVH-/G+subjects with abnormal regional strain, except one, had abnormal Echo/TDI score.ConclusionWe observed that regional longitudinal strain, but not global strain, was significantly reduced at early stage of HCM. This tool may be useful for clinical evaluation of relatives in daily practice, but does not provide significant additional information as compared to the Echo/TDI score

Effects of radionuclide contamination on leaf litter decomposition in the Chernobyl exclusion zone

The effects of radioactive contamination on ecosystem processes such as litter decomposition remain largely un- known. Because radionuclides accumulated in soil and plant biomass can be harmful for organisms, the function- ing of ecosystems may be altered by radioactive contamination. Here, we tested the hypothesis that decomposition is impaired by increasing levels of radioactivity in the environment by exposing uncontaminated leaf litter from silver birch and black alder at (i) eleven distant forest sites differing in ambient radiation levels (0.22–15 μGy h−1) and (ii) along a short distance gradient of radioactive contamination (1.2–29 μGy h−1) within a single forest in the Chernobyl exclusion zone. In addition to measuring ambient external dose rates, we estimat- ed the average total dose rates (ATDRs) absorbed by decomposers for an accurate estimate of dose-induced eco- logical consequences of radioactive pollution. Taking into account potential confounding factors (soil pH, moisture, texture, and organic carbon content), the results from the eleven distant forest sites, and from the single forest, showed increased litter mass loss with increasing ATDRs from 0.3 to 150 μGy h−1. This unexpected result may be due to (i) overcompensation of decomposer organisms exposed to radionuclides leading to a higher decomposer abundance (hormetic effect), and/or (ii) from preferred feeding by decomposers on the un- contaminated leaf litter used for our experiment compared to locally produced, contaminated leaf litter. Our data indicate that radio-contamination of forest ecosystems over more than two decades does not necessarily have detrimental effects on organic matter decay. However, further studies are needed to unravel the underlying mechanisms of the results reported here, in order to draw firmer conclusions on how radio-contamination affects decomposition and associated ecosystem processes

Erratum: Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders (The American Journal of Human Genetics (2020) 106(3) (356–370), (S0002929720300197), (10.1016/j.ajhg.2020.01.019))

(The American Journal of Human Genetics 106, 356–370; March 5, 2020) In the version of this paper originally published, the underlying cause for Hunter McAlpine syndrome was incorrectly described in Table 1. The relevant description has been changed to read “Chr5q35-qter duplication involving NSD1” in the updated Table 1 reflected here. The authors apologize for this error

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called episignatures ). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

Purpose Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. Methods We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. Results We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. Conclusion Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping

Why and How Did Narrative Fictions Evolve? Fictions as Entertainment Technologies

International audienceNarrative fictions have surely become the single most widespread source of entertainment in the world. In their free time, humans read novels and comics, watch movies and TV series, and play video games: they consume stories that they know to be false. Such behaviors are expanding at lightning speed in modern societies. Yet, the question of the origin of fictions has been an evolutionary puzzle for decades: Are fictions biological adaptations, or the by-products of cognitive mechanisms that evolved for another purpose? The absence of any consensus in cognitive science has made it difficult to explain how narrative fictions evolve culturally. We argue that current conflicting hypotheses are partly wrong, and partly right: narrative fictions are by-products of the human mind, because they obviously co-opt some pre-existing cognitive preferences and mechanisms, such as our interest for social information, and our abilities to do mindreading and to imagine counterfactuals. But humans reap some fitness benefits from producing and consuming such appealing cultural items, making fictions adaptive . To reconcile these two views, we put forward the hypothesis that narrative fictions are best seen as entertainment technologies that is, as items crafted by some people for the proximate goal to grab the attention of other people, and with the ultimate goal to fulfill other evolutionary-relevant functions that become easier once other people’s attention is caught. This hypothesis explains why fictions are filled with exaggerated and entertaining stimuli, why they fit so well the changing preferences of the audience they target, and why producers constantly make their fictions more attractive as time goes by, in a cumulative manner

Why Imaginary Worlds? The psychological foundations and cultural evolution of fictions with imaginary worlds

International audienceWhy do fiction makers spend much time and money inventing imaginary worlds? Why are fictions with such imaginary worlds so successful? Current views in cultural evolution do not explain this massive cultural phenomenon. We argue that imaginary worlds tap into exploratory preferences which have evolved in a wide range of species to propel individuals toward new environments. After reviewing research on exploratory behaviors and preferences, we argue that this hypothesis explains the way imaginary worlds evolved culturally, their recent striking success, their shape and their distribution across time and populations

Imaginary worlds through the evolutionary lens: Ultimate functions, proximate mechanisms, cultural distribution

International audienceWe received several commentaries both challenging and supporting our hypothesis. We thank the commentators for their thoughtful contributions, bringing together alternative hypotheses, complementary explanations, and appropriate corrections to our model. Here, we explain further our hypothesis, using more explicitly the framework of evolutionary social sciences. We first explain what we believe is the ultimate function of fiction in general (i.e., entertainment) and how this hypothesis differs from other evolutionary hypotheses put forward by several commentators. We then turn to the proximate features that make imaginary worlds entertaining and, therefore, culturally successful. We finally explore how these insights may explain the distribution of imaginary worlds across time, space, age, and social classes

When instrumental inference hides behind seemingly arbitrary conventions

We review recent evidence that game rules, rules of etiquette, and supernatural beliefs, that the authors see as “ritualistic” conventions, are in fact shaped by instrumental inference. In line with such examples, we contend that cultural practices that may appear, from the outside, to be devoid of instrumental utility, could in fact be selectively acquired and preserved because of their perceived utility