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Abstract Background Hibernation (torpor) is a strategy to survive extreme environmental conditions, associated with a significant decrease in metabolism and body temperature. The inducibility by the environment of torpor for facultative hibernators designates epigenetic mechanisms as likely candidates for regulation. Therefore, we set out to unravel epigenetics in the liver of a facultative hibernator, Syrian hamster (Mesocricetus auratus), sampled at different phases during hibernation, by assessing the expression of epigenetic writer and eraser enzymes, histone acetylation dynamics, and DNA methylation levels. Results Expression of epigenetic writers/erasers confirmed previously reported results obtained in obligatory hibernators, but might point to a mechanism specific for facultative hibernators, e.g., differential expression of histone acetyltransferases (HATs; KAT6A, KAT6B, KAT7, and KAT13D/CLOCK). These findings were in accordance with observed changes in histone H3 and H4 acetylation changes. Overall histone deacetylase (HDAC) activity was highest in torpor. No differences were detected in DNA methylation throughout all phases. Conclusion Our study thus points to histone acetylation as an important player in facultative hamster hibernation, which may underlie the orchestration of gene expression changes throughout hibernation.

Human induced Pluripotent Stem Cells (hiPSCs) represent an invaluable source of primary cells to investigate development, establish cell and disease models, provide material for regenerative medicine and allow more physiological high-content screenings. Here, we generated three healthy hiPSC control lines - IPi001-A/B/C - from primary amniotic fluid cells (AFCs), an infrequently used source of cells, which can be readily obtained from amniocentesis for the prenatal diagnosis of numerous genetic disorders. These AFCs were reprogrammed by non-integrative viral transduction. The resulting hiPSCs displayed normal karyotype and expressed classic pluripotency hallmarks.

Immune checkpoint inhibitors and immune-related biomarkers are increasingly investigated in rectal cancer (RC). We retrospectively analysed PD-L1 expression in diagnostic biopsy and resection samples from RC patients treated at our centre between 2000 and 2020. PD-L1 immunostaining (22C3 clone) was evaluated according to tumour proportion (TPS), immune cell (ICS), and the combined positive score (CPS). Eighty-three patients were included. At diagnosis, PD-L1 expression ≥1%/≥5% was observed in 15.4%/0%, 80.7%/37.4%, and 69.2%/25.6% of patients based on TPS, ICS, and CPS, respectively. At surgery, the respective figures were 4.6%/1.5%, 60.2%/32.5%, and 50.7%/26.2%. Using the 1% cut-off and regardless of the scoring system, PD-L1 was less expressed in surgery than biopsy samples (p ≤ 0.04). In paired specimens, PD-L1-ICS reduction was especially observed following neoadjuvant long-course (chemo)radiotherapy (p = 0.03). PD-L1-ICS of ≥5% in surgical samples (HR: 0.17; p = 0.02), and a biopsy-to-surgery increase in PD-L1-ICS (HR: 0.19; p = 0.04) was predictive for longer disease-free survival, while the PD-L1-ICS of either ≥1% (HR 0.28; p = 0.04) or ≥5% (HR 0.19; p = 0.03) in surgical samples and the biopsy-to-surgery increase in PD-L1-ICS (HR: 0.20; p = 0.04) were associated with better overall survival. Our study suggests that PD-L1 expression in RC is largely reflective of immune cell infiltration, and its presence/increase in surgical samples predicts better outcomes.

Abstract Background DNA hypermethylation is an epigenetic feature that modulates gene expression, and its deregulation is observed in cancer. Previously, we identified a neural-related DNA hypermethylation fingerprint in colon cancer, where most of the top hypermethylated and downregulated genes have known functions in the nervous system. To evaluate the presence of this signature and its relevance to carcinogenesis in general, we considered 16 solid cancer types available in The Cancer Genome Atlas (TCGA). Results All tested cancers showed significant enrichment for neural-related genes amongst hypermethylated genes. This signature was already present in two premalignant tissue types and could not be explained by potential confounders such as bivalency status or tumor purity. Further characterization of the neural-related DNA hypermethylation signature in colon cancer showed particular enrichment for genes that are overexpressed during neural differentiation. Lastly, an analysis of upstream regulators identified RE1-Silencing Transcription factor (REST) as a potential mediator of this DNA methylation signature. Conclusion Our study confirms the presence of a neural-related DNA hypermethylation fingerprint in various cancers, of genes linked to neural differentiation, and points to REST as a possible regulator of this mechanism. We propose that this fingerprint indicates an involvement of DNA hypermethylation in the preservation of neural stemness in cancer cells.

BackgroundBrine shrimp Artemia have an unequalled ability to endure extreme salinity and complete anoxia. This study aims to elucidate its strategies to cope with these stressors.Results and discussionHere, we present the genome of an inbred A. franciscana Kellogg, 1906. We identified 21,828 genes of which, under high salinity, 674 genes and under anoxia, 900 genes were differentially expressed (42%, respectively 30% were annotated). Under high salinity, relevant stress genes and pathways included several Heat Shock Protein and Leaf Embryogenesis Abundant genes, as well as the trehalose metabolism. In addition, based on differential gene expression analysis, it can be hypothesized that a high oxidative stress response and endocytosis/exocytosis are potential salt management strategies, in addition to the expression of major facilitator superfamily genes responsible for transmembrane ion transport. Under anoxia, genes involved in mitochondrial function, mTOR signalling and autophagy were differentially expressed. Both high salt and anoxia enhanced degradation of erroneous proteins and protein chaperoning. Compared with other branchiopod genomes, Artemia had 0.03% contracted and 6% expanded orthogroups, in which 14% of the genes were differentially expressed under high salinity or anoxia. One phospholipase D gene family, shown to be important in plant stress response, was uniquely present in both extremophiles Artemia and the tardigrade Hypsibius dujardini, yet not differentially expressed under the described experimental conditions.ConclusionsA relatively complete genome of Artemia was assembled, annotated and analysed, facilitating research on its extremophile features, and providing a reference sequence for crustacean research.

Valincidenten treden frequent op en hebben vaak heel wat nadelige effecten, zo is er niet alleen de kans op een verwonding maar vaak zijn er ook psychologische - en financiële gevolgen die aanzienlijk kunnen zijn. Als men deze problematiek grondig wil aanpakken, zal men zowel aandacht dienen te besteden aan een reductie van het valrisico als van het fractuurrisico. De afdeling Gerontologie en Geriatrie van de Katholieke Universiteit Leuven is op beide domeinen actief betrokken en dit zowel onderzoeksmatig als op het maatschappelijke vlak.

The non-premixed filtered tabulated chemistry for large eddy simulations employs numerical filtering to resolve a thin flame front on practical LES numerical grids. The flame structure is modified to be coherent with the domain discretization. The first turbulent combustion application of the non-premixed filtered tabulated chemistry approach is presented. A keen comparison of the flamelet filtering transformation in the premixed and non-premixed regimes is carried out. Three distinctive features are outlined: the flame thickness variation, the filtered manifold transformation, and the model activation dependence on the chosen diffusion flamelet configuration for a non-premixed filtered approach. The model performance is assessed on two real turbulent flame configurations, Sandia flames D and E, employing a three-dimensional tabulation strategy, where the numerical grid is coupled with the model by the third parameter, i.e., the computational cell size. The repercussions of the above cited aspects are carefully assessed. The results demonstrate that the formalism coupling with an SGS modeling function can adequately describe wrinkled flame front effects. The predictions for both the major stable species and the minor ones accurately correspond with the underlying physics. It turns out that there is a substantial variation of the filter effect as a function of the strain rate of the flame and the considered species. The varying filter sensitivity along the manifold influences the response of the model correction terms and the retrieved variables. The non-premixed FTACLES formalism possibilities and conditions for the model’s utilization and optimal performance are clearly stated, to confirm the idea that SGS closure in diffusive combustion can be derived based on filtering arguments, and not only based on statistical approaches.

In many reacting flow systems, the thermo-chemical state-space is known or assumed to evolve close to a low-dimensional manifold (LDM). Various approaches are available to obtain those manifolds and subsequently express the original high-dimensional space with fewer parameterizing variables. Principal component analysis (PCA) is one of the dimensionality reduction methods that can be used to obtain LDMs. PCA does not make prior assumptions about the parameterizing variables and retrieves them empirically from training data. In this paper, we show that PCA applied in local clusters of data (local PCA) is capable of detecting physically meaningful parameterization of the thermo-chemical state-space. We first demonstrate that utilizing three common combustion models of varying complexity: the Burke–Schumann model, the chemical equilibrium model, and the homogeneous reactor. Parameterization of these models is known a priori which allows for benchmarking with the local PCA approach. We further extend the application of local PCA to a more challenging case of a turbulent non-premixed n-heptane/air jet flame for which the parameterization is no longer obvious. Our results suggest that meaningful parameterization can be obtained also for more complex datasets. We show that local PCA finds variables that can be linked to local stoichiometry, reaction progress and soot formation processes. We shed the light on how data-driven techniques, such as local PCA, can be enhanced by using the available knowledge of the system.

Abstract Background Brine shrimp Artemia have an unequalled ability to endure extreme salinity and complete anoxia. This study aims to elucidate its strategies to cope with these stressors. Results and discussion Here, we present the genome of an inbred A. franciscana Kellogg, 1906. We identified 21,828 genes of which, under high salinity, 674 genes and under anoxia, 900 genes were differentially expressed (42%, respectively 30% were annotated). Under high salinity, relevant stress genes and pathways included several Heat Shock Protein and Leaf Embryogenesis Abundant genes, as well as the trehalose metabolism. In addition, based on differential gene expression analysis, it can be hypothesized that a high oxidative stress response and endocytosis/exocytosis are potential salt management strategies, in addition to the expression of major facilitator superfamily genes responsible for transmembrane ion transport. Under anoxia, genes involved in mitochondrial function, mTOR signalling and autophagy were differentially expressed. Both high salt and anoxia enhanced degradation of erroneous proteins and protein chaperoning. Compared with other branchiopod genomes, Artemia had 0.03% contracted and 6% expanded orthogroups, in which 14% of the genes were differentially expressed under high salinity or anoxia. One phospholipase D gene family, shown to be important in plant stress response, was uniquely present in both extremophiles Artemia and the tardigrade Hypsibius dujardini, yet not differentially expressed under the described experimental conditions. Conclusions A relatively complete genome of Artemia was assembled, annotated and analysed, facilitating research on its extremophile features, and providing a reference sequence for crustacean research.

Abstract Despite the large-scale dissemination of mindfulness-based interventions, debates persist about the very nature of mindfulness. To date, one of the dominant views is the five-facet approach, which suggests that mindfulness includes five facets (i.e., Observing, Describing, Nonjudging, Nonreactivity, and Acting with Awareness). However, uncertainty remains regarding the potential interplay between these facets. In this study, we investigated the five-facet model via network analysis in an unselected sample (n = 1704). We used two distinct computational network approaches: a Gaussian graphical model (i.e., undirected) and a directed acyclic graph, with each model determining the relations between the facets and their relative importance in the network. Both computational approaches pointed to the facet denoting Acting with Awareness as playing an especially potent role in the network system. Altogether, our findings offer novel data-driven clues for the field's larger quest to ascertain the very foundations of mindfulness.

In her prose romance The Countesse of Montgomery’s Urania (1621), Lady Mary Wroth inserted many more ekphraseis compared to the number found in her uncle Sir Philip Sidney’s prose romance The Countess of Pembroke’s Arcadia (1593). Wroth’s ekphraseis are more numerous, yet they are often incomplete and repetitive, as if the author was more interested in the reflexive potential of the ekphrasis, foregrounding the « mise en abyme » of the act of writing, rather than in the detailed description of a « living picture » inherited from Antiquity. Both the multiplication and the incompleteness of ekphraseis in Urania testify to Mary Wroth’s use and transformation of this rhetorical device recurrent in the pastoral tradition in order to emphasize the act of writing which was essential for her as an author trying to assert her legitimacy.

The flame front filtering is a well-known strategy in turbulent premixed combustion. An extension of this approach for the non-premixed combustion context has been proposed by means of directly filtering counterflow diffusion flamelets. Promising results were obtained for the non-premixed filtered tabulated chemistry formalism on 1-D and 2-D unresolved counterflow flame configurations. The present paper demonstrates the soundness of this approach on a 3-D real laminar non-premixed coflow flame. The model results are compared against the direct filtering of the fully resolved laminar diffusion flame showing that the formalism adequately describes the underlying physics. The study reveals the importance of the one-dimensional counterflow flamelet hypothesis, so that the model activation under this condition is ensured by means of a flame sensor. The consistent coupling between the model and the flame sensor adequately retrieves the flame lift-off and satisfactorily predicts the profile extension due to the filtering process.

The objective of this work is to build a Digital Twin of a semi-industrial furnace using Gaussian Process Regression coupled with dimensionality reduction via Proper Orthogonal Decomposition. The Digital Twin is capable of integrating different sources of information, such as temperature, chemiluminescence intensity and species concentration at the outlet. The parameters selected to build the design space are the equivalence ratio and the benzene concentration in the fuel stream. The fuel consists of a H2/CH4/CO blend, doped with a progressive addition of C6H6. It is an H2-rich fuel mixture, representing a surrogate of a more complex Coke Oven Gas industrial mixture. The experimental measurements include the flame temperature distribution, measured on a 6×8 grid using an air-cooled suction pyrometer, spatially resolved chemiluminescence measurements of OH* and CH*, and the species concentration (i.e., NO, NO2, CO, H2O, CO2, O2) measured in the exhaust gases. The GPR-based Digital Twin approach has already been successfully applied on numerical datasets coming from CFD simulations. In this work, we demonstrate that the same approach can be applied on heterogeneous datasets, obtained from experimental measurements.

The notion of climate change anxiety has gained traction in the last years. Clayton & Karazsia (2020) recently developed the 22-item Climate Change Anxiety Scale (CAS), which assesses climate change anxiety via a four-factor structure. Yet other research has cast doubts on the very structure of the CAS by calling either for a shorter (i.e. 13 items) two-factor structure or for a shorter single-factor structure (i.e. 13 items). So far, these three different models have not yet been compared in one study. Moreover, uncertainty remains regarding the associations between the CAS and other psychological constructs, especially anxiety and depression. This project was designed to overcome these limitations. In a first preregistered study ('n' = 305), we translated the scale into French and tested, via confirmatory factor analyses (CFA), whether the French version would better fit with a four-, two-, or single-factor structure, as implied by previous works. We also examined how the CAS factors related to depression, anxiety, and environmental identity. In a second preregistered study, we aimed at replicating our comparison between the three CFA models in a larger sample ('n' = 905). Both studies pointed to a 13-item version of the scale with a two-factor structure as the best fitting model, with one factor reflecting cognitive and emotional features of climate change anxiety and the other reflecting the related functional impairments. Each factor exhibited a positive association with depression and environmental identity but not with general anxiety. We discuss how this two-factor structure impacts the conceptualization of climate change anxiety.

Introduction: Major Depression Disorder (MDD) and Generalized Anxiety Disorder (GAD) often co-occur, but the neurocognitive mechanisms of this co-occurrence remain unknown. Prominent views have pointed to attentional processes as potent mechanisms at play in MDD and GAD, respectively. Yet uncertainty remains regarding the very nature of attentional impairments in patients with co-occurring MDD and GAD. Methods: Inspired by contemporary models of attentional networks, we compared the three main attentional networks, namely the orienting, alerting, and executive networks of the Attention Network Task's model, in four groups of patients with, respectively, co-occurring DSM-5 MDD and GAD (n = 30), DSM-5 MDD only (n = 30), DSM-5 GAD only (n = 30), or free from any DSM-5 diagnosis (n = 30). To capture the multivariate nature of our data, we examined between-group differences in the attentional networks through a multivariate analysis of variance. Results: Patients with co-occurring MDD and GAD exhibited more severe impairments in the executive control network than those with only one of the disorders. Although patients with MDD or GAD solely did not differ in terms of attentional impairments, both groups showed significantly more impairments in the executive control network than those free from any DSM-5 diagnosis (all Bonferonni-corrected post-hoc ps < 0.05). Conclusions: Our findings align with a longstanding staging approach to comorbidity whereby, via synergistic effects, co-occurring disorders produce more damages than the sum of each disorder. Here, for the first time, we extended this approach to the executive network of attention in the context of the co-occurrence between MDD and GAD.

Abstract Background The observed rate of termination of pregnancy (TOP) for Turner syndrome varies worldwide and even within countries. In this vignette study we quantified agreement among ten multidisciplinary prenatal diagnosis centers in Paris. Methods We submitted online three cases of Turner syndrome (increased nuchal translucency, normal ultrasound, aortic coarctation) to fetal medicine experts: one obstetrician, one pediatrician and one geneticist in each of the ten Parisian centers. Each case was presented in the form of a progressive clinical history with conditional links dependent upon responses. The background to each case was provided, along with the medical history of the parents and the counseling they got from medical staff. The experts indicated online whether or not they would accept the parents’ request for TOP. We assessed the percentage of agreement for acceptance or refusal of TOP. We also used a multilevel logistic regression model to evaluate differences among obstetrician-gynecologists, pediatricians and cytogeneticists. Results Overall agreement among the experts to accept or refuse TOP was, respectively, 25 and 28%. The percentage of disagreement was 47%. The percentage of agreement to accept TOP was 33, 8 and 33% for obstetrician-gynecologists, pediatricians and cytogeneticists, respectively. The respective percentages of agreement to refuse TOP were 19, 47 and 26%. Conclusion Our results show the lack of consensus with regard to decisions related to termination of pregnancy for Turner Syndrome. This lack of consensus in turn underscores the importance of multidisciplinary management of these pregnancies in specialized fetal medicine centers.

The combination of Proper Orthogonal Decomposition (POD) with Kriging has been shown to be a reliable choice for the development of Reduced-Order Models (ROMs) for the prediction of combustion data at unexplored operating conditions. In this study, POD is combined with Polynomial Chaos Expansion (PCE), with a combination of PCE and Kriging (PC-Kriging) and with Artificial Neural Networks (ANN) for the development of a ROM that can predict 2D combustion data for unexplored operating conditions. The choice of Non-negative Matrix Factorization (NMF) instead of POD as compression method is also investigated. This method is chosen because it can intrinsically guarantee the non-violation of physical constraints such as positivity of chemical species mass fractions, although POD's data reconstruction errors are lower. The performances of the POD and NMF in combination with the proposed supervised methods are compared, with prediction normalized root mean squared errors (NRMSE) being less than 10% for spatial fields of temperature, CH4 and O2 for all approaches.

Background: Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Understanding the impact of DNA methylation in cSCC may provide avenues for new therapeutic strategies. Methods: We used reduced-representation bisulfite sequencing for DNA methylation analysis of murine cSCC. Differential methylation was assessed at the CpG level using limma. Next, we compared with human cSCC Infinium HumanMethylation BeadArray data. Genes were considered to be of major relevance when they featured at least one significantly differentially methylated CpGs (RRBS) / probes (Infinium) with at least a 30% difference between tumour vs. control in both a murine gene and its human orthologue. The human EPIC Infinium data were used to distinguish two cSCC subtypes, stem-cell-like and keratinocyte-like tumours. Findings: We found increased average methylation in mouse cSCC (by 12.8%, p = 0.0011) as well as in stem-cell like (by 3.1%, p=0.002), but not keratinocyte-like (0.2%, p = 0.98), human cSCC. Comparison of differentially methylated genes revealed striking similarities between human and mouse cSCC. Locus specific methylation changes in mouse cSCC often occurred in regions of potential regulatory function, including enhancers and promoters. A key differentially methylated region was located in a potential enhancer of the tumour suppressor gene Filip1l and its expression was reduced in mouse tumours. Moreover, the FILIP1L locus showed hypermethylation in human cSCC and lower expression in human cSCC cell lines. Interpretation: Deregulation of DNA methylation is an important feature of murine and human cSCC that likely contributes to silencing of tumour suppressor genes, as shown for Filip1l. Funding: British Skin Foundation, Cancer Research UK

Song learning in zebra finches (Taeniopygia guttata) is a prototypical example of a complex learned behavior, yet knowledge of the underlying molecular processes is limited. Therefore, we characterized transcriptomic (RNA-sequencing) and epigenomic (RRBS, reduced representation bisulfite sequencing; immunofluorescence) dynamics in matched zebra finch telencephalon samples of both sexes from 1 day post hatching (1 dph) to adulthood, spanning the critical period for song learning (20 and 65 dph). We identified extensive transcriptional neurodevelopmental changes during postnatal telencephalon development. DNA methylation was very low, yet increased over time, particularly in song control nuclei. Only a small fraction of the massive differential expression in the developing zebra finch telencephalon could be explained by differential CpG and CpH DNA methylation. However, a strong association between DNA methylation and age-dependent gene expression was found for various transcription factors (i.e., OTX2, AR, and FOS) involved in neurodevelopment. Incomplete dosage compensation, independent of DNA methylation, was found to be largely responsible for sexually dimorphic gene expression, with dosage compensation increasing throughout life. In conclusion, our results indicate that DNA methylation regulates neurodevelopmental gene expression dynamics through steering transcription factor activity, but does not explain sexually dimorphic gene expression patterns in zebra finch telencephalon.