Exonic enhancers (EEs) occupy an under-appreciated niche in gene regulation. By integrating transcription factor binding, chromatin accessibility, and high-throughput enhancer-reporter assays, we demonstrate that many protein-coding exons possess enhancer activity across species. These candidate EEs (cEEs) exhibit characteristic epigenomic signatures, form long-range interactions with gene promoters, and can be altered by both nonsynonymous and synonymous variants. CRISPR-mediated inactivation demonstrated the involvement of cEEs in the cis-regulation of host and distal gene expression. Through large-scale cancer genome analyses, we reveal that cEE mutations correlate with dysregulated target-gene expression and clinical outcomes, highlighting their potential relevance in disease. Evolutionary comparisons show that cEEs exhibit both strong sequence constraint and lineage-specific plasticity, suggesting that they serve ancient regulatory functions while also contributing to species divergence. Our findings expand the landscape of functional elements by establishing cEEs as a component of gene regulation, while revealing how coding regions can simultaneously fulfil both protein-coding and cis-regulatory roles.

This cross-sectional study aimed to establish whether a difference exists between the mandibular bone density and the mandibular angle values of adult bruxer and non-bruxer patients, based on a CBCT analysis. CBCT scans of bruxer and non-bruxer patients were analysed with two software packages, 3D Slicer® and Romexis®. Bone density in the alveolar bone below and immediately adjacent to the apices of teeth 31, 33, 34, 41, 43, 44, and the mesial apices of teeth 36 and 46, was recorded in Hounsfield units with 3D Slicer®. The mandibular angle between the corpus and ramus tangent lines was measured using Romexis® software. 113 CBCT scans were included in the study of alveolar bone density, of which 78 were used to study mandibular angle values. A statistically significant difference (p < 0.05) was noted between the density values of the two groups, with higher values in bruxers than in non-bruxers. Mandibular angle values were significantly lower in bruxers (p < 0.05). This cross-sectional study based on CBCT imaging showed certain morphological differences between the mandibles of bruxers and those of non-bruxers. Further studies are needed to supplement this preliminary research, in particular prospective studies.

This cross-sectional study aimed to investigate morphological changes in the human mandible in archaeological collections associated with the presence of bony exostoses at the mandibular angle, which is described in the literature as related to specific behaviours of the masticatory apparatus like parafunctional activities. The skeletal sample investigated comprised adult individuals from two archaeological series. Sixteen measurements of the mandible were selected to evaluate anatomic variation in the two populations. Mandibles from both series were pooled for statistical analysis into two groups according to the number of exostoses at the mandibular angles: group 1 (number of exostoses ≤1) and group 2 (number of exostoses ≥ 2). Measurements could be made on eighty mandibles. A statistically significant difference was demonstrated between group 1 and group 2 for the following parameters: distance between mandibular angles, bicondylar width, ramus height, left condyle length, and right and left coronoid process height. For each of these parameters, values were higher in group 2 than in group 1. This study presents an original methodology for studying anatomical variations of the mandible in the context of parafunctional activity, highlighting certain mandibular modifications. The impact of parafunctional behaviours such as bruxism on the mandible therefore has many anatomical expressions. The considerable variability of results found in the literature shows that more studies are needed to reach a consensus on the impact of parafunctional activities on the mandible.

Understanding how genetic variation impacts transcription factor (TF) binding remains a major challenge, limiting our ability to model disease-associated variants. Here, we used a highly controlled system of F1 crosses with extensive genetic diversity to profile allele-specific binding of four TFs at several time points during Drosophila embryogenesis. Using a combined haplotype test, we identified 9%-18% of TF-bound regions impacted by genetic variation even for essential regulators. By expanding WASP (a tool for allele-specific read mapping) to examine indels, we increased detection of allelically imbalanced peaks by 30%-50%. This fine-grained "mutagenesis" can reconstruct functionalized binding motifs for all factors. To prioritize causal variants, we trained a convolutional neural network (Basenji) to accurately predict binding from DNA sequence. The model can also predict measured allelic imbalance for strong effect variants, providing a mechanistic interpretation for how the variant impacts binding. This reveals unexpected relationships between TFs, including potential cooperative pairs, and mechanisms of tissue-specific recruitment of the ubiquitous factor CTCF.

This repository contains the data required to run the example notebooks and to reproduce the figures from the paper : MUFFIN : A suite of tools for the analysis of functional sequencing data Pierre de Langen, Benoit Ballester bioRxiv 2023.12.11.570597; doi: https://doi.org/10.1101/2023.12.11.570597 Source code is located here : https://github.com/pdelangen/Muffin 10k_pbmc_gene/ contains the data for 10k pbmc dataset in standard 10x sparse count table format. genome_annot/ contains gencode v38 and chromosomes for the human (used for gene set enrichment analyses) GO_files/ contains gene set information retrieved from the g:ProfileR website. immune_chip/ contains the data required to re-run the ChIP-seq analyses, it will require to also launch the dl_data.smk to retrieve the data from ENCODE. tcga_atac/ contains the sample-genomic region ATAC tag count table, as well as the sample metadata and a gene set file of cancer hallmark genes. muffin_apptainer.img is a singularity/apptainer image file which contains the muffin package.

Understanding how genetic variation impacts transcription factor (TF) binding remains a major challenge, limiting our ability to model disease-associated variants. Here, we used a highly controlled system of F1 crosses with extensive genetic diversity to profile allele-specific binding of four TFs at several embryonic time-points, using Drosophila as a model. Using a combined haplotype test, we identified 9-18% of TF bound regions impacted by genetic variation. By expanding WASP (a tool for allele-specific read mapping) to examine INDELs, we increased detection of allele imbalanced (AI) peaks by 30-50%. This fine-grained mutagenesis could reconstruct functionalized binding motifs of all factors. To prioritise potential causal variants, we trained a convolutional neural network (Basenji) to predict TF binding from DNA sequence. The model could accurately predict experimental AI for strong effect variants, providing a mechanistic interpretation for how genetic variation impacted TF binding. This revealed unexpected relationships between TFs, including potential cooperative pairs, and mechanisms of tissue specific recruitment of the ubiquitous factor CTCF. ### Competing Interest Statement The authors have declared no competing interest.

There is growing evidence that a wide range of human diseases and physiological traits are influenced by genetic variation of cis-regulatory elements. We and others have shown that a subset of promoter elements, termed Epromoters, also function as enhancer regulators of distal genes. This opens a paradigm in the study of regulatory variants, as single nucleotide polymorphisms (SNPs) within Epromoters might influence the expression of several (distal) genes at the same time, which could disentangle the identification of disease-associated genes. Here, we built a comprehensive resource of human Epromoters using newly generated and publicly available high-throughput reporter assays. We showed that Epromoters display intrinsic and epigenetic features that distinguish them from typical promoters. By integrating Genome-Wide Association Studies (GWAS), expression Quantitative Trait Loci (eQTLs) and 3D chromatin interactions, we found that regulatory variants at Epromoters are concurrently associated with more disease and physiological traits, as compared with typical promoters. To dissect the regulatory impact of Epromoter variants, we evaluated their impact on regulatory activity by analyzing allelic-specific high-throughput reporter assays and provided reliable examples of pleiotropic Epromoters. In summary, our study represents a comprehensive resource of regulatory variants supporting the pleiotropic role of Epromoters.

The large diversity of functional genomic assays allows for the characterization of non-coding and coding events at the tissue level or at a single-cell resolution. However, this diversity also leads to protocol differences, widely varying sequencing depths, substantial disparities in sample sizes, and number of features. In this work, we have built a Python package, MUFFIN, which offers a wide variety of tools suitable for a broad range of genomic assays and brings many tools that were missing from the Python ecosystem. First, MUFFIN has specialized tools for the exploration of the non-coding regions of genomes, such as a function to identify consensus peaks in peak-called assays, as well as linking genomic regions to genes and performing Gene Set Enrichment Analyses. MUFFIN also possesses a robust and flexible count table processing pipeline, comprising normalization, count transformation, dimensionality reduction, Differential Expression, and clustering. Our tools were tested on three widely different scRNA-seq, ChIP-seq and ATAC-seq datasets. MUFFIN integrates with the popular Scanpy ecosystem and is available on Conda and at https://github.com/pdelangen/Muffin.

INTRODUCTION Teaching caries lesion management with operative care requires tooth models with highly realistic anatomical detail and caries lesions that can be assessed using ICDAS. This study aimed to develop and evaluate a new 3D-printed teeth model for ICDAS assessment and caries removal for pre-clinical hands-on education. METHODS Printable tooth with different layers for enamel, dentin and carious lesions was designed and tested by 31 dental students. They were asked to visually and radiologically assess the ICDAS severity of the simulated carious lesions, establish the therapeutic strategy according to CariesCare 4D, and perform a qualitative assessment of the models based on five-point Likert scale items. RESULTS Concerning carious lesions, the texture was realistic, and the shade was adequate for 94% and 97% of the participants. Ninety per cent of the participants found the model adequate to perform an ICDAS visual assessment. Seventy-four per cent of the students found the hardness adequate. Concerning the difference in shade and the noticeable hardness difference between enamel and dentin, participants have mixed agreement with a proportion of 61% and 55%, respectively. All the participants agreed these 3D-printed models provide a good caries simulation, are suitable for hands-on operative dentistry courses, and that learning outcomes better than the standard model. CONCLUSION The present work shows that rapid prototyping paves the way for customized educational models capable of supporting operative but also preoperative skills. 3D printing opens up new opportunities by reducing the gap between pre-clinical training and clinical reality in caries management, which can positively impact the quality of patient care.

This Zenodo record refers to the "input data" used in the manuscript titled "Characterising intergenic transcription at RNA polymerase II binding sites in normal and cancer tissues" by de Langen et al. This Zenodo record allows to replicate the results presented in the manuscript, please refer to the instructions available on Github at https://github.com/benoitballester/Pol2Atlas. The results presented in the manuscript can be accessed at https://zenodo.org/record/8091826. In short : Data "in" : this record Data "out" : https://zenodo.org/record/8091826 Github Code : https://github.com/benoitballester/Pol2Atlas# uncompress the gz files $ cat repro_data.gz.part* | gunzip -c > repro_data.gz

Objectives This scoping review aimed to assess the current state of knowledge regarding the relationship between bruxism and changes in density or volume of mandibular bone, based on medical imaging. Methods Literature review was conducted following the PRISMA-ScR protocol. PubMed, Web of Science and Cochrane library databases were searched for peer-reviewed articles by two blinded reviewers. Studies based on the evaluation of mandibular bone density and/or bone volume with imaging examination in adult patients were examined. The selected articles were summarized in PICOS tables and assessed for methodological quality. Results Nine articles were included, according to the inclusion criteria. They showed that bruxer patients had more bony exostoses of the mandibular angle, smaller condyles, and morphological changes for cancellous and cortical mandibular bone compared to non-bruxer patients. Conclusion Bruxism seems to induce morphological and anatomical changes in the different regions of the mandibular bone (condyles, mandibular angle, mandible body). Given the heterogeneity of the included studies, these results should be interpreted with caution. Further studies are needed to support these results, in particular via the analysis of three-dimensional imaging to overcome the limitations of panoramic radiograph.

Chagas disease is a parasitical disease caused by Trypanosoma cruzi which affects ∼7 million people worldwide. Per year, ∼10 000 people die from this pathology. Indeed, ∼30% of humans develop severe chronic forms, including cardiac, digestive or neurological disorders, for which there is still no treatment. In order to facilitate research on Chagas disease, a manual curation of all papers corresponding to 'Chagas disease' referenced on PubMed has been performed. All deregulated molecules in hosts (all mammals, humans, mice or others) following T. cruzi infection were retrieved and included in a database, named ChagasDB. A website has been developed to make this database accessible to all. In this article, we detail the construction of this database, its contents and how to use it. Database URL https://chagasdb.tagc.univ-amu.fr.

This study aimed to establish a difference in mandibular bone density between bruxer and non-bruxer patients, based on panoramic radiographs. Panoramic radiographs of bruxer and non-bruxer patients were analyzed with ImageJ®. Several radiological determinants were studied on the patients' panoramic radiographs: gray values of cancellous bone and cortical bone, and bony exostoses at the mandibular angle. Thirty-seven bruxers and forty-seven non-bruxers were included in the study. A statistically significant difference (p < 0.05) was noted in the cancellous to cortical bone ratios of bruxers and non-bruxers: the density of cancellous bone was greater in bruxers than in non-bruxers. The number of bony exostoses at the mandibular angle was significantly higher in bruxers (p < 0.05). This study obtained radiological determinants of bruxism from panoramic radiographs. Further studies are needed to supplement this preliminary approach, especially via the analysis of three-dimensional imaging to overcome the limitations of panoramic radiography.

Intergenic transcription in normal and cancerous tissues is pervasive but incompletely understood. To investigate this, we constructed an atlas of over 180,000 consensus RNA polymerase II (RNAPII)-bound intergenic regions from 900 RNAPII chromatin immunoprecipitation sequencing (ChIP-seq) experiments in normal and cancer samples. Through unsupervised analysis, we identified 51 RNAPII consensus clusters, many of which mapped to specific biotypes and revealed tissue-specific regulatory signatures. We developed a meta-clustering methodology to integrate our RNAPII atlas with active transcription across 28,797 RNA sequencing (RNA-seq) samples from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Encyclopedia of DNA Elements (ENCODE). This analysis revealed strong tissue- and disease-specific interconnections between RNAPII occupancy and transcriptional activity. We demonstrate that intergenic transcription at RNAPII-bound regions is a novel per-cancer and pan-cancer biomarker. This biomarker displays genomic and clinically relevant characteristics, distinguishing cancer subtypes and linking to overall survival. Our results demonstrate the effectiveness of coherent data integration to uncover intergenic transcriptional activity in normal and cancer tissues.

Intergenic transcription in normal and cancerous tissue is pervasive and incompletely understood. To investigate this activity at a global level, we constructed an atlas of over 180,000 consensus RNA Polymerase II (RNAP2) bound intergenic regions from more than 900 RNAP2 ChIP-seq experiments across normal and cancer samples. Using unsupervised analysis, we identified 51 RNAP2 consensus clusters, many of which map to specific biotypes and identify tissue-specific regulatory signatures. We developed a meta-clustering methodology to integrate our RNAP2 atlas with active transcription across 28,797 RNA-seq samples from TCGA, GTEx and ENCODE, which revealed strong tissue- and disease-specific interconnections between RNAP2 occupancy and transcription. We demonstrate that intergenic transcription at RNAP2 bound regions are novel per-cancer and pan-cancer biomarkers showing genomic and clinically relevant characteristics including the ability to differentiate cancer subtypes and are associated with overall survival. Our results demonstrate the effectiveness of coherent data integration to uncover and characterise intergenic transcriptional activity in both normal and cancer tissues.

This repository contains the first part of the JASPAR 2022 LOLA databases used by the JASPAR TFBS enrichment tool. For each organism, we provide the LOLA databases for all JASPAR 2022 TFBS sets as compressed directories containing a set of .RDS R objects. Databases are organised by genome assembly. Due to file sizes, we had to split the repository into two different parts. Part 2 of the repository containing the databases for human can be found here.

Dental caries management requires individualized follow-up and prophylaxis based on patients' caries risk (PCR). In large pre-doctoral clinics, the use of institutional quality measures (QMs) is essential to control the quality of patient follow-up and to evaluate the need for improvement measures. The aim of this retrospective study was to evaluate the suitability of reusing student activity data for the development of QMs of caries risk. Two approaches for predicting PCR using student activity data were evaluated and compared. The first approach used the procedure codes recommended by the Dental Quality Alliance and the second used these same codes along with three educational codes. The sensitivity, specificity, overall accuracy of the two approaches were evaluated. A Receiver Operating Characteristic (ROC) curve analysis was carried out, and the areas under the ROC curve of the two approaches were compared using Delong's test. A two-tailed P value ≤0.05 was considered statistically significant. While the two approaches were able to correctly predict PCR, the approach using both procedure and educational codes showed better predictive performance. The reuse of student activity data is an easy and robust method for the development of QMs of caries risk that can help improve monitoring and quality of patient care.

ReMap (https://remap.univ-amu.fr) aims to provide manually curated, high-quality catalogs of regulatory regions resulting from a large-scale integrative analysis of DNA-binding experiments in Human, Mouse, Fly and Arabidopsis thaliana for hundreds of transcription factors and regulators. In this 2022 update, we have uniformly processed >11 000 DNA-binding sequencing datasets from public sources across four species. The updated Human regulatory atlas includes 8103 datasets covering a total of 1210 transcriptional regulators (TRs) with a catalog of 182 million (M) peaks, while the updated Arabidopsis atlas reaches 4.8M peaks, 423 TRs across 694 datasets. Also, this ReMap release is enriched by two new regulatory catalogs for Mus musculus and Drosophila melanogaster. First, the Mouse regulatory catalog consists of 123M peaks across 648 TRs as a result of the integration and validation of 5503 ChIP-seq datasets. Second, the Drosophila melanogaster catalog contains 16.6M peaks across 550 TRs from the integration of 1205 datasets. The four regulatory catalogs are browsable through track hubs at UCSC, Ensembl and NCBI genome browsers. Finally, ReMap 2022 comes with a new Cis Regulatory Module identification method, improved quality controls, faster search results, and better user experience with an interactive tour and video tutorials on browsing and filtering ReMap catalogs.

Background Over the past 50 years, dental informatics has developed significantly in the field of health information systems. Accordingly, several studies have been conducted on standardized clinical coding systems, data capture, and clinical data reuse in dentistry. Methods Based on the definition of health information systems, the literature search was divided into three specific sub-searches: “standardized clinical coding systems,” “data capture,” and “reuse of routine patient care data.” PubMed and Web of Science were searched for peer-reviewed articles. The review was conducted following the PRISMA-ScR protocol. Results A total of 44 articles were identified for inclusion in the review. Of these, 15 were related to “standardized clinical coding systems,” 15 to “data capture,” and 14 to “reuse of routine patient care data.” Articles related to standardized clinical coding systems focused on the design and/or development of proposed systems, on their evaluation and validation, on their adoption in academic settings, and on user perception. Articles related to data capture addressed the issue of data completeness, evaluated user interfaces and workflow integration, and proposed technical solutions. Finally, articles related to reuse of routine patient care data focused on clinical decision support systems centered on patient care, institutional or population-based health monitoring support systems, and clinical research. Conclusions While the development of health information systems, and especially standardized clinical coding systems, has led to significant progress in research and quality measures, most reviewed articles were published in the US. Clinical decision support systems that reuse EDR data have been little studied. Likewise, few studies have examined the working environment of dental practitioners or the pedagogical value of using health information systems in dentistry.