MUFFIN: a suite of tools for the analysis of functional sequencing data.

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.

Evaluation of a new 3D-printed tooth model allowing preoperative ICDAS assessment and caries removal.

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.

Characterizing intergenic transcription at RNA polymerase II binding sites in normal and cancer tissues.

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.

Relationship between bruxism and mandibular bone modifications based on medical imaging: a scoping review.

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.

ChagasDB: 80 years of publicly available data on the molecular host response to Trypanosoma cruzi infection in a single database.

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.

Evaluation of mandibular bone density in bruxers: the value of panoramic radiographs.

OBJECTIVES: This study aimed to establish a difference in mandibular bone density between bruxer and non-bruxer patients, based on panoramic radiographs. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Suitability of Reusing Pre-Doctoral Student Activity Data from an Educational Information System for Quality Measures of Caries Risk.

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.

ECHO: An Information System for the Monitoring and Evaluation of Dental Student Activity in a Pre-Doctoral Clinic.

The main goal of dental education is to develop health professionals who will maintain and improve the oral health of patients. This requires the quantitative and qualitative assessment of dental student activity. The aim of this work is to describe the ECHO information system that was developed at Timone Hospital (France) for the monitoring and evaluation of dental student activity and to present the results of a qualitative evaluation of student perceptions of this system. According to the analysis of the UML model of care-related procedures and data, the pre-existing process of student evaluation was characterized by redundancy between administrative and educational data. ECHO was developed in PHP/MySQL and designed to centralize the two types of data in a unified computerized process. The qualitative evaluation of dental student perceptions of ECHO was performed using an anonymous online Google Form questionnaire. Among the respondents (102/254 students), 96% stated that ECHO is easy to use, 86% that it saves time, and 81% that it gives them a better overview of their activity. After several years of use, ECHO has solved many of the difficulties related to the use of internship paper booklets, while also providing a documentary database of the activities of our dental department. The student activity data stored in ECHO are directly accessible by faculty members and can be reused to facilitate departmental management and research and to improve patient follow-up.

JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net/) is an open-access database containing manually curated, non-redundant transcription factor (TF) binding profiles for TFs across six taxonomic groups. In this 9th release, we expanded the CORE collection with 341 new profiles (148 for plants, 101 for vertebrates, 85 for urochordates, and 7 for insects), which corresponds to a 19% expansion over the previous release. We added 298 new profiles to the Unvalidated collection when no orthogonal evidence was found in the literature. All the profiles were clustered to provide familial binding profiles for each taxonomic group. Moreover, we revised the structural classification of DNA binding domains to consider plant-specific TFs. This release introduces word clouds to represent the scientific knowledge associated with each TF. We updated the genome tracks of TFBSs predicted with JASPAR profiles in eight organisms; the human and mouse TFBS predictions can be visualized as native tracks in the UCSC Genome Browser. Finally, we provide a new tool to perform JASPAR TFBS enrichment analysis in user-provided genomic regions. All the data is accessible through the JASPAR website, its associated RESTful API, the R/Bioconductor data package, and a new Python package, pyJASPAR, that facilitates serverless access to the data.

ReMap 2022: a database of Human, Mouse, Drosophila and Arabidopsis regulatory regions from an integrative analysis of DNA-binding sequencing experiments.

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.

Current strategies for conservative endodontic access cavity preparation techniques-systematic review, meta-analysis, and decision-making protocol.

OBJECTIVES: To assess related studies and discuss the clinical implications of endodontic access cavity (AC) designs. MATERIALS AND METHODS: A systematic review of studies comparing the fracture resistance and/or endodontic outcomes between different AC designs was conducted in two electronic search databases (PubMed and Web of Science) following the PRISMA guidelines. Study selection, data extraction, and quality assessment were performed. Meta-analyses were undertaken for fracture resistance and root canal detection, with the level of significance set at 0.05 (P = 0.05). RESULTS: A total of 33 articles were included in this systematic review. The global evaluation of the risk of bias in the included studies was assessed as moderate, and the level of evidence was rated as low. Four types of AC designs were categorized: traditional (TradAC), conservative (ConsAC), ultraconservative (UltraAC), and truss (TrussAC). Their impact on fracture resistance, cleaning/disinfection, procedural errors, root canal detection, treatment time, apical debris extrusion, and root canal filling was discussed. Meta-analysis showed that compared to TradAC, (i) there is a significant higher fracture resistance of teeth with ConsAC, TrussAC, or ConsAC/TrussAC when all marginal ridges are preserved (P < 0.05), (ii) there is no significant effect of the type of AC on the fracture resistance of teeth when one or two marginal ridges are lost (P > 0.05), and (iii) there is a significantly higher risk of undetected canals with ConsAC if not assisted by dental operating microscope and ultrasonic troughing (P < 0.05). CONCLUSIONS: Decreasing the AC extent does not necessarily present mechanical and biological advantages especially when one or more surfaces of the tooth structure are lost. To date, the evidence available does not support the application of TrussAC. UltraAC might be applied in limited occasions. CLINICAL RELEVANCE: Maintaining the extent of AC design as small as practical without jeopardizing the root canal treatment quality remains a pragmatic recommendation. Different criteria can guide the practitioner for the optimal extent of AC outline form which varies from case to case.

Anomaly detection in genomic catalogues using unsupervised multi-view autoencoders.

BACKGROUND: Accurate identification of Transcriptional Regulator binding locations is essential for analysis of genomic regions, including Cis Regulatory Elements. The customary NGS approaches, predominantly ChIP-Seq, can be obscured by data anomalies and biases which are difficult to detect without supervision. RESULTS: Here, we develop a method to leverage the usual combinations between many experimental series to mark such atypical peaks. We use deep learning to perform a lossy compression of the genomic regions' representations with multiview convolutions. Using artificial data, we show that our method correctly identifies groups of correlating series and evaluates CRE according to group completeness. It is then applied to the ReMap database's large volume of curated ChIP-seq data. We show that peaks lacking known biological correlators are singled out and less confirmed in real data. We propose normalization approaches useful in interpreting black-box models. CONCLUSION: Our approach detects peaks that are less corroborated than average. It can be extended to other similar problems, and can be interpreted to identify correlation groups. It is implemented in an open-source tool called atyPeak.

A predictable conserved DNA base composition signature defines human core DNA replication origins.

DNA replication initiates from multiple genomic locations called replication origins. In metazoa, DNA sequence elements involved in origin specification remain elusive. Here, we examine pluripotent, primary, differentiating, and immortalized human cells, and demonstrate that a class of origins, termed core origins, is shared by different cell types and host ~80% of all DNA replication initiation events in any cell population. We detect a shared G-rich DNA sequence signature that coincides with most core origins in both human and mouse genomes. Transcription and G-rich elements can independently associate with replication origin activity. Computational algorithms show that core origins can be predicted, based solely on DNA sequence patterns but not on consensus motifs. Our results demonstrate that, despite an attributed stochasticity, core origins are chosen from a limited pool of genomic regions. Immortalization through oncogenic gene expression, but not normal cellular differentiation, results in increased stochastic firing from heterochromatin and decreased origin density at TAD borders.

Author Correction: Involvement of G-quadruplex regions in mammalian replication origin activity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Insights gained from a comprehensive all-against-all transcription factor binding motif benchmarking study.

BACKGROUND: Positional weight matrix (PWM) is a de facto standard model to describe transcription factor (TF) DNA binding specificities. PWMs inferred from in vivo or in vitro data are stored in many databases and used in a plethora of biological applications. This calls for comprehensive benchmarking of public PWM models with large experimental reference sets. RESULTS: Here we report results from all-against-all benchmarking of PWM models for DNA binding sites of human TFs on a large compilation of in vitro (HT-SELEX, PBM) and in vivo (ChIP-seq) binding data. We observe that the best performing PWM for a given TF often belongs to another TF, usually from the same family. Occasionally, binding specificity is correlated with the structural class of the DNA binding domain, indicated by good cross-family performance measures. Benchmarking-based selection of family-representative motifs is more effective than motif clustering-based approaches. Overall, there is good agreement between in vitro and in vivo performance measures. However, for some in vivo experiments, the best performing PWM is assigned to an unrelated TF, indicating a binding mode involving protein-protein cooperativity. CONCLUSIONS: In an all-against-all setting, we compute more than 18 million performance measure values for different PWM-experiment combinations and offer these results as a public resource to the research community. The benchmarking protocols are provided via a web interface and as docker images. The methods and results from this study may help others make better use of public TF specificity models, as well as public TF binding data sets.

JASPAR 2020: update of the open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In this 8th release of JASPAR, the CORE collection has been expanded with 245 new PFMs (169 for vertebrates, 42 for plants, 17 for nematodes, 10 for insects, and 7 for fungi), and 156 PFMs were updated (125 for vertebrates, 28 for plants and 3 for insects). These new profiles represent an 18% expansion compared to the previous release. JASPAR 2020 comes with a novel collection of unvalidated TF-binding profiles for which our curators did not find orthogonal supporting evidence in the literature. This collection has a dedicated web form to engage the community in the curation of unvalidated TF-binding profiles. Moreover, we created a Q&A forum to ease the communication between the user community and JASPAR curators. Finally, we updated the genomic tracks, inference tool, and TF-binding profile similarity clusters. All the data is available through the JASPAR website, its associated RESTful API, and through the JASPAR2020 R/Bioconductor package.

ReMap 2020: a database of regulatory regions from an integrative analysis of Human and Arabidopsis DNA-binding sequencing experiments.

ReMap (http://remap.univ-amu.fr) aims to provide the largest catalogs of high-quality regulatory regions resulting from a large-scale integrative analysis of hundreds of transcription factors and regulators from DNA-binding experiments in Human and Arabidopsis (Arabidopsis thaliana). In this 2020 update of ReMap we have collected, analyzed and retained after quality control 2764 new human ChIP-seq and 208 ChIP-exo datasets available from public sources. The updated human atlas totalize 5798 datasets covering a total of 1135 transcriptional regulators (TRs) with a catalog of 165 million (M) peaks. This ReMap update comes with two unique Arabidopsis regulatory catalogs. First, a catalog of 372 Arabidopsis TRs across 2.6M peaks as a result of the integration of 509 ChIP-seq and DAP-seq datasets. Second, a catalog of 33 histone modifications and variants across 4.5M peaks from the integration of 286 ChIP-seq datasets. All catalogs are made available through track hubs at Ensembl and UCSC Genome Browsers. Additionally, this update comes with a new web framework providing an interactive user-interface, including improved search features. Finally, full programmatically access to the underlying data is available using a RESTful API together with a new R Shiny interface for a TRs binding enrichment analysis tool.

Involvement of G-quadruplex regions in mammalian replication origin activity.

Genome-wide studies of DNA replication origins revealed that origins preferentially associate with an Origin G-rich Repeated Element (OGRE), potentially forming G-quadruplexes (G4). Here, we functionally address their requirements for DNA replication initiation in a series of independent approaches. Deletion of the OGRE/G4 sequence strongly decreased the corresponding origin activity. Conversely, the insertion of an OGRE/G4 element created a new replication origin. This element also promoted replication of episomal EBV vectors lacking the viral origin, but not if the OGRE/G4 sequence was deleted. A potent G4 ligand, PhenDC3, stabilized G4s but did not alter the global origin activity. However, a set of new, G4-associated origins was created, whereas suppressed origins were largely G4-free. In vitro Xenopus laevis replication systems showed that OGRE/G4 sequences are involved in the activation of DNA replication, but not in the pre-replication complex formation. Altogether, these results converge to the functional importance of OGRE/G4 elements in DNA replication initiation.