CasPEDIA Database: a functional classification system for class 2 CRISPR-Cas enzymes.

CRISPR-Cas enzymes enable RNA-guided bacterial immunity and are widely used for biotechnological applications including genome editing. In particular, the Class 2 CRISPR-associated enzymes (Cas9, Cas12 and Cas13 families), have been deployed for numerous research, clinical and agricultural applications. However, the immense genetic and biochemical diversity of these proteins in the public domain poses a barrier for researchers seeking to leverage their activities. We present CasPEDIA (http://caspedia.org), the Cas Protein Effector Database of Information and Assessment, a curated encyclopedia that integrates enzymatic classification for hundreds of different Cas enzymes across 27 phylogenetic groups spanning the Cas9, Cas12 and Cas13 families, as well as evolutionarily related IscB and TnpB proteins. All enzymes in CasPEDIA were annotated with a standard workflow based on their primary nuclease activity, target requirements and guide-RNA design constraints. Our functional classification scheme, CasID, is described alongside current phylogenetic classification, allowing users to search related orthologs by enzymatic function and sequence similarity. CasPEDIA is a comprehensive data portal that summarizes and contextualizes enzymatic properties of widely used Cas enzymes, equipping users with valuable resources to foster biotechnological development. CasPEDIA complements phylogenetic Cas nomenclature and enables researchers to leverage the multi-faceted nucleic-acid targeting rules of diverse Class 2 Cas enzymes.

Continuing medical and student education in dermatology during the coronavirus pandemic - a major challenge.

Continuing medical education (CME) is the essential basis for student teaching and for training and further development of physicians. Without it, modern and adequate patient care is unthinkable. Recently, the coronavirus pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV2), forced the entire medical community to change its usual habits of advanced medical training, teaching and learning. As a result, digital training and teaching via social media, online medical encyclopedias, web-based learning platforms and educational podcasts moved to the fore. Here, we give an overview on current concepts for online medical education, with special consideration of dermatology.

Altered levels of focal adhesion and extracellular matrix-receptor interacting proteins were identified in Hailey-Hailey disease by quantitative iTRAQ proteome analysis.

Benign chronic familial pemphigus or Hailey-Hailey disease (HHD, OMIM 169600) is a rare, autosomal dominant blistering skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. To date, the proteomic changes in skin lesions from HHD patients has not been reported yet. In this study, a sample of skin lesions from HHD patients was collected for isobaric tags for relative and absolute quantitation to analyze proteome changes compared with unaffected individuals. The 134 differentially expressed proteins were assigned to at least one Gene Ontology term, and 123 annotated proteins with significant matches were assigned to 187 known metabolic or signaling pathways listed in the Kyoto Encyclopedia of Genes and Genomes. Most of the altered proteins in skin lesions of HHD patients were enriched in pathways involved in the PI3K-Akt signaling, focal adhesion, extracellular matrix (ECM)-receptor interaction, and protein digestion and absorption, such as collagen family members, microfibril-associated glycoprotein 4 and plakophilin. The changes of proteins related to cell adhesion, ECM-receptor interaction, and protein folding and glycosylation suggested that strategy targeted to alter cell junction and extracellular microenvironment might provide a potential treatment for HHD.

The reCAPTCHA of medical education.

This article focuses on what Luis von Ahn called the "twofer," that is, a single solution that elegantly addresses two problems on a large scale. We describe two of von Ahn's creations: reCAPTCHA, which validates a human web presence while also digitizing hard-to-read words, and Duolingo, which teaches new languages while translating the web. We then consider how this approach can be applied to medical education. Embedding Wikipedia-editing into educational settings is one such solution that could both improve the quality of health information available to the public while enhancing the learning of future health professionals.

Integrating Wikipedia Articles and Images into an Information Resource for Radiology Patients.

Wikipedia-an open-access online encyclopedia-contains a large number of medically relevant articles and images that may help supplement glossaries of radiology terms. We sought to determine the extent to which concepts from a large online radiology glossary developed as part of the Patient-Oriented Radiology Reporter (PORTER) initiative could be mapped to relevant Wikipedia web pages and images using automated or semi-automated approaches. The glossary included 4090 concepts with their definitions; the concept's preferred name and lexical variants, such as plurals, adjectival forms, synonyms, and abbreviations, yielded a total of 13,030 terms. Of the 4090 concepts, 3063 (74.9%) had a corresponding English-language Wikipedia page identified by automated search with subsequent manual review. We applied the MediaWiki application programming interface (API) to generate web-service calls to identify the images from each concept's corresponding Wikipedia page; three reviewers selected relevant images to associate with the glossary's concepts. Licensing terms for the images were reviewed. For 800 randomly sampled concepts that had associated Wikipedia pages, 362 distinct images were identified from the MediaWiki library and matched to 404 concepts (51%). Three images (1%) had unspecified licensing terms; the rest were in the public domain or available via a Creative Commons license. Wikipedia and the MediaWiki library offer a large collection of medical articles and images that can be incorporated into an online lay-language glossary of radiology terms though a semi-automated approach.

Is Wikipedia a complete and accurate source for musculoskeletal anatomy?

PURPOSE: Wikipedia is a popular online encyclopedia generating over 5.4 billion visits per month, and it is also a common resource for the general public and professionals for medical information. The goal of this study is to determine the accuracy and completeness of Wikipedia as a resource for musculoskeletal anatomy. METHODS: The origin, insertion, innervation, and function of all muscles of the upper and lower extremities as detailed on Wikipedia was compared to the available corresponding information in Grant's Atlas of Anatomy (14th edition). Entries were scored for both accuracy and completeness. Descriptive statistics were calculated and associations between and within entries for accuracy and completeness were assessed by McNemar's tests. Information on Wikipedia's references was also collected. RESULTS: Overall, data on Wikipedia was 97.6% complete and 98.8% accurate when compared to Grant's Atlas of Anatomy. 78.6% of all entries were fully complete and accurate, with 15.3% of entries containing one error and 6.1% containing two errors. There were no associations between or within entries' accuracy and completeness. Only 62% of references from Wikipedia included were from academic sources. CONCLUSIONS: Musculoskeletal anatomy entries on Wikipedia are imperfect; they have inaccurate and missing information. Furthermore, a considerable proportion of references cited in entries are from poorly identified sources. While Wikipedia is an easily accessible resource for a large number of people and much of the anatomic information is appropriate, it cannot be considered to be an equivalent resource when compared to anatomic texts.

Italian Wikipedia and epilepsy: An infodemiological study of online information-seeking behavior.

Wikipedia is the most commonly accessed source of health information by both healthcare professionals and the lay public worldwide. We aimed to evaluate information-seeking behavior of Internet users searching the Italian Wikipedia for articles related to epilepsy and its treatment. Using Pageviews Analysis, we assessed the total and mean monthly views of articles from the Italian Wikipedia devoted to epilepsy, epileptic syndromes, seizure type, and antiepileptic drugs (AEDs) from January 1, 2015 to October 31, 2017. We compared the views of the article on epilepsy with those of articles focusing on Alzheimer's disease, migraine, multiple sclerosis, syncope, and stroke and adjusted all results for crude disease prevalence. With the only exception of the article on multiple sclerosis, the adjusted views for the Italian Wikipedia article on epilepsy were higher than those for the other neurological disorders. The most viewed articles on seizure type were devoted to tonic-clonic seizure, typical absence seizure, tonic convulsive seizures, and clonic convulsive seizures. The most frequently accessed articles on epilepsy syndromes were about temporal lobe epilepsy and Lennox-Gastaut syndrome. The most frequently viewed articles on AEDs were devoted to valproic acid, carbamazepine, and levetiracetam. Wikipedia searches seem to mirror patients' fears and worries about epilepsy more than its actual epidemiology. The ultimate reasons for searching online remain unknown. Epileptologists and epilepsy scientific societies should make greater efforts to work jointly with Wikipedia to convey more accurate and up-to-date information about epilepsy.

An expansive human regulatory lexicon encoded in transcription factor footprints.

Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.

The accessible chromatin landscape of the human genome.

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.

Architecture of the human regulatory network derived from ENCODE data.

Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.

Landscape of transcription in human cells.

Eukaryotic cells make many types of primary and processed RNAs that are found either in specific subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic subcellular localizations are also poorly understood. Because RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell's regulatory capabilities are focused on its synthesis, processing, transport, modification and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three-quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations, taken together, prompt a redefinition of the concept of a gene.

The long-range interaction landscape of gene promoters.

The vast non-coding portion of the human genome is full of functional elements and disease-causing regulatory variants. The principles defining the relationships between these elements and distal target genes remain unknown. Promoters and distal elements can engage in looping interactions that have been implicated in gene regulation. Here we have applied chromosome conformation capture carbon copy (5C) to interrogate comprehensively interactions between transcription start sites (TSSs) and distal elements in 1% of the human genome representing the ENCODE pilot project regions. 5C maps were generated for GM12878, K562 and HeLa-S3 cells and results were integrated with data from the ENCODE consortium. In each cell line we discovered >1,000 long-range interactions between promoters and distal sites that include elements resembling enhancers, promoters and CTCF-bound sites. We observed significant correlations between gene expression, promoter-enhancer interactions and the presence of enhancer RNAs. Long-range interactions show marked asymmetry with a bias for interactions with elements located ∼120 kilobases upstream of the TSS. Long-range interactions are often not blocked by sites bound by CTCF and cohesin, indicating that many of these sites do not demarcate physically insulated gene domains. Furthermore, only ∼7% of looping interactions are with the nearest gene, indicating that genomic proximity is not a simple predictor for long-range interactions. Finally, promoters and distal elements are engaged in multiple long-range interactions to form complex networks. Our results start to place genes and regulatory elements in three-dimensional context, revealing their functional relationships.

An integrated encyclopedia of DNA elements in the human genome.

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity.

The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.

Pharmacy students can improve access to quality medicines information by editing Wikipedia articles.

BACKGROUND: Pharmacy training programs commonly ask students to develop or edit drug monographs that summarize key information about new medicines as an academic exercise. We sought to expand on this traditional approach by having students improve actual medicines information pages posted on Wikipedia. METHODS: We placed students (n = 119) in a required core pharmacy course into groups of four and assigned each group a specific medicines page on Wikipedia to edit. Assigned pages had high hit rates, suggesting that the topics were of interest to the wider public, but were of low quality, suggesting that the topics would benefit from improvement efforts. We provided course trainings about editing Wikipedia. We evaluated the assignment by surveying student knowledge and attitudes and reviewing the edits on Wikipedia. RESULTS: Completing the course trainings increased student knowledge of Wikipedia editing practices. At the end of the assignment, students had a more nuanced understanding of Wikipedia as a resource. Student edits improved substantially the quality of the articles edited, their edits were retained for at least 30 days after course completion, and the average number page views of their edited articles increased. CONCLUSIONS: Our results suggest that engaging pharmacy students in a Wikipedia editing assignment is a feasible alternative to writing drug monographs as a classroom assignment. Both tasks provide opportunities for students to demonstrate their skills at researching and explaining drug information but only one serves to improve wider access to quality medicines information. Wikipedia editing assignments are feasible for large groups of pharmacy students and effective in improving publicly available information on one of the most heavily accessed websites globally.

Schizophrenia: four examples of historical retrospective diagnosis.

It is difficult to know precisely the history of a functional disease, unlike the natural history of infectious agents, tumour processes or poly-malformative syndromes. In the case of psychiatry, and especially schizophrenia and psychotic disorders, a retrospective look at artistic productions (writings and drawings) makes it possible to reconstitute a whole section of this pathological context. Through four medieval and modern examples, we will see how it is possible to do a paleo-psychiatry: Opicinus de Canistris (14th c.), the Voynich manuscript (15th c.), Hieronymus Bosch (15th-16th c.), and the Codex Seraphinianus (20th c.).

Introduction to anatomy on Wikipedia.

Wikipedia (www.wikipedia.com) is the largest encyclopaedia in existence. Of over five million English-language articles, about 6000 relate to Anatomy, which are viewed roughly 30 million times monthly. No work parallels the amount of attention, scope or interdisciplinary layout of Wikipedia, and it offers a unique opportunity to improve the anatomical literacy of the masses. Anatomy on Wikipedia is introduced from an editor's perspective. Article contributors, content, layout and accuracy are discussed, with a view to demystifying editing for anatomy professionals. A final request for edits or on-site feedback from anatomy professionals is made.

Dermatite atopíque : images hístoriques: Historical images of atopic dermatitis.

Atopic dermatitis has been described under many names before the XXth century, and first illustrated in the early XIXth century. This article presents historical images from the first volumes of Robert Willan to the Pratique dermatologique, the first encyclopedy published in 1900. Many accurate clinical descriptions of the disease can be found in the early treaties of dermatology, including the one published by Thomas Carrere in 1740. Since then, Alibert and Rayer in France, Hebra and Neumann in Vienna and Duhring and Fox in the USA illustrated their atlases with spectacular images of adults or children suffering from AD, or from other diseases that might have been considered as eczema infantile. Color engravings, color lithographs and black and white photographs showed with an increasing precision the semiology of AD, in the context of artistic representations of high quality, that have not been surpassed by modern photographs. At the beginning of the XXth century the clinical presentation, the course and heredity of the disease were perfectly established, introducing a new era of research in physiopathology and treatment in the following decades.

'Anyone can edit', not everyone does: Wikipedia's infrastructure and the gender gap.

Feminist STS has long established that science's provenance as a male domain continues to define what counts as knowledge and expertise. Wikipedia, arguably one of the most powerful sources of information today, was initially lauded as providing the opportunity to rebuild knowledge institutions by providing greater representation of multiple groups. However, less than ten percent of Wikipedia editors are women. At one level, this imbalance in contributions and therefore content is yet another case of the masculine culture of technoscience. This is an important argument and, in this article, we examine the empirical research that highlights these issues. Our main objective, however, is to extend current accounts by demonstrating that Wikipedia's infrastructure introduces new and less visible sources of gender disparity. In sum, our aim here is to present a consolidated analysis of the gendering of Wikipedia.