The mechanical career of Councillor Orffyreus, confidence man

In the early 18th century, J. E. E. Bessler, known as Orffyreus, constructed several wheels that he claimed could keep turning forever, powered only by gravity. He never revealed the details of his invention, but he conducted demonstrations (with the machine's inner workings covered) that persuaded competent observers that he might have discovered the secret of perpetual motion. Among Bessler's defenders were Gottfried Leibniz, Johann Bernoulli, Professor Willem 's Gravesande of Leiden University (who wrote to Isaac Newton on the subject), and Prince Karl, ruler of the German state of Hesse-Kassel. We review Bessler's work, placing it within the context of the intellectual debates of the time about mechanical conservation laws and the (im)possibility of perpetual motion. We also mention Bessler's long career as a confidence man, the details of which were discussed in popular 19th-century German publications, but have remained unfamiliar to authors in other languages.UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Físic

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock