Combined drug design of potential Mycobacterium tuberculosis and HIV-1 inhibitors: 3′,4′-di-substituted -4′H-spiro [isothiochromene-3,5′-isoxazol]-4(1H)-one

We report herein the design and synthesis of 17 new spiroheterocycles 10-26, on the basis of two hypothetical pharmacophore structures designed to interact with both of Mycobacterium tuberculosis bacteria and HIV-1 virus. The in vitro biological evaluation of these compounds allowed us to point out seven new potential non-nucleoside hits, with MIC values in the range of 6.25 μg/mL and two new potential anti-HIV-1 inhibitors. ©ARKAT USA, Inc

Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 mendelian neurodevelopmental disorders

Published: February 27, 2020Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called “episignatures”). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.Erfan Aref-Eshghi ... Marie Shaw, Jozef Gecz ... et al