La Vigie marocaine

21 juin 19341934/06/21 (A25,N8280)-1934/06/21

Additional file 2: of Peak shape clustering reveals biological insights

Random forest analysis. (XLSX 74 kb

Sequences for Tyr2R and Tyr2F gRNAs.

<p>Sequences for Tyr2R and Tyr2F gRNAs.</p

Summary of off-target scores for selected gRNAs.

<p>Off-targets numbers as determined by Cas-OFFinder [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007503#pgen.1007503.ref009" target="_blank">9</a>] for Tyr2F, Tyr2R used in our experiment and Schaeffer (15).</p

Sequences of primers flanking expected on-target sites for Tyr2R and Tyr2F.

<p>Sequences of primers flanking expected on-target sites for Tyr2R and Tyr2F.</p

Analysis of CRISPR off-targets by whole genome sequencing.

<p>(a) Experimental design: Four sets of C57BL/6N parents gave rise to 9 control embryos (3 “no injection”, 3 “sham injection” with water only and 3 “Cas9 only”), and 10 treated embryos (5 were injected with Cas9 and Tyr2F gRNA and 5 were injected with Cas9 and Tyr2R gRNA). (b) Whole genome sequencing: All 27 mice / embryos were subjected to whole genome sequencing with median depth 39.5x and an average of 3.4% of bases with read depth less than 11x. (c) Variant calling and filtering: starting from the joint variant call (<i>bcftools mpileup + bcftools call</i>), a sequence of filter steps were performed to detect <i>de novo</i> mutations and remove likely false positives arising from low-level parental mosaicism and alignment errors at repeat regions. Parental-noise: alternate-allele reads present in either parent. Cross-noise: alternate reads from all other (non-parental) samples. (d) Filtered SNV and Indel counts are not significantly different within control groups, within treatment groups, or between control and treatment groups.</p

Concentration of reagent injected for each experimental group.

<p>Concentration of reagent injected for each experimental group.</p

Additional file 1: of LowMACA: exploiting protein family analysis for the identification of rare driver mutations in cancer

It contains detailed results of our analyses in Figures S1-S4. (PDF 1180 kb

Additional file 2: of LowMACA: exploiting protein family analysis for the identification of rare driver mutations in cancer

It contains detailed results of our analyses in Table S5 and S6. (XLSX 232 kb

Discovery of CMX990: A Potent SARS-CoV‑2 3CL Protease Inhibitor Bearing a Novel Warhead

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance), with good in vitro-to-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2