Despite recent advances, improvements to long-term survival in metastatic carcinomas, such as pancreatic or ovarian cancer, remain limited. Current therapies suppress growth-promoting biochemical signals, ablate cells expressing tumor-associated antigens, or promote adaptive immunity to tumor neoantigens. However, these approaches are limited by toxicity to normal cells using the same signaling pathways or expressing the same antigens, or by the low frequency of neoantigens in most carcinomas.
View Article and Find Full Text PDFInhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M more efficiently than existing drugs.
View Article and Find Full Text PDFInjury induces systemic responses, but their functions remain elusive. Mechanisms that can rapidly synchronize wound responses through long distances are also mostly unknown. Using planarian flatworms capable of whole-body regeneration, we report that injury induces extracellular signal-regulated kinase (Erk) activity waves to travel at a speed 10-100 times faster than those in other multicellular tissues.
View Article and Find Full Text PDFInjury induces systemic, global responses whose functions remain elusive. In addition, mechanisms that rapidly synchronize wound responses through long distances across the organismal scale are mostly unknown. Using planarians, which have extreme regenerative ability, we report that injury induces Erk activity to travel in a wave-like manner at an unexpected speed (∼1 mm/h), 10-100 times faster than those measured in other multicellular tissues.
View Article and Find Full Text PDFRecent advances in DNA synthesis technology have made it possible to rewrite the entire genome of an organism. The major hurdles in this process are efficiently identifying and fixing the defect-inducing sequences (or "bugs") during rewriting. Here, we describe a high-throughput, semiquantitative phenotype assay for evaluating the fitness of synthetic yeast and identifying potential bugs.
View Article and Find Full Text PDFAn important goal in synthetic biology is to engineer biochemical pathways to address unsolved biomedical problems. One long-standing problem in molecular medicine is the specific identification and ablation of cancer cells. Here, we describe a method, named Rewiring of Aberrant Signaling to Effector Release (RASER), in which oncogenic ErbB receptor activity, instead of being targeted for inhibition as in existing treatments, is co-opted to trigger therapeutic programs.
View Article and Find Full Text PDFOptical control of CRISPR-Cas9-derived proteins would be useful for restricting gene editing or transcriptional regulation to desired times and places. Optical control of Cas9 functions has been achieved with photouncageable unnatural amino acids or by using light-induced protein interactions to reconstitute Cas9-mediated functions from two polypeptides. However, these methods have only been applied to one Cas9 species and have not been used for optical control of different perturbations at two genes.
View Article and Find Full Text PDFWe designed and synthesized a 976,067-base pair linear chromosome, synXII, based on native chromosome XII in SynXII was assembled using a two-step method, specified by successive megachunk integration and meiotic recombination-mediated assembly, producing a functional chromosome in Minor growth defect "bugs" detected in synXII, caused by deletion of tRNA genes, were rescued by introducing an ectopic copy of a single tRNA gene. The ribosomal gene cluster (rDNA) on synXII was left intact during the assembly process and subsequently replaced by a modified rDNA unit used to regenerate rDNA at three distinct chromosomal locations. The signature sequences within rDNA, which can be used to determine species identity, were swapped to generate a synXII strain that would be identified as by standard DNA barcoding procedures.
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