Highlights d Lung ACE2 levels do not vary by age or sex, but smokers exhibit upregulated ACE2 d ACE2 is expressed in several lung cell types, including the secretory lineage d Chronic smoking triggers the expansion of ACE2 + secretory cells d ACE2 is also upregulated by viral infections and interferon exposure

Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that—contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors—the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit.

Aneuploidy decreases cellular fitness, yet it is also associated with cancer, a disease of enhanced proliferative capacity. To investigate one mechanism by which aneuploidy could contribute to tumorigenesis, we examined the effects of aneuploidy on genomic stability. We analyzed 13 budding yeast strains that carry extra copies of single chromosomes and found that all aneuploid strains exhibited one or more forms of genomic instability. Most strains displayed increased chromosome loss and mitotic recombination, as well as defective DNA damage repair. Aneuploid fission yeast strains also exhibited defects in mitotic recombination. Aneuploidy-induced genomic instability could facilitate the development of genetic alterations that drive malignant growth in cancer.

Women make up over one-half of all doctoral recipients in biologyrelated fields but are vastly underrepresented at the faculty level in the life sciences. To explore the current causes of women's underrepresentation in biology, we collected publicly accessible data from university directories and faculty websites about the composition of biology laboratories at leading academic institutions in the United States. We found that male faculty members tended to employ fewer female graduate students and postdoctoral researchers (postdocs) than female faculty members did. Furthermore, elite male faculty-those whose research was funded by the Howard Hughes Medical Institute, who had been elected to the National Academy of Sciences, or who had won a major career award-trained significantly fewer women than other male faculty members. In contrast, elite female faculty did not exhibit a gender bias in employment patterns. New assistant professors at the institutions that we surveyed were largely comprised of postdoctoral researchers from these prominent laboratories, and correspondingly, the laboratories that produced assistant professors had an overabundance of male postdocs. Thus, one cause of the leaky pipeline in biomedical research may be the exclusion of women, or their self-selected absence, from certain high-achieving laboratories. etween 1969 and 2009, the percentage of doctorates awarded to women in the life sciences increased from 15% to 52% (1, 2). Despite the vast gains at the doctoral level, women still lag behind in faculty appointments. Currently, only 36% of assistant professors and 18% of full professors in biology-related fields are women (3). The attrition of women from academic careersknown as the leaky pipeline problem (4)-undermines the meritocratic ideals of science and represents a significant underuse of the skills that are present in the pool of doctoral trainees.A variety of factors has been suggested to influence the leaky pipeline in science, technology, engineering, and math (STEM) fields. Early career aspirations and choice of undergraduate major are significant departure points for women in certain disciplines (5, 6). For instance, women are awarded only 19% of bachelor's degrees in physics and 18% of bachelor's degrees in engineering, and correspondingly fewer women go on to graduate school in those subjects (1). In contrast, women are awarded >50% of both bachelor's and doctoral degrees in biology, suggesting that major leaks in the pipeline occur at later points in professional development. Gender differences in individuals' personal aspirations may explain some attrition from the academy (7). For instance, in surveys of graduate students and postdoctoral researchers (postdocs), women tend to rank work-life balance and parenthood-related issues as more important than men do, and the perceived difficulty of raising a family while working as a tenure-track faculty member causes more women than men to leave the academic pipeline (8-12). Such preferences are likely constrained by societal ...