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 ...

Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a metaanalysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, and genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical antiproliferative response that must be overcome before transformation.stress response | trisomy | chromosomal instability E ukaryotic organisms have evolved elaborate mechanisms that ensure that chromosomes are partitioned equally during cell division (1). Aberrant segregation events can result in aneuploidy, a condition in which cells acquire a karyotype that is not a whole-number multiple of the haploid complement. In humans, aneuploidy is the leading cause of spontaneous abortions and developmental disabilities, and aneuploid karyotypes are observed in greater than 90% of solid tumors (2-4). Thus, understanding the consequences of aneuploidy has broad relevance for the study of mammalian development and cancer.The cause of aneuploidy-induced syndromes remains an open question. For instance, it has been hypothesized that the phenotypes associated with Down syndrome (trisomy 21) are caused by the triplication of a small set of genes that lie within a 5.4-Mb "Down syndrome critical region" on chromosome 21 (5, 6). However, evidence from mouse models suggest that this region is not sufficient to recapitulate Down syndrome-like phenotypes, and genetic mapping of partially trisomic individuals has revealed that numerous regions of chromosome 21 affect clinical presentation (7-9). Alternately, changes in gene dosage across an entire chromosome might have additive effects on organismal development (10). It has been observed that the three human trisomies that survive until birth (trisomy 13, 18, and 21) have the fewest proteincoding genes on them, implying that these karyotypes can be tolerated in utero because they have the lowest net dosage imbalances (11). However, the consequences of copy number variation range from benign to extremely deleterious, demonstrating that different genes exhibit varying levels of dosage sensitivity (12).To examine the consequences of aneuploidy, we have previously constructed and analyzed a series of haploid budding yeast strains and mouse embryonic fibroblasts (MEFs) that carry single extra chromosomes (13-17). These aneuploid cells...

Aneuploidy has a paradoxical effect on cell proliferation. In all normal cells analyzed to date, aneuploidy has been found to decrease the rate of cell proliferation. Yet, aneuploidy is also a hallmark of cancer, a disease of enhanced proliferative capacity, and aneuploid cells are frequently recovered following the experimental evolution of microorganisms. Thus, in certain contexts, aneuploidy may also have growth-advantageous properties. New models of aneuploidy and chromosomal instability have shed light on the diverse effects that karyotypic imbalances have on cellular phenotypes, and suggest novel ways of understanding aneuploidy’s role in development and disease.

Background Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. Methods We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. Findings We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. Interpretation Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. Funding NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.

SUMMARY Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness. Thus, while single-chromosome gains can suppress transformation, the genome-destabilizing effects of aneuploidy confer an evolutionary flexibility that may contribute to the aggressive growth of advanced malignancies with complex karyotypes.