• Antihypertensive drug treatment and susceptibility to SARS-CoV-2 infection in human PSC-derived cardiomyocytes and primary endothelial cells

      Iwanski, J.; Kazmouz, S.G.; Li, S.; Stansfield, B.; Salem, T.T.; Perez-Miller, S.; Kazui, T.; Jena, L.; Uhrlaub, J.L.; Lick, S.; et al. (Cell Press, 2021)
      The pathogenicity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been attributed to its ability to enter through the membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor. Therefore, it has been heavily speculated that angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy may modulate SARS-CoV-2 infection. In this study, exposure of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and human endothelial cells (hECs) to SARS-CoV-2 identified significant differences in protein coding genes involved in immunity, viral response, and cardiomyocyte/endothelial structure. Specifically, transcriptome changes were identified in the tumor necrosis factor (TNF), interferon α/β, and mitogen-activated protein kinase (MAPK) (hPSC-CMs) as well as nuclear factor kappa-B (NF-κB) (hECs) signaling pathways. However, pre-treatment of hPSC-CMs or hECs with two widely prescribed antihypertensive medications, losartan and lisinopril, did not affect the susceptibility of either cell type to SARS-CoV-2 infection. These findings demonstrate the toxic effects of SARS-CoV-2 in hPSC-CMs/hECs and, taken together with newly emerging multicenter trials, suggest that antihypertensive drug treatment alone does not alter SARS-CoV-2 infection. © 2021 The Authors
    • Cooperative Communication with Humans Evolved to Emerge Early in Domestic Dogs

      Salomons, Hannah; Smith, Kyle C.M.; Callahan-Beckel, Megan; Callahan, Margaret; Levy, Kerinne; Kennedy, Brenda S.; Bray, Emily E.; Gnanadesikan, Gitanjali E.; Horschler, Daniel J.; Gruen, Margaret; et al. (Cell Press, 2021-07)
      Although we know that dogs evolved from wolves, it remains unclear how domestication affected dog cognition. One hypothesis suggests dog domestication altered social maturation by a process of selecting for an attraction to humans.1–3 Under this account, dogs became more flexible in using inherited skills to cooperatively communicate with a new social partner that was previously feared and expressed these unusual social skills early in development.4–6 Here, we comparedog (n = 44) and wolf (n = 37) puppies, 5–18 weeks old, on a battery of temperament and cognition tasks. We find that dog puppies are more attracted to humans, read human gestures more skillfully, and make more eye contact with humans than wolf puppies. The two species are similarly attracted to familiar objects and perform similarly on non-social measures of memory and inhibitory control. These results are consistent with the idea that domestication enhanced the cooperative-communicative abilities of dogs as selection for attraction to humans altered social maturation. © 2021 Elsevier Inc.
    • Early-emerging and highly heritable sensitivity to human communication in dogs

      Bray, Emily E.; Gnanadesikan, Gitanjali E.; Horschler, Daniel J.; Levy, Kerinne M.; Kennedy, Brenda S.; Famula, Thomas R.; MacLean, Evan L.; Arizona Canine Cognition Center, School of Anthropology, University of Arizona; Cognitive Science Program, University of Arizona; Department of Psychology, University of Arizona; et al. (Cell Press, 2021-07)
      Human cognition is believed to be unique in part because of early-emerging social skills for cooperative communication.1 Comparative studies show that at 2.5 years old, children reason about the physical world similarly to other great apes, yet already possess cognitive skills for cooperative communication far exceeding those in our closest primate relatives.2,3 A growing body of research indicates that domestic dogs exhibit functional similarities to human children in their sensitivity to cooperative-communicative acts. From early in development, dogs flexibly respond to diverse forms of cooperative gestures.4,5 Like human children, dogs are sensitive to ostensive signals marking gestures as communicative, as well as contextual factors needed for inferences about these communicative acts.6–8 However, key questions about potential biological bases for these abilities remain untested. To investigate their developmental and genetic origins, we tested 375 8-week-old dog puppies on a battery of social-cognitive measures. We hypothesized that if dogs’ skills for cooperating with humans are biologically prepared, then they should emerge robustly in early development, not require extensive socialization or learning, and exhibit heritable variation. Puppies were highly skillful at using diverse human gestures, and we found no evidence that their performance required learning. Critically, over 40% of the variation in dogs’ point-following abilities and attention to human faces was attributable to genetic factors. Our results suggest that these social skills in dogs emerge early in development and are under strong genetic control. © 2021 Elsevier Inc.
    • Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer

      Witkiewicz, Agnieszka K.; Balaji, Uthra; Eslinger, Cody; McMillan, Elizabeth; Conway, William; Posner, Bruce; Mills, Gordon B.; O’Reilly, Eileen M.; Knudsen, Erik S.; Department of Pathology, University of Arizona; et al. (Cell Press, 2016-08)
      Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC.