Look before you leap: is risk of injury a foraging cost?

Theory states that an optimal forager should exploit a patch so long as its harvest rate of resources from the patch exceeds its energetic, predation, and missed opportunity costs for foraging. However, for many foragers, predation is not the only source of danger they face while foraging. Foragers also face the risk of injuring themselves. To test whether risk of injury gives rise to a foraging cost, we offered red foxes pairs of depletable resource patches in which they experienced diminishing returns. The resource patches were identical in all respects, save for the risk of injury. In response, the foxes exploited the safe patches more intensively. They foraged for a longer time and also removed more food (i.e., had lower giving up densities) in the safe patches compared to the risky patches. Although they never sustained injury, video footage revealed that the foxes used greater care while foraging from the risky patches and removed food at a slower rate. Furthermore, an increase in their hunger state led foxes to allocate more time to foraging from the risky patches, thereby exposing themselves to higher risks. Our results suggest that foxes treat risk of injury as a foraging cost and use time allocation and daring—the willingness to risk injury—as tools for managing their risk of injury while foraging. This is the first study, to our knowledge, which explicitly tests and shows that risk of injury is indeed a foraging cost. While nearly all foragers may face an injury cost of foraging, we suggest that this cost will be largest and most important for predators

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis

Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. Methods: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting–purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. Results: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB–IL34/CCL8 signaling that promotes macrophage chemotaxis. Conclusions: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC

Native homing endonucleases can target conserved genes in humans and in animal models

In recent years, both homing endonucleases (HEases) and zinc-finger nucleases (ZFNs) have been engineered and selected for the targeting of desired human loci for gene therapy. However, enzyme engineering is lengthy and expensive and the off-target effect of the manufactured endonucleases is difficult to predict. Moreover, enzymes selected to cleave a human DNA locus may not cleave the homologous locus in the genome of animal models because of sequence divergence, thus hampering attempts to assess the in vivo efficacy and safety of any engineered enzyme prior to its application in human trials. Here, we show that naturally occurring HEases can be found, that cleave desirable human targets. Some of these enzymes are also shown to cleave the homologous sequence in the genome of animal models. In addition, the distribution of off-target effects may be more predictable for native HEases. Based on our experimental observations, we present the HomeBase algorithm, database and web server that allow a high-throughput computational search and assignment of HEases for the targeting of specific loci in the human and other genomes. We validate experimentally the predicted target specificity of candidate fungal, bacterial and archaeal HEases using cell free, yeast and archaeal assays

A candidate super-Earth planet orbiting near the snow line of Barnard’s star

Barnard’s star is a red dwarf, and has the largest proper motion (apparent motion across the sky) of all known stars. At a distance of 1.8 parsecs, it is the closest single star to the Sun; only the three stars in the α Centauri system are closer. Barnard’s star is also among the least magnetically active red dwarfs known and has an estimated age older than the Solar System. Its properties make it a prime target for planetary searches; various techniques with different sensitivity limits have been used previously, including radial-velocity imaging, astrometry and direct imaging, but all ultimately led to negative or null results. Here we combine numerous measurements from high-precision radial-velocity instruments, revealing the presence of a low-amplitude periodic signal with a period of 233 days. Independent photometric and spectroscopic monitoring, as well as an analysis of instrumental systematic effects, suggest that this signal is best explained as arising from a planetary companion. The candidate planet around Barnard’s star is a cold super-Earth, with a minimum mass of 3.2 times that of Earth, orbiting near its snow line (the minimum distance from the star at which volatile compounds could condense). The combination of all radial-velocity datasets spanning 20 years of measurements additionally reveals a long-term modulation that could arise from a stellar magnetic-activity cycle or from a more distant planetary object. Because of its proximity to the Sun, the candidate planet has a maximum angular separation of 220 milliarcseconds from Barnard’s star, making it an excellent target for direct imaging and astrometric observations in the future. © 2018, Springer Nature Limited.The results are based on observations made with the CARMENES instrument at the 3.5-m telescope of the Centro Astronomico Hispano-Aleman de Calar Alto (CAHA, Almeria, Spain), funded by the German Max-Planck-Gesellschaft (MPG), the Spanish Consejo Superior de Investigaciones Cientificas (CSIC), the European Union and the CARMENES Consortium members; the 90-cm telescope at the Sierra Nevada Observatory (Granada, Spain) and the 40-cm robotic telescope at the SPACEOBS observatory (San Pedro de Atacama, Chile), both operated by the Instituto de Astrofisica de Andalucia (IAA); and the 80-cm Joan Oro Telescope (TJO) of the Montsec Astronomical Observatory (OAdM), owned by the Generalitat de Catalunya and operated by the Institute of Space Studies of Catalonia (IEEC). This research was supported by the following institutions, grants and fellowships: Spanish MINECO ESP2016-80435-C2-1-R, ESP2016-80435-C2-2-R, AYA2016-79425-C3-1-P, AYA2016-79245-C3-2-P, AYA2016-79425-C3-3-P, AYA2015-69350-C3-2-P, ESP2014-54362-P, AYA2014-56359-P, RYC-2013-14875; Generalitat de Catalunya/CERCA programme; Fondo Europeo de Desarrollo Regional (FEDER); German Science Foundation (DFG) Research Unit FOR2544, project JE 701/3-1; STFC Consolidated Grants ST/P000584/1, ST/P000592/1, ST/M001008/1; NSF AST-0307493; Queen Mary University of London Scholarship; Perren foundation grant; CONICYT-FONDECYT 1161218, 3180405; Swiss National Science Foundation (SNSF); Koshland Foundation and McDonald-Leapman grant; and NASA Hubble Fellowship grant HST-HF2-51399.001. J.T. is a Hubble Fellow

Integrating Pharmacoproteomics into Early-Phase Clinical Development: State-of-the-Art, Challenges, and Recommendations

Pharmacoproteomics is the study of disease-modifying and toxicity parameters associated with therapeutic drug administration, using analysis of quantitative and temporal changes to specific, predetermined, and select proteins, or to the proteome as a whole. Pharmacoproteomics is a rapidly evolving field, with progress in analytic technologies enabling processing of complex interactions of large number of unique proteins and effective use in clinical trials. Nevertheless, our analysis of clinicaltrials.gov and PubMed shows that the application of proteomics in early-phase clinical development is minimal and limited to few therapeutic areas, with oncology predominating. We review the history, technologies, current usage, challenges, and potential for future use, and conclude with recommendations for integration of pharmacoproteomic in early-phase drug development