A cell-based assay system for activators of the environmental cell stress response

This work was funded by The Scottish Government Rural and Environment Science and Analytical Services Division (RESAS), Scotland, United Kingdom and the Biotechnology and Biological Sciences Research Council (BBSRC; East-Bio Doctoral Training Partnership), United Kingdom. The funders had no role in the design of the study, the analysis and interpretation of the data, or the publication process. The authors wish to thank Prof. John Hayes, University of Dundee, for the NQO1-luciferase construct and Prof. Gary Felsenfeld, NIH, Bethesda for the plasmid pJC13-1.Peer reviewedPostprin

Site specific insertion of a transgene into the murine α-casein (CSN1S1) gene results in the predictable expression of a recombinant protein in milk

Gene loci of highly expressed genes provide ideal sites for transgene expression. Casein genes are highly expressed in mammals leading to the synthesis of substantial amounts of casein proteins in milk. We have assessed the α-casein (CSN1S1) gene as a site of transgene expression in transgenic mice and a mammary gland cell line. A transgene encoding an antibody light chain gene (A1L) was inserted into the α-casein gene using sequential homologous and site-specific recombination. Expression of the inserted transgene is directed by the α-casein promoter, is responsive to lactogenic hormone activation, leads to the synthesis of a chimeric α-casein/A1L transgene mRNA and secretion of the recombinant A1L protein into milk. Transgene expression is highly consistent in all transgenic lines, but lower than that of the α-casein gene (4%). Recombinant A1L protein accounted for 0.5% and 1.6% of total milk protein in heterozygous and homozygous transgenic mice, respectively. The absence of the α-casein protein in homozygous A1L transgenic mice leads to a reduction of total milk protein and delayed growth of the pups nursed by these mice. Overall, the data demonstrate that the insertion of a transgene into a highly expressed endogenous gene is insufficient to guarantee its abundant expression. This article is protected by copyright. All rights reserved.</p

Chiral pharmaceutical drug adsorption to natural and synthetic particulates in water and their desorption in simulated gastric fluid

Natural and synthetic particulates in aquatic environments can act as a vector for chiral pharmaceutical drugs. Understanding enantiomer enrichment in the particulate phase of water matrices is essential considering the enantiospecific effects that chiral drugs can have on exposed organisms. Therefore, the enantiospecific adsorption of the cationic drugs fluoxetine and propranolol to polyhydroxyalkanoate bioplastic, polyamide microplastic, and cellulose particulates was investigated in 0.01 M calcium chloride (CaCl2) buffer and real environmental matrices. Fluoxetine enantiomers adsorbed to all particulate types under all conditions studied. Yet, propranolol only adsorbed to polyamide in 0.01 M CaCl2 buffer at pH 11, and in samples prepared using real matrices (river water and wastewater). No enantioselectivity was observed in the adsorption of fluoxetine or propranolol, or their subsequent desorption in a simulated gastric environment. Findings showed the enantiomeric composition of the adsorbed drug will reflect that of the dissolved drug assuming no degradation takes place. However, further enantiospecific adsorption studies are now needed on a broader range of chiral drugs and particulate matter found in water. Importantly, drug adsorption was considerably greater in river water and wastewater compared to 0.01 M CaCl2 buffer (2.1 to 5.3 times for fluoxetine). Most adsorption studies reported in the literature use 0.01 M CaCl2 buffer to conform with international guidelines for assessing the adsorption behaviour of chemicals. Although such conditions enable direct comparison with similar studies, they can underestimate cationic drug adsorption to particulates in engineered and natural environments. This needs consideration in future studies on drug adsorption to microplastics and other particulate matter in laboratory studies

Semaglutide and cardiovascular outcomes by baseline HbA1c in diabetes: the SUSTAIN 6 and PIONEER 6 trials.

No abstract available

A cross-institutional analysis of the effects of broadening trainee professional development on research productivity

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Brandt, P. D., Sturzenegger Varvayanis, S., Baas, T., Bolgioni, A. F., Alder, J., Petrie, K. A., Dominguez, I., Brown, A. M., Stayart, C. A., Singh, H., Van Wart, A., Chow, C. S., Mathur, A., Schreiber, B. M., Fruman, D. A., Bowden, B., Wiesen, C. A., Golightly, Y. M., Holmquist, C. E., Arneman, D., Hall, J. D., Hyman, L. E., Gould, K. L., Chalkley, R., Brennwald, P. J., Layton, R. L. A cross-institutional analysis of the effects of broadening trainee professional development on research productivity. Plos Biology, 19(7), (2021): e3000956, https://doi.org/10.1371/journal.pbio.3000956.PhD-trained scientists are essential contributors to the workforce in diverse employment sectors that include academia, industry, government, and nonprofit organizations. Hence, best practices for training the future biomedical workforce are of national concern. Complementing coursework and laboratory research training, many institutions now offer professional training that enables career exploration and develops a broad set of skills critical to various career paths. The National Institutes of Health (NIH) funded academic institutions to design innovative programming to enable this professional development through a mechanism known as Broadening Experiences in Scientific Training (BEST). Programming at the NIH BEST awardee institutions included career panels, skill-building workshops, job search workshops, site visits, and internships. Because doctoral training is lengthy and requires focused attention on dissertation research, an initial concern was that students participating in additional complementary training activities might exhibit an increased time to degree or diminished research productivity. Metrics were analyzed from 10 NIH BEST awardee institutions to address this concern, using time to degree and publication records as measures of efficiency and productivity. Comparing doctoral students who participated to those who did not, results revealed that across these diverse academic institutions, there were no differences in time to degree or manuscript output. Our findings support the policy that doctoral students should participate in career and professional development opportunities that are intended to prepare them for a variety of diverse and important careers in the workforce.Funding sources included the Common Fund NIH Director’s Biomedical Research Workforce Innovation Broadening Experiences in Scientific Training (BEST) Award. The following institutional NIH BEST awards (alphabetical by institution) included: DP7OD020322 (Boston University; AFB, ID, BMS, LEH); DP7OD020316 (University of Chicago; CAS); DP7OD018425 (Cornell University; SSV); DP7OD018428 (Virginia Polytechnic Institute; AVW, BB); DP7OD020314 (Rutgers University; JA); DP7OD020315 (University of Rochester; TB); DP7OD018423 (Vanderbilt University; KAP, AMB, KLG, RC); DP7OD020321 (University of California, Irvine; HS, DAF); DP7OD020317 (University of North Carolina, Chapel Hill; PDB, PJB, RLL); DP7 OD018427 (Wayne State University; CSC, AM). National Institutes of Health (NIH) General Medical Sciences - Science of Science Policy Approach to Analyzing and Innovating the Biomedical Research Enterprise (SCISIPBIO) Award (GM-19-011) - 1R01GM140282-01 (University of North Carolina at Chapel Hill; RLL, PDB, PJB)

Film remakes, the black sheep of translation

Film remakes have often been neglected by translation studies in favour of other forms of audiovisual translation such as subtitling and dubbing. Yet, as this article will argue, remakes are also a form of cinematic translation. Beginning with a survey of previous, ambivalent approaches to the status of remakes, it proposes that remakes are multimodal, adaptive translations: they translate the many modes of the film being remade and offer a reworking of that source text. The multimodal nature of remakes is explored through a reading of Breathless, Jim McBride's 1983 remake of Jean-Luc Godard's À bout de souffle (1959), which shows how remade films may repeat the narrative of, but differ on multiple levels from, their source films. Due to the collaborative nature of film production, remakes involve multiple agents of translation. As such, remakes offer an expanded understanding of audiovisual translation