KRAS
has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" ...target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS
to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS
inhibitor currently in phase I clinical trials (NCT03600883).
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this ...long-“undruggable” target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).
Research examining the link between media attention and breast cancer concern has been frequently conducted with middle/old-age women, even though young women (<40 years old) have been ...overrepresented media stories about breast cancer. Accordingly, little is known about young women's emotional reactions to breast cancer media messages and the psychological factors modulating such reactions. This study examined the impact of breast cancer media messages and cognitive fusion on negative affect, fear of breast cancer (FBC), and perceived susceptibility to breast cancer. 207 young women were randomly assigned to watch a low- or high-threat video about breast cancer. A MANCOVA revealed that participants who viewed the high-threat video reported greater negative affect and perceived susceptibility, but not FBC; however, participants in both conditions showed moderate/high FBC. Correlational analyses and a MANOVA showed that participants reporting higher cognitive fusion reported higher negative affect across conditions, as well as higher FBC in the high-threat condition. Taken together, these results suggest that young women may show habituation to alarmist media messages, but may nonetheless construe breast cancer as a significant threat. Moreover, young women showing medium/high cognitive fusion seem more likely to show heightened concern upon exposure to alarmist media messages about breast cancer.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
This article has been retracted at the ...request of the corresponding author due to similarities identified with a previously published paper, 'Performance of a Low Energy Ion Source with Carbon Nanotube Electron Emitters under the Influence of Various Operating Gases', in Nanomaterials (Nanomaterials 2020, 10(2), 354; https://doi.org/10.3390/nano10020354). The author wishes to apologise for any confusion or inconvenience caused.
Topoisomerases are enzymes with crucial functions in DNA metabolism. They are ubiquitously present in prokaryotes and eukaryotes and modify the steady-state level of DNA supercoiling. Biochemical ...analyses indicate that Topoisomerase 3α (TOP3α) functions together with a RecQ DNA helicase and a third partner, RMI1/BLAP75, in the resolution step of homologous recombination in a process called Holliday Junction dissolution in eukaryotes. Apart from that, little is known about the role of TOP3α in higher eukaryotes, as knockout mutants show early lethality or strong developmental defects. Using a hypomorphic insertion mutant of
Arabidopsis thaliana
(
top3α-2
), which is viable but completely sterile, we were able to define three different functions of the protein in mitosis and meiosis. The
top3α-2
line exhibits fragmented chromosomes during mitosis and sensitivity to camptothecin, suggesting an important role in chromosome segregation partly overlapping with that of type IB topoisomerases. Furthermore, AtTOP3α, together with AtRECQ4A and AtRMI1, is involved in the suppression of crossover recombination in somatic cells as well as DNA repair in both mammals and
A. thaliana
. Surprisingly, AtTOP3α is also essential for meiosis. The phenotype of chromosome fragmentation, bridges, and telophase I arrest can be suppressed by At
SPO11
and At
RAD51
mutations, indicating that the protein is required for the resolution of recombination intermediates. As At
rmi1
mutants have a similar meiotic phenotype to At
top3α
mutants, both proteins seem to be involved in a mechanism safeguarding the entangling of homologous chromosomes during meiosis. The requirement of AtTOP3α and AtRMI1 in a late step of meiotic recombination strongly hints at the possibility that the dissolution of double Holliday Junctions via a hemicatenane intermediate is indeed an indispensable step of meiotic recombination.
The topoisomerases of the class IA are present in all three eukaryotic kingdoms—plants, fungi, and animals—and are involved in DNA replication and DNA repair. During the course of their action, they introduce transient single-strand nicks into DNA. In higher eukaryotes, two different classes of the enzymes are present: TOP3α and TOP3β. TOP3α is essential, as disruption of its function usually results in lethality of the affected organism. Using a mutant of TOP3α that retains some activity, we show that the protein has multiple, different functions in the model plant
A. thaliana
. Besides its action in somatic cells, where it is required for mitosis as well as DNA repair, we demonstrate that TOP3α together with its protein partner RMI1 is essential for meiosis. Here, both proteins are involved in DNA recombination—the exchange of information between parental chromosomes. Disruption of either TOP3α or RMI1 leads to grave defects and an early termination of meiosis, resulting in the sterility of the mutant plants. Our detailed analysis indicates that both proteins are involved in a late step of meiotic recombination, in a mechanism that prevents entanglement of the parental chromosomes. Thus, meiotic recombination seems to be more complex than previously anticipated.
Objective:
Exercise is beneficial for individuals who have been diagnosed with cardiovascular disease or cancer. Healthcare providers are well placed to discuss exercise with their patients, but ...their referral practices and the content of exercise recommendations remain unclear.
Method:
Cardiologists and oncologists completed an online survey comprising four closed-ended questions and one open-ended question to assess exercise recommendation and referral practices. Chi-square tests were used to compare the frequency of closed-ended responses, and open-ended responses were coded and analysed using qualitative content analysis.
Results:
Of the 154 surveys, 58 were returned (n = 25; 43.1% cardiologists, and n = 33; 56.9% oncologists). Respondents (Mage = 45.5 ± 11.1) were mostly men (62.1%). The majority of cardiologists (95.8%) and oncologists (78.1%) reported referring patients to hospital-based exercise programmes. In this study, the cardiologists were more likely to refer patients to certified exercise physiologists (χ2(1) = 6.140, p = .021), whereas oncologists were more likely to refer to physical therapists (χ2(1) = 11.764, p = .001).
Conclusion:
Findings reveal that cardiologists and oncologists discussed and recommended exercise to their patients at least some or most of the time; there were differences in the type of exercise professionals they were referred to; and exercise recommendations were variable and infrequently concurred with established guidelines.
The ice giants Uranus and Neptune are the least understood class of planets in our solar system but the most frequently observed type of exoplanets. Presumed to have a small rocky core, a deep ...interior comprising ∼70% heavy elements surrounded by a more dilute outer envelope of H2 and He, Uranus and Neptune are fundamentally different from the better-explored gas giants Jupiter and Saturn. Because of the lack of dedicated exploration missions, our knowledge of the composition and atmospheric processes of these distant worlds is primarily derived from remote sensing from Earth-based observatories and space telescopes. As a result, Uranus's and Neptune's physical and atmospheric properties remain poorly constrained and their roles in the evolution of the Solar System not well understood. Exploration of an ice giant system is therefore a high-priority science objective as these systems (including the magnetosphere, satellites, rings, atmosphere, and interior) challenge our understanding of planetary formation and evolution. Here we describe the main scientific goals to be addressed by a future in situ exploration of an ice giant. An atmospheric entry probe targeting the 10-bar level, about 5 scale heights beneath the tropopause, would yield insight into two broad themes: i) the formation history of the ice giants and, in a broader extent, that of the Solar System, and ii) the processes at play in planetary atmospheres. The probe would descend under parachute to measure composition, structure, and dynamics, with data returned to Earth using a Carrier Relay Spacecraft as a relay station. In addition, possible mission concepts and partnerships are presented, and a strawman ice-giant probe payload is described. An ice-giant atmospheric probe could represent a significant ESA contribution to a future NASA ice-giant flagship mission.
The distant ice giants of the Solar System, Uranus and Neptune, have only been visited by one space mission, Voyager 2. The current knowledge on their composition remains very limited despite some ...recent advances. A better characterization of their composition is however essential to constrain their formation and evolution, as a significant fraction of their mass is made of heavy elements, contrary to the gas giants Jupiter and Saturn. An in situ probe like Galileo would provide us with invaluable direct ground-truth composition measurements. However, some of the condensibles will remain out of the grasp of a shallow probe. While additional constraints could be obtained from a complementary orbiter, thermochemistry and diffusion modeling can further help us to increase the science return of an in situ probe.
Measuring the Complexity of Lithic Technology Perreault, Charles; Brantingham, P. Jeffrey; Kuhn, Steven L. ...
Current anthropology,
12/2013, Letnik:
54, Številka:
S8
Journal Article, Conference Proceeding
Recenzirano
Assessments of the complexity of lithic technologies coming from different time periods, regions, or hominid species are recurrent features of the literature on Paleolithic archaeology. Yet the ...notion of lithic complexity is often defined intuitively and qualitatively, which can easily lead to circular arguments and makes difficult the comparison of assemblages across different regions and time periods. Here we propose, in the spirit of Oswalt’s techno-units, that the complexity of lithic technology can be quantified by counting the procedural units involved in tool manufacture. We define procedural units as mutually exclusive manufacturing steps that make a distinct contribution to the finished form of a technology. As a proof of concept, we use the procedural-unit approach to measure the complexity of 13 Paleolithic assemblages. While preliminary, these results provide a quantitative benchmark confirming that lithic technological complexity increased throughout the Paleolithic period. The method to measure lithic complexity outlined here will allow us to revisit several claims made about change in technological complexity during human evolution.
Context. Early measurements of Rosetta's target comet, 67P/Churyumov-Gerasimenko (67P), showed a strongly heterogeneous coma in H sub(2)O, CO, and CO sub(2). Aims. The purpose of this work is to ...further investigate the coma heterogeneity of 67P, and to provide predictions for the near-perihelion outgassing profile based on the proposed explanations. Methods. Measurements of various minor volatile species by ROSINA/DFMS on board Rosetta are examined. The analysis focuses on the currently poorly illuminated winter (southern) hemisphere of 67P. Results. Coma heterogeneity is not limited to the major outgassing species. Minor species show better correlation with either H sub(2)O or CO sub(2). The molecule CH sub(4) shows a different diurnal pattern from all other analyzed species. Such features have implications for nucleus heterogeneity and thermal processing. Conclusions. Future analysis of additional volatiles and modeling the heterogeneity are required to better understand the observed coma profile.
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