Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turn-over by the ubiquitin-proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by SCFFbxw7. However, N-Myc protein is stabilized in neuroblastoma by Aurora-A kinase in a manner that is sensitive to certain Aurora-A-selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCFFbxw7. We determine the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72 Å resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCFFbxw7 to disfavor the generation of Lys48-linked poly-Ub chains

Amygdala responses to emotionally valenced stimuli in older and younger adults

ABSTRACT—As they age, adults experience less negative emotion, come to pay less attention to negative than to positive emotional stimuli, and become less likely to remember negative than positive emotional materials. This profile of findings suggests that, with age, the amygdala may show decreased reactivity to negative information while maintaining or increasing its reactivity to positive information. We used event-related functional magnetic resonance imaging to assess whether amygdala activation in response to positive and negative emotional pictures changes with age. Both older and younger adults showed greater activation in the amygdala for emotional than for neutral pictures; however, for older adults, seeing positive pictures led to greater amygdala activation than seeing negative pictures, whereas this was not the case for younger adults. Older adults experience less negative affect than younger adults in both cross-sectional and longitudinal studies (Carstensen, Pasupathi

Rhino Conjunctivitis and Asthma Among Seafood Processing Workers in Greenland. A Cross-Sectional Study

Introduction: The fishing- and the seafood processing industries are the largest industrial sectors in Greenland. Despite this, only a few cases of occupational diseases in this industry have been reported to the Danish Labor Market Insurance. Occupational asthma and allergy are well-known occupational diseases in the seafood processing industry worldwide and underreporting of occupational diseases in Greenland is suspected.Objective: The aim of the current study was to examine the associations between job exposures and occupational asthma and rhino conjunctivitis in workers in the Greenlandic seafood processing industry and to compare the prevalence of sensitization by type and degree of exposure to snow crab, shrimp, fish, and the fish parasite, Anisakis simplex.Methods: Data from 382 Greenlandic seafood processing workers were collected during 2016–2018. Data included questionnaire answers, lung function measurements, skin prick tests, and blood samples with ImmunoCAP. For all analyses, p < 0.05 was considered the level of significance.Results: 5.5% of the workers had occupational asthma and 4.6% had occupational rhino conjunctivitis. A large proportion of the workers were sensitized to allergens specific to the workplace; 18.1% to snow crab, 13.6% to shrimp, 1.4% to fish, and 32.6% to the fish parasite, A. simplex. We found a dose-response relationship between the risk of being sensitized to snow crab and A. simplex and years of exposure to the allergens in the seafood processing industry.Conclusion: This study showed that a considerable proportion of workers in the Greenlandic seafood processing industry had occupational asthma and rhino conjunctivitis. Additionally, the study showed high sensitization levels toward snow crab, shrimp, and the fish parasite, A. simplex. This supports the hypothesis of a considerable degree of underreporting of occupational allergic airway disease in the Greenlandic seafood processing industry. Prospectively, it is important to inform workers, leaders, and health care professionals of the health problems and the law on worker's compensation, and to initiate preventive actions at factory and trawler level

Association with Aurora-A controls N-MYC-dependent promoter escape and pause release of RNA polymerase II during the cell cycle

MYC proteins bind globally to active promoters and promote transcriptional elongation by RNA polymerase II (Pol II). To identify effector proteins that mediate this function, we performed mass spectrometry on N-MYC complexes in neuroblastoma cells. The analysis shows that N-MYC forms complexes with TFIIIC, TOP2A, and RAD21, a subunit of cohesin. N-MYC and TFIIIC bind to overlapping sites in thousands of Pol II promoters and intergenic regions. TFIIIC promotes association of RAD21 with N-MYC target sites and is required for N-MYC-dependent promoter escape and pause release of Pol II. Aurora-A competes with binding of TFIIIC and RAD21 to N-MYC in vitro and antagonizes association of TOP2A, TFIIIC, and RAD21 with N-MYC during S phase, blocking N-MYC-dependent release of Pol II from the promoter. Inhibition of Aurora-A in S phase restores RAD21 and TFIIIC binding to chromatin and partially restores N-MYC-dependent transcriptional elongation. We propose that complex formation with Aurora-A controls N-MYC function during the cell cycle

Entrepreneurs’ age, institutions, and social value creation goals: a multi-country study

This study explores the relationship between an entrepreneur's age and his/her social value creation goals. Building on the lifespan developmental psychology literature and institutional theory, we hypothesize a U-shaped relationship between entrepreneurs’ age and their choice to create social value through their ventures, such that younger and older entrepreneurs create more social value with their businesses while middle age entrepreneurs are relatively more economically and less socially oriented with their ventures. We further hypothesize that the quality of a country’s formal institutions in terms of economic, social, and political freedom steepen the U-shaped relationship between entrepreneurs’ age and their choice to pursue social value creation as supportive institutional environments allow entrepreneurs to follow their age-based preferences. We confirm our predictions using multilevel mixed-effects linear regressions on a sample of over 15,000 entrepreneurs (aged between 18 and 64 years) in 45 countries from Global Entrepreneurship Monitor data. The findings are robust to several alternative specifications. Based on our findings, we discuss implications for theory and practice, and we propose future research directions