Recent years have brought a flood of interest in developing compounds that selectively degrade protein targets in cells, as exemplified by PROTACs. Fully realizing the promise of PROTACs to transform chemical biology by delivering degraders of diverse and undruggable protein targets has been impeded, however, by the fact that designing a suitable chemical linker between the functional moieties requires extensive trial and error. Here, we describe a structure-based computational method to predict PROTAC activity. We envision that this approach will allow design and optimization of PROTACs for efficient target degradation, selection of E3 ligases best suited for pairing with a given target protein, and understanding the basis by which PROTACs can exhibit different target selectivity than their component warheads..

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ImportanceA better understanding of the association between family structure and sex gaps in physician earnings and hours worked over the life cycle is needed to advance policies addressing persistent sex disparities.ObjectiveTo investigate differences in earnings and hours worked for male and female physicians at various ages and family status.Design, Setting, and ParticipantsThis retrospective, cross-sectional study used data on physicians aged 25 to 64 years responding to the American Community Survey between 2005 and 2019.ExposuresEarned income and work hours.Main Outcomes and MeasuresOutcomes included annual earned income, usual hours worked per week, and earnings per hour worked. Gaps in earnings and hours by sex were calculated by family status and physician age and, in some analyses, adjusted for demographic characteristics and year of survey. Data analyses were conducted between 2019 and 2022.ResultsThe sample included 95 435 physicians (35.8% female, 64.2% male, 19.8% Asian, 4.8% Black, 5.9% Hispanic, 67.3% White, and 2.2% other race or ethnicity) with a mean (SD) age of 44.4 (10.4) years. Relative to male physicians, female physicians were more likely to be single (18.8% vs 11.2%) and less likely to have children (53.3% vs 58.2%). Male-female earnings gaps grew with age and, when accumulated from age 25 to 64 years, were approximately $1.6 million for single physicians, $2.5 million for married physicians without children, and $3.1 million for physicians with children. Gaps in earnings per hour did not vary by family structure, with male physicians earning between 21.4% and 23.9% more per hour than female physicians. The male-female gap in hours worked was 0.6% for single physicians, 7.0% for married physicians without children, and 17.5% for physicians with children.Conclusions and RelevanceIn this cross-sectional study of US physicians, marriage and children were associated with a greater earnings penalty for female physicians, primarily due to fewer hours worked relative to men. Addressing the barriers that lead to women working fewer hours could contribute to a reduction in the male-female earnings gap while helping to expand the effective physician workforce.