Global signal peptide profiling reveals principles of selective Sec61 inhibition.

Cotransins target the Sec61 translocon and inhibit the biogenesis of an undefined subset of secretory and membrane proteins. Remarkably, cotransin inhibition depends on the unique signal peptide (SP) of each Sec61 client, which is required for cotranslational translocation into the endoplasmic reticulum. It remains unknown how an SP's amino acid sequence and biophysical properties confer sensitivity to structurally distinct cotransins. Here we describe a fluorescence-based, pooled-cell screening platform to interrogate nearly all human SPs in parallel. We profiled two cotransins with distinct effects on cancer cells and discovered a small subset of SPs, including the oncoprotein human epidermal growth factor receptor 3 (HER3), with increased sensitivity to the more selective cotransin, KZR-9873. By comparing divergent mouse and human orthologs, we unveiled a position-dependent effect of arginine on SP sensitivity. Our multiplexed profiling platform reveals how cotransins can exploit subtle sequence differences to achieve SP discrimination.

A Comparative Analysis of Gender Discrepancy Stress, Attitudes toward Intimate Partner Violence, and Perpetration among Young Adults in the USA and Uganda.

BACKGROUND: There is a dearth of data on the modifiable factors that contribute to violence in low- and middle-income countries, including attitudes regarding intimate partner violence (IPV) and perceptions of gender identity. We examined these factors using a cross-cultural comparison between young adults in Uganda and the United States. METHODS: A cross-sectional survey was distributed to young adults aged 18 to 25 in Uganda (n = 300) and the U.S. (n = 300). Survey questions assessed demographics, attitudes toward IPV, IPV victimization and perpetration, gender discrepancy, discrepancy stress, and alcohol use. We conducted chi-square tests, as well as bivariable and multivariable logistic regression analyses, separately for participants in each country. RESULTS: The prevalence of IPV perpetration differed significantly by country for men (58.06% in the U.S. vs. 42.73% in Uganda; p = 0.03) and women (40.00% in the U.S. vs. 14.00% in Uganda; p < 0.01). IPV victimization differed by country for men (67.74% in the U.S. vs. 51.82% in Uganda; p = 0.02) but not for women. Gender discrepancy and discrepancy stress also varied by country and by sex and were higher in the U.S. for both men and women. IPV victimization was a common risk factor for adults in both Uganda (Adj. OR = 23.47; 95% CI: 7.79, 70.22) and the U.S. (Adj. OR = 27.40; 95% CI: 9.97, 75.32). In Uganda, male sex was significantly associated with IPV perpetration in multivariable analyses (Adj. OR = 6.23; 95% CI: 2.45, 15.86), and so were IPV attitudes (Adj. OR = 2.22; 1.20, 4.10). In the U.S., a likely alcohol use disorder (AUD) was also significantly associated with IPV perpetration (Adj. OR = 7.11; 95% CI: 2.25, 22.54). CONCLUSIONS: Permissive IPV attitudes were associated with IPV perpetration among Ugandan participants, while likely AUD was associated with perpetration in U.S. PARTICIPANTS: Overall, IPV perpetration was significantly higher for U.S. males compared with Ugandan males. These findings indicate that cultural adaptations to global IPV interventions may be necessary to respond to differing needs in different countries.