Characterization of protein quality control components via dual reporter-containing misfolded cytosolic model substrates

Protein misfolding and protein aggregation are causes of severe diseases as neurodegenerative disorders, diabetes and cancer. Therefore, the cell has to constantly monitor the folding status of its proteome. Chaperones and components of the ubiquitin-proteasome system are key players in the cellular protein quality control process. In order to characterize components of the protein quality control system in a well-established model eukaryote - the yeast Saccharomyces cerevisiae - we established new cytosolic model substrates based on firefly luciferase and β-isopropylmalate dehydrogenase (Leu2). The use of these two different enzymes arranged in tandem as reporters enabled us to analyse the folding status and the degradation propensity of these new model substrates in yeast cells mutated in components of the cellular protein quality control system. The Hsp70 chaperone system known to be essential in the cellular protein quality control was chosen as a model for showing the high value of the luciferase-based model substrates in the characterization of components of the cytosolic protein quality control system in yeast.     

Enhanced stiffness of silk‐like fibers by loop formation in the corona leads to stronger gels

We study the self‐assembly of protein polymers consisting of a silk‐like block flanked by two hydrophilic blocks, with a cysteine residue attached to the C‐terminal end. The silk blocks self‐assemble to form fibers while the hydrophilic blocks form a stabilizing corona. Entanglement of the fibers leads to the formation of hydrogels. Under oxidizing conditions the cysteine residues form disulfide bridges, effectively connecting two corona chains at their ends to form a loop. We find that this leads to a significant increase in the elastic modulus of the gels. Using atomic force microscopy, we show that this stiffening is due to an increase of the persistence length of the fibers. Self‐consistent‐field calculations indicate a slight decrease of the lateral pressure in the corona upon loop formation. We argue that this small decrease in the repulsive interactions affects the stacking of the silk‐like blocks in the core, resulting in a more rigid fiber.     

Megafauna extinction,tree species range reduction,and carbon storage in Amazonian forests

During the Late Pleistocene and early Holocene 59 species of South American megafauna went extinct. Their extinction potentially triggered population declines of large‐seeded tree species dispersed by the large‐bodied frugivores with which they co‐evolved, a theory first proposed by Janzen and Martin (1982). We tested this hypothesis using species range maps for 257 South American tree species, comparing 63 species thought to be primarily distributed by megafauna with 194 distributed by other animals. We found a highly significant (p < 0.001) decreased mean range size of 26% for the megafauna dispersed fruit (n = 63 species) versus fruit dispersed by other animals (n = 194), results which support the hypothesis. We then developed a mathematical model of seed dispersal to estimate the theoretical impact of megafauna extinction on tree species range and found the estimated dispersal capacity (Φ_seed) of a 2 g seed decreases by > 95% following disperser extinction. A numerical gap dynamic simulations suggests that over a 10 000 yr period following the disperser extinctions, the average convex hull range size of large‐seeded tree species decreased by ～ 31%, while the estimated decrease in population size was ～ 54%, indicating a likely greater decrease in species population size than indicated by the empirical range patterns. Finally, we found a positive correlation between seed size and wood density of animal‐dispersed tree species implying that the Late Pleistocene and early Holocene megafaunal extinctions reduced carbon content in the Amazon by ～ 1.5 ± 0.7%. In conclusion, we 1) provide some empirical evidence that megafauna distributed fruit species have a smaller mean range size than wind, water or other animal‐dispersed species, 2) demonstrate mathematically that such range reductions are expected from megafauna extinctions ca 12 000 yr ago, and 3) illustrate that these extinctions may have reduced the Amazon's carbon storage capacity.     

Socioeconomic and Other Demographic Disparities Predicting Survival among Head and Neck Cancer Patients

Background

The Institute of Medicine (IOM) report, “Unequal Treatment,” which defines disparities as racially based, indicates that disparities in cancer diagnosis and treatment are less clear. While a number of studies have acknowledged cancer disparities, they have limitations of retrospective nature, small sample sizes, inability to control for covariates, and measurement errors.

Objective

The purpose of this study was to examine disparities as predictors of survival among newly diagnosed head and neck cancer patients recruited from 3 hospitals in Michigan, USA, while controlling for a number of covariates (health behaviors, medical comorbidities, and treatment modality).

Methods

Longitudinal data were collected from newly diagnosed head and neck cancer patients (N = 634). The independent variables were median household income, education, race, age, sex, and marital status. The outcome variables were overall, cancer-specific, and disease-free survival censored at 5 years. Kaplan-Meier curves and univariate and multivariate Cox proportional hazards models were performed to examine demographic disparities in relation to survival.

Results

Five-year overall, cancer-specific, and disease-free survival were 65.4% (407/622), 76.4% (487/622), and 67.0% (427/622), respectively. Lower income (HR, 1.5; 95% CI, 1.1–2.0 for overall survival; HR, 1.4; 95% CI, 1.0–1.9 for cancer-specific survival), high school education or less (HR, 1.4; 95% CI, 1.1–1.9 for overall survival; HR, 1.4; 95% CI, 1.1–1.9 for cancer-specific survival), and older age in decades (HR, 1.4; 95% CI, 1.2–1.7 for overall survival; HR, 1.2; 95% CI, 1.1–1.4 for cancer-specific survival) decreased both overall and disease-free survival rates. A high school education or less (HR, 1.4; 95% CI, 1.0–2.1) and advanced age (HR, 1.3; 95% CI, 1.1–1.6) were significant independent predictors of poor cancer-specific survival.

Conclusion

Low income, low education, and advanced age predicted poor survival while controlling for a number of covariates (health behaviors, medical comorbidities, and treatment modality). Recommendations from the Institute of Medicine’s Report to reduce disparities need to be implemented in treating head and neck cancer patients.