Alanyl-tRNA Synthetase Quality Control Prevents Global Dysregulation of the \u3cem\u3eEscherichia coli\u3c/em\u3e Proteome

Mechanisms have evolved to prevent errors in replication, transcription, and translation of genetic material, with translational errors occurring most frequently. Errors in protein synthesis can occur at two steps, during tRNA aminoacylation and ribosome decoding. Recent advances in protein mass spectrometry have indicated that previous reports of translational errors have potentially underestimated the frequency of these events, but also that the majority of translational errors occur during ribosomal decoding, suggesting that aminoacylation errors are evolutionarily less tolerated. Despite that interpretation, there is evidence that some aminoacylation errors may be regulated, and thus provide a benefit to the cell, while others are clearly detrimental. Here, we show that while it has been suggested that regulated Thr-to-Ser substitutions may be beneficial, there is a threshold beyond which these errors are detrimental. In contrast, we show that errors mediated by alanyl-tRNA synthetase (AlaRS) are not well tolerated and induce a global stress response that leads to gross perturbation of the Escherichia coli proteome, with potentially catastrophic effects on fitness and viability. Tolerance for Ala mistranslation appears to be much lower than with other translational errors, consistent with previous reports of multiple proofreading mechanisms targeting mischarged tRNAAla. These results demonstrate the essential role of aminoacyl-tRNA proofreading in optimizing cellular fitness and suggest that any potentially beneficial effects of mistranslation may be confined to specific amino acid substitutions

Racial and ethnic disparities in the control of cardiovascular disease risk factors in Southwest American veterans with type 2 diabetes: the Diabetes Outcomes in Veterans Study

BACKGROUND: Racial/ethnic disparities in cardiovascular disease complications have been observed in diabetic patients. We examined the association between race/ethnicity and cardiovascular disease risk factor control in a large cohort of insulin-treated veterans with type 2 diabetes. METHODS: We conducted a cross-sectional observational study at 3 Veterans Affairs Medical Centers in the American Southwest. Using electronic pharmacy databases, we randomly selected 338 veterans with insulin-treated type 2 diabetes. We collected medical record and patient survey data on diabetes control and management, cardiovascular disease risk factors, comorbidity, demographics, socioeconomic factors, psychological status, and health behaviors. We used analysis of variance and multivariate linear regression to determine the effect of race/ethnicity on glycemic control, insulin treatment intensity, lipid levels, and blood pressure control. RESULTS: The study cohort was comprised of 72 (21.3%) Hispanic subjects (H), 35 (10.4%) African Americans (AA), and 226 (67%) non-Hispanic whites (NHW). The mean (SD) hemoglobin A1c differed significantly by race/ethnicity: NHW 7.86 (1.4)%, H 8.16 (1.6)%, AA 8.84 (2.9)%, p = 0.05. The multivariate-adjusted A1c was significantly higher for AA (+0.93%, p = 0.002) compared to NHW. Insulin doses (unit/day) also differed significantly: NHW 70.6 (48.8), H 58.4 (32.6), and AA 53.1 (36.2), p < 0.01. Multivariate-adjusted insulin doses were significantly lower for AA (-17.8 units/day, p = 0.01) and H (-10.5 units/day, p = 0.04) compared to NHW. Decrements in insulin doses were even greater among minority patients with poorly controlled diabetes (A1c ≥ 8%). The disparities in glycemic control and insulin treatment intensity could not be explained by differences in age, body mass index, oral hypoglycemic medications, socioeconomic barriers, attitudes about diabetes care, diabetes knowledge, depression, cognitive dysfunction, or social support. We found no significant racial/ethnic differences in lipid or blood pressure control. CONCLUSION: In our cohort, insulin-treated minority veterans, particularly AA, had poorer glycemic control and received lower doses of insulin than NHW. However, we found no differences for control of other cardiovascular disease risk factors. The diabetes treatment disparity could be due to provider behaviors and/or patient behaviors or preferences. Further research with larger sample sizes and more geographically diverse populations are needed to confirm our findings

Complications among colorectal cancer survivors: SF-6D preference-weighted quality of life scores

Background Societal preference-weighted health-related quality of life (HRQOL) scores enable comparing multi-dimensional health states across diseases and treatments for research and policy. Objective To assess the effects of living with a permanent intestinal stoma, compared to a major bowel resection, among colorectal cancer (CRC) survivors. Research Design Cross-sectional multivariate linear regression analysis to explain preference-weighted HRQOL scores. Subjects Six-hundred-forty CRC survivors (≥5 years) from three group-model HMOs; ostomates and non-ostomates with colorectal resections for CRC were matched on gender, age (±5 years), time since diagnosis, and tumor site (rectum vs. colon). Measures SF-6D scoring system applied to Medical Outcomes Study Short Form-36 version 2 (SF-36v2); City of Hope Quality of Life-Ostomy (mCOH-QOL-O); Charlson-Deyo comorbidity index. Methods Survey of CRC survivors linked to respondents’ clinical data extracted from HMO files. Results Response rate was 52%. Ostomates and non-ostomates had similar sociodemographic characteristics. Mean SF-6D score was 0.69 for ostomates, compared to 0.73 for non-ostomates (p <.001), but other factors explained this difference. Complications of initial cancer surgery, and prior-year comorbidity burden and hospital use were negatively associated with SF-6D scores, while household income was positively associated. Conclusions CRC survivors’ SF-6D scores were not associated with living with a permanent ostomy after other factors were taken into account. Surgical complications, comorbidities, and metastatic disease lowered the preference-weighted HRQOL of CRC survivors with and without ostomies. Further research to understand and reduce late complications from CRC surgeries as well as associated depression is warranted

Variable Nav1.5 Protein Expression from the Wild-Type Allele Correlates with the Penetrance of Cardiac Conduction Disease in the Scn5a+/− Mouse Model

BACKGROUND: Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. METHODOLOGY/PRINCIPAL FINDINGS: Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones. CONCLUSIONS: Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression

14-3-3 Amplifies Androgen Receptor Actions in Prostate Cancer

Androgen receptor (AR) abundance and AR-regulated gene expression in castration-recurrent prostate cancer (CaP) are indicative of AR activation in the absence of testicular androgen. AR transactivation of target genes in castration-recurrent CaP occurs in part through mitogen signaling that amplifies the actions of AR and its coregulators. Herein we report on the role of 14-3-3η in AR action

Reconstructing grassland fire history using sedimentary charcoal: Considering count, size and shape

Citation: Leys, B. A., Commerford, J. L., & McLauchlan, K. K. (2017). Reconstructing grassland fire history using sedimentary charcoal: Considering count, size and shape. Plos One, 12(4), 15. doi:10.1371/journal.pone.0176445Fire is a key Earth system process, with 80% of annual fire activity taking place in grassland areas. However, past fire regimes in grassland systems have been difficult to quantify due to challenges in interpreting the charcoal signal in depositional environments. To improve reconstructions of grassland fire regimes, it is essential to assess two key traits: (1) charcoal count, and (2) charcoal shape. In this study, we quantified the number of charcoal pieces in 51 sediment samples of ponds in the Great Plains and tested its relevance as a proxy for the fire regime by examining 13 potential factors influencing charcoal count, including various fire regime components (e.g. the fire frequency, the area burned, and the fire season), vegetation cover and pollen assemblages, and climate variables. We also quantified the width to length (W: L) ratio of charcoal particles, to assess its utility as a proxy of fuel types in grassland environments by direct comparison with vegetation cover and pollen assemblages. Our first conclusion is that charcoal particles produced by grassland fires are smaller than those produced by forest fires. Thus, a mesh size of 120 mu m as used in forested environments is too large for grassland ecosystems. We recommend counting all charcoal particles over 60 mu m in grasslands and mixed grass-forest environments to increase the number of samples with useful data. Second, a W: L ratio of 0.5 or smaller appears to be an indicator for fuel types, when vegetation surrounding the site is before composed of at least 40% grassland vegetation. Third, the area burned within 1060m of the depositional environments explained both the count and the area of charcoal particles. Therefore, changes in charcoal count or charcoal area through time indicate a change in area burned. The fire regimes of grassland systems, including both human and climatic influences on fire behavior, can be characterized by long-term charcoal records

Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

Background: We evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Methods and Results: Plasma Lp‐PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA2 activity levels and outcomes. At baseline, the median Lp‐PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA2 activity. There were no associations between on‐treatment Lp‐PLA2 activity or changes of Lp‐PLA2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA2 activity or changes in Lp‐PLA2 activity levels and the effects of darapladib on outcomes. Conclusions: Although high Lp‐PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA2 activity