A Distinct Translation Initiation Mechanism Generates Cryptic Peptides for Immune Surveillance

MHC class I molecules present a comprehensive mixture of peptides on the cell surface for immune surveillance. The peptides represent the intracellular protein milieu produced by translation of endogenous mRNAs. Unexpectedly, the peptides are encoded not only in conventional AUG initiated translational reading frames but also in alternative cryptic reading frames. Here, we analyzed how ribosomes recognize and use cryptic initiation codons in the mRNA. We find that translation initiation complexes assemble at non-AUG codons but differ from canonical AUG initiation in response to specific inhibitors acting within the peptidyl transferase and decoding centers of the ribosome. Thus, cryptic translation at non-AUG start codons can utilize a distinct initiation mechanism which could be differentially regulated to provide peptides for immune surveillance

A retrospective cohort study on lifestyle habits of cardiovascular patients: how informative are medical records?

Contains fulltext : 79771.pdf (publisher's version ) (Open Access)BACKGROUND: To evaluate the vigilance of medical specialists as to the lifestyle of their cardiovascular outpatients by comparing lifestyle screening as registered in medical records versus a lifestyle questionnaire (LSQ), a study was carried out at the cardiovascular outpatient clinic of the university hospital of Nijmegen, The Netherlands, between June 2004 and June 2005. METHODS: For 209 patients information from medical records on lifestyle habits, physician feedback, and interventions in the past year was compared to data gathered in the last month by a self-report LSQ. RESULTS: Doctors register smoking habits most consistently (90.4%), followed by alcohol use (81.8%), physical activity (50.2%), and eating habits (27.3%). Compared to the LSQ, smoking, unhealthy alcohol use, physical activity, and unhealthy eating habits are underreported in medical records by 31, 83, 54 and 97%, respectively. Feedback, advice or referral was documented in 8% for smoking, 3% for alcohol use, 12% for physical activity, and 26% for eating habits. CONCLUSION: Lifestyle is insufficiently registered or recognized by doctors providing routine care in a cardiovascular outpatient setting. Of the unhealthy lifestyle habits that are registered, few are accompanied by notes on advice or intervention. A lifestyle questionnaire facilitates screening and interventions in target patients and should therefore be incorporated in the cardiovascular setting as a routine patient intake procedure

Coronavirus Gene 7 Counteracts Host Defenses and Modulates Virus Virulence

Transmissible gastroenteritis virus (TGEV) genome contains three accessory genes: 3a, 3b and 7. Gene 7 is only present in members of coronavirus genus a1, and encodes a hydrophobic protein of 78 aa. To study gene 7 function, a recombinant TGEV virus lacking gene 7 was engineered (rTGEV-Δ7). Both the mutant and the parental (rTGEV-wt) viruses showed the same growth and viral RNA accumulation kinetics in tissue cultures. Nevertheless, cells infected with rTGEV-Δ7 virus showed an increased cytopathic effect caused by an enhanced apoptosis mediated by caspase activation. Macromolecular synthesis analysis showed that rTGEV-Δ7 virus infection led to host translational shut-off and increased cellular RNA degradation compared with rTGEV-wt infection. An increase of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation and an enhanced nuclease, most likely RNase L, activity were observed in rTGEV-Δ7 virus infected cells. These results suggested that the removal of gene 7 promoted an intensified dsRNA-activated host antiviral response. In protein 7 a conserved sequence motif that potentially mediates binding to protein phosphatase 1 catalytic subunit (PP1c), a key regulator of the cell antiviral defenses, was identified. We postulated that TGEV protein 7 may counteract host antiviral response by its association with PP1c. In fact, pull-down assays demonstrated the interaction between TGEV protein 7, but not a protein 7 mutant lacking PP1c binding motif, with PP1. Moreover, the interaction between protein 7 and PP1 was required, during the infection, for eIF2α dephosphorylation and inhibition of cell RNA degradation. Inoculation of newborn piglets with rTGEV-Δ7 and rTGEV-wt viruses showed that rTGEV-Δ7 virus presented accelerated growth kinetics and pathology compared with the parental virus. Overall, the results indicated that gene 7 counteracted host cell defenses, and modified TGEV persistence increasing TGEV survival. Therefore, the acquisition of gene 7 by the TGEV genome most likely has provided a selective advantage to the virus

Comment letters to the National Commission on Commission on Fraudulent Financial Reporting, 1987 (Treadway Commission) Vol. 2

https://egrove.olemiss.edu/aicpa_sop/1662/thumbnail.jp

Reducing Medication Regimen Complexity: A Controlled Trial

OBJECTIVE: To determine if a visual intervention (medication grid) delivered to physicians can reduce medication regimen complexity. DESIGN: Nonrandomized, controlled trial. SETTING: Veterans Affairs medical center. PATIENTS/PARTICIPANTS: Eight hundred thirty-six patients taking at least 5 medications at the time of admission and the 48 teams of physicians and students on the general medicine inpatient service. INTERVENTION: For intervention patients, a medication grid was created that displayed all of the patients' medicines and the times of administration for 1 week. This grid was delivered to the admitting resident soon after admission. MEASUREMENTS AND MAIN RESULTS: For the patients of each team of physicians, we calculated the change in the average number of medications and doses from admission to discharge. The number of medications in the intervention group decreased by 0.92 per patient, and increased by 1.65 in the control group (P < .001). The mean number of doses per day in the intervention group decreased by 2.47 per patient and increased by 3.83 in the control group (P < .001). CONCLUSIONS: This simple intervention had a significant impact on medication regimen complexity in this population. Apparently, physicians were able to address polypharmacy when the issue was brought to their attention