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The virus-encoded Tat protein strongly activates transcription of human immunodeficiency virus (HIV). A well-recognized mechanism involves interaction of Tat with the nascent RNA transcript of the viral tar gene; mutation of tar greatly decreases activation by Tat. However, Tat still provides a low level of activation, demonstrating that it also has a tar-independent mode of action. We propose that this tar-independent mode of Tat action is through activation of gene transcription to produce tumor necrosis factor alpha. This cytokine and other compounds that activate NF-kappa B up-regulate the HIV promoter at a low level, similarly to the second Tat action. Through this mechanism, they also activate promoters of tumor necrosis factor alpha and other cytokines and thereby establish an auto-up-regulatory loop. Activated NF-kappa B motifs in the HIV promoter synergize with Tat/tar. Mutations of these motifs decrease activation by Tat to a few percent of the wild-type value. In cooperation, the two modes of activation by Tat (tar dependent and cytokine based) set up positive up-regulatory loops which greatly superactivate transcription of HIV. Agents that block these synergistic pathways at three different steps and are more inhibitory in combination than is any one alone have been found. Thereby, multidrug modalities for transcription of HIV are proposed for virus suppression.
A Tat-induced auto-up-regulatory loop for superactivation of the human immunodeficiency virus type 1 promoter.
D K Biswas, T R Salas, F Wang, C M Ahlers, B J Dezube, and A B Pardee
A series of yeast mitochondrial mit- mutants with defects in the oli2 gene, coding for subunit 6 of the mitochondrial ATPase complex, has been analyzed at the DNA sequence level. Fifteen of sixteen primary mit- mutants were shown to contain frameshift or nonsense mutations predicting truncated subunit 6 polypeptides, in various strains ranging from about 20% to 95% of the wild-type length of 259 amino acids. In only one strain could the defect in subunit 6 function be assigned to amino acid substitution in an otherwise full-length subunit 6. Many mutants carried multiple base substitutions or insertions/deletions, presumably arising from the manganese chloride mutagenesis treatment. Revertants from three of the mit- mutants were analyzed: all contained full-length subunit 6 proteins with one or more amino acid substitutions. The preponderance of truncated proteins as opposed to substituted full-length proteins in oli2 mit- mutants is suggested to reflect the ability of subunit 6 to accommodate amino acid substitutions at many locations, with little or no change in its functional properties in the membrane FO-sector of the ATPase complex.
Biogenesis of mitochondria: DNA sequence analysis of mit- mutations in the mitochondrial oli2 gene coding for mitochondrial ATPase subunit 6 in Saccharomyces cerevisiae.
U P John, T A Willson, A W Linnane, and P Nagley
1986 Sep 25
Clinical outcomes after surgical treatment of mitral regurgitation (MR) are worse if intervention occurs after deterioration of left ventricular (LV) size and function. Trans-thoracic echocardiographic (TTE) surveillance of patients with MR is indicated to avoid adverse ventricular remodeling. Overly frequent TTEs can impair patient access and reduce value in care delivery. This balance between timely surveillance and over-utilization of TTE in valvular disease provides a model to study variation in the delivery of health care services. We investigated patient and provider factors contributing to variation in TTE utilization, and hypothesized that variation was attributable to provider practice even after adjustment for patient characteristics.
Methods and Results
We obtained records of all TTEs from 2001-2016 ordered at a large echocardiography laboratory. The outcome variable was time interval between TTEs. We constructed a mixed-effects linear regression model with the individual physician as the random effect in the model, and used intra-class correlation coefficient (ICC) to assess the proportion of outcome variation due to provider practice.
Our study cohort was 55,773 TTEs corresponding to 37,843 intervals ordered by 635 providers. The mean interval between TTEs was 12.4 months, 17.0 months, 18.3 months, and 17.4 months for severe, moderate, mild, and trace MR respectively, with 20% of providers deemed over-utilizers of TTEs, and 25% under-utilizers.
We conclude that there is substantial variation in follow-up intervals for TTE assessment of MR, despite risk-adjustment for patient variables, likely due to provider factors.
Mitral Regurgitation, Quality of Care and Outcomes, Variation, Echocardiography
Variation in the echocardiographic surveillance of primary mitral regurgitation
Varsha K. Tanguturi, MD,1,3 Michael K. Hidrue, PhD,2 Michael H. Picard, MD,1,2,3 Steven J. Atlas, MD, MPH,2,3 Jeffrey B. Weilburg, MD,2 Timothy G. Ferris, MD, MPH,2 Katrina Armstrong, MD, MPH,3 and Jason H. Wasfy, MD, MPhil1,2
2018 Aug 1.