Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes.

BackgroundGeneral translational cis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements include mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate to control translation rates are not well understood.ResultsHere, we show that these sequence features specify 42-81% of the variance in translation rates in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Mus musculus, and Homo sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25-60 nucleotide segments within mRNA 5' regions, that changes in tri-nucleotide frequencies between highly and poorly translated 5' regions are correlated between all species, and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.ConclusionsOur work shows that general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that directs translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and within cis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell

Towards a Critical Sociology of Dominant Ideologies: An Unexpected Reunion between Pierre Bourdieu and Luc Boltanski

This article aims to demonstrate the enduring relevance of Pierre Bourdieu and Luc Boltanski’s ‘La production de l’idéologie dominante’ [‘The production of the dominant ideology’], which was originally published in Actes de la recherche en sciences sociales in 1976. More than three decades later, in 2008, a re-edited version of this study was printed in book format as La production de l’idéologie dominante, which was accompanied by a detailed commentary, written by Luc Boltanski and entitled Rendre la réalité inacceptable. À propos de « La production de l’idéologie dominante » [Making Reality Unacceptable. Comments on ‘The production of the dominant ideology’]. In addition to containing revealing personal anecdotes and providing important sociological insights, this commentary offers an insider account of the genesis of one of the most seminal pieces Boltanski co-wrote with his intellectual father, Bourdieu. In the Anglophone literature on contemporary French sociology, however, the theoretical contributions made both in the original study and in Boltanski’s commentary have received little – if any – serious attention. This article aims to fill this gap in the literature, arguing that these two texts can be regarded not only as forceful reminders of the fact that the ‘dominant ideology thesis’ is far from obsolete but also as essential for understanding both the personal and the intellectual underpinnings of the tension-laden relationship between Bourdieu and Boltanski. Furthermore, this article offers a critical overview of the extent to which the unexpected, and partly posthumous, reunion between ‘the master’ (Bourdieu) and his ‘dissident disciple’ (Boltanski) equips us with powerful conceptual tools, which, whilst illustrating the continuing centrality of ‘ideology critique’, permit us to shed new light on key concerns in contemporary sociology and social theory. Finally, the article seeks to push the debate forward by reflecting upon several issues that are not given sufficient attention by Bourdieu and Boltanski in their otherwise original and insightful enquiry into the complexities characterizing the daily production of ideology

SARS‑CoV‑2 entry into and evolution within a skilled nursing facility

SARS-CoV-2 belongs to the family Coronaviridae which includes multiple human pathogens that have an outsized impact on aging populations. As a novel human pathogen, SARS-CoV-2 is undergoing continuous adaptation to this new host species and there is evidence of this throughout the scientific and public literature. However, most investigations of SARS-CoV-2 evolution have focused on largescale collections of data across diverse populations and/or living environments. Here we investigate SARS-CoV-2 evolution in epidemiologically linked individuals within a single outbreak at a skilled nursing facility beginning with initial introduction of the pathogen. The data demonstrate that SARSCoV- 2 was introduced to the facility multiple times without establishing an interfacility transmission chain, followed by a single introduction that infected many individuals within a week. This largescale introduction by a single genotype then persisted in the facility. SARS-CoV-2 sequences were investigated at both the consensus and intra-host variation levels. Understanding the variability in SARS-CoV-2 during transmission chains will assist in understanding the spread of this disease and can ultimately inform best practices for mitigation strategies

Transcriptome-wide sites of collided ribosomes reveal principles of translational pausing.

Translation initiation is the major regulatory step defining the rate of protein production from an mRNA. Meanwhile, the impact of nonuniform ribosomal elongation rates is largely unknown. Using a modified ribosome profiling protocol based on footprints from two closely packed ribosomes (disomes), we have mapped ribosomal collisions transcriptome-wide in mouse liver. We uncover that the stacking of an elongating onto a paused ribosome occurs frequently and scales with translation rate, trapping ∼10% of translating ribosomes in the disome state. A distinct class of pause sites is indicative of deterministic pausing signals. Pause site association with specific amino acids, peptide motifs, and nascent polypeptide structure is suggestive of programmed pausing as a widespread mechanism associated with protein folding. Evolutionary conservation at disome sites indicates functional relevance of translational pausing. Collectively, our disome profiling approach allows unique insights into gene regulation occurring at the step of translation elongation

Myocardial Blood Flow Quantification Using Stress Cardiac Magnetic Resonance Improves Detection of Coronary Artery Disease

Background: Myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) using stress cardiovascular magnetic resonance (CMR) have been shown to identify epicardial coronary artery disease. However, comparative analysis between quantitative perfusion and conventional qualitative assessment (QA) remains limited. Objectives: The aim of this multicenter study was to test the hypothesis that quantitative stress MBF (sMBF) and MPR analysis can identify obstructive coronary artery disease (obCAD) with comparable performance as QA of stress CMR performed by experienced physicians in interpretation. Methods: The analysis included 127 individuals (mean age 62 ± 16 years, 84 men [67%]) who underwent stress CMR. obCAD was defined as the presence of stenosis ≥50% in the left main coronary artery or ≥70% in a major vessel. Each patient, coronary territory, and myocardial segment was categorized as having either obCAD or no obCAD (noCAD). Global, per coronary territory, and segmental MBF and MPR values were calculated. QA was performed by 4 CMR experts. Results: At the patient level, global sMBF and MPR were significantly lower in subjects with obCAD than in those with noCAD, with median values of sMBF of 1.5 mL/g/min (Q1-Q3: 1.2-1.8 mL/g/min) vs 2.4 mL/g/min (Q1-Q3: 2.1-2.7 mL/g/min) (P < 0.001) and median values of MPR of 1.3 (Q1-Q3: 1.0-1.6) vs 2.1 (Q1-Q3: 1.6-2.7) (P < 0.001). At the coronary artery level, sMBF and MPR were also significantly lower in vessels with obCAD compared with those with noCAD. Global sMBF and MPR had areas under the curve (AUCs) of 0.90 (95% CI: 0.84-0.96) and 0.86 (95% CI: 0.80-0.93). The AUCs for QA by 4 physicians ranged between 0.69 and 0.88. The AUC for global sMBF and MPR was significantly better than the average AUC for QA. Conclusions: This study demonstrates that sMBF and MPR using dual-sequence stress CMR can identify obCAD more accurately than qualitative analysis by experienced CMR readers

Improvement of late gadolinium enhancement image quality using a deep learning–based reconstruction algorithm and its influence on myocardial scar quantification

Objectives: The aim of this study was to assess the effect of a deep learning (DL)–based reconstruction algorithm on late gadolinium enhancement (LGE) image quality and to evaluate its influence on scar quantification. Methods: Sixty patients (46 ± 17 years, 50% male) with suspected or known cardiomyopathy underwent CMR. Short-axis LGE images were reconstructed using the conventional reconstruction and a DL network (DLRecon) with tunable noise reduction (NR) levels from 0 to 100%. Image quality of standard LGE images and DLRecon images with 75% NR was scored using a 5-point scale (poor to excellent). In 30 patients with LGE, scar size was quantified using thresholding techniques with different standard deviations (SD) above remote myocardium, and using full width at half maximum (FWHM) technique in images with varying NR levels. Results: DLRecon images were of higher quality than standard LGE images (subjective quality score 3.3 ± 0.5 vs. 3.6 ± 0.7, p < 0.001). Scar size increased with increasing NR levels using the SD methods. With 100% NR level, scar size increased 36%, 87%, and 138% using 2SD, 4SD, and 6SD quantification method, respectively, compared to standard LGE images (all p values < 0.001). However, with the FWHM method, no differences in scar size were found (p = 0.06). Conclusions: LGE image quality improved significantly using a DL-based reconstruction algorithm. However, this algorithm has an important impact on scar quantification depending on which quantification technique is used. The FWHM method is preferred because of its independency of NR. Clinicians should be aware of this impact on scar quantification, as DL-based reconstruction algorithms are being used. Key Points: • The image quality based on (subjective) visual assessment and image sharpness of late gadolinium enhancement images improved significantly using a deep learning–based reconstruction algorithm that aims to reconstruct high signal-to-noise images using a denoising technique. • Special care should be taken when scar size is quantified using thresholding techniques with different standard deviations above remote myocardium because of the large impact of these advanced image enhancement algorithms. • The full width at half maximum method is recommended to quantify scar size when deep learning algorithms based on noise reduction are used, as this method is the least sensitive to the level of noise and showed the best agreement with visual late gadolinium enhancement assessment

Wideband radiofrequency pulse sequence for evaluation of myocardial scar in patients with cardiac implantable devices

BackgroundCardiac magnetic resonance is a useful clinical tool to identify late gadolinium enhancement in heart failure patients with implantable electronic devices. Identification of LGE in patients with CIED is limited by artifact, which can be improved with a wide band radiofrequency pulse sequence.ObjectiveThe authors hypothesize that image quality of LGE images produced using wide-band pulse sequence in patients with devices is comparable to image quality produced using standard LGE sequences in patients without devices.MethodsTwo independent readers reviewed LGE images of 16 patients with CIED and 7 patients without intracardiac devices to assess for image quality, device-related artifact, and presence of LGE using the American Society of Echocardiography/American Heart Association 17 segment model of the heart on a 4-point Likert scale. The mean and standard deviation for image quality and artifact rating were determined. Inter-observer reliability was determined by calculating Cohen's kappa coefficient. Statistical significance was determined by T-test as a p {less than or equal to} 0.05 with a 95% confidence interval.ResultsAll patients underwent CMR without any adverse events. Overall IQ of WB LGE images was significantly better in patients with devices compared to standard LGE in patients without devices (p = 0.001) with reduction in overall artifact rating (p = 0.05).ConclusionOur study suggests wide-band pulse sequence for LGE can be applied safely to heart failure patients with devices in detection of LV myocardial scar while maintaining image quality, reducing artifact, and following routine imaging protocol after intravenous gadolinium contrast administration