During inflammation, the resulting oxidative stress can damage surrounding host tissue, forming protein-carbonyls. The SJL mouse is an experimental animal model used to assess in vivo toxicological responses to reactive oxygen and nitrogen species from inflammation. The goals of this study were to identify the major serum proteins modified with a carbonyl functionality and to identify the types of carbonyl adducts. To select for carbonyl-modified proteins, serum proteins were reacted with an aldehyde reactive probe that biotinylated the carbonyl modification. Modified proteins were enriched by avidin affinity and identified by two-dimensional liquid chromatography tandem MS. To identify the carbonyl modification, tryptic peptides from serum proteins were subjected to avidin affinity and the enriched modified peptides were analyzed by liquid chromatography tandem MS. It was noted that the aldehyde reactive probe tag created tag-specific fragment ions and neutral losses, and these extra features in the mass spectra inhibited identification of the modified peptides by database searching. To enhance the identification of carbonyl-modified peptides, a program was written that used the tag-specific fragment ions as a fingerprint (in silico filter program) and filtered the mass spectrometry data to highlight only modified peptides. A de novo-like database search algorithm was written (biotin peptide identification program) to identify the carbonyl-modified peptides. Although written specifically for our experiments, this software can be adapted to other modification and enrichment systems. Using these routines, a number of lipid peroxidation-derived protein carbonyls and direct side-chain oxidation proteins carbonyls were identified in SJL mouse serum. Molecular & Cellular

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

Characterization of blood flow rheology in hematological disorders is critical for understanding disease pathophysiology. Existing methods to measure blood rheological parameters are limited in their physiological relevance, and there is...

No abstract

No abstract

Background Knowledge of tissue properties of the abdominal aorta can improve understanding of vascular disease and guide interventional approaches. Existing MRI methods to quantify aortic wall displacement and strain are unable to discern circumferential heterogeneity. Purpose To assess regional variation in abdominal aortic wall displacement and strain as a function of circumferential position using spiral cine displacement encoding with stimulated echoes (DENSE). Study Type Prospective. Population Cardiovascular disease‐free men (n = 8) and women (n = 9) ages 30–42. Sequences Prospective electrocardiogram (ECG)‐gated and navigator echo‐gated spiral, cine 2D DENSE and retrospective ECG‐gated phase contrast MR (PCMR) sequences at 3T. Assessment In‐plane displacement values of the aortic wall acquired with DENSE were used to determine radial and circumferential aortic wall motion. A quadrilateral‐based 2D strain calculation method was implemented to determine strain from the displacement field. Peak displacement and its radial and circumferential contributions as well as peak circumferential strain were compared among eight circumferential wall segments. Distensibility was calculated using PCMR and compared with homogenized circumferential strain. Statistical Tests To account for repeated measurements in volunteers, linear mixed models for mean sector values were created for displacement magnitude, circumferential displacement, radial displacement, and circumferential strain. Comparisons were made between sectors. Calculated distensibility and homogenized circumferential strain were compared using Bland–Altman analysis. Statistical significance was defined as P < 0.05. Results Displacement was highest in the anterior wall (1.5 ± 0.7 mm) and was primarily in the radial as compared with circumferential direction (1.04 ± 0.05 mm vs. 0.81 ± 0.42 mm). Circumferential strain was highest in the lateral walls (left 0.16 ± 0.05 and right 0.21 ± 0.12) with homogenized circumferential strain of 0.14 ± 0.05. Data Conclusion DENSE imaging in the abdominal aortic wall demonstrated that the anterior aortic wall exhibits the greatest displacement, while the lateral wall experiences the largest circumferential strain. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:731–743.

The role of early, serial measurements of protein biomarkers in sepsis-induced acute respiratory distress syndrome (ARDS) is not clear. OBJECTIVES:To determine the differences in soluble receptor for advanced glycation end-products (sRAGEs), angiopoietin-2, and surfactant protein-D (SP-D) levels and their changes over time between sepsis patients with and without ARDS. DESIGN, SETTING, AND PARTICIPANTS:Prospective observational cohort study of adult patients admitted to the medical ICU at Grady Memorial Hospital within 72 hours of sepsis diagnosis. MAIN OUTCOMES AND MEASURES:Plasma sRAGE, angiopoietin-2, and SP-D levels were measured for 3 consecutive days after enrollment. The primary outcome was ARDS development, and the secondary outcome of 28-day mortality. The biomarker levels and their changes over time were compared between ARDS and non-ARDS patients and between nonsurvivors and survivors. RESULTS:We enrolled 111 patients, and 21 patients (18.9%) developed ARDS. The three biomarker levels were not significantly different between ARDS and non-ARDS patients on all 3 days of measurement. Nonsurvivors had higher levels of all three biomarkers than did survivors on multiple days. The changes of the biomarker levels over time were not different between the outcome groups. Logistic regression analyses showed association between day 1 SP-D level and mortality (odds ratio, 1.52; 95% CI, 1.03-2.24; p = 0.03), and generalized estimating equation analyses showed association between angiopoietin-2 levels and mortality (estimate 0.0002; se 0.0001; p = 0.04). CONCLUSIONS AND RELEVANCE:Among critically ill patients with sepsis, sRAGE, angiopoietin-2, and SP-D levels were not significantly different between ARDS and non-ARDS patients but were higher in nonsurvivors compared with survivors. The trend toward higher levels of sRAGE and SP-D, but not of angiopoietin-2, in ARDS patients may indicate the importance of epithelial injury in sepsis-induced ARDS. Changes of the biomarker levels over time were not different between the outcome groups.

No abstract