DeepSuccinylSite: a deep learning based approach for protein succinylation site prediction.

BACKGROUND: Protein succinylation has recently emerged as an important and common post-translation modification (PTM) that occurs on lysine residues. Succinylation is notable both in its size (e.g., at 100 Da, it is one of the larger chemical PTMs) and in its ability to modify the net charge of the modified lysine residue from + 1 to - 1 at physiological pH. The gross local changes that occur in proteins upon succinylation have been shown to correspond with changes in gene activity and to be perturbed by defects in the citric acid cycle. These observations, together with the fact that succinate is generated as a metabolic intermediate during cellular respiration, have led to suggestions that protein succinylation may play a role in the interaction between cellular metabolism and important cellular functions. For instance, succinylation likely represents an important aspect of genomic regulation and repair and may have important consequences in the etiology of a number of disease states. In this study, we developed DeepSuccinylSite, a novel prediction tool that uses deep learning methodology along with embedding to identify succinylation sites in proteins based on their primary structure. RESULTS: Using an independent test set of experimentally identified succinylation sites, our method achieved efficiency scores of 79%, 68.7% and 0.48 for sensitivity, specificity and MCC respectively, with an area under the receiver operator characteristic (ROC) curve of 0.8. In side-by-side comparisons with previously described succinylation predictors, DeepSuccinylSite represents a significant improvement in overall accuracy for prediction of succinylation sites. CONCLUSION: Together, these results suggest that our method represents a robust and complementary technique for advanced exploration of protein succinylation.

Differential effects of EPA versus DHA on postprandial vascular function and the plasma oxylipin profile in men.

Our objective was to investigate the impact of EPA versus DHA on arterial stiffness and reactivity and underlying mechanisms (with a focus on plasma oxylipins) in the postprandial state. In a three-arm crossover acute test meal trial, men (n = 26, 35-55 years) at increased CVD risk received a high-fat (42.4 g) test meal providing 4.16 g of EPA or DHA or control oil in random order. At 0 h and 4 h, blood samples were collected to quantify plasma fatty acids, long chain n-3 PUFA-derived oxylipins, nitrite and hydrogen sulfide, and serum lipids and glucose. Vascular function was assessed using blood pressure, reactive hyperemia index, pulse wave velocity, and augmentation index (AIx). The DHA-rich oil significantly reduced AIx by 13% (P = 0.047) with the decrease following EPA-rich oil intervention not reaching statistical significance. Both interventions increased EPA- and DHA-derived oxylipins in the acute postprandial state, with an (1.3-fold) increase in 19,20-dihydroxydocosapentaenoic acid evident after DHA intervention (P < 0.001). In conclusion, a single dose of DHA significantly improved postprandial arterial stiffness as assessed by AIx, which if sustained would be associated with a significant decrease in CVD risk. The observed increases in oxylipins provide a mechanistic insight into the AIx effect.

Inward Displacement: A Novel Method of Regional Left Ventricular Functional Assessment for Left Ventriculoplasty Interventions in Heart Failure with Reduced Ejection Fraction (HFrEF).

BACKGROUND: Hybrid minimally invasive left ventricular reconstruction is used to treat patients with ischemic heart failure with reduced ejection fraction (HFrEF) and antero-apical scar. Pre- and post-procedural regional functional left ventricular assessment with current imaging techniques remains limited. We evaluated 'inward displacement' as a novel technique of assessing regional left ventricular function in an ischemic HFrEF population who underwent left ventricular reconstruction with the Revivent System. METHODS: Inward displacement adopts three standard long-axis views obtained during cardiac MRI or CT and assesses the degree of inward endocardial wall motion towards the true left ventricular center of contraction. For each of the standard 17 left ventricular segments, regional inward displacement is measured in mm and expressed as a percentage of the maximal theoretical distance each segment can contract towards the centerline. The left ventricle was divided into three regions, obtaining the arithmetic average of inward displacement or speckle tracking echocardiographic strain at the left ventricular base (segments 1-6), mid-cavity (segments 7-12) and apex (segments 13-17). Inward displacement was measured using computed tomography or cardiac magnetic resonance imaging and compared pre- and post-procedurally in ischemic HFrEF patients who underwent left ventricular reconstruction with the Revivent System (n = 36). In a subset of patients who underwent baseline speckle tracking echocardiography, pre-procedural inward displacement was compared with left ventricular regional echocardiographic strain (n = 15). RESULTS: Inward displacement of basal and mid-cavity left ventricular segments increased by 27% (p < 0.001) and 37% (p < 0.001), respectively, following left ventricular reconstruction. A significant overall decrease in both the left ventricular end systolic volume index and end diastolic volume index of 31% (p < 0.001) and 26% (p < 0.001), respectively, was detected, along with a 20% increase in left ventricular ejection fraction (p = 0.005). A significant correlation between inward displacement and speckle tracking echocardiographic strain was noted within the basal (R = -0.77, p < 0.001) and mid-cavity left ventricular segments (R = -0.65, p = 0.004), respectively. Inward displacement resulted in relatively larger measurement values compared to speckle tracking echocardiography, with a mean difference of absolute values of -3.33 and -7.41 for the left ventricular base and mid-cavity, respectively. CONCLUSIONS: Obviating the limitations of echocardiography, inward displacement was found to highly correlate with speckle tracking echocardiographic strain to evaluate regional segmental left ventricular function. Significant improvements in basal and mid-cavity left ventricular contractility were demonstrated in ischemic HFrEF patients following left ventricular reconstruction of large antero-apical scars, consistent with the concept of reverse left ventricular remodeling at a distance. Inward displacement holds significant promise in the HFrEF population being evaluated pre- and post-left ventriculoplasty procedures.

Reference Values for Inward Displacement in the Normal Left Ventricle: A Novel Method of Regional Left Ventricular Function Assessment.

BACKGROUND: Regional functional left ventricular (LV) assessment using current imaging techniques remains limited. Inward displacement (InD) has been developed as a novel technique to assess regional LV function via measurement of the regional displacement of the LV endocardial border across each of the 17 LV segments. Currently, normal ranges for InD are not available for clinical use. The aim of this study was to validate the normal reference limits of InD in healthy adults across all LV segments. METHODS: InD was analyzed in 120 healthy subjects with a normal LV ejection fraction, using the three standard long-axis views obtained during cardiac MRI that quantified the degree of inward endocardial wall motion towards the true LV center of contraction. For all LV segments, InD was measured in mm and expressed as a percentage of the theoretical degree of maximal segment contraction towards the true LV centerline. The arithmetic average InD was obtained for each of the 17 segments. The LV was divided into three regions, obtaining average InD at the LV base (segments 1-6), mid-cavity (segments 7-12) and apex (segments 13-17). RESULTS: Average InD was 33.4 ± 4.3%. InD was higher in basal and mid-cavity LV segments (32.8 ± 4.1% and 38.1 ± 5.8%) compared to apical LV segments (28.6 ± 7.7%). Interobserver variability correlations for InD were strong (R = 0.80, p < 0.0001). CONCLUSIONS: We provide clinically meaningful reference ranges for InD in subjects with normal LV function, which will emerge as an important screening and assessment imaging tool for a range of HFrEF therapies.

[Endovascular prosthetic repair of the infrarenal portion of the aorta with the aorfix bifurcated stent graft].

Reconstructive surgery or abdominal aortic aneurysms (AAA) currently remains one of the most complicated and dramatic divisions of the present-day vascular surgery. On the one hand, this is accounted for by the increased prevalence of the disease due to both improved diagnosis and a prolonged life span of the population, and hence more frequent occurrence ofabdominal aortic aneurysms. On the other hand, the conventional surgical treatment is known to be associated with a severe surgical injury and impairments of haemostasis on the background of a wide variety of accompanying diseases in patients who typically appear to be elderly and aged, thus sending us in search of less traumatic and more sparing techniques, with the endovascular aortic prosthetic repair being an encouraging example thereof (1-4). The recent advent of stent grafts has made it possible in the majority of cases to substantially avoid an otherwise inevitably traumatic and prolonged abdominal operation, which is particularly important in elderly and aged patients presenting with a severe concomitant pathology. The authors report herein a clinicalcase of successful endovascular prosthetic reconstruction of the infrarenal portion of the abdominal aortic aneurysm by means of the Aorfix bifurcated stent graft in a 78-year-old female patient.

Single-cell RNA sequencing reveals metallothionein heterogeneity during hESC differentiation to definitive endoderm.

Differentiation of human pluripotent stem cells towards definitive endoderm (DE) is the critical first step for generating cells comprising organs such as the gut, liver, pancreas and lung. This in-vitro differentiation process generates a heterogeneous population with a proportion of cells failing to differentiate properly and maintaining expression of pluripotency factors such as Oct4. RNA sequencing of single cells collected at four time points during a 4-day DE differentiation identified high expression of metallothionein genes in the residual Oct4-positive cells that failed to differentiate to DE. Using X-ray fluorescence microscopy and multi-isotope mass spectrometry, we discovered that high intracellular zinc level corresponds with persistent Oct4 expression and failure to differentiate. This study improves our understanding of the cellular heterogeneity during in-vitro directed differentiation and provides a valuable resource to improve DE differentiation efficiency.