Corrigendum: A Web Server for GPCR-GPCR Interaction Pair Prediction.

[This corrects the article DOI: 10.3389/fendo.2022.825195.].

A Web Server for GPCR-GPCR Interaction Pair Prediction.

The GGIP web server (https://protein.b.dendai.ac.jp/GGIP/) provides a web application for GPCR-GPCR interaction pair prediction by a support vector machine. The server accepts two sequences in the FASTA format. It responds with a prediction that the input GPCR sequence pair either interacts or not. GPCRs predicted to interact with the monomers constituting the pair are also shown when query sequences are human GPCRs. The server is simple to use. A pair of amino acid sequences in the FASTA format is pasted into the text area, a PDB ID for a template structure is selected, and then the 'Execute' button is clicked. The server quickly responds with a prediction result. The major advantage of this server is that it employs the GGIP software, which is presently the only method for predicting GPCR-interaction pairs. Our web server is freely available with no login requirement. In this article, we introduce some application examples of GGIP for disease-associated mutation analysis.

Efficacy of myocardial washout of 99mTc-MIBI/Tetrofosmin for the evaluation of inflammation in patients with cardiac sarcoidosis: comparison with 18F-fluorodeoxyglucose positron emission tomography findings.

OBJECTIVE: Both myocardial perfusion scintigraphy and 18F-fluorodeoxyglucose positron emission tomography (FDG PET) are useful for the diagnosis of cardiac sarcoidosis (CS). However, the association between the washout of 99mTc-labeled tracer and FDG PET has not been established. This study aimed to evaluate the association between the washout of 99mTc-labeled tracer and FDG PET findings in patients with CS. METHODS: We retrospectively analyzed 64 patients (65.0 ± 11.2 years, 53% male) with suspected CS who underwent myocardial single-photon emission computed tomography (SPECT) with 99mTc-labeled tracer and FDG PET. The SPECT images were acquired at 15 min (early images) and 3 h (delayed images) after injection and scored visually using a 17-segment model with a 5-point scoring system. The washout score was defined as the difference between the early and delayed total defect scores. FDG positivity was considered as focal or focal on diffuse patterns on visual assessment, and FDG uptake was quantified by measuring the standardized uptake value (SUV) of each of the 17 segments. RESULTS: The washout score was significantly higher for the CS group than for the non-CS group (3.0 [-1.0-5.0] vs. 0.0 [-0.5-1.0], p = 0.010). Receiver operating characteristic analysis showed that a washout score of ≥ 2 had the best accuracy for detecting CS (88% sensitivity and 56% specificity) and FDG positivity (71% sensitivity and 89% specificity). In the segment-based analysis of 833 segments from 49 patients, excluding 15 patients with diffuse FDG uptake, the median SUVs for FDG uptake for the washout scores of ≤ 0, 1, and 2 were 2.3 (1.8-3.6), 4.2 (2.9-7.8), and 8.3 (6.5-9.4), respectively (p < 0.001). CONCLUSIONS: The washout of 99mTc-labeled tracer can be a useful marker for the evaluation of FDG PET findings in patients with CS.

Diversity and determinants of the sigmoid septum and its impact on morphology of the outflow tract as revealed using cardiac computed tomography.

BACKGROUND: The sigmoid septum has been generally evaluated subjectively and qualitatively, without detailed examination of its diversity, impact on the morphology of the left ventricular outflow tract (LVOT), and anatomical background. METHODS: We enrolled 100 patients without any background cardiac diseases (67.5 ± 12.8 years old; 43% women) who underwent cardiac computed tomography. Basal septal morphology was evaluated using antero-superior and medial bulging angles (bidirectional angulation of the basal septum relative to the LVOT). The eccentricity index of the LVOT, area narrowing ratio (LVOT/virtual basal ring area), aortic-to-left ventricular axial angle (angulation of the aortic root relative to the left ventricle), and wedged height (non-coronary aortic sinus to inferior epicardium distance) were also quantified. RESULTS: The antero-superior bulging, medial bulging, aortic-to-left ventricular axial angles, LVOT eccentricity index, area narrowing ratio, and wedged height were 76° ± 17°, 166° ± 27°, 127° ± 9°, 1.8 ± 0.5, 1.0 ± 0.2, and 41.2 ± 9.1 mm, respectively. Both bulging angles were correlated with each other and contributed to the narrowing and deformation of the LVOT. Angulated aortic root was not correlated with either bidirectional septal bulge or LVOT narrowing. Clockwise rotation of the aortic root rotation was an independent predictor of prominent antero-superior septal bulge. Deeper aortic wedging was a common independent predictor of bidirectional septal bulge. CONCLUSIONS: The extent of septal bulge varies in normal hearts. Along with deep aortic wedging, the bidirectional bulge of the basal septum deforms and narrows the LVOT without affecting the virtual basal ring morphology.

Constraint of Base Pairing on HDV Genome Evolution.

The hepatitis delta virus is a single-stranded circular RNA virus, which is characterized by high self-complementarity. About 70% of the genome sequences can form base-pairs with internal nucleotides. There are many studies on the evolution of the hepatitis delta virus. However, the secondary structure has not been taken into account in these studies. In this study, we developed a method to examine the effect of base pairing as a constraint on the nucleotide substitutions during the evolution of the hepatitis delta virus. The method revealed that the base pairing can reduce the evolutionary rate in the non-coding region of the virus. In addition, it is suggested that the non-coding nucleotides without base pairing may be under some constraint, and that the intensity of the constraint is weaker than that by the base pairing but stronger than that on the synonymous site.

The impact of computed tomography-derived aortic atheroma volume on prognosis after transcatheter aortic valve replacement.

BACKGROUND: The impact of the extent of aortic atheroma on patients' prognosis after transcatheter aortic valve replacement (TAVR) has not been completely evaluated. This study aimed to evaluate the prognostic value of the aortic atheroma volume (AAV) derived from computed tomography, and the effect of its differences among the segments of the aorta, in patients undergoing TAVR. METHODS: In total, 143 patients with symptomatic severe aortic stenosis who underwent pre-procedural computed tomography before TAVR procedure indication were evaluated. AAV was calculated by measuring the aortic lumen and vessel volume using every 1-mm axial image and was further divided into thoracic (TAAV) and abdominal segments (AbAAV). RESULTS: During a median follow-up of 651 days, 24 all-cause and 14 cardiac deaths occurred. In the Kaplan-Meier analysis, the high AAV group had significantly higher all-cause and cardiac mortalities than the low AAV group (p = 0.016 and 0.023, respectively). Regarding segmental AAV, all-cause and cardiac mortalities did not have significant differences between the high and low TAAV groups. Moreover, all-cause and cardiac mortalities were significantly higher in the high AbAAV group than in the low AbAAV group (p = 0.0043 and 0.023, respectively). The multivariable analysis showed that only AbAAV was an independent predictor for all-cause mortality (hazard ratio: 1.06, p = 0.046). CONCLUSION: AAV was significantly associated with the mortality after TAVR. The current study suggests the pre-procedural assessment of AAV is valuable in predicting prognosis after TAVR. However, further investigation with a larger sample size is needed to validate our findings.

Varied Extent of Mitral Annular Disjunction Among Cases With Different Phenotypes of Mitral Valve Prolapse.

Detailed 3-dimensional analysis of mitral annular disjunction was undertaken in 3 comparative cases of mitral valve prolapse. A case of Barlow disease showed extensive disjunction, whereas cases of fibroelastic deficiency and forme fruste demonstrated less extensive disjunction. Considering the current controversies surrounding disjunction, these observations call for detailed research in the future. (Level of Difficulty: Advanced.).

Prognostic Impact of Myocardial Extracellular Volume Fraction Assessment Using Dual-Energy Computed Tomography in Patients Treated With Aortic Valve Replacement for Severe Aortic Stenosis.

Background Myocardial extracellular volume fraction (ECV), measured by cardiac magnetic resonance imaging, is a useful prognostic marker for patients who have undergone aortic valve replacement (AVR) for aortic stenosis. However, the prognostic significance of ECV measurements based on computed tomography (CT) is unclear. This study evaluated the association between ECV measured with dual-energy CT and clinical outcomes in patients with aortic stenosis who underwent transcatheter or surgical AVR. Methods and Results We retrospectively enrolled 95 consecutive patients (age, 84.0±5.0 years; 75% women) with severe aortic stenosis who underwent preprocedural CT for transcatheter AVR planning. ECV was measured using iodine density images obtained by delayed enhancement dual-energy CT. The primary end point was a composite outcome of all-cause death and hospitalization for heart failure after AVR. The mean ECV measured with CT was 28.1±3.8%. During a median follow-up of 2.6 years, 22 composite outcomes were observed, including 15 all-cause deaths and 11 hospitalizations for heart failure. In Kaplan-Meier analysis, the high ECV group (≥27.8% [median value]) had significantly higher rates of composite outcomes than the low ECV group (<27.8%) (log-rank test, P=0.012). ECV was the only independent predictor of adverse outcomes on multivariable Cox regression analysis (hazards ratio, 1.25; 95% CI, 1.10‒1.41; P<0.001). Conclusions Myocardial ECV measured with dual-energy CT in patients who underwent aortic valve intervention was an independent predictor of adverse outcomes after AVR.

Successful catheter ablation approach above the aortic sinus cusp eliminating a ventricular arrhythmia arising from the myocardial crescent beneath the interleaflet triangle: Late gadolinium enhancement magnetic resonance imaging assessment.

A 61-year-old female with 50 000 ventricular premature contractions and a reduced left ventricular ejection fraction of 35% was referred to our center. Although the origin was considered to originate from the junction between the left and right coronary cusp, a single radiofrequency application above the aortic sinus cusp could eliminate it. LGE-MRI was able to reveal the exact location of the single RF lesion.

Prevalence and extent of mitral annular disjunction in structurally normal hearts: comprehensive 3D analysis using cardiac computed tomography.

AIMS: Mitral annular disjunction is fibrous separation between the attachment of the posterior mitral leaflet and the basal left ventricular myocardium initially described in dissected hearts. Currently, it is commonly evaluated by echocardiography, and potential relationships with mitral valve prolapse and ventricular arrhythmia have been suggested. However, controversy remains as its prevalence and extent have not been fully elucidated in normal living subjects. METHODS AND RESULTS: Systolic datasets of cardiac computed tomography obtained from 98 patients (mean age, 69.1 ± 12.6 years; 81% men) with structurally normal hearts were assessed retrospectively. Circumferential extent of both mitral leaflets and disjunction was determined by rotating orthogonal multiplanar reconstruction images around the central axis of the mitral valvar orifice. Distribution angle within the circumference of the mitral valvar attachment and maximal height of disjunction were quantified. In total, 96.0% of patients demonstrated disjunction. Average distribution angles of the anterior and posterior mitral leaflets were 91.3 ± 9.4° and 269.8 ± 9.7°, respectively. Average distribution angle of the disjunction was 105.1 ± 49.2°, corresponding to 39.0 ± 18.2% of the entire posterior mitral valvar attachment. Median value of the maximal height of disjunction was 3.0 (1.5-7.0) mm. Distribution prevalence map of the disjunction revealed characteristic double peaks, with frequent sites of the disjunction located at the anterior to antero-lateral and inferior to infero-septal regions. CONCLUSION: Mitral annular disjunction is a rather common finding in the normal adult heart with bimodal distribution predominantly observed involving the P1 and P3 scallops of the posterior mitral leaflet.

Normative Aortic Valvar Measurements in Adults Using Cardiac Computed Tomography　- A Potential Guide to Further Sophisticate Aortic Valve-Sparing Surgery.

BACKGROUND: A thorough understanding of the anatomy of the aortic valve is necessary for aortic valve-sparing surgery. Normal valvar dimensions and their relationships in the living heart, however, have yet to be fully investigated in a 3-dimensional fashion.Methods and Results:In total, 123 consecutive patients (66±12 years, Men 63%) who underwent coronary computed tomographic angiography were enrolled. Mid-diastolic morphology of the aortic roots, including height of the interleaflet triangles, geometric height, free margin length of each leaflet, effective height, and coaptation length were measured using multiplanar reconstruction images. Average height of the interleaflet triangle, geometric height, free margin length, effective height, and the coaptation length were 17.3±1.8, 14.7±1.3, 32.6±3.6, 8.6±1.4, and 3.2±0.8 mm, respectively. The right coronary aortic leaflet displayed the longest free margin length and shortest geometric height. Geometric height, free margin length, and effective height showed positive correlations with aortic root dimensions. Coaptation length, however, remained constant regardless of aortic root dimensions. CONCLUSIONS: Diversities, as well as characteristic relationships among each value involving the aortic root, were identified using living-heart datasets. The aortic leaflets demonstrated compensatory elongation along with aortic root dilatation to maintain constant coaptation length. These measurements will serve as the standard value for revealing the underlying mechanism of aortic regurgitation to plan optimal aortic valve-sparing surgery.

Three-dimensional volumetric measurement of the aortic root compared to standard two-dimensional measurements using cardiac computed tomography.

INTRODUCTION: Two-dimensional measurements are self-evidently limited when seeking accurately to represent the three-dimensional complexity of the aortic root. Volumetric measurement, therefore, seems an ideal alternative for a more accurate assessment. MATERIALS AND METHODS: We retrospectively analyzed 123 individuals undergoing cardiac computed tomography. We measured the dimensions of the sinuses of Valsalva using routine multiplanar short axis imaging. Three conventional two-dimensional methods were applied to measure the dimensions of the sinuses. These involved bisecting center of sinus-to-center of interleaflet triangle measures, along with center of sinus-to-center of sinus, and largest sinus-to-sinus measurements. We then quantified the volumes of the root using the volume-rendering method. RESULTS: The mean dimensions of the sinuses were significantly greater when measured using the largest sinus-to-sinus method as opposed to center of sinus-to-center of interleaflet triangle and center of sinus-to-center of sinus methods (33.6 ± 3.6 mm vs. 31.1 ± 3.1 mm and 30.9 ± 3.3 mm, p < .0001). The mean root volume of 13.6 ± 4.2 ml showed the strongest correlation with the mean dimensions of the sinuses of Valsalva measured using the bisecting method (R2 = .8401, p < .0001). CONCLUSIONS: By using two- and three-dimensional measurements, we have provided average data for the structurally normal aortic root. The differences and correlations encountered should be noted when evaluating and following changes in the diseased root.

Update of the GRIP web service.

G protein-coupled receptors (GPCRs) can form homodimers, heterodimers, or higher-order molecular complexes (oligomers). The reports on the change of functions through the oligomerization have been accumulated. Inhibition of GPCR oligomerization without affecting the protomer's overall structure would clarify the oligomer-specific functions although inhibition experiments are costly and require accurate information about the interface location. Unfortunately, the number of experimentally determined interfaces is limited. The precise prediction of the oligomerization interfaces is, therefore, useful for inhibition experiments to examine the oligomer-specific functions, which would accelerate investigations of the GPCR signaling. However, interface prediction for GPCR oligomerization is difficult because different GPCR subtypes belonging to the same subfamily often use different structural regions as their interfaces. We previously developed a high-performance method to predict the interfaces for GPCR oligomerization, by identifying the conserved surfaces with the sequence and structure information. Then, the structural characteristic of a GPCR structure is regarded to be a thick-tube like conformation that is approximately perpendicular to the membrane plane. Our method had successfully predicted all of the interfaces available on that day. We had launched a web server for our interface prediction of GPCRs (GRIP). We have improved the previous version of GRIP server and enhanced its usability. First, we discarded the approximation of the GPCR structure as the thick-tube-like conformation. This improvement increased the number of structures for the prediction. Second, the FUGUE-based template recommendation service was introduced to facilitate the choice of an appropriate structure for the prediction. The new prediction server is available at http://grip.b.dendai.ac.jp/∼grip/.

Ascending aortic elongation and correlative change in overall configuration of the proximal aorta in elderly patients with severe aortic stenosis.

BACKGROUND: Configurational changes in the proximal aorta are relevant to the procedural difficulty of transcatheter aortic valve implantation (TAVI). Among several morphological changes involving the ascending aorta, elongation is characteristics of elderly patients with aortic stenosis and can compromise the success and safety of TAVI. However, the effect of ascending aortic elongation on the overall morphology of the proximal aorta has not been established. AIMS: Our primary purpose was to investigate the effect of ascending aortic elongation on structural changes in the proximal aorta in TAVI candidates. MATERIALS & METHODS: In total, 121 consecutive patients with severe aortic stenosis (mean age, 84.5 ± 5.3 years; 69% women) who had undergone preprocedural computed tomography before TAVI were enrolled. We examined the structural anatomy of the proximal aorta in detail, focusing on its elongation, dilatation, tilting, rotation, and wedging. RESULTS: The mean length of the ascending aorta was 68.0 ± 9.2 mm, and the length was significantly correlated with dilatation (R = .278, p = .002), rightward tilting (R = .437, p < .001), clockwise rotation (R = .228, p = .018), and deep wedging (R = -.366, p < .001) of the proximal aorta. Elongation of the ascending aorta was correlated with dilatation, rightward tilting, clockwise rotation, and deep wedging of the proximal aorta in an elderly population with severe aortic stenosis. DISCUSSION: Appreciation of the clinical anatomy around the proximal aorta is required for clinicians involved in TAVI to estimate the procedural difficulty. CONCLUSION: Elongation of the ascending aorta was associated with dilatation, rightward tilting, clockwise rotation, and deep wedging of the proximal aorta.

Living Anatomy of the Ventricular Myocardial Crescents Supporting the Coronary Aortic Sinuses.

The aortic valvar sinuses are supported, in part, by ventricular myocardium, so-called myocardial crescents. We elucidated individual variation in the extent of the myocardial support. We assessed the extent of the crescents in 84 patients who underwent cardiac computed tomography. We measured their maximal width, their extent within the circumference of the aortic root, and the influence of rotation of the root itself within the ventricular base. The maximal widths, and rotational locations, of the crescents supporting the base of the left coronary aortic sinus were significantly smaller than those supporting the right coronary aortic sinus (2.9 ± 0.8 mm vs 6.4 ± 1.2 mm, P < 0.001; 54.2 ± 12.0° vs 70.4 ± 13.5°, P < 0.001, respectively). Overall, 42.7 ± 4.3% of the circumference of the virtual basal ring was supported by myocardium as opposed to fibrous tissue. Clockwise rotation of the aortic root was correlated with a decrease in the extent of myocardial crescent supporting the left coronary aortic sinus, but an increase in the myocardial support of the right coronary aortic sinus (R2 = 0.3899 and R2 = 0.2752, P < 0.001). Clockwise rotation of the root was correlated in negative fashion with the ratio of its myocardial as opposed to fibrous support (R2 = 0.0527, P = 0.0356). The extent of myocardial support of the left coronary aortic sinus, on average, is less than that of the right coronary aortic sinus. This difference becomes greater when the aortic root is rotated in clockwise fashion.

Localized basal left ventricular dyssynchrony induced by manifest accessory pathway: Successful differentiation from cardiac involvement of sarcoidosis with administration of flecainide acetate.

We present a patient with non-cardiac sarcoidosis complicated with manifest ventricular preexcitation. Initially, cardiac involvement of sarcoidosis was suspected from the echocardiographic findings showing localized hypokinesia at the left ventricular basal inferior wall. We, however, considered that the hypokinesia was a preexcitation-induced mechanical dyssynchrony rather than cardiac sarcoidosis, because polarities of the delta-waves indicated a left ventricular inferior accessory pathway. Temporal administration of oral flecainide acetate eliminated the basal left ventricular motion abnormality. Accordingly, we could successfully differentiate the mechanism of hypokinesia. In this context, we could rule out cardiac sarcoidosis, and initiation of glucocorticoid therapy was reasonably withheld.

The rotational position of the aortic root related to its underlying ventricular support.

We aimed to assess the relationship of the rotational position of the aortic root to its underlying ventricular support, and to the position of the inferior margin of the membranous septum, which serves as a surrogate of the atrioventricular conduction axis. We analyzed 40 normal heart specimens (19 children, 21 adults). The inferior margin of the membranous septum was measured relative to the virtual basal ring. The rotational position of the aortic root was determined by assessing the relationship of the aortic leaflet of the mitral valve to the interleaflet triangle between the non- and left coronary leaflets. The extent of supporting fibrous versus myocardial tissues was measured. We also performed a similar investigation of 30 adult computed tomographic data sets. The median age was 0.25 years (44% male) for children, and 64 years (33% male) for adults. The aortic root was positioned centrally in 22 specimens (55%), rotated counterclockwise in 6 (15%), and clockwise in 12 (30%). In the setting of counterclockwise rotation, 53.4% (median) of the supporting circumference was myocardial, as opposed to 41.4% (median) in those with centrally positioned roots, and 31.9% (median) in those with clockwise rotation (P < 0.0001). The position of the inferior margin of the membranous septum was not associated with the rotational position. Analysis of the 30 adult computed tomographic data sets (median age 66.5 years, 57% male) confirmed the positive relationship between clockwise rotation of the aortic root and an increase in the extent of fibrous as opposed to myocardial support. The rotational position of the aortic root correlates with variation in the extent of its fibrous as opposed to myocardial ventricular support, but not with the position of the inferior margin of the membranous septum relative to the virtual basal ring. Clin. Anat. 32:1107-1117, 2019. © 2019 Wiley Periodicals, Inc.

Identification of Mouse and Human Antibody Repertoires by Next-Generation Sequencing.

The immense adaptability of antigen recognition by antibodies is the basis of the acquired immune system. Despite our understanding of the molecular mechanisms underlying the production of the vast repertoire of antibodies by the acquired immune systems, it has not yet been possible to arrive at a global view of a complete antibody repertoire. In particular, B cell repertoires have been regarded as a black box because of their astronomical number of antibody clones. However, next-generation sequencing technologies are enabling breakthroughs to increase our understanding of the B cell repertoire. In this report, we describe a simple and efficient method to visualize and analyze whole individual mouse and human antibody repertoires. From the immune organs, representatively from spleen in mice and peripheral blood mononuclear cells in humans, total RNA was prepared, reverse transcribed, and amplified using the 5'-RACE method. Using a universal forward primer and antisense primers for the antibody class-specific constant domains, antibody mRNAs were uniformly amplified in proportions reflecting their frequencies in the antibody populations. The amplicons were sequenced by next-generation sequencing (NGS), yielding more than 105 antibody sequences per immunological sample. We describe the protocols for antibody sequence analyses including V(D)J-gene-segment annotation, a bird's-eye view of the antibody repertoire, and our computational methods.