Benchmarking of protein descriptor sets in proteochemometric modeling (part 2): modeling performance of 13 amino acid descriptor sets.

Background While a large body of work exists on comparing and benchmarking descriptors of molecular structures, a similar comparison of protein descriptor sets is lacking. Hence, in the current work a total of 13 amino acid descriptor sets have been benchmarked with respect to their ability of establishing bioactivity models. The descriptor sets included in the study are Z-scales (3 variants), VHSE, T-scales, ST-scales, MS-WHIM, FASGAI, BLOSUM, a novel protein descriptor set (termed ProtFP (4 variants)), and in addition we created and benchmarked three pairs of descriptor combinations. Prediction performance was evaluated in seven structure-activity benchmarks which comprise Angiotensin Converting Enzyme (ACE) dipeptidic inhibitor data, and three proteochemometric data sets, namely (1) GPCR ligands modeled against a GPCR panel, (2) enzyme inhibitors (NNRTIs) with associated bioactivities against a set of HIV enzyme mutants, and (3) enzyme inhibitors (PIs) with associated bioactivities on a large set of HIV enzyme mutants. Results The amino acid descriptor sets compared here show similar performance ( 0.3 log units RMSE difference and >0.7 difference in MCC). Combining different descriptor sets generally leads to better modeling performance than utilizing individual sets. The best performers were Z-scales (3) combined with ProtFP (Feature), or Z-Scales (3) combined with an average Z-Scale value for each target, while ProtFP (PCA8), ST-Scales, and ProtFP (Feature) rank last. Conclusions While amino acid descriptor sets capture different aspects of amino acids their ability to be used for bioactivity modeling is still – on average – surprisingly similar. Still, combining sets describing complementary information consistently leads to small but consistent improvement in modeling performance (average MCC 0.01 better, average RMSE 0.01 log units lower). Finally, performance differences exist between the targets compared thereby underlining that choosing an appropriate descriptor set is of fundamental for bioactivity modeling, both from the ligand- as well as the protein side

Improved large-scale prediction of growth inhibition patterns using the NCI60 cancer cell line panel

Medicinal Chemistr

Modelling ligand selectivity of serine proteases using integrative proteochemometric approaches improves model performance and allows the multi-target dependent interpretation of features

FWN – Publicaties zonder aanstelling Universiteit Leide

Comment on: Nonexudative Perifoveal Vascular Anomalous Complex: The Subclinical Stage of Perifoveal Exudative Vascular Anomalous Complex?

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ANATOMICAL CHANGES ON SEQUENTIAL MULTIMODAL IMAGING IN PERIFOVEAL EXUDATIVE VASCULAR ANOMALOUS COMPLEX

PURPOSE: To report a series of 21 patients with perifoveal exudative vascular anomalous complex (PEVAC) and to investigate the anatomical changes over time. METHODS: We conducted a retrospective study. Clinical data of consecutive patients, presenting at the Rotterdam Eye Hospital between 2014 and 2019, were analyzed. The data collected included best-corrected visual acuity, fundus photography, optical coherence tomography (OCT), OCT-angiography, fluorescence angiography, and indocyanine green angiography. RESULTS: We included 21 patients with a PEVAC lesion with a mean follow-up of 24.3 ± 13.8 months (range, 9-46 months). Patients with PEVAC were on average 75.3 ± 11.1 years (range, 53-90 years). The large perifoveal vascular aneurysmal abnormality was associated with small retinal hemorrhages in six patients and hard exudates in three patients. The PEVAC lesion was associated with intraretinal cystic spaces on OCT in 15 patients. Twelve of 21 patients showed no changes in cystic spaces on OCT during follow-up: 9 patients had stable cystic spaces and 3 patients had no cystic spaces. In contrast, in 9 of 21 patients, we observed changes in cystic spaces on OCT during follow-up. In two patients, cystic spaces appeared during follow-up, and in seven patients, there was a spontaneous resolution of cystic spaces. In three of these seven patients, the PEVAC lesion completely disappeared. Two patients, with stable intraretinal cystic spaces on OCT, were treated with intravitreal injections of anti-vascular endothelial growth factor without improvement. CONCLUSION: Perifoveal exudative vascular anomalous complex is an idiopathic perifoveal retinal vascular abnormality that is associated with intraretinal cystic spaces. These intraretinal cystic spaces associated with a PEVAC lesion, and even the PEVAC lesion itself, can have a spontaneous resolution over time

Multimodal imaging comparison of perifoveal exudative vascular anomalous complex and resembling lesions

PURPOSE: Perifoveal exudative vascular anomalous complex (PEVAC) was initially described as an isolated aneurysmal lesion in healthy eyes. Similar aneurysmal abnormalities may occur in association with retinal vascular diseases such as diabetic retinopathy or retinal vein occlusions (PEVAC-resembling). The aim of this study was to compare several imaging characteristics of PEVAC and PEVAC-resembling lesions. METHODS: Ten eyes with a PEVAC and 27 eyes with a PEVAC-resembling lesion were included in this cross-sectional study. They were all imaged with optical coherence tomography (OCT), OCT angiography (OCT-A) and colour fundus photography (CFP). Several clinical, morphological and vascular characteristics were assessed and compared between both PEVAC types. RESULTS: All PEVAC lesions were unilateral, while PEVAC-resembling lesions appeared bilateral in 23% of patients (p > 0.05). Unilateral multifocal PEVAC-resembling lesions were more frequently observed (56%) than unilateral multifocal PEVAC lesions (10%, p  0.05). No notable differences were observed in other studied characteristics. CONCLUSIONS: The clinical, morphological and vascular features of PEVAC and PEVAC-resembling lesions are similar based on multimodal imaging. Given the bilaterality and multifocality seen in PEVAC-resembling lesions, an underlying retinal vascular disease may stimulate the quantity of aneurysmal abnormalities. Due to the similarities with PEVAC-resembling lesions, PEVAC may also be considered a microangiopathy but with an unknown origin

Prevalence and Severity of Diabetic Retinopathy in Patients with Macular Telangiectasia Type 2

PURPOSE: To study the prevalence and severity of diabetic retinopathy (DR) in patients with macular telangiectasia type 2 (MacTel 2). DESIGN: Retrospective case series. PARTICIPANTS: Patients with a diagnosis of MacTel 2 treated at the Rotterdam Eye Hospital or Erasmus Medical Center between 2014 and 2018 were included. METHODS: The following information was retrieved from patient files: demographics, history of diabetes mellitus and hypertension, presence of DR, and severity of DR, that is, mild, moderate, severe, or proliferative. Presence of diabetic macular edema (DME) was assessed using OCT. MAIN OUTCOME MEASURES: Presence and severity of DR. RESULTS: Two hundred six eyes of 103 patients were included. At the onset of MacTel 2, the mean age was 61 years (standard deviation [SD], 9.8 years) and 64 (62%) were women. Mean follow-up was 71 months (SD, 60 months). Diabetes mellitus type 2 was present in 50 patients (49%) and hypertension was present in 47 patients (46%). Mild DR was present in 22 eyes (11%), of which 14 eyes (7%) showed signs at baseline and 8 eyes (4%) showed signs at a later time during follow-up. Ten eyes (5%) demonstrated remission of mild DR during follow-up. Both eyes (1%) in 1 patient progressed to moderate DR. Severe DR, proliferative DR, and DME did not occur. CONCLUSIONS: Although diabetes mellitus was highly prevalent among MacTel 2 patients, no patients showed severe or proliferative DR or DME. These findings suggest that MacTel 2 could have a protective effect on the progression of DR. We hypothesize that our results may be explained by the role of Müller cells in the development of MacTel 2 and DR, and therefore a link between both diseases warrants additional studies

Improved large-scale prediction of growth inhibition patterns using the NCI60 cancer cell line panel

An improved methodology is reported for the regioselective nitration of the phenyl groups of meso-tetraphenylporphyrin 1, using NaNO2 and TFA. The degree of nitration is easily controlled by the equivalent amount of NaNO2 used and the reaction time. The nitroporphyrins are reduced to the corresponding aminoporphyrins under standard SnCl2/HCl conditions. Reaction of tri-aminoporphyrin 9 with 1-formyl-o-carborane followed by reduction using NaBH4 gave a novel tri-carboranylporphyrin bearing amine linkages between the porphyrin and the carborane groups. © 2004 Elsevier Ltd. All rights reserved

Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis.

Contains fulltext : 50548.pdf (publisher's version ) (Open Access)PURPOSE: To test the efficiency of a microarray chip as a diagnostic tool in a cohort of northwestern European patients with Leber congenital amaurosis (LCA) and to perform a genotype-phenotype analysis in patients in whom pathologic mutations were identified. METHODS: DNAs from 58 patients with LCA were analyzed using a microarray chip containing previously identified disease-associated sequence variants in six LCA genes. Mutations identified by chip analysis were confirmed by sequence analysis. On identification of one mutation, all protein coding exons of the relevant genes were sequenced. In addition, sequence analysis of the RDH12 gene was performed in 22 patients. Patients with mutations were phenotyped. RESULTS: Pathogenic mutations were identified in 19 of the 58 patients with LCA (32.8%). Four novel sequence variants were identified. Mutations were most frequently found in CRB1 (15.5%), followed by GUCY2D (10.3%). The p.R768W mutation was found in 8 of 10 GUCY2D alleles, suggesting that it is a founder mutation in the northwest of Europe. In early childhood, patients with AIPL1 or GUCY2D mutations show normal fundi. Those with AIPL1-associated LCA progress to an RP-like fundus before the age of 8, whereas patients with GUCY2D-associated LCA still have relatively normal fundi in their mid-20s. Patients with CRB1 mutations present with distinct fundus abnormalities at birth and consistently show characteristics of RP12. Pathogenic GUCY2D mutations result in the most severe form of LCA. CONCLUSIONS: Microarray-based mutation detection allowed the identification of 32% of LCA sequence variants and represents an efficient first-pass screening tool. Mutations in CRB1, and to a lesser extent, in GUCY2D, underlie most LCA cases in this cohort. The present study establishes a genotype-phenotype correlation for AIPL1, CRB1, and GUCY2D

Clinical spectrum of severe chronic central serous chorioretinopathy and outcome of photodynamic therapy

Contains fulltext : 197206.pdf (publisher's version ) (Open Access