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Four cultures of a Candida sp. that lacked alpha-glucosidase activity were isolated from clinical specimens. Physiological, morphological, and serological characterizations of the yeasts and deoxyribonucleic acid reassociation studies supported their classification as a variant of C. tropicalis.
Glaucoma is a blinding eye disease that affects approximately 70 000 000 people world-wide. Mutations in the gene TIGR / MYOC have been shown to cause the most common form of the disease, primary open angle glaucoma, in selected families. Amino acid sequence variants of the gene have been found in 2-4% of sporadic primary open angle glaucoma cases. Most variants are rare and it is often difficult to definitively distinguish between a deleterious mutation and a benign variant solely on the basis of relative frequencies in patient and control groups. The function of the TIGR/myocilin protein is unknown and an assay to functionally classify variants is lacking. We sought to develop a biochemical assay to distinguish different forms of TIGR/myocilin. We investigated the Triton X-100 detergent solubility characteristics of mutant and normal forms of the protein, expressed by transfection in cultured cells. We observed a clear difference in the behavior of the two types of TIGR/myocilin; all confirmed mutant proteins tested were substantially Triton insoluble, while normal protein and controls were completely soluble. We also tested seven ambiguous variant proteins and classified them as mutant or normal on the basis of their Triton solubility. The results in some cases validated, and in other cases contradicted, earlier classifications of these variants. To our knowledge, Triton solubility is the first example of a general difference in the properties of mutant and normal forms of TIGR/myocilin. The assay we have developed will be useful for discerning protein functional information from the location of mutations, will aid genetic counseling of individuals with TIGR/myocilin variants and may provide a clue to understanding a mechanism by which mutations in TIGR / MYOC cause glaucoma.
The present-day classification of gunshot penetrating abdominal wounds has a several number of limitations, namely: sometimes it is difficult to classify correctly the gravity of wounds, thus patients with different gravity status frequently form the same group of wounded. The authors propose to concretize the existing classification. A new variant will provide for a straight definition between the groups, the wounded who belong to the same group could be comparable in their gravity status. Generally, this new classification give a more complete and precise notion concerning the character of modern gunshot penetrating abdominal injuries.
The authors give the analysis of the best known systems of nematodes, parasitizing vertebrates. The classifications of Chitwood (1933, 1937); Skrjabin et Schultz (1940) and Chabaud (1974) are discussed. A new variant of the system of the mentioned nematode groups is proposed, the classification of Chabaud being assumed as its basis. In the subclass Adenophorea the authors distinguish two orders--Trichocephalida and Dioctophymida. The subclass Secernentea includes according to Chabauds system five orders: Rhabditida, Strongylida, Oxyurida, Ascaridida and Spirurida. Two suborders--Ascaridina and Heterakina are distinguished in the order Ascaridida, three suborders--Spirurina, Cammallanina and Filariina--in the order Spirurida. The suborders Gnathostomatina and Cucullanina are admitted to be not enough valid. Both these groups are considered as superfamilies in the new variant of classification. A conception of the close phylogenetic relationships between the orders of the subclass Seurina, Cammallanina and Filariina--in the order Spirurida. The suborders Gnathostomatina and Cucullanina are admitted to be not enough valid. Both these groups are considered as superfamilies in the new variant of classification. A conception of the close phylogenetic relationships between the orders of the subclass Seurina, Cammallanina and Filariina--in the order Spirurida. The suborders Gnathostomatina and Cucullanina are admitted to be not enough valid. Both these groups are considered as superfamilies in the new variant of classification. A conception of the close phylogenetic relationships between the orders of the subclass Secernentea is championed. The authors believe that the historical development of the representatives of this nematode group occurred from the rabditiform worms towards the strictly specialized parasitic forms, which are met in the order Spirurida. The representatives of the order Rhabditida are the most closely related to the ancestral forms of the subclass Secernentea.
The partial revision of the generally accepted classification of the morphological forms of trypanosomatid flagellates (Hoare, Wallace, 1966) is proposed. Only "flagellar" characteristics without evaluation of the form of the body and systematic position of the flagellates are used in the new variant of the classification. Six basic morphological forms of trypanosomatids have been included in proposed scheme: amastigotes, endomastigotes, promastigotes, opisthomastigotes, epimastigotes, trypomastigotes.
Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise from interactions between environmental factors and predisposing genotypes and include common Mendelian lipid disorders, cardiomyopathies and arrhythmia syndromes. The identification of a pathogenic variant through genetic testing can inform disease diagnosis, risk prediction, treatment and family screening. However, a major roadblock in genomic medicine is that for many variants, especially missense variants, we lack sufficient evidence to enable a definitive classification, and therefore these variants are deemed as 'variants of uncertain significance'. In this Review, we describe how multiplexed assays of variant effects can enable the functional assessment of nearly all coding variants in a target sequence, potentially offering a proactive approach to identifying the functional significance of gene variants that are observed later in a patient. We discuss validation, including the role of in silico variant effect predictors, and how multiplexed experimental methods are informing cardiovascular disease biology and ultimately resolving the problem of variants of uncertain significance at scale.
Polymorphism of an alpha-protease inhibitor, PI3, in pig serum samples was detected using 2D agarose gel (pH 5.4)--polyacrylamide gel (pH 9.0) electrophoresis. Evidence was obtained that the five variants observed (A, B1, B2, C and D) are under genetic control by codominant alleles (Pi3A, Pi3B1, Pi3B2, Pi3C and Pi3D) at one autosomal locus. Variants A, B1, B2 and C inhibited chymotrypsin; there was no appreciable inhibition of trypsin and papain. Variant D did not inhibit chymotrypsin, and therefore its classification as a PI3 variant was put in question. PI3 typing was not possible in about 50% of the studied pigs since in those cases the PI3 variants were either too weak or absent. On the basis of backcross matings and haplotyping in complete families for protease inhibitor loci Pi1, Po1A, Pi2 and Pi3 it was proved that the Pi3 locus belongs to the protease inhibitor gene cluster, and the position of the locus in the linkage group was proposed as being Pi1-Po1A-(Po1B)-Pi3-Pi2-(Igh1, Igh2, Igh3, Igh4).
The authors provide the working classification of rheumatic diseases prepared by a large group of scientists under the aegis of the All-Union Society of Rheumatologists and under the guidance of V. A. Nasonova, Academician of the USSR AMS. In preparing the final variant of the classification use was made of the experience gained by therapists in cooperation with pediatricians.
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Reaction-time studies of numerical comparison have used essentially two paradigms: classification, in which a target number must be labelled "larger" or "smaller" in comparison to a fixed standard, and selection, in which the larger (or smaller) number of a pair must be picked out. In previous studies, classification has yielded only a distance effect in RTs, whereas selection has also revealed magnitude (or minimum) and congruity effects. We used two experiments with two-digit number comparisons to find the reason for this discrepancy. In Experiment 1, we used a variant of the classification task with the standard changing on each trial. RTs increased along with the standard for "smaller" responses and decreased along with the standard for "larger" responses, in a manner reminiscent of magnitude and congruity effects. In Experiment 2, we again used classification, but the fixed standard 75 was not at the center of the range of target numbers (20, 21, ... 99). Close to the standard, RTs were faster for "larger" than for "smaller" responses, again a congruity effect. Our data show that magnitude and congruity effects can be obtained with two-digit numbers in classification as well as in selection tasks. A single equation, which implies that numbers are compared with respect to reference points at both ends of the continuum, describes the results from both tasks.
OBJECTIVES: To investigate the genetic etiology of a three-generation pedigree affected with piebaldism. METHODS: Next-generation sequencing and Sanger sequencing were employed to detect and verify gene variants. Bioinformatics tools were used to predict the effects of candidate variants on splicing and protein function. RT-PCR and Sanger sequencing were further performed to validate the impact of the variant on RNA splicing, and homology modeling was applied to predict its effect on the three-dimensional structure of the KIT protein. The pathogenicity of the variant was then classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the UK Association for Clinical Genomic Science (ACGS). RESULTS: A heterozygous insertion variant near the splice site, c.1990+8_1990+9insTGCACCATTGGAGGTAAA, was identified in the KIT gene in the proband and was found to co-segregate with the phenotype within the family. RT-PCR and cDNA sequencing revealed that this variant led to aberrant splicing during transcription, resulting in a 21 bp in-frame insertion in the mRNA, which encodes an extra 7 amino acids within the tyrosine kinase domain and may thus affect protein function. In silico predictions, together with the experimental findings, supported classification of this variant as likely pathogenic according to relevant variant interpretation guidelines. CONCLUSIONS: The heterozygous splice-site insertion variant KIT:c.1990+8_1990+9insTGCACCATTGGAGGTAAA is the genetic cause of piebaldism in this pedigree.
A total of 40 strains of Orientia tsutsugamushi (34 isolates from patients and trombiculid mites in Japan, and 6 prototype strains of antigenic variants) were examined for classification based on the reactivities with type-specific monoclonal antibodies in indirect immunofluorescence tests, and on the restriction fragment length polymorphism of a polymerase chain reaction (PCR)-amplified 56-kilodalton type-specific antigenic protein gene. By these methods, several antigenic and genotypic variants were found among the strains, and these variants were classified into types and further into subtypes. These results suggest that there are many variants in O. tsutsugamushi, and the methods used here seem to be useful for the systematic classification of the numerous variants. A strain which may be a new type distinguishable from those identified previously was also found in this study. Furthermore, variety in the degree of pathogenicity in mice related to type and/or subtype classification were observed.
IMPORTANCE: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome. OBJECTIVE: To examine the results of genetic testing for early-onset AF. DESIGN, SETTING, AND PARTICIPANTS: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021. EXPOSURES: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. MAIN OUTCOMES AND MEASURES: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders. RESULTS: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8). CONCLUSIONS AND RELEVANCE: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.
The nonlinear regimes of convection in a system of three immiscible viscous fluids are investigated by the finite-difference method. We study new phenomena caused by direct and indirect interaction of thermocapillary and buoyancy (Rayleigh and anticonvective) instability mechanisms. Two variants of heating-from below and from above-are considered. The interfaces are assumed to be flat. We focus on nonlinear evolution of steady and oscillatory motions and selection of stable convective structures depending on the parameters of systems. The influence of the lateral boundary conditions is also investigated. A classification of different variants of interaction between Rayleigh and thermocapillary instability mechanisms is presented, and several typical examples are studied. Specifically, we considered six different configurations where the Rayleigh convection arises mainly in a definite layer, and the thermocapillary convection appears mainly near the definite interface. Also, the case where both interfaces are active and alternatively play a dominant role is investigated. Some configurations of interaction between anticonvective and thermocapillary instability mechanisms are considered.
The study is based on the analysis of 268 patients with chronic postinfarction aneurysms of the heart, 190 of whom were operated. Clinical characteristics of postinfarction cardiac aneurysms are presented, and several symptoms typical for this pathology are singled out: pericardial pulsation, low pulse volume, tachycardia, outward shift of the left margin of the heart, galloping atrial rhythm. Proceeding from a careful analysis of the clinical material an original classification of the variants of the clinical course of chronic postinfarction carrdiac aneurysms is introduced: 1) with prevailing chronic coronary insufficiency; 2) with combined chronic coronary and cardiac insufficiency; 3) with prevailing cardiac insufficiency.
Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.
MOTIVATION: Rare diseases collectively affect 5% of the population. However, fewer than 50% of rare disease patients receive a molecular diagnosis after whole genome sequencing. Supervised machine learning is a valuable approach for the pathogenicity scoring of human genetic variants. However, existing methods are often trained on curated but limited central repositories, resulting in poor accuracy when tested on external cohorts. Yet, large collections of variants generated at hospitals and research institutions remain inaccessible to machine-learning purposes because of privacy and legal constraints. Federated learning (FL) algorithms have been recently developed enabling institutions to collaboratively train models without sharing their local datasets. RESULTS: Here, we present a proof-of-concept study evaluating the effectiveness of FL for the clinical classification of genetic variants. A comprehensive array of diverse FL strategies was assessed for coding and non-coding Single Nucleotide Variants as well as Copy Number Variants. Our results showed that federated models generally achieved comparable or superior performance to traditional centralized learning. In addition, federated models reached a robust generalization to independent sets with smaller data fractions as compared to their centralized model counterparts. Our findings support the adoption of FL to establish secure multi-institutional collaborations in human variant interpretation. AVAILABILITY AND IMPLEMENTATION: All source code required to reproduce the results presented in this article, implemented in Python, is available under the GNU General Public License v3 at https://github.com/RausellLab/FedLearnVar.