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PubMed2005

DNA repair gene polymorphisms in relation to chromosome aberration frequencies in retired radiation workers.

Polymorphic variation in DNA repair genes was examined in a group of retired workers from the British Nuclear Fuels plc facility at Sellafield in relation to previously determined translocation frequencies in peripheral blood lymphocytes. Variation at seven polymorphisms in four genes involved in the base excision repair (XRCC1 R194W, R399Q and a [AC]n microsatellite in the 3' UTR) and double strand break repair (XRCC3 T241M and a [AC]n microsatellite in intron 3 of XRCC3, XRCC4 I134T, and a GACTAn microsatellite located 120 kb 5' of XRCC5) pathways was determined for 291 retired radiation workers who had received cumulative occupational external radiation doses of between 0 and 1873 mSv. When the interaction between radiation dose and each DNA repair gene polymorphism was examined in relation to translocation frequency there was no evidence for any of the polymorphisms studied influencing the response to occupational exposure. A positive interaction observed between genotype (individuals with at least one allele > or =20 repeat units) at a microsatellite locus in the XRCC3 gene and smoking status should be interpreted cautiously because interactions were investigated for seven polymorphisms and two exposures. Nonetheless, further research is warranted to examine whether this DNA repair gene variant might be associated with a sub-optimal repair response to smoking-induced DNA damage and hence an increased frequency of translocations.

Aged↗

PubMed2003

Bifid mandibular canal.

PURPOSE: To determine the incidence and characteristics of bifid mandibular canals. METHODS: A retrospective study was performed using panoramic radiographs of 2012 patients subjected to dental treatment in the Dental Clinic of the Valencia University Dental School (Valencia, Spain) between 1996 and 1999. The goal was to investigate the presence of double mandibular canals. RESULTS: The extraoral panoramic radiographs revealed a total of 7 images suggestive of bifid canals. Mandibular computed tomography revealed the existence of this anatomic variant in 2 of 3 patients. An analysis was performed on the incidence of this type of image in extraoral panoramic radiography, its possible interpretations, and the clinical implications of bifid mandibular canals. CONCLUSIONS: In this study, 0.35% of canals were bifid. All cases were in women.

Adolescent↗

PubMed2005

Thermodynamic prediction of protein neutrality.

We present a simple theory that uses thermodynamic parameters to predict the probability that a protein retains the wild-type structure after one or more random amino acid substitutions. Our theory predicts that for large numbers of substitutions the probability that a protein retains its structure will decline exponentially with the number of substitutions, with the severity of this decline determined by properties of the structure. Our theory also predicts that a protein can gain extra robustness to the first few substitutions by increasing its thermodynamic stability. We validate our theory with simulations on lattice protein models and by showing that it quantitatively predicts previously published experimental measurements on subtilisin and our own measurements on variants of TEM1 beta-lactamase. Our work unifies observations about the clustering of functional proteins in sequence space, and provides a basis for interpreting the response of proteins to substitutions in protein engineering applications.

Amino Acid Substitution↗

PubMed1999

Assessment of linkage disequilibrium by the decay of haplotype sharing, with application to fine-scale genetic mapping.

Linkage disequilibrium (LD) is of great interest for gene mapping and the study of population history. We propose a multilocus model for LD, based on the decay of haplotype sharing (DHS). The DHS model is most appropriate when the LD in which one is interested is due to the introduction of a variant on an ancestral haplotype, with recombinations in succeeding generations resulting in preservation of only a small region of the ancestral haplotype around the variant. This is generally the scenario of interest for gene mapping by LD. The DHS parameter is a measure of LD that can be interpreted as the expected genetic distance to which the ancestral haplotype is preserved, or, equivalently, 1/(time in generations to the ancestral haplotype). The method allows for multiple origins of alleles and for mutations, and it takes into account missing observations and ambiguities in haplotype determination, via a hidden Markov model. Whereas most commonly used measures of LD apply to pairs of loci, the DHS measure is designed for application to the densely mapped haplotype data that are increasingly available. The DHS method explicitly models the dependence among multiple tightly linked loci on a chromosome. When the assumptions about population structure are sufficiently tractable, the estimate of LD is obtained by maximum likelihood. For more-complicated models of population history, we find means and covariances based on the model and solve a quasi-score estimating equation. Simulations show that this approach works extremely well both for estimation of LD and for fine mapping. We apply the DHS method to published data sets for cystic fibrosis and progressive myoclonus epilepsy.

Algorithms↗

PubMed2026

DeepGeSeq: deep learning library for genomic sequence modeling and analysis.

MOTIVATION: Deep learning methods have demonstrated significant potential in genomics, enabling broad applications such as sequence activity prediction, regulatory rule identification, and variant effect quantification. However, their widespread adoption is often hindered by the steep computational learning curve required for model construction, training, and downstream biological interpretation. Here, we introduce DeepGeSeq, a user-friendly Deep-learning library tailored for Genomic Sequence modeling and analysis. RESULTS: By integrating state-of-the-art architectural modules, DeepGeSeq streamlines the entire deep learning workflow, requiring minimal user input via a simple configuration file and an intuitive agentic skill. We comprehensively validate the efficacy of DeepGeSeq through diverse case studies, encompassing pipeline verification using synthetic datasets, the reproduction and application of established models, and model fine-tuning coupled with biological interpretation on user-defined data. Furthermore, we demonstrate DeepGeSeq's versatility in domain-specific applications, including single-cell ATAC-seq modeling for cell-type clustering, and MPRA data modeling coupled with in silico saturation mutagenesis to dissect cis-regulatory elements. Ultimately, DeepGeSeq bridges the gap between computational complexity and biological discovery, providing an accessible resource that facilitates the development and broad application of deep learning methods in genomics research. AVAILABILITY AND IMPLEMENTATION: https://github.com/JiaqiLi1024/DeepGeSeq.

Deep Learning↗

PubMed1991

Histologic classification of the combined nevus. Analysis of the variable expression of melanocytic nevi.

The designation combined nevus gives recognition to mixed cytologic patterns. In the common variant, plump, pigmented spindle cells form fascicles among nests of ordinary nevus cells. In other variants, one or several cellular components that share cytologic features with either a blue nevus or a Spitz nevus are represented. Ninety-five cases, 49% of which were of the common type, were studied. Grossly, most of the lesions were darkly pigmented papules or nodules. The clinical diagnosis in three-fourths of the cases was nevus, blue nevus, or melanoma. Fifteen percent had concomitant histologic features of melanocytic dysplasia, and most of these lesions were of the common type. For the common variant, the cytologic features, pattern of apparent infiltration, and variable representation of the features of a premalignant melanocytic dysplasia often mislead a pathologist in interpreting and predicting biologic potential. In combined nevi, the phenotypic diversity and genetic lability of melanocytic nevus cells is manifested.

Adolescent↗

PubMed2003

Phase variation in Bartonella henselae.

Bartonella henselae is a fastidious, Gram-negative bacterial pathogen of cats and humans. Previous workers have shown that serial passage in vitro leads to attenuation of virulence-associated attributes such as expression of pili, invasion of human epithelial cell lines and the stimulation of endothelial cell proliferation. In contrast to the published data, it was found that pilin expression is frequently preserved in organisms which have undergone phase variation in vitro. Transition from a slow-growing, dry agar-pitting (DAP) to a faster-growing, smooth non-agar-pitting (SNP) form appears to occur predictably and may reflect competition between two populations growing at different rates. Better survival of the slower-growing (DAP) form may explain its relatively easy retrieval from piliated SNP populations allowed to age on solid media. Pilin expression is associated with auto-agglutination in liquid suspension or broth cultures, and appears to be necessary but not sufficient for expression of the agar-pitting phenotype and for the formation of biofilms. Outer-membrane protein variation is seen in association with phase variation, but lipopolysaccharide expression is preserved in piliated as well as extensively passaged non-piliated isolates. The EagI/HhaI infrequent restriction site-PCR fingerprint, which has been previously used to discriminate between serotypes Marseille and Houston, is shown to alter with phase variation in vitro, and there is evidence that genetic change accompanies these events. The extent of genetic and phenotypic variability of phase-variant B. henselae has previously been underestimated. It may lead to new insights into the pathogenicity of this organism, and must be considered when interpreting data arising from such studies.

Animals↗

PubMed2004

Conditions associated with very low values of glycohaemoglobin measured by an HPLC method.

AIMS: To identify the causes of very low glycohaemoglobin (GHb) values in a sample of patients with diabetes in southern Brazil using high performance liquid chromatography. METHODS: Between August 1996 and December 2001 all samples from patients with diabetes at a university hospital with GHb values below the reference range (4.7-6.0% HbA(1c)) were submitted to cellulose acetate electrophoresis. Medical records were reviewed to identify conditions that might be associated with these low values. RESULTS: Among 29 657 samples analysed, 130 patients had GHb < 4.7%. Seventy three patients (56%) were heterozygous for HbS, HbC, or HbD (19 black, two mulatto, and 52 white patients). The other 57 patients (44%) without Hb variants had low haematocrit and haemoglobin values (42 patients) or other conditions such as pregnancy, lipaemia, malignancy, cirrhosis, acetylsalicylic acid use, and absence of diabetes (15 patients). CONCLUSIONS: The presence of an Hb variant may falsely lower GHb measurements. However, anaemia is also a source of negative interference. The haematological status should be considered for the correct interpretation of GHb results.

Adolescent↗

PubMed2000

Fine-needle aspiration of secondary neoplasms involving the salivary glands. A report of 36 cases.

Metastases or secondary deposits account for 16% of the malignant neoplasms involving the major salivary glands. A correct diagnosis of a secondary neoplasm is important to avoid unnecessary radical surgery and to guide further therapy. Fine-needle aspiration biopsy (FNAB) is an excellent noninvasive diagnostic tool for evaluating salivary gland lesions. We reviewed 36 secondary malignant salivary gland neoplasms evaluated by FNAB. Ancillary studies were performed in selected cases. Follow-up included clinical correlation and review of histologic material. For 4 adenocarcinomas, 4 squamous cell carcinomas, 1 undifferentiated carcinoma, 1 cutaneous basal cell carcinoma, 10 cutaneous melanomas including 1 desmoplastic variant, 3 osteosarcomas, 11 non-Hodgkin lymphomas, and 2 multiple myelomas, there was 1 false-negative FNAB result. The desmoplastic melanoma was interpreted as reactive lymphoid hyperplasia. A malignant diagnosis was given in all remaining cases except the secondary basal cell carcinoma, which was diagnosed as a neoplasm with basal cell features. FNAB is a reliable tool to differentiate hematologic malignant neoplasms and melanomas from other salivary gland neoplasms. A complete knowledge of the clinical history, review of previous pathologic materials, and, in some instances, the use of ancillary studies are crucial for recognizing solid malignant neoplasms secondarily involving the salivary glands.

Adult↗

PubMed1993

MR imaging of the ankle and foot: normal structures and anatomic variants that may simulate disease.

In the past, MR imaging of the ankle and foot has been performed by scanning both extremities simultaneously to provide a normal side for comparison. More recently, unilateral imaging with small local coils has been favored to maximize spatial resolution through use of small fields of view or large matrices. Such clarity of detail, however, demands a greater knowledge of normal anatomy and anatomic variants. We illustrate the MR appearances of a number of variants involving muscle, tendons, ligaments, and osseous structures of the foot and ankle. Familiarity with these findings is essential to prevent errors in the interpretation of MR images.

Ankle Joint↗

PubMed2002

Computer-supported interpretation of protein profiles after capillary electrophoresis.

BACKGROUND: Electrophoretic patterns of proteins in serum/plasma are useful in the diagnosis and evaluation of many diseases. Capillary zone electrophoresis (CZE) allows rapid and automated protein separation and produces digital absorbance data, appropriate for mathematical analysis. We previously demonstrated success in detection of monoclonal immunoglobulins in such a system. This study tests new algorithms to produce rapid standardized computer-supported interpretation of the entire electropherogram. METHODS: Data from Beckman Paragon CZE 2000 electropherograms were compared with quantitative protein data from >800 routine clinical samples. Algorithms were designed to produce semiquantitative analyses of major proteins and to define different patterns of inflammation based on the electropherogram. RESULTS: The algorithms produced reliable semiquantitative evaluations of prealbumin, albumin, alpha1-antitrypsin, haptoglobin, and transferrin, but were less accurate for alpha1-acid glycoprotein. Some genetic variants of albumin and deficiency variants of alpha1-antitrypsin were easily recognized. Complex clinical traits such as degree and type of inflammation could be evaluated. When used together with previously developed algorithms addressing immunoglobulins, the new algorithms provide relevant clinical interpretation. Selected outputs indicate the need for reflex testing or evaluation by specialists. CONCLUSIONS: Automation of both electrophoresis and interpretation can provide a rapid, inexpensive, standardized analysis that can hopefully improve the diagnostic information and clinical outcome for large groups of patients. It also provides objective criteria for clinical interpretations, to be validated or adjusted in future clinical studies.

Adult↗

PubMedDate not supplied

Flow cytometric analysis of proteoglycan expression on murine tumor cells with different metastatic capacity.

Proteoglycan epitopes recognized by poly- or monoclonal antibodies were studied at the cell surface of 3LL murine tumor cell lines with different metastatic capacity. A decreased expression of heparan sulphate and chondroitin sulphate core protein epitopes was observed in the highly metastatic variant HM compared to the low metastatic counterpart LM. Interestingly, the biochemical analysis demonstrated an increased glycosaminoglycan-especially heparan sulphate-production in highly metastatic HM cells. A similar decrease in heparan sulphate proteoglycan core epitope expression was observed in the highly metastatic B16F10 cell line compared to its low metastatic variant F1. The under-representation of proteoglycan core protein epitopes at the cell surface of highly metastatic murine tumor cell lines could be interpreted by the increased glycosylation, or by the loss of those particular epitopes.

Animals↗

PubMed1975

[Certain practical problems of recognition and treatment of cardiac rhythm disorders].

Having briefly touched upon the problem of terminology and classification of arrhythmias the authors consider the diagnosis and clinical evaluation of some disorders, including the extrasystole (the significance of the extrasystolic interval), ectopic arrhythmias from the region of the atrio-ventricular junction (with simultaneous consistent or transent disruption of the intraventricular conduction), isolated atrial tachycardia, some variants of auricular fibrillation, flutter paroxysms, paroxysms of ventricular tachycardia, with continued auricular fibrillation in particular, and also the earlier described electrocardiographic phenomenon tentatively interpreted as sinistroatrial fibrillation with dextraatrial tachycardia, as well as major types of disrupted condution. The authors give a brief exposure of their views as to the principles of the treatment. Emphasis is placed on the importance of a comprehensive clinical approach to the diagnostic matters and to the evaluation of arrhythmias, as well as to the fundamental need to define more precisely the pathogenesis of the disturbed rhythm in a concrete patient so as to adopt an effective treatment.

Ajmaline↗

PubMed1980

[Method of evaluating the psychological conflict in patients who have had a myocardial infarct].

A test for quantitative appraisal of psychological confliction is described. A variant of the "Polar personality profiles" method (SDF) is used as the basis of the test. The corresponding scheme for presenting the SDF and interpreting the data obtained is elaborated. Data obtained during clinical interrogations were used for validation of the test. One hundred and forty-five males were examined 1.5 to 2 months after recovery from myocardial infarction. A close correlatin was noted between the clinical data and the results of SDF. The results of the study show that the suggested method makes it possible to obtain reliable quantitative data concerning the psychological confliction of patients who had myocardial infarction.

Conflict, Psychological↗

PubMed1993

Pulmonary aspergillosis: pathologic and pathogenetic features.

Pulmonary aspergillosis is a relatively common fungal infection in individuals who are immunocompromised or have intrinsic lung disease. Clinical, radiological, and pathologic manifestations are quite varied and depend to a large extent on the type and severity of local or systemic host defense abnormalities. In individuals with only structural lung damage, saprophytic growth alone is the rule. Patients with atopy or other hypersensitivity state typically develop allergic disease, most often allergic bronchopulmonary aspergillosis. Individuals with other immunologic abnormalities, particularly immunodeficiency, and with granulocytopenia characteristically develop invasive disease, which may take several morphological forms. Identification of Aspergillus as the cause of all these disease variants is usually not a problem. However, recognition of the different patterns of disease is useful in understanding the pathogenesis of disease and in interpreting premortem clinical and radiographic abnormalities.

Aspergillosis↗

PubMed1993

Analysis of heat shock element recognition by saturation mutagenesis of the human HSP70.1 gene promoter.

We analyzed the human HSP70.1 gene promoter heat shock element by saturation point mutagenesis and performed quantitative assays of in vitro heat shock factor binding and of in vivo transcription activity in HeLa cells with this extensive set of mutants. These results showed a significant correlation between measurements of heat shock factor binding and heat-inducible expression and provided a detailed thermodynamic description of the preferred recognition consensus sequence. In particular, this work demonstrated that outer positions 1 and 5 of the 5-base pair motif NGAAN, in addition to the most conserved triplet in the center, can have a strong influence on activity. Optimal activity occurred with the sequence AGAAC, and the levels of activity for all single base substitution variants were established. This analysis should be useful both for predicting the activity of potential heat shock element sequences near mammalian promoters and for interpreting structural features of protein-nucleic acid interactions in this system.

Animals↗

PubMed1997

Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations.

BACKGROUND: The dietary reference values for folate, as for other nutrients, are targeted to the general and supposedly normal population, not people with special needs, such as those with genetic or metabolic abnormalities or diseases. However, 5-15% of general populations are homozygous for a thermolabile variant of 5,10-methylenetetrahydrofolate reductase (C677T) which causes mild hyperhomocysteinaemia and is positively associated with the development of vascular disease and the risk of neural-tube defects. If tissue-folate status is compromised in large sectors of the population by this or other genetic variants, the present dietary reference values may need to be changed. METHODS: We identified the C677T genotype and measured red-cell folate concentrations in two groups of healthy women (pregnant, 242, not pregnant, 318). We then analysed the effect of genotype on red-cell folates, which are a reliable marker for tissue folate stores. FINDINGS: In the pregnant group there were 20 TT homozygotes, 114 wild-type CC homozygotes, and 108 CT heterozygotes. In the non-pregnant group, the numbers were 41, 148, and 129. In both pregnant and non-pregnant groups, red-cell folate was significantly lower among TT homozygous than CC homozygous women (mean 252 [95% CI 202-317] vs 347 [321-372] micrograms/L, p = 0.002 for pregnant women; 284 [250-327] vs 347 [342-372] micrograms/L, p = 0.01 for non-pregnant women). Plasma folate was also significantly lower in TT homozygous than in CC homozygous women in the pregnant group (p = 0.009) but not in the non-pregnant group. INTERPRETATION: These results suggest that a substantial minority of people in general populations may have increased folate needs. Future studies may show the presence of other common genetic variants that interact with particular nutrients and place doubts on the validity of assuming "normality" for nutrient requirements in any general population.

Diet↗

PubMed1989

Meiotic behavior of gonosomically variant females of Akodon azarae (Rodentia, Cricetidae).

The meiotic behavior of sex chromosomes has been investigated in variant females of Akodon azarae, both in pachytene oocytes and metaphase I. In somatic cells, these females have a heteromorphic sex pair, in which the minor chromosome has been previously interpreted as a major deletion of the long arm of the X chromosome (dX). After microspreading for synaptonemal complex analysis, pachytene oocytes show two axes of very different lengths (100:17.1), which correspond to the sex chromosomes X and dX. True synapsis is abnormally restricted (43.3%) between these sex chromosomes; on the other hand, self-synapsis of both the X and dX chromosomes is frequent (60%). Single, nonsynapsed axes or axial segments are thickened. Strong chromatin condensation occurs around nonsynapsed axes or axial segments, giving many of these sex pairs an appearance similar to an XY body ("sex vesicle"). The minor gonosome axis differs from that of the Y chromosome of male meiosis, as the former is shorter (relative to the X) and has a different synaptic behavior. In 17 metaphases I from XdX variant females, only heteromorphic, end-to-end joined sex pairs were observed. These variant females differ from the variant females of the wood lemming Myopus schisticolor in several respects, but a similar mechanism seems to be prevalent in other species of the genus Akodon. Self-synapsis of unequal gonosomes in oocytes is assumed as an escape from functional deterioration, following the hypothesis put forward by others.

Animals↗