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At least 1,783 records · Page 99Linked to original sources
PubMed2002

The role of vitamin D receptor gene polymorphisms in bone biology.

The role of vitamin D and its receptor (VDR) in skeletal metabolism is well known but the vitamin D endocrine system seems to play an important role in other metabolic pathways as well, such as those involved in osteoarthritis, the immune response and cancer. One approach to understand the vitamin D endocrine system is to study the influence of variations in the DNA sequence of important proteins of this system. For example, deleterious mutations in the VDR gene cause 1,25-dihydroxyvitamin D-resistant rickets, a rare monogenetic disease. More subtle sequence variations (polymorphisms) in the VDR gene occur much more frequently but their effects are poorly understood. Their influence on the vitamin D endocrine system is currently under scrutiny in relation to a number of so-called complex diseases and traits such as osteoporosis. The interpretation of polymorphic variations in the VDR gene is severely hindered by the fact that several of the polymorphisms used have unknown effects. However, current data indicate that dozens of additional polymorphic variations exist in the VDR gene that could each have different types of consequences. Therefore, efforts are focussed on finding novel sequence variations and to study their interaction in molecular- and cell-biological experiments as well as in genomic epidemiological studies. The ultimate goal of this approach is to identify the combinations of functional sequence variants that modulate the vitamin D endocrine system and confer risk of disease.

Bone and Bones↗
PubMed2025

PROTRIDER: protein abundance outlier detection from mass spectrometry-based proteomics data with a conditional autoencoder.

MOTIVATION: Detection of gene regulatory aberrations enhances our ability to interpret the impact of inherited and acquired genetic variation for rare disease diagnostics and tumor characterization. While numerous methods for calling RNA expression outliers from RNA-sequencing data have been proposed, the establishment of protein expression outliers from mass spectrometry data is lacking. RESULTS: Here, we propose and assess various modeling approaches to call protein expression outliers across three datasets from rare disease diagnostics and oncology. We use as independent evidence the enrichment for outlier calls in matched RNA-seq samples and the enrichment for rare variants likely disrupting protein expression. We show that controlling for hidden confounders and technical covariates, while simultaneously modeling the occurrence of missing values, is largely beneficial and can be achieved using conditional autoencoders. Moreover, we find that the differences between experimental and fitted log-transformed intensities by such models exhibit heavy tails that are poorly captured with the Gaussian distribution and report stronger statistical calibration when instead using the Student's t-distribution. Our resulting method, PROTRIDER, outperformed baseline approaches based on raw log-intensities Z-scores, PCA, and isolation-based anomaly detection with Isolation forests. The application of PROTRIDER reveals significant enrichments of AlphaMissense pathogenic variants in protein expression outliers. Overall, PROTRIDER provides a method to confidently identify aberrantly expressed proteins applicable to rare disease diagnostics and cancer proteomics. AVAILABILITY AND IMPLEMENTATION: PROTRIDER is freely available at github.com/gagneurlab/PROTRIDER and also available on Zenodo under the DOI zenodo.15569781.

Proteomics↗
PubMed1985

Length variation and heteroplasmy are frequent in mitochondrial DNA from parthenogenetic and bisexual lizards (genus Cnemidophorus).

Samples of mtDNA isolated from each of 92 lizards representing all color pattern classes of Cnemidophorus tesselatus and two populations of C. tigris marmoratus were digested with the restriction endonucleases MboI, TaqI, RsaI and MspI. The mtDNA fragment sizes were compared after radioactive labeling and gel electrophoresis. Three features were notable in the comparisons: there was little variation due to gain or loss of cleavage sites, two fragments varied noticeably in length among the samples, one by a variable amount up to a maximum difference of approximately 370 base pairs (bp) and the other by a discrete amount of 35 bp, these two fragments occasionally varied within, as well as between, samples. Two regions that corresponded in size to these variants were identified by restriction endonuclease cleavage mapping. One of these is adjacent to the D-loop. Heteroplasmy, heretofore rarely observed, occurred frequently in these same two regions. Variability in the copy number of a tandemly repeated 64-bp sequence appears to be one component of the variation, but others (e.g., base substitutions or small additions/deletions) must also be involved. The frequent occurrence of these length variations suggests either that they can be generated rapidly or that they were inherited from a highly polymorphic ancestor. The former interpretation is favored.

Animals↗
PubMed1998

Dissecting the key recognition features of the MS2 bacteriophage translational repression complex.

The MS2 RNA operator capsid offers an unparalleled opportunity to study sequence-specific protein-protein and RNA-protein interactions in molecular detail. RNA molecules encompassing the minimal translational operator recognition elements can be soaked into crystals of RNA-free coat protein shells, allowing the RNA to access the interior of the capsids and make contact with the operator binding sites. Correct interpretation of these structural studies depends critically on functional analysis in solution to confirm that the interactions seen in the crystal are not an artefact of the unusual approach used to generate the RNA-protein complexes. Here we present a series of in vivo and in vitro functional assays, using coat proteins carrying single amino acid substitutions at residues which either interact with the operator RNA or are involved in stabilizing the conformation of the FG loop, the site of the major quasi-equivalent conformational change. Variant operator RNAs have been assayed for coat protein affinity in vitro. The results reveal the robustness of the operator-coat protein interaction and the requirement for both halves of a protein dimer to contact RNA in order to achieve tight binding. They also suggest that there may be a direct link between the conformation of the FG loop and RNA binding.

Base Sequence↗
PubMed2000

Economic fluctuations and anomalous diffusion

We quantify the relation between trading activity - measured by the number of transactions N(Deltat)-and the price change G(Deltat) for a given stock, over a time interval [t, t+Deltat]. To this end, we analyze a database documenting every transaction for 1000 U.S. stocks for the two-year period 1994-1995. We find that price movements are equivalent to a complex variant of classic diffusion, where the diffusion constant fluctuates drastically in time. We relate the analog for stock price fluctuations of the diffusion constant-known in economics as the volatility-to two microscopic quantities: (i) the number of transactions N(Deltat) in Deltat, which is the analog of the number of collisions and (ii) the variance W(2)(Deltat) of the price changes for all transactions in Deltat, which is the analog of the local mean square displacement between collisions. Our results are consistent with the interpretation that the power-law tails of P(G(Deltat)) are due to P(W(Deltat)), and the long-range correlations in |G(Deltat)| are due to N(Deltat).

Journal Article↗
PubMedDate not supplied

The ribs: anatomic and radiologic considerations.

The ribs are essential structures of the osseous thorax and provide information that aids in the interpretation of radiologic images. Techniques for making precise identification of the ribs are useful in detection of rib lesions and localization of lung lesions. The big rib sign and the vertical displacement sign can be used to differentiate the right and left ribs on lateral chest radiographs. The clavicle, the xiphoid process, and the sternal angle may be used as anatomic landmarks for rib counting on computed tomographic scans. For rib counting on lateral chest radiographs, the sternal angle or the 12th rib may be used. Anatomic rib variants include developmental deformities, cervical rib, and short rib and may mimic true rib diseases. Detection of thoracic deformities such as funnel chest (pectus excavatum) and barrel-shaped thorax requires an awareness of the strong correlation between the transverse appearance of the thorax and costal shape. Shadows around the rib cage (eg, rib companion shadows, sharp lines along the lower margin of the ribs, rib overlying shadows) may mimic pleural and extrapleural disease on frontal chest radiographs. It is imperative that the radiologist be familiar with normal rib anatomy, normal rib variants, and the radiologic appearance of the ribs to prevent misdiagnosis.

Humans↗
PubMed1999

Regulation of growth and apoptosis of breast cancer cells by a 54 kDa lymphokine.

A normal human lymphocyte-derived 54 kDa polypeptide, capable of regulating cell growth has been identified as an isoform variant (abbreviated as NP54) of protein neuroleukin-phosphoglucose isomerase (PGI). Since distinct PGI variants undetectable in normal tissues had been identified in breast cancer tissues, the effect of NP54 on the growth of human breast cancer cells SK-Br-3 in cultures was analyzed. Exposure to NP54 caused a dose-dependent growth modulation. Approximately 40% reduction of cell density was detected at 40 pM of NP54, along with a blocking of G1 cells entering into S phase. The growth modulation was correlated with a significantly reduced expression of epidermal growth factor receptor (EGF-R) gene transcript, supporting the interpretation that the level of EGF-R expression and cell growth are related mechanisms. NP54 treatment also significantly increased cells with apoptotic morphological feature and fragmented DNA. Incubation with a monoclonal anti-NP54 antibody negated NP54 activity, confirming a regulatory activity in cell growth and apoptosis.

Antibodies, Monoclonal↗
PubMed2006

Measurement of glycated hemoglobin (HbA1c) with an automated POCT instrument in comparison with HPLC and automated immunochemistry method: evaluation of the influence of hemoglobin variants.

Our study evaluates a fast and easy way to perform point-of-care testing (POCT) measurements of glycated hemoglobin HbA1c in comparison with an immunoassay on an automated biochemistry analyzer and cation exchange chromatography, the two methods routinely used in clinical laboratories for the measurement of HbA1c. A significant finding of our study is that although the POCT instrument insert claims that the method is not affected by the presence of HbS in the heterozygous state or in combination with beta-thalassemia, discrepant results were found in some cases with such hemoglobinopathies. In these cases, the two POCT and laboratory immunoassay methods showed clinically significant positive interferences with samples containing the HbS trait. We conclude that samples with the HbS trait should be interpreted with caution when tested using the POCT instrument.

Autoanalysis↗
PubMed1975

Borderline variants of the normal pituitary fossa.

Endocrinologists tend to accept minor variations of the pituitary fossa as evidence of the presence of a pituitary gland abnormality. Neuroradiologists tend to be sceptical. Normal criteria have not been established. In a consecutive series of 85 cases without any clinical evidence of a pituitary lesion, the plain films in 31.7 per cent demonstrated minor duplication of the floor or anterior wall of the pituitary fossa (with or without associated thinning and possible erosion of the lamina dura), which could be mistaken for the early signs of pituitary enlargement by an intrasellar tumour. 16.5 percent showed thinning of the lamina dura on tomography a feature previously taken as suggesting early enlargement. It is suggested that these particular diagnostic signs should be interpreted with caution.

Adolescent↗
PubMed2006

Unusually strong positive cooperativity in binding of peptides to latent membrane protein-1 DNA fragments of the Epstein-Barr viral gene.

The DNA-binding preferences of two oligopeptide amides, (His-Pro-Arg-Lys)(3)NH(2) (HR-12) and (Ser-Pro-Arg-Lys)(3)NH(2) (SP-12), have been examined by quantitative DNase I footprinting studies. Two different DNA fragments were investigated: a pair of 5'-(32)P-labeled duplexes from pBR322 with one or other of the complementary strands labeled and a corresponding pair of 5'-(32)P-labeled duplexes representing fragments of the latent membrane protein (LMP-1) gene from a pathogenic Epstein-Barr virus variant derived from nasopharyngeal carcinoma. The major objective was to examine molecular recognition and cooperative features associated with sequence-selective binding of synthetic peptides to the LMP-1 fragments. At various binding sites on the pBR322 fragments, Hill coefficients (n(H)) ranging from 1.9-2.2 were observed; these results indicate modest positive cooperativity between binding sites for both peptides. By contrast, unusually high values of n(H), ranging from 4.0-9.3, were observed at various binding sites on the LMP-1 fragments. Allosteric models can be constructed to interpret the observed cooperative interactions between different DNA recognition sites in the LMP-1 gene upon binding of the peptide ligands. It is noteworthy that these models feature a novel network of cooperativity interconnecting multiple DNA allosteric sites. The evidence of sequence selectivity and strong cooperativity discovered in this work may prove to be a general feature of peptide interactions with some nucleic acids.

Base Sequence↗
PubMed2002

Regressive threshold model for familial analysis of complex diseases with variable age of onset.

Few models for segregation (or combined segregation-linkage) analysis have been developed to account for variable age of onset. The unified model (UM) can only take into account age at examination. In the logistic hazard model (LHM), Abel and Bonney ([1990] Genet. Epidemiol. 7:391-407) incorporated survival analysis concepts into the regressive logistic model of Bonney ([1986] Am. J. Med. Genet. 18:731-749), but interpretation of familial dependence parameters is difficult. In this article, we extended the regressive threshold model (RTM) proposed by Demenais ([1991] Am. J. Hum. Genet. 49:773-785) to account for a variable age of onset of complex diseases. This model assumes an underlying liability to disease and is more general than the original logistic formulation, since the phenotypes of each individual's antecedents can be adjusted for their own genotypes and covariate effects. The variation of risk with age can be expressed as a general step function, and variants of the model have been proposed by imposing different types of constraints among the time-dependent thresholds. The performances of the three models (UM, LHM, and RTM) were compared in the context of segregation analysis of family data generated with variable age of onset. All analysis models were robust with respect to false conclusion of a major gene, and the best results were obtained under RTM. The power to detect the major gene was higher under LHM than RTM, but the best fit of the estimated cumulative age-dependent penetrance with respect to the true value was obtained under RTM. This new model may thus prove helpful in contributing to identification of genes underlying complex diseases, since it can easily include linked marker loci and linkage disequilibrium.

Age of Onset↗
PubMed2000

Marcus rate theory applied to enzymatic proton transfer.

The hydration of CO(2) and the dehydration of HCO(3)(-) catalyzed by the carbonic anhydrases is accompanied by the transfer of protons between solution and the zinc-bound water molecule in the active site. This transfer is facilitated by amino acid residues of the enzyme which act as intramolecular proton shuttles; variants of carbonic anhydrase lacking such shuttle residues are enhanced or rescued in catalysis by intermolecular proton transfer from donors such as imidazole in solution. The resulting rate constants for proton transfer when compared with the values of the pK(a) of the donor and acceptor give Bronsted plots of high curvature. These data are described by Marcus theory which shows an intrinsic barrier for proton transfer from 1 to 2 kcal/mol and work terms or thermodynamic contributions to the free energy of reaction from 4 to10 kcal/mol. The interpretation of these Marcus parameters is discussed in terms of the well-studied pathway of the catalysis and structure of the enzymes.

Animals↗
PubMedDate not supplied

Optimization of brachytherapy dose distributions by simulated annealing.

An algorithm based on the method of simulated annealing is presented for optimizing brachy-therapy dose distributions. The algorithm accommodates either static configurations of multiple sources or single stepping sources, hence in principle can be used to optimize both low- and high-dose rate treatments delivered with remote afterloading equipment. Required inputs include the specification of target dose rates and dose rate limits, expressed in absolute or relative terms, at operator selected points near the treatment site. The influence of the dose rate limits can be adjusted continuously through the use of one or more penalty factors. The algorithm generates a set of integer weights, one for each available source position, which are interpreted in terms of configuration occupancy numbers for static source arrangements and relative dwell times for stepping sources. Application is made to several variations of a hypothetical low-dose rate vaginal vault planning problem involving one rectal and six applicator calculation points. The algorithm's performance for different source strengths, annealing schedules, target dose rates, dose rate limits, and values of a single penalty factor lambda was examined. With a simple annealing schedule and value of lambda = 25, the algorithm found solutions of high quality for all problem variants. The CPU time required for optimization on a Vax 11/750 computer ranged from 2 min for a single configuration to 25 min for a solution consisting of four configurations. These results support the use of simulated annealing for clinical planning of low dose rate vaginal treatments, and encourage investigation of other applications in brachytherapy.

Algorithms↗
PubMed1991

Evaluation of the E test for quantitative antimicrobial susceptibility testing of Helicobacter pylori.

The Progressive Diagnostics Manufacturers epsilometer test (E test; AB Biodisk, Solna, Sweden), a quantitative variant of the disk diffusion technique, was evaluated comparatively to an agar dilution method for the antimicrobial susceptibility testing of Helicobacter pylori. A collection of 79 H. pylori clinical strains, including isolates with known resistance to various antimicrobial agents, was tested against 12 different antimicrobial agents. All strains were tested on Columbia agar supplemented with 10% horse blood. Plates were incubated at 37 degrees C in microaerobic atmosphere (5% O2, 10% CO2), and readings were done after 3 days of incubation. In general, E test MICs were easy to interpret and the correlation between MICs by the agar dilution method and the E test was good, with 86 and 99.5% of results being within, respectively, 1 and 2 log2 dilution steps in a total of 936 tests. All strains of H. pylori with documented resistance to the tested agents were detected by the E test. Thus, the E test appears to be an easy and reliable method for determination of MICs of antibiotics for H. pylori, and it may offer an interesting alternative to MIC determination by the agar dilution technique.

Drug Resistance, Microbial↗
PubMed2005

In vivo aggregation properties of the nuclear poly(A)-binding protein PABPN1.

A broad range of degenerative diseases is associated with intracellular inclusions formed by toxic, aggregation-prone mutant proteins. Intranuclear inclusions constitute a pathological hallmark of oculopharyngeal muscular dystrophy (OPMD), a dominantly inherited disease caused by (GCG) repeat expansions in the gene that encodes for nuclear poly(A) binding protein (PABPN1). The mutation results in an extended polyalanine stretch that has been proposed to induce protein aggregation and formation of intranuclear inclusions. Here we show that normal PABPN1 is inherently aggregation-prone when exogenously expressed in either HeLa or myogenic C2 cells. Similar deposits of insoluble PABPN1 are formed by variant forms of the protein containing either a polyalanine expansion or a complete deletion of the polyalanine tract, indicating that the mutation responsible for OPMD is not essential for formation of PABPN1 inclusions. In contrast, interfering with any of the protein domains required for stimulation of poly(A) polymerase prevents the formation of inclusions. Most surprisingly, photobleaching experiments reveal that both normal and expanded PABPN1 molecules are not irreversibly sequestered into aggregates, but rather move rapidly in and out of the inclusions. These findings have important implications for the interpretation of OPMD model systems based on exogenous expression of PABPN1.

Animals↗
PubMed2001

Rabies postexposure prophylaxis. Human and domestic animal considerations.

The emphasis on rabies control and prevention in the United States seems to be a function of our perception of proximity of the threat. Wildlife rabies epizootics within a state may be of little concern to the uninformed urban dweller. Additionally, many parts of the western United States are free of terrestrial rabies; were it not for the presence of bat rabies, people in those areas would likely interpret rabies control as a minor public health concern. It is essential that federal, state, and local public health programs emphasize the importance of rabies control through activities that include rabies education, sponsorship of legislated requirements for domestic animal vaccination, support for local animal control programs, and the promotion of recommendations that encourage the appropriate use of PEP. We are almost guaranteed that rabies is going to remain a major public health issue well into the next century because of expanding wildlife rabies epizootics, identification of new rabies viral variants with increased public health concern, emotional and legal concerns associated with rabies exposure, and increasing national cost associated with rabies control and prevention. Nevertheless, the development of new laboratory technology that allows an understanding of the epidemiologic nature of the rabies virus based on an evolving genetic history and the interrelationship with wildlife reservoirs should allow access to valuable tools for rabies control. When combined with programs using new developments in oral rabies vaccine that can immunize whole populations of wildlife reservoirs, that technology offers encouragement in our effort to control one of the diseases of antiquity.

Animals↗
PubMed2003

Molecular variation of human HSP90alpha and HSP90beta genes in Caucasians.

Understanding DNA variation within the human genome is fundamental to the identification and interpretation of genetic components underlying complex traits and diseases. Despite their role in many crucial cellular pathways and their reported involvement in many complex diseases no data are available on the molecular variability of the genes coding for Heat Shock Proteins 90Kda (HSP90). Towards this purpose we have used DHPLC methodology to survey, a sample of Caucasians for genetic polymorphisms in the exons and exon-flanking regions of the expressed genes of human HSP90 gene families, HSP90alpha (HSPCAL4, 14q31.3) and HSP90beta (HSPCB, 6p12). A total of 18 and 11 variants were found in the HSP90-alpha and -beta genes respectively, providing an initial view of human genetic variation in these important genes. Only three of the observed mutations altered the genic product. Interestingly, one of the variations observed was a missense mutation leading to the impairment of the hsp90alpha protein.

DNA↗
PubMed1989

DNA typing of an HLA-DR bilocus specificity by gene amplification and oligonucleotide hybridization.

The structure of the DRB1*03 gene has been interpreted as the product of a gene conversion event involving a DRB3 gene as donor and resulting in the introduction of two short segments of the DRB3 sequence into the DRB1 locus. The serological counterpart of this double insertion is the TR81 specificity. Consequently, the TR81-specifying sequences can reside on either DRB1 or DRB3, or on both loci. Within each of the two sequence stretches a single nucleotide may be responsible for the generation of the TR81 alloantigen. Oligonucleotide probes corresponding to these stretches and to their allelic variants were constructed. They were used, under stringent hybridization conditions, to detect TR81-specifying sequences in the DNA of HLA-homozygous cell lines carrying different haplotypes of the DRw52 family. Prior to hybridization the DNA was amplified with either DRB1-specific or DRB3-specific primers. Using this approach it was possible to perform a "DNA typing" of the TR81-specifying sites separately on both the DRB1 locus and the DRB3 locus.

Alleles↗