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Biomedical subjects

I Simon

Publications and source records attributed to I Simon.

At least 19 recordsLinked to original sources
PubMed2002

[Nosocomial infections in geriatric facilities].

EPIDEMIOLOGY: In long term geriatric facilities, the prevalence of nosocomial infections (to the order of 10% in the surveys) is greater than that observed in short-term medical care centers. An endemia of methicillin-resistant Staphylococcus aureus, of between 24 and 57% of hospitalized patients, is noted in many geriatric facilities. In decreasing order, the infections that predominate are: urinary (1/3), lower respiratory tract (1/4) and cutaneous tissue infections (1/5). However, these are often manifested by misleading semiology, and orient towards an organ other that which is infected. TRANSMISSION AND PREVENTION: Nosocomial infections are frequently related to the general health of the patient and/or to transmission during handling. Invasive treatments are rarely the cause in geriatry. Preventive measures are identical to those used in short-term care centers (handwashing, source isolation and appropriate use of antibiotics). PROBLEMS: Encountered However, their application raises many problems. The living conditions (few facilities with single beds), the state of health of these elderly patients, often exhibiting multiple diseases and requiring assistance for their daily gestures, and the reduced number of staff at the bedside, require that these measures be adapted to each particularity.

Age Factors↗
PubMed2002

The role of hydrophobic microenvironments in modulating pKa shifts in proteins.

The screened Coulomb potential (SCP) method, combined with a quantitative description of the microenvironments around titratable groups, based on the Hydrophobic Fragmental Constants developed by Rekker, has been applied to calculate the pK(a) values of groups embedded in extremely hydrophobic microenvironments in proteins. This type of microenvironment is not common; but constitutes a small class, where the protein's architecture has evolved to lend special properties to the embedded residue. They are of significant interest because they are frequently important in catalysis and in proton and electron transfer reactions. In the SCP treatment these special cases are treated locally and therefore do not affect the accuracy of the pK(a) values calculated for other residues in less hydrophobic environments. Here the calibration of the algorithm is extended with the help of earlier results from lysozyme and of three mutants of staphylococcal nuclease (SNase) that were specially designed to measure the energetics of ionization of titratable groups buried in extremely hydrophobic microenvironments. The calibrated algorithm was subsequently applied to a fourth mutant of SNase and then to a very large dimeric amine oxidase of 1284 residues, where 334 are titratable. The observed pK(a) shifts of the buried residues are large (up to 4.7 pK units), and all cases are well reproduced by the calculations with a root mean square error of 0.22. These results support the hypothesis that protein electrostatics can only be described correctly and self-consistently if the inherent heterogeneity of these systems is properly accounted for.

Algorithms↗
PubMed2002

Role of stabilization centers in 4 helix bundle proteins.

Stabilization centers (SCs) were shown to play an important role in preventing decay of three-dimensional protein structures. These residue clusters, stabilized by cooperative long-range interactions, were proposed to serve as anchoring points for arranging secondary structure elements. In all-alpha proteins, SC elements appear less frequently than in all-beta, alpha/beta, and alpha+beta proteins suggesting that tertiary structure formation of all-alpha proteins is governed by different principles than in other protein classes. Here we analyzed the relation between the formation of stabilization centers and the inter-axial angles (Omega) of alpha-helices in 4 helix bundle proteins. In the distance range, where dipoles have dominant effect on the helix pair arrangement, those helix pairs, where residues from both helices participate in SC elements, appear as parallel more frequently than those helices where no SC elements are present. For SC containing helix pairs, the energetic difference between the parallel and anti-parallel states decreases considerably from 1.1 kcal/mol to 0.4 kcal/mol. Although the observed effect is weak for more distant helices, a competition between the SC element formation and the optimal dipole-dipole interaction of alpha-helices is proposed as a mechanism for tertiary structure formation in 4 helix bundle proteins. The SC-forming potential of different arrangements as well as the pitfalls of the SC definition are also discussed.

Molecular Structure↗
PubMed2002

Modeling MHC class II molecules and their bound peptides as expressed at the cell surface.

A detailed insight to the structure of a given major histocompatibility complex (MHC)-peptide complex can strongly support and also improve the analysis of the peptide binding capabilities of the MHC molecule and the characterization of the developing T cell response. The number of MHC class II-peptide crystal structures is limited, therefore constructing and analyzing computer models can serve as efficient complementary tools when someone deals with experimentally determined binding and/or functional data. Commercial programs are available for modeling protein and protein-protein complexes, in general. However, more accurate results can be obtained if the parameters are directly optimized to a given complex, especially in the case of special proteins as MHC class II, an integral membrane protein, whose functional parts behave like regular globular proteins. Here, we present the optimization of an approach used for modeling MHC class II molecules complexed with various peptides fitting into the binding groove and several ways to analyze them with the help of experimental data.

Amino Acid Sequence↗
PubMed2001

Developmental regulation of DNA replication timing at the human beta globin locus.

The human beta globin locus replicates late in most cell types, but becomes early replicating in erythroid cells. Using FISH to map DNA replication timing around the endogenous beta globin locus and by applying a genetic approach in transgenic mice, we have demonstrated that both the late and early replication states are controlled by regulatory elements within the locus control region. These results also show that the pattern of replication timing is set up by mechanisms that work independently of gene transcription.

Animals↗
PubMed2001

Predicting protein conformation by statistical methods.

The unique folded structure makes a polypeptide a functional protein. The number of known sequences is about a hundred times larger than the number of known structures and the gap is increasing rapidly. The primary goal of all structure prediction methods is to obtain structure-related information on proteins, whose structures have not been determined experimentally. Besides this goal, the development of accurate prediction methods helps to reveal principles of protein folding. Here we present a brief survey of protein structure predictions based on statistical analyses of known sequence and structure data. We discuss the background of these methods and attempt to elucidate principles, which govern structure formation of soluble and membrane proteins.

Membrane Proteins↗
PubMed2001

Serial regulation of transcriptional regulators in the yeast cell cycle.

Genome-wide location analysis was used to determine how the yeast cell cycle gene expression program is regulated by each of the nine known cell cycle transcriptional activators. We found that cell cycle transcriptional activators that function during one stage of the cell cycle regulate transcriptional activators that function during the next stage. This serial regulation of transcriptional activators forms a connected regulatory network that is itself a cycle. Our results also reveal how the nine transcriptional regulators coordinately regulate global gene expression and diverse stage-specific functions to produce a continuous cycle of cellular events. This information forms the foundation for a complete map of the transcriptional regulatory network that controls the cell cycle.

Cell Cycle↗
PubMed2001

Role of Rab9 GTPase in facilitating receptor recruitment by TIP47.

Mannose 6-phosphate receptors (MPRs) deliver lysosomal hydrolases from the Golgi to endosomes and then return to the Golgi complex. TIP47 recognizes the cytoplasmic domains of MPRs and is required for endosome-to-Golgi transport. Here we show that TIP47 also bound directly to the Rab9 guanosine triphosphatase (GTPase) in its active, GTP-bound conformation. Moreover, Rab9 increased the affinity of TIP47 for its cargo. A functional Rab9 binding site was required for TIP47 stimulation of MPR transport in vivo. Thus, a cytosolic cargo selection device may be selectively recruited onto a specific organelle, and vesicle budding might be coupled to the presence of an active Rab GTPase.

Amino Acid Substitution↗
PubMed2001

Prion protein: evolution caught en route.

The prion protein displays a unique structural ambiguity in that it can adopt multiple stable conformations under physiological conditions. In our view, this puzzling feature resulted from a sudden environmental change in evolution when the prion, previously an integral membrane protein, got expelled into the extracellular space. Analysis of known vertebrate prions unveils a primordial transmembrane protein encrypted in their sequence, underlying this relocalization hypothesis. Apparently, the time elapsed since this event was insufficient to create a "minimally frustrated" sequence in the new milieu, probably due to the functional constraints set by the importance of the very flexibility that was created in the relocalization. This scenario may explain why, in a structural sense, the prion protein is still en route toward becoming a foldable globular protein.

Evolution, Molecular↗
PubMed2001

[Epidemic of Staphylococcus aureus nosocomial infections resistant to methicillin in a maternity ward].

Methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infections frequently occur in the hospital environment, but their incidence is less often observed in neonates. In the present investigation, seventeen cases were recorded over a nine-week period (two cases per week). Pulsed field gradient gel electrophoresis confirmed the clonal character of the strain. The hypothesis of manually-transmitted infection due to contamination from multiple sources was reinforced by the fact the epidemic persisted in spite of the elimination of the main human infectious source and an absence of risk factors determined by the case-control study. The role of environmental factors in the persistence of this outbreak of MRSA infection has been considered.

Adult↗
PubMed2001

The HMMTOP transmembrane topology prediction server.

UNLABELLED: The HMMTOP transmembrane topology prediction server predicts both the localization of helical transmembrane segments and the topology of transmembrane proteins. Recently, several improvements have been introduced to the original method. Now, the user is allowed to submit additional information about segment localization to enhance the prediction power. This option improves the prediction accuracy as well as helps the interpretation of experimental results, i.e. in epitope insertion experiments. AVAILABILITY: HMMTOP 2.0 is freely available to non-commercial users at http://www.enzim.hu/hmmtop. Source code is also available upon request to academic users.

Algorithms↗
PubMed2001

Prenatal diagnosis and postnatal follow-up of pericallosal lipoma: report of seven new cases.

BACKGROUND AND PURPOSE: Pericallosal lipomas are rare tumors. Few reports have included their imaging characteristics. Furthermore, little is known about their evolutive course. Our purpose was to describe the imaging features of seven cases of pericallosal lipoma diagnosed in utero and followed up after birth. METHODS: We reviewed seven cases of pericallosal lipoma diagnosed by obstetric sonography (n = 7) and examined by fetal MR imaging (n = 5). Analysis of the complementary findings provided by fetal MR imaging was conducted. All findings were correlated with the postnatal imaging and clinical findings. RESULTS: Obstetric sonography easily showed the pericallosal lipoma in all seven patients. In one, however, it was misinterpreted as intracranial hemorrhage. The morphology and integrity of the underlying corpus callosum were less easy to assess by using sonography. Fetal MR imaging confirmed the fatty content and location of the lesion in all five cases. It showed the choroidal extension in two patients and the type of associated callosal anomaly in another patient better than did sonography. In two patients, the lipoma grew, as revealed by subsequent postnatal MR imaging. The results of the neurologic examinations remained normal for the five surviving patients at a mean follow-up of 3 years (1 month-9 years). CONCLUSION: Obstetric sonography is able to easily show pericallosal lipoma. Fetal MR imaging may be useful to characterize the lipomatous nature and the extension of the lipoma and the status of the corpus callosum. Long-term follow-up is necessary to understand the clinical consequences of such lesions.

Agenesis of Corpus Callosum↗
PubMed2001

[Prenatal semiology of diastematomyelia].

Diastematomyelia is a rare spinal malformation characterized by a division of the spinal cord. More often, the two hemicords are separated by a midline and sagittal osseous or fibrocartilaginous spur. In this report we describe two cases of diastematomyelia detected at routine second trimester detailed sonography and further assessed by MRI and spiral CT with surface shaded 3D-reconstructions. In addition to providing diagnosis, prenatal evaluation helps differentiate between diastematomyelia with good or bad prognosis.

Adult↗
PubMed2000

Genome-wide location and function of DNA binding proteins.

Understanding how DNA binding proteins control global gene expression and chromosomal maintenance requires knowledge of the chromosomal locations at which these proteins function in vivo. We developed a microarray method that reveals the genome-wide location of DNA-bound proteins and used this method to monitor binding of gene-specific transcription activators in yeast. A combination of location and expression profiles was used to identify genes whose expression is directly controlled by Gal4 and Ste12 as cells respond to changes in carbon source and mating pheromone, respectively. The results identify pathways that are coordinately regulated by each of the two activators and reveal previously unknown functions for Gal4 and Ste12. Genome-wide location analysis will facilitate investigation of gene regulatory networks, gene function, and genome maintenance.

Binding Sites↗
PubMed2000

Today men with prostate cancer have larger prostates.

OBJECTIVES: To examine the relationship between prostate size and the method of cancer detection in men with organ-confined prostate cancer, and compare prostate size in men with and without cancer. METHODS: Prostate volume was evaluated in 720 men who had undergone radical prostatectomy for Stage T1c or Stage T2 cancer. Men with Stage T2 cancer were divided into those treated before 1989 (when widespread prostate-specific antigen [PSA] testing began), or not. Gland volume was also examined in 265 men participating in the Baltimore Longitudinal Study of Aging who had no clinical evidence of cancer. Volumes were compared using linear regression to allow for age. RESULTS: Prostate volume in men with Stage T1c cancer was statistically significantly larger than in men with Stage T2 cancer diagnosed in the pre-PSA era after adjusting for age (P = 0.0001), and statistically significantly larger than in men without cancer above age 47 years based on 95% confidence intervals. Prostate volumes in men with Stage T2 cancer diagnosed in the pre-PSA era and in men without cancer were not statistically significantly different. CONCLUSIONS: Prostate volume in men with PSA-detected, organ-confined cancer is larger than in men with palpable organ-confined cancer diagnosed in either the pre-PSA era or PSA era. These discrepancies may reflect a diagnostic bias due to the effect of benign prostatic hyperplasia on serum PSA that results in the selection of men with larger prostates for biopsy.

Adult↗
PubMed2000

Allele-specific expression patterns of interleukin-2 and Pax-5 revealed by a sensitive single-cell RT-PCR analysis.

Autosomal genes that are subject to random allelic inactivation (RAI), like imprinted genes [1] and genes subject to X-inactivation [2], require mechanisms that dictate the differential transcriptional regulation of two sequence-identical alleles. RAI genes include olfactory receptor genes [3], and the various genes encoding antigen receptors on lymphocytes (immunoglobulin genes, T cell receptor genes and NK receptor genes [4] [5] [6] [7]). These observations raise the possibility that other genes might be similarly regulated. Moreover, an interesting possibility is that certain genes might be monoallelically expressed in some cells and biallelically expressed in others. Recently, reports of monoallelic expression of interleukin-2 (IL-2) [8] [9] and IL-4 [10] [11] have raised the possibility that the cytokine gene family may be subject to monoallelic expression. Another report suggests that the gene encoding the transcription factor Pax-5, which is involved in B-cell (and cerebellar) development [12] [13], is also subject to monoallelic expression [14]. Using a novel single-cell reverse transcription-polymerase chain reaction (RT-PCR) approach, we have analyzed the IL-2 and Pax-5 genes in mice. We found that IL-2 is monoallelically transcribed in some T cells and biallelically transcribed in others, raising interesting questions regarding cytokine gene regulation. Additionally, our analyses suggest that Pax-5 is consistently biallelically transcribed. Thus, the IL-2 gene and other cytokine genes may be regulated in a stochastic manner that results in 0, 1 or 2 alleles of a given cytokine gene expressed in each T cell. This type of regulation could account for the wide variety of different combinations of cytokine genes expressed in individual T cells and therefore plays a role in the generation of T cells with a range of different effector functions.

Alleles↗
PubMed2000

Mapping of a protective helper T cell epitope of human influenza A virus hemagglutinin.

The synthetic peptide comprising the 317-341 region of human influenza A virus (H1N1 subtype) hemagglutinin elicits peptide-specific antibody and helper T cell responses and confers protection against lethal virus infection. Molecular mapping of the 317-329 region, which encompasses the epitope recognized by peptide-specific T cells, revealed that the minimal size required for T cell activation was the 317-326 segment. The most likely peptide alignment, which placed 320Leu to pocket 1 of the I-E(d) peptide binding groove, was predicted by molecular mechanics calculations performed with the parental and with the Ala-substituted analogs. In line with the prediction data, the results of the peptide binding assay, where the relative binding efficiency to I-E(d) molecules expressed on the surface of antigen-presenting cells was monitored, identified the 320-326 core sequence interacting with the major histocompatibility class II peptide binding groove. Functional analysis of Ala-substituted variants by functional assays and by calculating the surface-accessible areas of the single peptidic amino acids in the I-E(d)-peptide complexes demonstrated that 324Pro is a primary contact residue for the T cell receptor. Our results show that this type of analysis offers a suitable tool for molecular mapping of helper T cell epitopes and thus provides valuable data for subunit vaccine design.

Alanine↗