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PubMed2000

Measurement of protein interaction bioenergetics: application to structural variants of anti-sCD4 antibody.

This chapter has described a bioenergetic analysis of the interaction of sCD4 with an IgG1 and two IgG4 derivatives of an anti-sCD4 MAb. The MAbs have identical VH and VL domains but differ markedly in their CH and CL domains, raising the question of whether their antigen-binding chemistries are altered. We find the sCD4-binding kinetics and thermodynamics of the MAbs are indistinguishable, which indicates rigorously that the molecular details of the binding interactions are the same. We also showed the importance of using multiple biophysical methods to define the binding model before the bioenergetics can be appropriately interpreted. Analysis of the binding thermodynamics and kinetics suggests conformational changes that might be coupled to sCD4 binding by these MAbs are small or absent.

Antibodies, Monoclonal↗
PubMed1989

Interaction of stimulus parameters on the auditory brain stem response: a normal variant.

The purpose of this investigation was to further define the effect that stimulus parameters of phase, intensity, and rate have in significantly reducing the wave V amplitude. Two separate experiments were conducted to determine whether an interactive effect exists and how robust the effect was on wave V. Results revealed that wave V amplitude was reduced to less than half the absolute amplitude of the wave IV-V complex in 9 of the 39 subjects. The phenomenon was dependent upon stimulus parameters of rarefaction phase, high intensity, and low repetition rate. Conversely, the phenomenon was independent of cochlear integrity, sex, and test equipment. The implications to diagnostic interpretation during routine auditory brain stem response testing are discussed.

Adult↗
PubMed1993

The role of class II molecules in Mls 1a recognition by CD4+ T cells is independent of the CD4 molecule.

The interpretation of previous antibody inhibition and cell depletion experiments was that major histocompatibility complex (MHC) class II molecules are involved in presentation of Mls molecules to T cell receptors. However, a possible conclusion of several subsequent studies was that T cell receptors may in fact recognize Mls molecules in a class II-unassociated manner. We considered that if this interpretation of the relevant data was correct, the earlier demonstrated role of MHC class II molecules on Mls 1a antigen presenting cells in the response of CD4+ T cells might be only to serve as a ligand for the CD4 molecule on the responder cells. To test the possibility that the inhibition of the anti-Mls 1a response by anti-class II antibodies solely reflected such a CD4:class II molecular interaction, we derived CD4- variants of two independent T cell receptor V beta 6-expressing, Mls 1a-responsive T hybrid clones. Since preliminary experiments to screen for responsiveness revealed that the CD4- variants of both T hybrid clones retained responsiveness to Mls 1a and the variants of one that was also responsive to staphylococcal enterotoxin B retained that responsiveness, we concluded that there is no qualitative dependency of the responses of V beta 6 T cells to these two superantigens on a CD4-mediated activity. More importantly, the responses of the CD4- variants of the two T hybrid clones to Mls 1a retain the same susceptibility to inhibition by antibodies to MHC class II molecules exhibited by the parental T hybrids. These results indicate that the blocking of responses of CD4+ T cells to Mls 1a by both anti-H-2A and anti-H-2E antibodies is not due only to disruption of interactions between CD4 and H-2A or H-2E molecules. The data are thus consistent with the class II molecule-dependent models of Mls 1a presentation to the T cell receptor which are discussed in the light of recent findings on the biochemical nature of the Mls 1a molecule.

Animals↗
PubMed1989

Low-temperature unfolding of a mutant of phage T4 lysozyme. 2. Kinetic investigations.

A disulfide-bridged variant of bacteriophage T4 lysozyme has been found to undergo a low- as well as high-temperature unfolding transition in guanidinium chloride [see Chen and Schellman (1989)]. The kinetics for this process have been followed for several temperatures, a range of guanidinium chloride concentrations, and a number of values of pH. Microscopic rate constants for protein unfolding and refolding were extracted from these data to explore the nature of the cold unfolding transition. The data were interpreted using transition-state theory. It was found that the Arrhenius energy is temperature dependent. The transition state is characterized by (1) a high energy and low entropy compared to the native state, (2) a heat capacity which is closer to the native state than to the unfolded state, and (3) a low exposure to solvent compared to the unfolded state, as judged by its interaction with guanidinium chloride. With increasing concentration of guanidinium chloride, the low-temperature unfolding rate increases strongly, and the refolding rate decreases very strongly.

Escherichia coli↗
PubMed2001

[Syndromes in environmental medicine: variants of somatoform disorders].

Concerning the syndromes in environmental medicine, like Multiple Chemical Sensitivities (MCS), Idiopathic Environmental Intolerances (IEI), Sick Building Syndrome (SBS), Chronic Fatigue Syndrome (CFS), Candida Syndrome (CS), and Burnout Syndrome (BS), scientific knowledge in etiology, pathology, pathophysiology, diagnosis, therapy, prevention and prognosis is still lacking until now. A critical comparison shows that it is still impossible to find a scientifically satisfying delimitation. Syndromes in environmental medicine show clinical similarities to somatoform disorders. Furthermore, there are the following possible explanations for the existence of these syndromes: Firstly, they may be a complex interaction of environmental impacts, individual predispositions, psychological influences, as well as processes of mental perception and interpretation. Secondly, they may be an effect of distress influenced by culture and social structures and/or thirdly, they may be an latrogenic determination. A more comprehensive characterisation which better considers the complex clinical manifestations is overdue. Although there are neither scientifically validated procedures for diagnosis or therapy nor prophylactic measures, a hardly comprehensible number of partly unvalidated methods is in practical use. Until the syndromes are not finally defined the terms for the syndromes should not be applied to a certain disease. Despite all uncertainities in the evaluation of syndromes in environmental medicine, physicians have the duty to take the affected persons' problems seriously.

Environmental Medicine↗
PubMed2003

Molecular epidemiology of extended-spectrum beta-lactamases produced by clinical isolates in a university hospital in Greece: detection of SHV-5 in Pseudomonas aeruginosa and prevalence of SHV-12.

To assess the nature and diversity of various types of SHV and TEM derivatives in our hospital a survey was conducted. Sixty-seven extended-spectrum beta-lactamases (ESBL)-producing nosocomial pathogens, isolated over a 12-month period, were analyzed by means of PCR and direct sequencing. SHV-5 was the predominant ESBL found in our region (38 strains). Other less frequent variants included SHV-2 and SHV-12 with two and three isolates, respectively. For the first time, an outbreak of 11 Pseudomonas aeruginosa producing SHV-5 was encountered. All blaTEM-positive strains carried the non-ESBL TEM-1. The incidence of non-SHV non-TEM ESBLs was remarkably high as almost one out of three isolates harbored such an ESBL. The epidemiological and clinical impact of these findings must be carefully investigated and interpreted.

DNA, Bacterial↗
PubMed2004

Dynamic simulation of protein complex formation on a genomic scale.

MOTIVATION: One of the central questions in the post-genomic era is the understanding of protein-protein interactions and of protein complex formation. It has been observed that protein complex size distributions of the yeast Saccharomyces cerevisiae decay exponentially. The shape of these size distributions reflects mechanisms of protein complex association and dissociation. RESULTS: We present the most simple dynamic model that is able to reproduce the observed protein complex size distribution for yeast. This protein association-dissociation model (PAD-model) simulates the dynamics of protein complex formation on a genomic scale for about 50 million protein molecules. By ruling out different model variants it is possible to elucidate fundamental features of the protein complex dynamics, e.g. complex association is independent of complex size. In addition, the PAD-model provides information about the complexity of the yeast proteome and it gives an idea of how many complexes could not be identified during the measurements. AVAILABILITY: All programs used for this publication are available on request from the authors. CONTACT: beyer@imb-jena.de SUPPLEMENTARY INFORMATION: Supplementary information about the model and its interpretation can be downloaded from http://www.imb-jena.de/tsb/pad.

Computer Simulation↗
PubMed2002

Standardization of Neisseria meningitidis serogroup B colorimetric serum bactericidal assay.

The correlate of protection for serogroup B meningococci is not currently known, but for serogroup C it is believed to be the serum bactericidal assay (SBA). The current SBAs are labor intensive and the variations in protocols among different laboratories make interpretation of results difficult. A colorimetric SBA (cSBA), based on the ability of Neisseria meningitidis serogroup B to consume glucose, leading to acid production, was standardized by using group B strain Cu385-83 as the target. The cSBA results were compared to those obtained for a traditional colony-counting microassay (mSBA). Glucose and bromocresol purple pH indicator were added to the medium in order to estimate growth of cSBA target cell survivors through color change. Different variants of the assay parameters were optimized: growth of target cells (Mueller Hinton agar plates), target cell number (100 CFU/per well), and human complement source used at a final concentration of 25%. After the optimization, three other group B strains (H44/76, 490/91, and 511/91) were used as targets for the cSBA. The selection of the assay parameters and the standardization of cSBA were done with 13 sera from vaccinated volunteers. The titers were determined as the higher serum dilution that totally inhibited the bacterial growth marked by the color invariability of the pH indicator. This was detected visually as well as spectrophotometrically and was closely related to a significant difference in the growth of target cell survivors determined using Student's t test. Intralaboratory reproducibility was +/-1 dilution. The correlation between bactericidal median titers and specific immunoglobulin G serum concentration by enzyme immunoassay was high (r = 0.910, P < 0.01). The bactericidal titers generated by the cSBA and the mSBA were nearly identical, and there was a high correlation between the two assays (r = 0.974, P < 0.01). The standardized cSBA allows easy, fast, and efficient evaluation of samples.

Adolescent↗
PubMed2003

Complexity of the genetic contribution to factor VII deficiency in two Spanish families: clinical and biological implications.

BACKGROUND AND OBJECTIVES: Although many F7 DNA variants have been described to be associated with alterations in factor VII (FVII) levels, the correlation of functional levels of FVII with disease (i.e. bleeding) is highly variable indicating that other factors are likely involved in producing this phenotype. DESIGN AND METHODS: We studied two unrelated Spanish families, identified from two asymptomatic propositi with FVII:C levels lower than 1% and 3%. Family members showed a wide range of FVII:C levels. Amplification and direct DNA sequencing of the F7 (promoter, exons, 3'-UTR and a large proportion of introns) identified the genetic variants involved. RESULTS: We characterized 3 mutations in the F7 coding region (homozygous Q100R in one patient, and double heterozygosity for M298I and G331S in another patient). We also found 16 new DNA polymorphisms. The high variability of FVII levels in family members with the same mutation shows that the inheritance of FVII phenotypes is extremely complex and suggests that polymorphisms might play an important role in modulating FVII levels, and ensuring hemostatic balance under pathologic conditions. INTERPRETATION AND CONCLUSIONS: These results highlight the importance of a concerted effect of multiple genetic factors in determining FVII levels. Since there is evidence that FVII levels constitute a risk factor for coronary heart disease and considering the importance of F7 DNA polymorphisms in determining FVII levels, further analyses of these polymorphisms should yield information to aid the understanding of the quantitative variation in FVII levels and the relative genetic risk for cardiovascular disease in the general population.

3' Untranslated Regions↗
PubMed1983

TOr1 is a novel, variant form of mouse chromosome 17 with a deletion in a partial t haplotype.

Moutier discovered, in a mouse from a noninbred Swiss/Orleans laboratory stock, a spontaneous dominant mutation which mapped to the T locus, and which was named TOr1. Genetic analyses indicated that TOr1 was not a simple mutation at one locus, but rather a deletion over a 3-centimorgan region of chromosome 17 that included both T and quaking (qk). Further experiments reported by Erickson et al., and a more comprehensive study by Hammerberg, have demonstrated that TOr1 is associated with recessive genetic properties affecting sperm function, characteristic of the proximal region of complete t haplotypes. These results were interpreted as evidence for the location of proximal t haplotype 'sperm factors' within the region deleted by TOr1. We now provide conclusive biochemical and genetic evidence that the 'TOr1 haplotype' is inseparably associated with a chromosomal region derived from a naturally occurring mouse t haplotype. Hence, it is likely that the t haplotype properties of TOr1 are a consequence not of the deletion itself, but of closely linked mutant t haplotype genes.

Animals↗
PubMedDate not supplied

[The electrophysiological correlates of the individual-typological variants in stimulus assessment in 10- to 12-year-old children].

In children with various types of description of indefinite verbal and visual images stimuli the evoked potentials (EPs) were studied to these stimuli and control ones. Semantic reconstruction of indefinite stimuli is accompanied by an increase of activation level of late EPs components of the associative zones of the left hemisphere at perception of verbal stimuli and of the associative zones of the right hemisphere at perception of images. The subjects realizing semantic reconstruction of images produce EPs with predominance of activating influences by a number of EP parameters both at perception of indefinite images and of those definitely interpreted.

Child↗
PubMed1995

Periodic selection and hitchhiking in a bacterial population.

The accumulation of a neutral marker in a bacterial population under balanced growth in a chemostat follows a jagged curve as adaptive variants continuously appear and sweep the population. Such periodic selection curves are simulated in the present work using deterministic equations that, in contrast to previous models, take full account of the stochastic character of the process. The uncertainties due to the appearance time, the survival probability, and the extent of early growth at small numbers are included as stochastic initial conditions for every new variant--adaptive or neutral--that appears. The model is used to calculate the substitution rate via hitchhiking where a neutral or weakly selected mutation is carried along when a new adaptive one takes over the population. The expected ratio for the probabilities of the presence or absence of a weakly selected or counterselected mutation in the population is also calculated. This can be related to the standard result without hitchhiking if the average time between adaptive shifts is interpreted as an effective population size.

Bacteria↗
PubMed1981

H-21-linked control of immunological resistance to viral leukemogenesis as a response to preleukemic cells.

The mechanism of resistance to leukemogenesis by two radiation leukemia virus variants, A-RadLV and D-RadLV, was investigated. Resistance to these viruses is linked to H-21 in both B10.S and C57BL/10 mice. The resistance of virus-infected mice to transplantation of syngeneic. A- or D-RadLV-induced lymphoma cells was similar to their resistance to leukemogenesis by the same viruses. This resistance could be transferred by lymphoid cells from immune donors to normal recipients, and it was specific for RadLV lymphomas. Virus-primed (responder x sensitive)F1 hybrids rejected only resistant-type parental lymphoma cells. Hence, it appears that H-21-linked resistance to RadLV leukemogenesis is regulated by Ir genes. Resistant mice immunized by A- or D-RadLV rejected syngeneic lymphoma cells, irrespective of whether they were sensitive or resistant to the RadLV variant used for the induction of the lymphoma cells. It follows that resistant and sensitive type lymphomas are antigenically similar for the effector mechanism, and that the Ir genes may be expressed in the sensitization phase of the reaction. In virus-infected mice which are resistant to A- or D-RadLV we were able to demonstrate the presence of preleukemic lymphocytes. Normal mice could be immunized by these preleukemic cells against lymphoma challenge. These data are interpreted to suggest that mice having H-21-linked resistance to RadLV infection may be sensitized by their preleukemic cells, and that these preleukemic cells are then arrested in their development as a result of the immune response.

Animals↗
PubMed2004

Marginal median SOM for document organization and retrieval.

The self-organizing map algorithm has been used successfully in document organization. We now propose using the same algorithm for document retrieval. Moreover, we test the performance of the self-organizing map by replacing the linear Least Mean Squares adaptation rule with the marginal median. We present two implementations of the latter variant of the self-organizing map by either quantifying the real valued feature vectors to integer valued ones or not. Experiments performed using both implementations demonstrate a superior performance against the self-organizing map based method in terms of the number of training iterations needed so that the mean square error (i.e. the average distortion) drops to the e(-1) = 36.788% of its initial value. Furthermore, the performance of a document organization and retrieval system employing the self-organizing map architecture and its variant is assessed using the average recall-precision curves evaluated on two corpora; the first comprises of manually selected web pages over the Internet having touristic content and the second one is the Reuters-21578, Distribution 1.0.

Algorithms↗
PubMed2005

FDG PET in the differential diagnosis of parkinsonian disorders.

The differential diagnosis of parkinsonian disorders can be challenging, especially early in the disease course. PET imaging with [(18)F]-fluorodeoxyglucose (FDG) has been used to identify characteristic patterns of regional glucose metabolism in patient cohorts with idiopathic Parkinson's disease (PD), as well as variant forms of parkinsonism such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBGD). In this study, we assessed the utility of FDG PET in the differential diagnosis of individual patients with clinical parkinsonism. 135 parkinsonian patients were referred for FDG PET to determine whether their diagnosis could be made accurately based upon their scans. Imaging-based diagnosis was obtained by visual assessment of the individual scans and also by computer-assisted interpretation. The results were compared with 2-year follow-up clinical assessments made by independent movement disorders specialists who were blinded to the original PET findings. We found that blinded computer assessment agreed with clinical diagnosis in 92.4% of all subjects (97.7% early PD, 91.6% late PD, 96% MSA, 85% PSP, 90.1% CBGD, 86.5% healthy control subjects). Concordance of visual inspection with clinical diagnosis was achieved in 85.4% of the patients scanned (88.4% early PD, 97.2% late PD, 76% MSA, 60% PSP, 90.9% CBGD, 90.9% healthy control subjects). This study demonstrates that FDG PET performed at the time of initial referral for parkinsonism accurately predicted the clinical diagnosis of individual patients made at subsequent follow-up. Computer-assisted methodologies may be particularly helpful in situations where experienced readers of FDG PET images are not readily available.

Aged↗
PubMed2002

Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status.

BACKGROUND: Management of early-stage breast cancer in young women with mutations in BRCA1 or BRCA2 remains controversial. This study assessed the long-term risks of ipsilateral and contralateral breast cancer in a cohort of young women who underwent breast-conserving surgery followed by radiotherapy. METHODS: Between 1975 and 1998, 290 women with breast cancer diagnosed at age 42 years or younger underwent lumpectomy followed by radiotherapy at our hospital. We recruited 127 of these women for complete sequencing of BRCA1 and BRCA2. Demographic, clinical, pathological, and outcome data were recorded. The primary endpoints were rates of ipsilateral and contralateral breast cancer, in relation to germline BRCA1/2 status. FINDINGS: 105 women were classified as having sporadic disease (94 with wild-type or known polymorphisms and 11 with variants of unclear significance) and 22 as having genetic predisposition (deleterious mutations in BRCA1 [15] or BRCA2 [seven]). At 12 years of follow-up, the genetic group had significantly higher rates of ipsilateral (49% vs 21%, p=0.007) and contralateral events (42% vs 9%, p=0.001) than the sporadic group. The majority of events were classified as second primary tumours. No patient in the genetic group had undergone oophorectomy or was taking prophylactic agents such as tamoxifen. INTERPRETATION: Patients with germline mutations in BRCA1 or BRCA2 have a high risk of developing late ipsilateral and contralateral second primary tumours. With breast-conserving therapy, chemoprophylaxis or other interventions to reduce the rate of second cancers may be valuable. Alternatively, bilateral mastectomy may be considered, to minimise the risk of second tumours in the breasts.

Adult↗
PubMed2000

So-called malignant and extra-ventricular neurocytomas: reality or wrong diagnosis? A critical review about two overdiagnosed cases.

Central neurocytoma (CN) is described as a rare intra-ventricular benign neuronal tumor of the brain. Two primary tumors first diagnosed as malignant and extra-ventricular neurocytomas are reported here. Histologically, the tumor of the first patient, a forty-one-year-old man, consisted of monotonous cells with round nuclei, but no fibrillar background. The second tumor, in a nineteen-year-old girl, showed areas of moderately pleomorphic round cells, with numerous rosettes and ganglion cell differentiation, in an abundant fibrillary network. Both presented calcifications. Mitoses were more frequent in recurrences and spinal locations than in the primaries. All tumors stained strongly for synaptophysin, and GFAP was partly positive in the first case only. Patients received post-surgical radiotherapy and were still alive eight and six years, respectively, after initial surgery. The interpretation of atypical cases, such as ours is not easy: the diagnoses finally retained were oligodendroglioma in the first case and ganglioneuroblastoma in the second case. Furthermore, neurocytomas atypical either by their unusual topographical or histological presentation or by their poor prognosis, have been frequently entitled in this way on synaptophysin positivity. So, we were prompted to reassess the entity of CN, seventeen years after the first description, to re-appreciate the reality of anatomo-clinical variants and to discuss the value of synaptophysin positivity in these tumors. In conclusion, it seems preferable to individualize true classical CN, which has a favorable outcome, from so-called extra-ventricular, atypical and anaplastic, clinically malignant neurocytomas for which complementary treatment is required.

Adolescent↗
PubMed2002

The Mouse Genome Database (MGD): the model organism database for the laboratory mouse.

The Mouse Genome Database (MGD) is the community database resource for the laboratory mouse, a key model organism for interpreting the human genome and for understanding human biology and disease (http://www.informatics.jax.org). MGD strives to provide a highly curated, highly integrated information resource that not only includes the consensus view of current knowledge about the mouse, but also provides comparative genomic information particularly for human and rat genomes. MGD includes extensive information about mouse genes, supporting all gene attribute assertions with experimental data, statements of evidence and citation. Detailed information about alleles and mouse mutants includes genotype, molecular variant and phenotype descriptions. Extensive collaboration with other data providers such as NCBI, RIKEN and SWISS-PROT provides standardization of gene:sequence associations and robust interconnections between large information systems based on shared sequence curation. Recent integration of large datasets of mouse full-length cDNAs and radiation-hybrid mapped ESTs, the continued development and use of extensive structured vocabularies and the expansion of the representation of phenotypes highlight this year's developments.

Alleles↗