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PubMed1988

MHC-unrestricted T-cell cytotoxicity against tumour cells.

F9 embryonal carcinoma cells (EC) grow as tumours in their strain of origin, 129/Sv, but can be rejected by mouse strains differing at the H-2 and/or non-H-2 loci. The presence of H-2 class I and/or minor H antigens on F9 and other EC cells is implied by (i) the rejection of EC cells by mice immunized with appropriate H-2 class I transfectants, and (ii) the ability of appropriate EC cells to prime mice for second-set in vivo skin-graft rejection responses to H-Y, and secondary MLC responses to multiple minor H antigens. However, EC cells express no H-2 class I antigens in vitro, and for in vivo rejection by T-cell responses directed either at allogeneic class I molecules or at minor H antigens restricted by self class I molecules, one would need to postulate that EC cells growing in vivo could express sufficient class I antigens for recognition by T cells. In the course of investigating this question, we found evidence for class I expression but also evidence for an additional antigen(s), shared by EC and tumour cells and recognized in a non-MHC-restricted manner.

Animals↗
PubMed2004

QRS subtraction and the ECG analysis of atrial ectopics.

The recognition of the ubiquitous role of short coupled ectopics in the initiation of paroxysmal atrial fibrillation has renewed interest in their localization with the ultimate aim of facilitating their neutralization by catheter ablation. The P-waves resulting from such ectopics are partly or completely concealed by the QRST of the preceding beat and therefore their morphology has been underutilized for localization purposes. Subtraction has been the most commonly used technique for QRST suppression and though an averaged template offers a higher signal-to-noise ratio, the immediately preceding QRST provides the best match between template and target and allows simple, nearly real-time, and accurate subtraction without distorting the underlying P-wave. Algorithms derived from clinical tachycardias as well as pacemapping have permitted a rational analysis and accurate prediction (81%) of the correct pulmonary vein of origin. Other nonpulmonary sources may also be similarly localized, particularly with the help of a catalogue of pacemaps from various sites. Incessant arrhythmia and frequent aberrancy limit the effectiveness of QRST suppression by subtraction. Further improvements in the localizing resolution of the P-wave may depend upon knowledge of the relationship between recording electrodes and the underlying atria.

Atrial Fibrillation↗
PubMed2005

A hybrid framework for 3D medical image segmentation.

In this paper we propose a novel hybrid 3D segmentation framework which combines Gibbs models, marching cubes and deformable models. In the framework, first we construct a new Gibbs model whose energy function is defined on a high order clique system. The new model includes both region and boundary information during segmentation. Next we improve the original marching cubes method to construct 3D meshes from Gibbs models' output. The 3D mesh serves as the initial geometry of the deformable model. Then we deform the deformable model using external image forces so that the model converges to the object surface. We run the Gibbs model and the deformable model recursively by updating the Gibbs model's parameters using the region and boundary information in the deformable model segmentation result. In our approach, the hybrid combination of region-based methods and boundary-based methods results in improved segmentations of complex structures. The benefit of the methodology is that it produces high quality segmentations of 3D structures using little prior information and minimal user intervention. The modules in this segmentation methodology are developed within the context of the Insight ToolKit (ITK). We present experimental segmentation results of brain tumors and evaluate our method by comparing experimental results with expert manual segmentations. The evaluation results show that the methodology achieves high quality segmentation results with computational efficiency. We also present segmentation results of other clinical objects to illustrate the strength of the methodology as a generic segmentation framework.

Algorithms↗
PubMed1981

Reduced humoral and cellular cytotoxic sensitivity in histocompatibility variants of the YAC (Moloney) lymphoma.

Previously we have reported that two sublines of the YAC lymphoma selected for reduced expression of H-2a and Moloney-virus determined cell-surface (MCSA) antigens are, in contrast to YAC, allotransplantable in H-2-incompatible recipients, and resistant to rejection by preimmunized semisyngeneic hosts. A third YAC variant with reduced MCSA but unchanged H-2-antigen expression, was not allotransplantable and showed only a slight decrease in its immunosensitivity in preimmunized semisyngeneic hosts in vivo. This suggested that H-2-antigen expression may be more important than MCSA expression for recognition and rejection by semisyngeneic mice. We have not tested the sublines expressing low H-2a for their in vitro sensitivity to humoral and cell-mediated lysis. - The variants were more resistant than YAC to complement lysis by anti-H-2a , anit-MCSA, anti-Thy 1.2 and antispecies sera. Absorption tests with antispecies serum indicated that the decreased cytolytic sensitivity of the variants was not related to the concentration of the relevant antigens, which was similar to that of the original YAC tumor. As expected from the low amount of H-2a the variants showed a decreased sensitivity to the killing effect of allogeneic cytotoxic T lymphocytes (CTL). They were also lysed to a lesser extent than YAC by semisyngeneic CTL, probably directed against virally determined antigens. However, they were also less sensitive to lysis by natural killer (NK) cells, although NK lysis is probably unrelated to MHC expression. In conclusion, our selection for reduced H-2-expression appears to have resulted in the isolation of variants with a generally increased resistance to various humoral and cell-mediated lytic functions.

Animals↗
PubMed2005

A novel approach for clustering proteomics data using Bayesian fast Fourier transform.

MOTIVATION: Bioinformatics clustering tools are useful at all levels of proteomic data analysis. Proteomics studies can provide a wealth of information and rapidly generate large quantities of data from the analysis of biological specimens. The high dimensionality of data generated from these studies requires the development of improved bioinformatics tools for efficient and accurate data analyses. For proteome profiling of a particular system or organism, a number of specialized software tools are needed. Indeed, significant advances in the informatics and software tools necessary to support the analysis and management of these massive amounts of data are needed. Clustering algorithms based on probabilistic and Bayesian models provide an alternative to heuristic algorithms. The number of clusters (diseased and non-diseased groups) is reduced to the choice of the number of components of a mixture of underlying probability. The Bayesian approach is a tool for including information from the data to the analysis. It offers an estimation of the uncertainties of the data and the parameters involved. RESULTS: We present novel algorithms that can organize, cluster and derive meaningful patterns of expression from large-scaled proteomics experiments. We processed raw data using a graphical-based algorithm by transforming it from a real space data-expression to a complex space data-expression using discrete Fourier transformation; then we used a thresholding approach to denoise and reduce the length of each spectrum. Bayesian clustering was applied to the reconstructed data. In comparison with several other algorithms used in this study including K-means, (Kohonen self-organizing map (SOM), and linear discriminant analysis, the Bayesian-Fourier model-based approach displayed superior performances consistently, in selecting the correct model and the number of clusters, thus providing a novel approach for accurate diagnosis of the disease. Using this approach, we were able to successfully denoise proteomic spectra and reach up to a 99% total reduction of the number of peaks compared to the original data. In addition, the Bayesian-based approach generated a better classification rate in comparison with other classification algorithms. This new finding will allow us to apply the Fourier transformation for the selection of the protein profile for each sample, and to develop a novel bioinformatic strategy based on Bayesian clustering for biomarker discovery and optimal diagnosis.

Algorithms↗
PubMed1994

Functional differences between the two splice variants of the nucleolar transcription factor UBF: the second HMG box determines specificity of DNA binding and transcriptional activity.

The nucleolar transcription factor UBF consists of two proteins, UBF1 and UBF2, which originate by alternative splicing. Here we show that deletion of 37 amino acids within the second of five HMG box motifs in UBF2 is important for the dual role of UBF as transcriptional activator and antirepressor. UBF1 is a potent antirepressor and transcriptional activator, whereas the ability of UBF2 to counteract histone H1-mediated repression and to stimulate ribosomal gene transcription both in vivo and in vitro is at least one order of magnitude lower. The difference in transcriptional activity between UBF1 and UBF2 is due to their different binding to the ribosomal gene promoter and enhancer. Apparently, the presence of an intact HMG box2 modulates the sequence-specific binding of UBF to rDNA control elements. However, the interaction of UBF with rDNA does not entirely depend on sequence recognition. Both UBF isoforms bind efficiently to four-way junction DNA, indicating that they recognize defined DNA structures rather than specific sequences. The results demonstrate that the HMG boxes are functionally diverse and that HMG box2 plays an important role in specific binding of UBF to rDNA.

3T3 Cells↗
PubMed2000

Epidemiology, stage at diagnosis, and tumor biology of breast carcinoma in multiracial and multiethnic populations.

All women, regardless of their racial or ethnic origin or heritage, are at risk of developing breast cancer. Variations in breast carcinoma incidence rates among multicultural populations suggest that etiologic factors differ in their biologic expression and impact on disease outcome. Key among those factors that affect breast carcinoma development are the roles of genetics and the environment, the reproductive experience and the effects of endogenous and exogenous hormones in women, the change in immune status and host vulnerability, and the biologic determinants of breast carcinoma. Cultural dynamics, sociodemographic differences, and behavioral characteristics across population subgroups modulate how biologic disease is expressed among different races and ethnic groups. These interactions contribute to the observed variations in breast carcinoma incidence, mortality, and survival. Stage, a measure of disease status, is used to assess prognosis, plan treatment, and evaluate outcome. Numerous studies have reported a more advanced stage of breast carcinoma at diagnosis in racial/ethnic subgroups, especially among women from African American, Hispanic, American Indian, and native Hawaiian cultures. Factors associated with advanced stage at diagnosis in multicultural populations range from changes in the basic biological characteristics at the molecular and cellular level, to more complex behavioral attributes unique to a particular multicultural population, to societal issues-such as access to care and socioeconomic conditions-all of which impact on the health measure called "stage at diagnosis." Rapid advancements in knowledge of cancer biology and of genetic markers and tumor products are providing new mechanisms for identifying etiologic pathways that can be utilized for better screening, detection, treatment and monitoring of disease. Further studies are needed that evaluate the biologic and molecular alterations in tumor development, progression, and response to therapy. Public health attention needs to be directed toward the societal influences that impact breast carcinoma development, as well as augmenting recognition of the need for culturally appropriate, broad-based behavioral changes at the community level. In addition, continued efforts are needed to ensure the inclusion of multicultural population subgroups and minority investigators in all aspects of research-basic, clinical and applied.

Adult↗
PubMed2002

Interaction of the DnaK and DnaJ chaperone system with a native substrate, P1 RepA.

DnaK, the Hsp70 chaperone of Escherichia coli interacts with protein substrates in an ATP-dependent manner, in conjunction with DnaJ and GrpE co-chaperones, to carry out protein folding, protein remodeling, and assembly and disassembly of multisubunit protein complexes. To understand how DnaJ targets specific proteins for recognition by the DnaK chaperone system, we investigated the interaction of DnaJ and DnaK with a known natural substrate, bacteriophage P1 RepA protein. By characterizing RepA deletion derivatives, we found that DnaJ interacts with a region of RepA located between amino acids 180 and 200 of the 286-amino acid protein. A peptide corresponding to amino acids 180-195 inhibited the interaction of RepA and DnaJ. Two site-directed RepA mutants with alanine substitutions in this region were about 4-fold less efficiently activated for oriP1 DNA binding by DnaJ and DnaK than wild type RepA. We also identified by deletion analysis a site in RepA, in the region of amino acids 35-49, which interacts with DnaK. An alanine substitution mutant in amino acids 36-39 was constructed and found defective in activation by DnaJ and DnaK. Taken together the results suggest that DnaJ and DnaK interact with separate sites on RepA.

Alanine↗
PubMed2006

Recognition of ribonuclease A by 3'-5'-pyrophosphate-linked dinucleotide inhibitors: a molecular dynamics/continuum electrostatics analysis.

The proteins of the pancreatic ribonuclease A (RNase A) family catalyze the cleavage of the RNA polymer chain. The development of RNase inhibitors is of significant interest, as some of these compounds may have a therapeutic effect in pathological conditions associated with these proteins. The most potent low molecular weight inhibitor of RNase reported to date is the compound 5'-phospho-2'-deoxyuridine-3-pyrophosphate (P-->5)-adenosine-3-phosphate (pdUppA-3'-p). The 3',5'-pyrophosphate group of this compound increases its affinity and introduces structural features which seem to be unique in pyrophosphate-containing ligands bound to RNase A, such as the adoption of a syn conformation by the adenosine base at RNase subsite B(2) and the placement of the 5'-beta-phosphate of the adenylate (instead of the alpha-phosphate) at subsite P(1) where the phosphodiester bond cleavage occurs. In this work, we study by multi-ns molecular dynamics simulations the structural properties of RNase A complexes with the ligand pdUppA-3'-p and the related weaker inhibitor dUppA, which lacks the 3' and 5' terminal phosphate groups of pdUppA-3'-p. The simulations show that the adenylate 5'-beta-phosphate binding position and the adenosine syn orientation constitute robust structural features in both complexes, stabilized by persistent interactions with specific active-site residues of subsites P(1) and B(2). The simulation structures are used in conjunction with a continuum-electrostatics (Poisson-Boltzmann) model, to evaluate the relative binding affinity of the two complexes. The computed relative affinity of pdUppA-3'-p varies between -7.9 kcal/mol and -2.8 kcal/mol for a range of protein/ligand dielectric constants (epsilon(p)) 2-20, in good agreement with the experimental value (-3.6 kcal/mol); the agreement becomes exact with epsilon(p) = 8. The success of the continuum-electrostatics model suggests that the differences in affinity of the two ligands originate mainly from electrostatic interactions. A residue decomposition of the electrostatic free energies shows that the terminal phosphate groups of pdUppA-3'-p make increased interactions with residues Lys(7) and Lys(66) of the more remote sites P(2) and P(0), and His(119) of site P(1).

Adenosine Monophosphate↗
PubMed1997

CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia: a distinct hematolymphoid disease entity.

The disease spectrum of natural killer (NK) cell leukemias and lymphomas has recently been expanding with the continuing evolution in diagnostic concepts. We describe here seven cases of acute leukemia of conceivable myeloid and NK cell precursor phenotype in six men and one woman varying from 19 to 59 years of age (median, 46 years). Striking extramedullary involvement was evident at initial presentation, with peripheral lymphadenopathy and/or mediastinal masses. Two lacked any leukemic cells in the bone marrow at diagnosis. Using cytochemical myeloperoxidase staining, less than 3% of the leukemic cells showed positive reactivity. However, expression of CD7, CD33, CD34, CD56, and frequently HLA-DR, but not other NK, T-cell, and B-cell markers was observed. Cytoplasmic CD3 was detected in three of the cases by flow cytometry and in six by Northern blotting, suggesting an origin from common progenitors between the NK cell and myeloid lineages. All but one presented germline configurations of the T-cell receptor beta and gamma chain genes and Ig heavy chain gene. With regard to morphology, the cells were generally L2-shaped, with variation in cell size, round to moderately irregular nuclei and prominent nucleoli, pale cytoplasm, and a lack of azurophilic granules. Histopathologic examination of biopsied specimens of extramedullary tumors showed a lymphoblast-like morphology, implying the differential diagnostic problem from lymphoblastic lymphomas, especially in cases lacking bone marrow involvement. Three patients were successfully treated with chemotherapy for acute myeloid leukemia (AML), whereas three other patients proved refractory to chemotherapeutic regimens for lymphoid malignancies, although two responded to subsequent AML chemotherapy. However, despite intensive chemotherapy, including allogeneic bone marrow transplantation, most persued fatal courses within 41 months. These data suggested that the CD7+ and CD56+ myeloid/NK cell precursor acute leukemia might constitute a distinct biologic and clinical disease entity. Its recognition appears to be particularly important for the clinicopathologic evaluation of CD56+ hematolymphoid malignancies and the development of therapeutic approaches to such disease.

Acute Disease↗
PubMed2004

A practical approach to prevent gantry-couch collision for linac-based radiosurgery.

Gantry-couch collision is a serious concern for treatment planning of the linear accelerator (linac) based stereotactic radiosurgery (SRS). The ability to detect collision at the time of planning eliminates the need for backup plans and preserves the useful beam angles that would be deemed unsafe and discarded otherwise. Most collision-detection schemes embedded in commercial planning software guard only against the most apparent collisions. On the other hand, a fool-proof collision-map or lookup table often requires detailed measurement of machine geometry and complex graphic operations. In this study, we have developed a simple analytical method for collision detection with the use of quick machine-specific measurements. The collision detection is mathematically solved by determining whether two facets in three-dimensional space, representing gantry and couch surfaces, intersect with each other. A computer code was implemented and tested on a Varian Clinac 600C linac equipped with a BrainLab micromultileaf collimator (MLC) device. To measure machine-specific parameters, the lesion isocenter was set to the origin of the stereotactic coordinate system. The reference coordinates of couch bracket corners and micro-MLC to the linac isocenter were measured only once in the treatment room before they were incorporated into the computer program. Couch, gantry, and collimator were subsequently translated and rotated to study the clearance of various beam arrangements and lesion locations. Predicted results were verified at the machine. Our method correctly confirmed clearance for a retrospective study of 54 previously treated SRS plans (76 isocenters). It also accurately predicted the collisions for all ten artificially created cases. In conclusion, we have developed an analytical method for SRS collision detection that is accurate, easy to implement, and computationally inexpensive.

Algorithms↗
PubMed1998

5-fluorouracil: a pharmacological paradigm in the use of cytotoxics.

1. Painstaking progress in drug development is well illustrated by 5-fluorouracil (5FU), originally designed 40 years ago as a fluorinated analogue of the naturally occurring base uracil. Innovative pharmacokinetic and pharmacodynamic strategies have seen significant clinical improvements for cancer patients over the past decade. 2. 5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxyuridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. 3. Biomodulation of 5FU has been attempted with methotrexate (MTX), folinic acid, interferons, cisplatin and radiotherapy. Methotrexate augments the actions of 5FU by inhibiting dihydrofolate reductase and decreasing the folate pool required for pyrimidine biosynthesis, inhibiting TS via MTX-polyglutamate and directly inhibiting purine biosynthesis. Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. 5-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.

Antimetabolites, Antineoplastic↗
PubMed2002

[Ultrasonography in acute pelvic pain].

Acute pelvic pain may be the manifestation of various gynecologic and non-gynecologic disorders from less alarming rupture of the follicular cyst to life threatening conditions such as rupture of ectopic pregnancy or perforation of inflamed appendix. In order to construct an algorithm for differential diagnosis we divide acute pelvic pain into gynecologic and non-gynecologic etiology, which is than subdivided into gastrointestinal and urinary causes. Appendicitis is the most common surgical emergency and should always be considered in differential diagnosis if appendix has not been removed. Apart of clinical examination and laboratory tests, an ultrasound examination is sensitive up to 90% and specific up to 95% if graded compression technique is used. Still it is user-depended and requires considerable experience in order to perform it reliably. Meckel's diverticulitis, acute terminal ileitis, mesenteric lymphadenitis and functional bowel disease are conditions that should be differentiated from other causes of low abdominal pain by clinical presentation, laboratory and imaging tests. Dilatation of renal pelvis and ureter are typical signs of obstructive uropathy and may be efficiently detected by ultrasound. Additional thinning of renal parenchyma suggests long-term obstructive uropathy. Ruptured ectopic pregnancy, salpingitis and hemorrhagic ovarian cysts are three most commonly diagnosed gynecologic conditions presenting as an acute abdomen. Degenerating leiomyomas and adnexal torsion occur less frequently. For better systematization, gynecologic causes of acute pelvic pain could be divided into conditions with negative pregnancy test and conditions with positive pregnancy test. Pelvic inflammatory disease may be ultrasonically presented with numerous signs such as thickening of the tubal wall, incomplete septa within the dilated tube, demonstration of hyperechoic mural nodules, free fluid in the "cul-de-sac" etc. Color Doppler ultrasound contributes to more accurate diagnosis of this entity since it enables differentiation between acute and chronic stages based on analysis of the vascular resistance. Hemorrhagic ovarian cysts may be presented by variety of ultrasound findings since intracystic echoes depend upon the quality and quantity of the blood clots. Color Doppler investigation demonstrates moderate to low vascular resistance typical of luteal flow. Leiomyomas undergoing degenerative changes are another cause of acute pelvic pain commonly present in patients of reproductive age. Color flow detects regularly separated vessels at the periphery of the leiomyoma, which exhibit moderate vascular resistance. Although the classic symptom of endometriosis is chronic pelvic pain, in some patients acute pelvic pain does occur. Most of these patients demonstrate an endometrioma or "chocolate" cyst containing diffuse carpet-like echoes. Sometimes, solid components may indicate even ovarian malignancy, but if color Doppler ultrasound is applied it is less likely to obtain false positive results. One should be aware that pericystic and/or hillar type of ovarian endometrioma vascularization facilitate correct recognition of this entity. Pelvic congestion syndrome is another condition that can cause an attack of acute pelvic pain. It is usually consequence of dilatation of venous plexuses, arteries or both systems. By switching color Doppler gynecologist can differentiate pelvic congestion syndrome from multilocular cysts, pelvic inflammatory disease or adenomyosis. Ovarian vein thrombosis is a potentially fatal disorder occurring most often in the early postpartal period. Hypercoagulability, infection and stasis are main etiologic factors, and transvaginal color Doppler ultrasound is an excellent diagnostic tool to diagnose it. Acute pelvic pain may occur even in normal intrauterine pregnancy. This may be explained by hormonal changes, rapid growth of the uterus and increased blood flow. Ultrasound is mandatory for distinguishing normal intrauterine pregnancy from threatened or spontaneous abortion, ectopic pregnancy and other complications that may occur in patients with positive pregnancy test. Incomplete abortion is visualized as thickened and irregular endometrial echo with certain amount of intracavitary fluid. If applied, color Doppler ultrasound reveals low vascular resistance signals in richly perfused intracavitary area. Transvaginal sonography has high sensitivity and specificity in visualization of uterine and adnexal signs of ectopic pregnancy. Color Doppler examination may aid in detection of the peritrophoblastic flow. Furthermore, it facilitates detection of ectopic living embryo, tubal ring or unspecific adnexal tumor. Corpus luteum cysts and leiomyomas are another cause of pelvic pain during pregnancy, which can be correctly diagnosed by ultrasound. Detection of uterine dehiscence and rupture in patients with history of prior surgical intervention on uterine wall relies exclusively on correct ultrasound diagnosis. In patients with placental abruption sonographer detects hypoechoic complex representing either retroplacental hematoma, subchorionic hematoma or subamniotic hemorrhage. In closing, ultrasound has already become important and easily available tool which can efficiently recognize patients with possibly threatening conditions of different origins.

Acute Disease↗
PubMed1995

Sequence determinants for -2 frameshift mutagenesis at NarI-derived hot spots.

The recognition sequence of the NarI restriction enzyme is known to be a strong hot spot for -2 frameshift mutations (G1G2CG3CC-->GGCC) induced by the chemical carcinogen N-2-acetylaminofluorene (AAF). In an attempt to define a "consensus sequence" for this mutation hot spot, we have investigated the role of the bases flanking the central dinucleotide GpC repeat in the NarI sequence (NaGCGCNb) on the mutation frequency induced by the carcinogen. Construction and random modification with AAF of the 16 plasmids resulting from the replacement of Na and Nb by A,T,G and C, respectively, have been undertaken. All 16 sequences tested are found to be -2 frameshift mutation hot spots. Indeed, a level of modification of approximately five AAF adducts per plasmid molecule induces a mutation frequency ranging between 500 and 5000-fold above background. The mutations observed are mainly (90%) deletion of a dinucleotide CpG in the targeted sequence NaGCGCNb. Previous studies on NarI mutagenesis (G1G2CG3CC-->GGCC) have shown that only AAF adducts at G3 in the template for lagging strand synthesis induce -2 frameshift mutagenesis at a high level. When the mutation data obtained in this work are analyzed as originating essentially from adducts to guanines in this strand, we find that it is the nucleotide Nb located 3' to the central dinucleotide GpC repeat that strongly modulates the mutation frequency, while the nucleotide Na located on the 5' side has little effect. Our present model of frameshift mutagenesis at NarI sites involves a template-primer misalignment step with a two-nucleotide slipped mutagenic intermediate. In the context of this model, the modulation of mutagenesis by nucleotide Nb located two nucleotides 3' from the putative adduct site in the template strand can be explained in view of the fact that the replication complex encounters this nucleotide before it encounters the adduct.

2-Acetylaminofluorene↗
PubMed2004

Mapping high-dimensional data onto a relative distance plane--an exact method for visualizing and characterizing high-dimensional patterns.

We introduce a distance (similarity)-based mapping for the visualization of high-dimensional patterns and their relative relationships. The mapping preserves exactly the original distances between points with respect to any two reference patterns in a special two-dimensional coordinate system, the relative distance plane (RDP). As only a single calculation of a distance matrix is required, this method is computationally efficient, an essential requirement for any exploratory data analysis. The data visualization afforded by this representation permits a rapid assessment of class pattern distributions. In particular, we can determine with a simple statistical test whether both training and validation sets of a 2-class, high-dimensional dataset derive from the same class distributions. We can explore any dataset in detail by identifying the subset of reference pairs whose members belong to different classes, cycling through this subset, and for each pair, mapping the remaining patterns. These multiple viewpoints facilitate the identification and confirmation of outliers. We demonstrate the effectiveness of this method on several complex biomedical datasets. Because of its efficiency, effectiveness, and versatility, one may use the RDP representation as an initial, data mining exploration that precedes classification by some classifier. Once final enhancements to the RDP mapping software are completed, we plan to make it freely available to researchers.

Algorithms↗
PubMed2000

Identifying cytotoxic T cell epitopes from genomic and proteomic information: "The human MHC project.".

Complete genomes of many species including pathogenic microorganisms are rapidly becoming available and with them the encoded proteins, or proteomes. Proteomes are extremely diverse and constitute unique imprints of the originating organisms allowing positive identification and accurate discrimination, even at the peptide level. It is not surprising that peptides are key targets of the immune system. It follows that proteomes can be translated into immunogens once it is known how the immune system generates and handles peptides. Recent advances have identified many of the basic principles involved. The single most selective event is that of peptide binding to MHC, making it particularly important to establish accurate descriptions and predictions of peptide binding for the most common MHC variants. These predictions should be integrated with those of other steps involved in antigen processing, as these become available. The ability to translate the accumulating primary sequence databases in terms of immune recognition should enable scientists and clinicians to analyze any protein of interest for the presence of potentially immunogenic epitopes. The computational tools to scan entire proteomes should also be developed, as this would enable a rational approach to vaccine development and immunotherapy. Thus, candidate vaccine epitopes might be predicted from the various microbial genome projects, tumor vaccine candidates from mRNA expression profiling of tumors ("transcriptomes") and auto-antigens from the human genome.

Antigen Presentation↗
PubMed1995

Differential recognition of the type I interferon receptor by interferons tau and alpha is responsible for their disparate cytotoxicities.

Interferon tau (IFN tau), originally identified as a pregnancy recognition hormone, is a type I interferon that is related to the various IFN alpha species (IFN alpha s). Ovine IFN tau has antiviral activity similar to that of human IFN alpha A on the Madin-Darby bovine kidney (MDBK) cell line and is equally effective in inhibiting cell proliferation. In this study, IFN tau was found to differ from IFN alpha A in that is was > 30-fold less toxic to MDBK cells at high concentrations. Excess IFN tau did not block the cytotoxicity of IFN alpha A on MDBK cells, suggesting that these two type I IFNs recognize the type I IFN receptor differently on these cells. In direct binding studies, 125I-IFN tau had a Kd of 3.90 x 10(-10) M for receptor on MDBK cells, whereas that of 125I-IFN alpha A was 4.45 x 10(-11) M. Consistent with the higher binding affinity, IFN alpha A was severalfold more effective than IFN tau in competitive binding against 125I-IFN tau to receptor on MDBK cells. Paradoxically, the two IFNs had similar specific antiviral activities on MDBK cells. However, maximal IFN antiviral activity required only fractional occupancy of receptors, whereas toxicity was associated with maximal receptor occupancy. Hence, IFN alpha A, with the higher binding affinity, was more toxic than IFN tau. The IFNs were similar in inducing the specific phosphorylation of the type I receptor-associated tyrosine kinase Tyk2, and the transcription factors Stat1 alpha and Stat2, suggesting that phosphorylation of these signal transduction proteins is not involved in the cellular toxicity associated with type I IFNs. Experiments using synthetic peptides suggest that differences in the interaction at the N terminal of IFN tau and IFN alpha with the type I receptor complex contribute significantly to differences in high-affinity equilibrium binding of these molecules. It is postulated that such a differential recognition of the receptor is responsible for the similar antiviral but different cytotoxic effects of these IFNs. Moreover, these data imply that receptors are "spare'' with respect to certain biological properties, and we speculate that IFNs may induce a concentration-dependent selective association of receptor subunits.

Animals↗
PubMed2005

Regression-based prediction for blocking artifact reduction in JPEG-compressed images.

In order to reduce the blocking artifact in the Joint Photographic Experts Group (JPEG)-compressed images, a new noniterative postprocessing algorithm is proposed. The algorithm consists of a two-step operation: low-pass filtering and then predicting. Predicting the original image from the low-pass filtered image is performed by using the predictors, which are constructed based on a broken line regression model. The constructed predictor is a generalized version of the projector onto the quantization constraint set, or the narrow quantization constraint set. We employed different predictors depending on the frequency components in the discrete cosine transform (DCT) domain since each component has different statistical properties. Further, by using a simple classifier, we adaptively applied the predictors depending on the local variance of the DCT block. This adaptation enables an appropriate blurring depending on the smooth or detail region, and shows improved performance in terms of the average distortion and the perceptual view. For the major-edge DCT blocks, which usually suffer from the ringing artifact, the quality of fit to the regression model is usually not good. By making a modification of the regression model for such DCT blocks, we can also obtain a good perceptual view. The proposed algorithm does not employ any sophisticated edge-oriented classifiers and nonlinear filters. Compared to the previously proposed algorithms, the proposed algorithm provides comparable or better results with less computational complexity.

Algorithms↗